bluuebunny/crossref_metadata_2025 huggingface dataset:
A Pharmacokinetic Study of Intravenous Itraconazole Followed by Oral Administration of Itraconazole Capsules in Patients with Advanced Human Immunodeficiency Virus Infection
Authors: Zhou Honghui , Goldman Mitchell , Wu Jane , Woestenborghs Robert , Hassell Alan E. , Lee Peter , Baruch Alice , Pesco‐Koplowitz Luana , Borum Julie , Wheat L. Joseph
Published: March 2013

A randomized, open‐label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1‐hour infusion in 40% hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady‐state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady‐state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow‐up with administration of 200‐mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice‐daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice‐daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP‐β‐CD was excreted unchanged in urine within 12 hours of administration. The HP‐β‐CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.
A Placebo‐Controlled, Randomized Study of Glimepiride in Patients with Type 2 Diabetes Mellitus for Whom Diet Therapy is Unsuccessful
Authors: Schade David S. , Jovanovic Lois , Schneider Jill
Published: March 2013

This multicenter, randomized, placebo‐controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151–300 mg/dL) during a 1‐week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10‐week dose‐titration period, then maintained on an individually determined optimal dose (1–8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2‐hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C‐peptide responses without producing clinically meaningful increases in fasting insulin or C‐peptide levels. Good glycemic control (HbA1 ≤ 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful.
Teaching Clinical Pharmacology and Therapeutics: Selective for Fourth‐Year Medical Students
Authors: Tofovic Stevan P. , Branch Robert A. , Jackson Edwin K. , Cressman Michael D. , Kost Curtis K.
Published: March 2013

Teaching clinical pharmacology remains both a lifelong learning process and a lifelong challenge for clinical pharmacologists and other medical educators. In the current information age, with an explosion of drug‐related data, the prime topic for discussion is how to teach clinical pharmacology. This article describes our response to the challenges in developing a selective course in clinical pharmacology, and our experience from the first 2 years of the course. Our emphasis is on how to provide in an efficient way knowledge, skills, and attitudes students will need as physicians in the coming decades. Faculty from the Center for Clinical Pharmacology at the University of Pittsburgh in conjunction with faculty from the University of Pittsburgh School of Medicine have developed a one‐month intensive course in clinical pharmacology. The integrated course program consists of four overlapping components: 1) general clinical pharmacology (focused on individualization of drug therapy); 2) rational prescribing principles (general principles of drug selection, how to prepare a personal formulary); 3) disease‐specific clinical topics (pharmacotherapy of diseases and medical conditions most commonly seen in routine medical practice); and 4) workshops for special attention topics (pharmacokinetics, pain treatment, toxicology, dialysis). In congruence with established educational goals, the course includes drug‐, patient‐, and disease‐oriented concepts. A variety of learning formats (didactic and interactive lectures, one‐day problem‐based learning sessions, small group case discussions, self‐directed and small group directed learning, quizzes, and computer‐assisted learning) are used to teach students how to apply the general concepts of clinical pharmacology and rational pharmacotherapy to clinical medicine, and to prepare them to become independent lifelong learners in therapeutics. Student feedback from the first 2 years of this course indicates that this multi‐modal teaching format is effective. The majority of students who took the course in clinical pharmacology in 1997 found it to be very beneficial.
Pharmacokinetics and Pharmacodynamics of Zolmitriptan in Patients with Mild to Moderate Hypertension: A Double‐Blind, Placebo‐Controlled Study
Authors: Smith Deborah A. , Cleary Elena W. , Watkins Stephanie , Huffman Cameron S. , Dilzer Stacy C. , Lasseter Kenneth C.
Published: March 2013

Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may cause slight elevations of blood pressure in subjects without hypertension. Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and 20 mg) were evaluated in 16 patients with mild to moderate hypertension (controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age‐ and sex‐matched control subjects in a randomized, placebo‐controlled, double‐blind, four‐period crossover study. The pharmacokinetics of zolmitriptan and its metabolites were dose proportional. Although area under the concentration‐time curve (AUC0‐∞) and maximum concentration (Cmax) were slightly higher in patients with hypertension at all doses, this was only statistically significant for AUC at the 20‐mg dose. Differences between subjects with and without hypertension were not clinically significant. Zolmitriptan produced a small increase in blood pressure, but this was similar in subjects with and without hypertension and was of no clinical significance. Zolmitriptan was well tolerated in both groups. Zolmitriptan plasma concentrations were higher in women than in men, with higher values of AUC and Cmax and lower total clearance in women. These results indicate that zolmitriptan can be administered for treatment of migraine in patients with controlled hypertension without dose adjustment.
Safety, Pharmacokinetics, and Antiretroviral Activity of the Potent, Specific Human Immunodeficiency Virus Protease Inhibitor Nelfinavir: Results of a Phase I/II Trial and Extended Follow‐up in Patients Infected with Human Immunodeficiency Virus
Authors: Moyle Graeme J. , Youle Michael , Higgs Chris , Monaghan Jo , Prince William , Chapman Sharon , Clendeninn Neil , Nelson Mark R.
Published: March 2013

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open‐label phase I/II dose‐ranging study in protease inhibitor‐naive HIV‐positive men. A total of 22 patients with baseline plasma HIV RNA ≥ 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy. A capsule formulation of nelfinavir was used. The initial study period was 28 days; patients showing a virologic response of 1 log10 reduction were eligible for enrollment in an extension phase and addition of nucleoside analogues. A maximally tolerated dose of nelfinavir was not established. A dose‐response relationship was observed for four (40%) patients in the 771‐mg group and six (60%) patients in the 1,026‐mg group experiencing a reduction from baseline in plasma HIV RNA of at least 1 log during the 28‐day study. Of these patients, five sustained the reduction in plasma HIV RNA beyond day 28 (2 patients receiving 771 mg/day and 3 patients receiving 1,026 mg/day). Median increases from baseline in CD4+ counts at day 28 were 216 cell/mm3 and 86 cell/mm3 in the 771‐mg and 1,026‐mg groups, respectively. After oral administration, median nelfinavir plasma concentrations on day 28 reached a maximum at 1 hour (2,966 ng/mL) in the 771‐mg group and at 3 hours (3,157 ng/mL) in the 1,026‐mg group. Data for 22 patients were included in the safety analysis; 12 patients (55%) reported at least one grade 2 or worse (moderate, severe, or very severe) adverse event. The most common grade 2 or worse adverse event was diarrhea, reported by two patients (20%) receiving 771 mg/day and seven patients (70%) receiving 1,026 mg/day; followed by nausea, flatulence, asthenia, and headache (each reported in 1 patient [10%] in the 771‐mg group) and dizziness (reported in 1 patient [10%] receiving 1,026 mg/day). In the small subgroup (n = 6) who continued taking nelfinavir for longer periods (between 8 and 15 months), virologic responses were sustained in the majority of patients with good tolerability. Nelfinavir is an active HIV‐protease inhibitor with favorable pharmacokinetics, good tolerability, and sustained antiviral effects. Results of this early phase I/II dose‐ranging study provided data for the safety and antiretroviral activity of nelfinavir and led to the selection of higher doses for phase II/III trials to further optimize virologic and immunologic responses.
Metabolic Disposition of 14C‐Bromfenac in Healthy Male Volunteers
Authors: Osman Mohamed , Chandrasekaran Appavu , Chan Kelvin , Scatina JoAnn , Ermer James , Cevallos William , Sisenwine Samuel F.
Published: March 2013

The metabolic disposition of 14C‐bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50‐mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 ± 1.8 μgṁequiv/mL, which was reached 1.0 ± 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4‐day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0‐ to 24‐hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an α‐keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.
Atorvastatin does not Produce a Clinically Significant Effect on the Pharmacokinetics of Terfenadine
Authors: Stern Ralph H. , Smithers Jacquelyn A. , Olson Stephen C.
Published: March 2013

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120‐mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80‐mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration‐time curve extrapolated to infinity (AUC0‐∞), and a 2% decrease in elimination half‐life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0‐∞, and a 51% increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.
Synthesis of Polysubstituted‐1,2,4‐Triazoles
Authors: Liu Guiyan , Wu Xueli , Shi Xuefang
Published: March 2013

A new series of substituted 1,2,4‐triazole derivatives have been synthesized using substituted imido derivatives and isonicotinyl hydrazine (or 4‐nitrobenzoylhydrazine) as the key intermediates. These compounds include different donor or acceptor substituents on the 1,2,4‐triazole derivatives. The structures of these compounds were confirmed by FTIR, 1H‐NMR, 13C‐NMR, and elemental analysis.
A Facile and Simple Synthesis of Novel 2‐(substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐Oxazole Derivatives
Authors: Reddy E. Vishnu Vardhan , Ramanatham J. , Devanna N. , Srinivasa Reddy K. , Rajender D.
Published: March 2013

Novel 2‐(substituted)‐5‐(1‐methyl‐1H‐indazol‐3‐yl)‐oxazoles (13) were synthesized in moderate yields, from 1‐methyl‐1H‐Indazole 3‐carboxylic acid (1), by converting it into a variety of amides (12) and further its heterocyclization. The structures of all the compounds have been elucidated on the basis of IR, 1H‐NMR, and HRMS.
Synthesis and Characterization of Eight Arylpentazoles
Authors: Ek Stefan , Rehn Stanley , Wahlström Larisa Yudina , Östmark Henric
Published: March 2013

p‐Nitrophenyl‐, p‐methoxyphenyl‐, p‐hydroxyphenyl‐, p‐t‐butylphenyl‐, p‐HOSO2‐phenyl‐, 15N‐p‐N,N‐dimethylaminophenyl‐, 15N2‐p‐N,N‐dimethylaminophenyl‐, and dicyanoimidazopentazole were obtained via different synthetic routes. Cesium, barium, potassium, and sodium salts of the arylpentazoles bearing acidic hydrogens were prepared. NMR spectra (1H, 13C) are reported for the arylpentazoles, their corresponding arylazides, and their salts.
Comparative ultrastructure of the spermatozoa of three crayfish species: Austropotamobius torrentium, Pacifastacus leniusculus, and Astacus astacus (Decapoda: Astacidae)
Authors: Niksirat Hamid , Kouba Antonín , Rodina Marek , Kozák Pavel
Published: March 2013

This study reports about the spermatozoal ultrastructure of three species of astacid crayfish, i.e., the stone crayfish Austropotamobius torrentium, signal crayfish Pacifastacus leniusculus, and noble crayfish Astacus astacus. The acrosome is a cup shaped and electron‐dense structure at the anterior of the spermatozoon and comprises three layers of differing electron densities filled with parallel filaments that extend from the base to the apical zone. The acrosome was significantly longer in A. astacus than in P. leniusculus and the shortest acrosome belongs to A. torrentium. The width of the acrosome was significantly narrower in A. torrentium than in P. leniusculus and the widest acrosome belongs to A. astacus. The L:W ratio was significantly greater in A. torrentium than in P. leniusculus and the lowest ratio belongs to A. astacus. Radial arms are visible on each side of the acrosome or nucleus in sagittal view and wrap around the spermatozoon. Each radial arm comprises a parallel bundle of microtubules arranged along the long axis within a sheath. The nucleus, with decondensed material, is located in the posterior of the cell. All parts of the spermatozoon are tightly enclosed within an extracellular capsule. Despite a well‐conserved general structure and similarity of pattern among these spermatozoa, differences in the dimensions of the acrosome within the studied species may be useful to help distinguish the different crayfish species. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc.
Soluble soy protein peptic hydrolysate stimulates adipocyte differentiation in 3T3‐L1 cells
Authors: Goto Tsuyoshi , Mori Ayaka , Nagaoka Satoshi
Published: March 2013

Scope

The molecular mechanisms underlying the potential health benefit effects of soybean proteins on obesity‐associated metabolic disorders have not been fully clarified. In this study, we investigated the effects of soluble soybean protein peptic hydrolysate (SPH) on adipocyte differentiation by using 3T3‐L1 murine preadipocytes.

Methods and results

The addition of SPH increased lipid accumulation during adipocyte differentiation. SPH increased the mRNA expression levels of an adipogenic marker gene and decreased that of a preadipocyte marker gene, suggesting that SPH promotes adipocyte differentiation. SPH induced antidiabetic and antiatherogenic adiponectin mRNA expression and secretion. Moreover, SPH increased the mRNA expression levels of insulin‐responsive glucose transporter 4 and insulin‐stimulated glucose uptake. The expression levels of peroxisome proliferator‐activated receptor γ (PPARγ), a key regulator of adipocyte differentiation, during adipocyte differentiation were up‐regulated in 3T3‐L1 cells treated with SPH, and lipid accumulation during adipocyte differentiation induced by SPH was inhibited in the presence of a PPARγ antagonist. However, SPH did not exhibit PPARγ ligand activity.

Conclusion

These findings indicate that SPH stimulates adipocyte differentiation, at least in part, via the up‐regulation of PPARγ expression levels. These effects of SPH might be important for the health benefit effects of soybean proteins on obesity‐associated metabolic disorders.
The drug resistance suppression induced by curcuminoids in colon cancer SW‐480 cells is mediated by reactive oxygen species‐induced disruption of the microRNA‐27a‐ZBTB10‐Sp axis
Authors: Noratto Giuliana D. , Jutooru Indira , Safe Stephen , Angel‐Morales Gabriela , Mertens‐Talcott Susanne U.
Published: March 2013

Scope

Mechanisms involving the curcuminoids effects in decreasing the prooncogenic specificity protein (Sp) transcription factors, and Sp‐regulated genes in SW‐480 colon cancer cells and how the multidrug resistance protein (MDR1) inhibition is mediated by Sp suppression.

Methods and results

HT‐29 and SW‐480 colon cancer and normal CCD‐18Co colon fibroblast cells were treated with curcuminoids previously analyzed by HPLC. Gene and protein expression regulation were assessed by RT‐PCR, transfections with expression constructs, and Western blots. Curcuminoids (2.5–10 μg/mL) suppressed preferentially the growth of SW‐480 and HT‐29 compared to CCD‐18Co cells and enhanced the anticancer activity of the chemotherapeutic drug 5‐fluorouracil due to the suppression of MDR1. Additionally, Sp1, Sp3, and Sp4 and Sp‐regulated genes were downregulated by curcuminoids in SW‐480 and this was accompanied by suppression of microRNA‐27a (miR‐27a) and induction of ZBTB10, an mRNA target of miR‐27a and a transcriptional repressor of Sp expression. This mechanism was mediated by the induction of ROS. RNA‐interference and transfection with ZBTB10‐expression plasmid demonstrated that MDR1 was regulated by Sp1 and Sp3 and the disruption of the miR‐27a‐ZBTB10‐Sp axis.

Conclusion

Colon cancer treatment with curcuminoids will enhance the therapeutic effects of drugs in patients who have developed drug resistance.
In vivo 1HMR spectroscopic imaging of aggressive prostate cancer: Can we detect lactate?
Authors: Kobus Thiele , Wright Alan J. , Van Asten Jack J. A. , Heerschap Arend , Scheenen Tom W. J.
Published: March 2013

Purpose

A semi‐LASER sequence was optimized for in vivo lactate detection in the prostate.

Methods

The ethical committee waived the need for informed consent to measure 17 patients with high grade prostate cancer on a 3T system. A semi‐LASER sequence was used with an echo time of 144 ms and optimized interpulse timing for a spectral citrate shape with high signal intensity. An LCModel basis set was developed for fitting choline, creatine, spermine, citrate, and lactate and was used to fit all spectra in tumor‐containing voxels. For patients without detectable lactate, the minimal detectable lactate concentration was determined by adding in all spectra of tumor tissue a simulated lactate signal. The amplitude of the simulated lactate signal was iteratively decreased until its fit reached a Cramér Rao lower bound >20%, which was then set as the patient‐specific detection limit.

Results

In none of the patients a convincing lactate signal was found. We estimated that on average the lactate levels in high grade prostate cancer are below 1.5 mM (range 0.9–3.5 mM), Interestingly, in one patient with extensive necrosis in the tumor biopsy samples (Gleason score 5+5), large lipid resonances were observed, which originated from the tumor.

Conclusion

The minimal detectable lactate concentration of 1.5 mM in high grade prostate cancer indicates that if lactate is increased it remains at low concentrations. Magn Reson Med 71:26–34, 2014. © 2013 Wiley Periodicals, Inc.
Non‐invasive quantification of absolute cerebral blood volume during functional activation applicable to the whole human brain
Authors: Ciris Pelin Aksit , Qiu Maolin , Constable Robert Todd
Published: March 2013

Purpose

Cerebral blood volume (CBV) changes in many diverse pathologic conditions, and in response to functional challenges along with changes in blood flow, blood oxygenation, and the cerebral metabolic rate of oxygen. The feasibility of a new method for non‐invasive quantification of absolute cerebral blood volume that can be applicable to the whole human brain was investigated.

Methods

Multi‐slice data were acquired at 3 T using a novel inversion recovery echo planar imaging (IR‐EPI) pulse sequence with varying contrast weightings and an efficient rotating slice acquisition order, at rest and during visual activation. A biophysical model was used to estimate absolute cerebral blood volume at rest and during activation, and oxygenation during activation, on data from 13 normal human subjects.

Results

Cerebral blood volume increased by 21.7% from 6.6 ± 0.8 mL/100 mL of brain parenchyma at rest to 8.0 ± 1.3 mL/100 mL of brain parenchyma in the occipital cortex during visual activation, with average blood oxygenation of 84 ± 2.1% during activation, comparing well with literature.

Conclusion

The method is feasible, and could foster improved understanding of the fundamental physiological relationship between neuronal activity, hemodynamic changes, and metabolism underlying brain activation; complement existing methods for estimating compartmental changes; and potentially find utility in evaluating vascular health. Magn Reson Med 71:580–590, 2014. © 2013 Wiley Periodicals, Inc.
Use of a computer‐controlled motion phantom to investigate the temporal and spatial fidelity of HYPR processing
Authors: Keith Lauren , Rahimi Mahdi , Holmes James , Brittain Jean , Korosec Frank
Published: March 2013

Purpose

In this work, we investigate the spatial and temporal fidelity of highly constrained backPRojection (HYPR) processing using a computer‐controlled motion phantom. The goal of this experimental set‐up was to provide not only well‐defined temporal dynamics and spatial characteristics of the motion phantom, but also circumstances that imitate in vivo scenarios.

Methods

The phantom was designed to represent an artery flanked on both sides by vein. Both arterial and venous components have different temporal dynamics but are confluent, which corresponds to a difficult scenario for HYPR. Spatial and temporal fidelity was investigated by measuring signal intensity profiles through the phantom both orthogonal to as well as along the direction of motion.

Results

Spatial fidelity profiles measured from the HYPR processed images yielded full‐width‐at‐half‐maximum values very similar to those measured in non‐HYPR‐processed images. Furthermore, there was no significant spreading of the motion phantom leading edge in HYPR processed images.

Conclusion

Although HYPR processing has certain characteristic artifacts that are discussed, the technique can be used to improve image quality of highly undersampled time frame images with minimal loss of spatial or temporal fidelity. Magn Reson Med 71:702–710, 2014. © 2013 Wiley Periodicals, Inc.
Improved precision in CHARMED assessment of white matter through sampling scheme optimization and model parsimony testing
Authors: De Santis S. , Assaf Y. , Evans C. J. , Jones D. K.
Published: March 2013

Purpose

The composite hindered and restricted model of diffusion provides microstructural indices that are potentially more specific than those from diffusion tensor imaging. However, in comparison to diffusion tensor imaging, the acquisition time is longer, limiting clinical applications. Moreover, the model requires several parameters to be estimated whose confidence intervals can be large. Here, the composite hindered and restricted model of diffusion acquisition and data processing pipelines are optimized to extend the utility of this approach.

Methods

A multishell sampling scheme was optimized using the electrostatic repulsion algorithm, combined with optimal ordering. The optimal protocol, using as few measurements as possible, was determined through leave‐n‐out analyses. Parsimonious model selection criteria were used to select between nested models, comprising up to three restricted compartments. The schemes were evaluated using both through Monte‐Carlo simulations and in vivo data.

Results

The optimization/model selection procedure resulted in increased accuracy and precision on the estimated parameters, allowing for a reduction in acquisition time and marked improvements in data quality. The final protocol provided whole brain coverage data in only 12 min.

Conclusion

Through careful optimization of the acquisition and analysis pipeline for the composite hindered and restricted model of diffusion, it is possible to reduce acquisition time for whole brain datasets to a time that is clinically applicable. Magn Reson Med 71:661–671, 2014. © 2013 Wiley Periodicals, Inc.
Detecting neuronal currents with MRI: A human study
Authors: Huang Jie
Published: March 2013

Purpose

Recently developed neuronal current magnetic resonance imaging aims to directly detect neuronal currents associated with brain activity, but controversial results have been reported in different studies on human subjects. Although there is no dispute that local neuronal currents produce weak transient magnetic fields that would attenuate local MR signal intensity, there is not yet consensus as to whether this attenuation is detectable with present magnetic resonance imaging techniques. This study investigates the magnitude of neuronal current‐induced signal attenuation in human visual cortex.

Theory

A temporally well‐controlled visual stimulation paradigm with a known neuronal firing pattern in monkey visual cortex provides a means of detecting and testing the magnitude of the neuronal current‐induced attenuation in neuronal current magnetic resonance imaging.

Methods

Placing a series of acquisition windows to fully cover the entire response duration enables a thorough detection of any detectable MR signal attenuation induced by the stimulus‐evoked neuronal currents.

Results

No significant neuronal current‐induced MR signal attenuation was observed in the putative V1 in any participated subjects.

Conclusion

The present magnetic resonance imaging technique is not sensitive enough to detect neuronal current‐induced MR signal attenuation, and the upper limit of this attenuation was found to be less than 0.07% under the study condition. Magn Reson Med 71:756–762, 2014. © 2013 Wiley Periodicals, Inc.
Extension of GKB‐FP algorithm to large‐scale general‐form Tikhonov regularization
Authors: Viloche Bazán Fermín S. , Cunha Maria C.C. , Borges Leonardo S.
Published: March 2013

In a recent paper an algorithm for large‐scale Tikhonov regularization in standard form called GKB‐FP was proposed and numerically illustrated. In this paper, further insight into the convergence properties of this method is provided, and extensions to general‐form Tikhonov regularization are introduced. In addition, as alternative to Tikhonov regularization, a preconditioned LSQR method coupled with an automatic stopping rule is proposed. Preconditioning seeks to incorporate smoothing properties of the regularization matrix into the computed solution. Numerical results are reported to illustrate the methods on large‐scale problems. Copyright © 2013 John Wiley & Sons, Ltd.
The Z‐eigenvalues of a symmetric tensor and its application to spectral hypergraph theory
Authors: Li Guoyin , Qi Liqun , Yu Gaohang
Published: March 2013

In this paper, using variational analysis and optimization techniques, we examine some fundamental analytic properties of Z‐eigenvalues of a real symmetric tensor with even order. We first establish that the maximum Z‐eigenvalue function is a continuous and convex function on the symmetric tensor space and so provide formulas of the convex conjugate function and ε‐subdifferential of the maximum Z‐eigenvalue function. Consequently, for an mth‐order N‐dimensional tensor , we show that the normalized eigenspace associated with maximum Z‐eigenvalue function is ρth‐order Hölder stable at with . As a by‐product, we also establish that the maximum Z‐eigenvalue function is always at least ρth‐order semismooth at . As an application, we introduce the characteristic tensor of a hypergraph and show that the maximum Z‐eigenvalue function of the associated characteristic tensor provides a natural link for the combinatorial structure and the analytic structure of the underlying hypergraph. Finally, we establish a variational formula for the second largest Z‐eigenvalue for the characteristic tensor of a hypergraph and use it to provide lower bounds for the bipartition width of a hypergraph. Some numerical examples are also provided to show how one can compute the largest/second‐largest Z‐eigenvalue of a medium size tensor, using polynomial optimization techniques and our variational formula. Copyright © 2013 John Wiley & Sons, Ltd.
Mechanical characterization in laminated composite for cryogenic application
Authors: Oh Bong Taek , Lagoudas Dimitris C. , Moon SungCheal
Published: March 2013

Damage in cryogenic composite fuel tanks induced during manufacturing and advanced by thermomechanical cycling can accelerate leakage of the propellant. Whether the leakage exceeds tolerable levels depends on many factors, including pressure gradients, microcrack density, other damage such as delamination, connectivity of the cracks, residual stresses from manufacture, service‐induced stresses from thermal and mechanical loads, and composite lay‐up. This article is concerned with the creation and the detection of damage in cryogenic composites due to thermomechanical loading. The first part deals with cryocycling (cycling between two temperatures) test procedures, that were developed to understand the damage produced in cryogenic composite laminates under thermomechanical loading. An apparatus was developed to thermomechanically cycle coupon test specimens under different thermomechanical loadings. IM7/977‐2 and IM7/5250‐4 graphite/epoxy cross‐ply [902/02]S and angle‐ply [0/‐45/90/45/0/45090/‐45/0]S laminates were tested using these systems. Ply‐by‐ply microcrack density was measured as a function of thermomechanical cycles. The second part of this article deals with effect of thermal gradients due to sudden exposure to a cryogenic temperature. The sudden exposure to cryogenic temperatures may have caused the microcracks, due to large temperature variations through the thickness and the resulting thermal stresses. In this work, an investigation of the sudden exposure to cryogenic temperatures is conducted experimentally with and without an insulating layer. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
Dependence of electrical properties of polyethylene nanocomposites on aspect ratio of carbon nanotubes
Authors: Rahaman Mostafizur , Thomas Selvin P. , Hussein Ibnelwaleed A. , De S.K.
Published: March 2013

Low density polyethylene nanocomposites filled with carbon nanotubes (CNT) having three different aspect ratios have been prepared by melt mixing technique. The effects of CNT loading, its aspect ratio, and frequency of electric field on electrical and dielectric properties of the nanocomposites have been investigated. DC and AC electrical resistivity are found to decrease with the increase in CNT loading in the composites, while the dielectric constant and loss increase with the increase in CNT loading in the composites. AC electrical resistivity, dielectric constant, and dielectric loss decrease with the increase in frequency. Furthermore, the electrical resistivity decreases with the increase in aspect ratio of CNT, whereas the dielectric constant and loss increase with the increase in aspect ratio of CNT. While probable mechanisms for electrical conduction have been proposed, dielectric results have been explained by considering CNT as nanocapacitors. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
Silicon carbide‐strengthened magnetorheological elastomer: Preparation and mechanical property
Authors: Yang Jie , Gong Xinglong , Zong Luhang , Peng Chao , Xuan Shouhu
Published: March 2013

A novel silicon carbide (SiC)‐strengthened magnetorheological elastomers (MREs) was developed to enhance its viscoelastic performance. The influences of the size and weight content of the SiC particles on the viscoelastic performance of the MREs were systematically studied. The shear storage modulus, damping property, and magnetorheological effects were analyzed to evaluate their dynamic properties. Under optimum condition, the initial storage modulus (G0) of the MRE‐0.06‐SiC‐3 (SiC weight content 3.2 wt%, mean diameter 0.06 μm) is about 2.16 times larger than the MRE‐0.06‐SiC‐0 (nondoped MRE), whereas the magnetorheological effect was almost kept constant. In addition, the damping properties of the as‐prepared MREs which were obtained from the intrinsic damping, the magnetomechanical hysteresis, and the interface damping were also analyzed. These results provided a meaningful method for developing MREs with controllable storage modulus and damping capacity. POLYM. ENG. SCI., 53:2615–2623, 2013. © 2013 Society of Plastics Engineers
Effect of biaxial orientation on dielectric and breakdown properties of poly(ethylene terephthalate)/poly(vinylidene fluoride‐co‐tetrafluoroethylene) multilayer films
Authors: Carr Joel M. , Mackey Matthew , Flandin Lionel , Schuele Donald , Zhu Lei , Baer Eric
Published: March 2013

Polymer films with enhanced dielectric and breakdown properties are essential for the production of high energy density polymer film capacitors. By capitalizing on the synergistic effects of forced assembly nanolayer coextrusion and biaxial orientation, polymer multilayer films using poly(ethylene terephthalate) (PET) and a poly(vinylidene fluoride‐co‐tetrafluoroethylene) [P(VDF‐TFE)] copolymer were produced. These films exhibited breakdown fields, under a divergent field using needle/plane electrodes, as high as 1000 kV mm−1. The energy densities of these same materials, under a uniform electric field measured using plane/plane electrodes, were as high as 16 J cm−3. The confined morphologies of both PET and P(VDF‐TFE) were correlated to the observed breakdown properties and damage zones. On‐edge P(VDF‐TFE) crystals induced from solid‐state biaxial stretching enhanced the effective P(VDF‐TFE) layer dielectric constant and therefore increased the dielectric contrast between the PET and P(VDF‐TFE) layers. This resulted in additional charge buildup at the layer interface producing larger tree diameters and branches and ultimately increasing the breakdown and energy storage properties. In addition to energy storage and breakdown properties, the hysteresis behavior of these materials was also evaluated. By varying the morphology of the P(VDF‐TFE) layer, the low‐field dielectric loss (or ion migration behavior) could be manipulated, which in turn also changed the observed hysteresis behavior. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013, 51, 882–896
Crystal structure of the dimer of two essential Salmonella typhimurium proteins, YgjD & YeaZ and calorimetric evidence for the formation of a ternary YgjD–YeaZ–YjeE complex
Authors: Nichols C. E. , Lamb H.K. , Thompson P. , Omari K. El , Lockyer M. , Charles I. , Hawkins A. R. , Stammers D. K.
Published: March 2013

YgjD from COG0533 is amongst a small group of highly conserved proteins present in all three domains of life. Various roles and biochemical functions (including sialoprotease and endonuclease activities) have been ascribed to YgjD and orthologs, the most recent, however, is involvement in the post transcriptional modification of certain tRNAs by formation of N6‐threonyl‐adenosine (t6A) at position 37. In bacteria, YgjD is essential and along with YeaZ, YjeE, and YrdC has been shown to be ‘necessary and sufficient’ for the tRNA modification. To further define interactions and possible roles for some of this set of proteins we have undertaken structural and biochemical studies. We show that formation of the previously reported heterodimer of YgjD–YeaZ involves ordering of the C‐terminal region of YeaZ which extends along the surface of YgjD in the crystal structure. ATPγS or AMP is observed in YgjD while no nucleotide is bound on YeaZ. ITC experiments reveal previously unreported binary and ternary complexes which can be nucleotide dependent. The stoichiometry of the YeaZ–YgjD complex is 1:1 with a KD of 0.3 µM. YgjD and YjeE interact only in the presence of ATP, while YjeE binds to YgjD‐YeaZ in the presence of ATP or ADP with a KD of 6 µM. YgjD doesn't bind the precursors of t6A, threonine, and bicarbonate. These results show a more complex set of interactions than previously thought, which may have a regulatory role. The understanding gained should help in deriving inhibitors of these essential proteins that might have potential as antibacterial drugs.
A polymetamorphic protein
Authors: Stewart Katie L. , Dodds Eric D. , Wysocki Vicki H. , Cordes Matthew H. J.
Published: March 2013

Arc repressor is a homodimeric protein with a ribbon‐helix–helix fold. A single polar‐to‐hydrophobic substitution (N11L) at a solvent‐exposed position leads to population of an alternate dimeric fold in which 310 helices replace a β‐sheet. Here we find that the variant Q9V/N11L/R13V (S‐VLV), with two additional polar‐to‐hydrophobic surface mutations in the same β‐sheet, forms a highly stable, reversibly folded octamer with approximately half the✠α‐helical content of wild‐type Arc. At low protein concentration and low ionic strength, S‐VLV also populates both dimeric topologies previously observed for N11L, as judged by NMR chemical shift comparisons. Thus, accumulation of simple hydrophobic mutations in Arc progressively reduces fold specificity, leading first to a sequence with two folds and then to a manifold bridge sequence with at least three different topologies. Residues 9–14 of S‐VLV form a highly hydrophobic stretch that is predicted to be amyloidogenic, but we do not observe aggregates of higher order than octamer. Increases in sequence hydrophobicity can promote amyloid aggregation but also exert broader and more complex effects on fold specificity. Altered native folds, changes in fold coupled to oligomerization, toxic pre‐amyloid oligomers, and amyloid fibrils may represent a near continuum of accessible alternatives in protein structure space.
Improving ranking of models for protein complexes with side chain modeling and atomic potentials
Authors: Viswanath Shruthi , Ravikant D. V. S. , Elber Ron
Published: March 2013

An atomically detailed potential for docking pairs of proteins is derived using mathematical programming. A refinement algorithm that builds atomically detailed models of the complex and combines coarse grained and atomic scoring is introduced. The refinement step consists of remodeling the interface side chains of the top scoring decoys from rigid docking followed by a short energy minimization. The refined models are then re‐ranked using a combination of coarse grained and atomic potentials. The docking algorithm including the refinement and re‐ranking, is compared favorably to other leading docking packages like ZDOCK, Cluspro, and PATCHDOCK, on the ZLAB 3.0 Benchmark and a test set of 30 novel complexes. A detailed analysis shows that coarse grained potentials perform better than atomic potentials for realistic unbound docking (where the exact structures of the individual bound proteins are unknown), probably because atomic potentials are more sensitive to local errors. Nevertheless, the atomic potential captures a different signal from the residue potential and as a result a combination of the two scores provides a significantly better prediction than each of the approaches alone. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Salvianolic acid B inhibits the amyloid formation of human islet amyloid polypeptideand protects pancreatic beta‐cells against cytotoxicity
Authors: Cheng Biao , Gong Hao , Li Xiaochao , Sun Yue , Chen Hong , Zhang Xin , Wu Qian , Zheng Ling , Huang Kun
Published: March 2013

The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of type 2 diabetes mellitus (T2DM). Salvia miltiorrhiza (Danshen), one of the most commonly used of traditional Chinese medicines, is often used in Compound Recipes for treating diabetes, however with unclear mechanisms. Since salvianolic acid B (SalB) is the most abundant bioactive ingredient of salvia miltiorrhiza water‐extract. In this study, we tested whether SalB has any effect on the amyloidogenicity of hIAPP. Our results clearly suggest that SalB can significantly inhibit the formation of hIAPP amyloid and disaggregate hIAPP fibrils. Furthermore, photo‐crosslinking based oligomerization studies suggest SalB significantly suppresses the toxic oligomerization of hIAPP monomers. Cytotoxicity protection effects on pancreatic INS‐1 cells by SalB were also observed using MTT‐based assays, potentially due to the inhibition on the membrane disruption effects and attenuated mitochondria impairment induced by hIAPP. These results provide evidence that SalB may further be studied on the possible pharmacological treatment for T2DM. Proteins 2013. © 2012 Wiley Periodicals, Inc.
LabCaS: Labeling calpain substrate cleavage sites from amino acid sequence using conditional random fields
Authors: Fan Yong‐Xian , Zhang Yang , Shen Hong‐Bin
Published: March 2013

The calpain family of Ca2+‐dependent cysteine proteases plays a vital role in many important biological processes which is closely related with a variety of pathological states. Activated calpains selectively cleave relevant substrates at specific cleavage sites, yielding multiple fragments that can have different functions from the intact substrate protein. Until now, our knowledge about the calpain functions and their substrate cleavage mechanisms are limited because the experimental determination and validation on calpain binding are usually laborious and expensive. In this work, we aim to develop a new computational approach (LabCaS) for accurate prediction of the calpain substrate cleavage sites from amino acid sequences. To overcome the imbalance of negative and positive samples in the machine‐learning training which have been suffered by most of the former approaches when splitting sequences into short peptides, we designed a conditional random field algorithm that can label the potential cleavage sites directly from the entire sequences. By integrating the multiple amino acid features and those derived from sequences, LabCaS achieves an accurate recognition of the cleave sites for most calpain proteins. In a jackknife test on a set of 129 benchmark proteins, LabCaS generates an AUC score 0.862. The LabCaS program is freely available at: http://www.csbio.sjtu.edu.cn/bioinf/LabCaS. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Assessing interactions for fixed‐dose drug combinations in subcutaneous tumor xenograft studies
Authors: Wu Jianrong
Published: March 2013

Drug combinations in preclinical tumor xenograft studies are often assessed using fixed doses. Assessing the joint action of drug combinations with fixed doses has not been well developed in the literature. Here, an interaction index is proposed for fixed‐dose drug combinations in a subcutaneous tumor xenograft model. Furthermore, a bootstrap percentile interval of the interaction index is also developed. The joint action of two drugs can be assessed on the basis of confidence limits of the interaction index. Tumor xenograft data from actual two‐drug combination studies are analyzed to illustrate the proposed method. Copyright © 2013 John Wiley & Sons, Ltd.
Rapid field application of hydraulic tomography for resolving aquifer heterogeneity in unconsolidated sediments
Authors: Brauchler R. , Hu R. , Hu L. , Jiménez S. , Bayer P. , Dietrich P. , Ptak T.
Published: March 2013

Key Points

Rapid field application of hydraulic tomography

Further development of hydraulic attenuation tomography

Comparison of direct‐push profiling and hydraulic tomography