bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential of collagen‐like triple helical peptides as drug carriers: Their in vivo distribution, metabolism, and excretion profiles in rodents
Authors: Yasui Hiroyuki , Yamazaki Chisato M. , Nose Hiroshi , Awada Chihiro , Takao Toshifumi , Koide Takaki
Published: March 2013

Collagen‐model peptides composed of (X‐Y‐Gly)n sequences were used to study the triple helical structure of collagen. We report the stability of these collagen‐like peptides in biological fluids, and their pharmacokinetics including distribution, metabolism, and excretion in animals. A typical collagen‐model peptide, H‐(Pro‐Hyp‐Gly)10‐OH, was found to be extremely stable in the plasma and distributed mainly in the vascular blood space, and was eliminated through glomerular filtration in the kidneys. Triple helical peptides of (X‐Y‐Gly)n sequences were quantitatively recovered from the urine of rats after intravenous injection regardless of the differences in peptide net charge between −3 and +6 per triple helix. In contrast, the renal clearance became less efficient when the number of triplet repeats (n) was 12 or more. We also demonstrated the application of a collagen‐like triple helical peptide as a novel drug carrier in the blood with a high urinary excretion profile. We further demonstrated that a collagen‐like triple helical peptide conjugated to a spin probe, PROXYL, has the potential to evaluate the redox status of oxidative stress‐induced animals in vivo. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 705–713, 2013.
Opportunities for improvement in the management of patients who die from haemorrhage after trauma
Authors: O'Reilly D , Mahendran K , West A , Shirley P , Walsh M , Tai N
Published: March 2013

Background

Bleeding is the leading cause of preventable death after injury. This retrospective study aimed to characterize opportunities for performance improvement (OPIs) identified in patients who died from bleeding and were considered by the quality improvement system of a major trauma centre.

Methods

All trauma deaths in 2006–2010 were discussed at the trauma morbidity and mortality meeting. Deaths from haemorrhage were identified and subjected to qualitative and quantitative evaluation. OPIs were identified and remedial action was taken.

Results

During the study interval there were 7511 trauma team activations; 423 patients died. Haemorrhage was the second most common cause of death, in 112 patients, and made a substantial contribution to death in a further 15. For 84 of these 127 patients, a total of 150 OPIs were identified. Most arose in the emergency department, but involved personnel from many departments. Problems with decision-making were more common than errors in technical skill. OPIs frequently involved the decision between surgery, radiology and further investigation. Delayed and inappropriate surgery occurred even when investigation and diagnosis were appropriate. The mortality rate among patients presenting in shock fell significantly over the study interval (P < 0·026).

Conclusion

Problems with judgement are more common than those of skill. Death from traumatic haemorrhage is associated with identifiable, remediable failures in care. The implementation of a systematic trauma quality improvement system was associated with a fall in the mortality rate among patients presenting in shock.
Development and validation of a sensitive and high‐throughput LC‐MS/MS method for the simultaneous determination of esomeprazole and naproxen in human plasma
Authors: Gopinath Shanmugam , Kumar Ramadass Satiesh , Shankar Madhira bhawani , Danabal Palanisamy
Published: March 2013

A sensitive and high‐throughput LC‐MS/MS method has been developed and validated for the combined determination of esomeprazole and naproxen in human plasma with ibuprofen as internal standard. Solid‐phase extraction was used to extract both analytes and internal standard from human plasma. Chromatographic separation was achieved in 4.0 min on XBridge C18 column using acetonitrile–25 mM ammonium formate (70:30, v/v) as mobile phase. Mass detection was achieved by ESI/MS/MS in negative ion mode, monitoring at m/z 344.19 → 194.12, 229.12 → 169.05 and 205.13 → 161.07 for esomeprazole, naproxen and IS, respectively. The calibration curves were linear from 3.00 to 700.02 ng/mL for esomeprazole and 0.50 to 150.08 ng/mL for naproxen. The intra‐ and inter‐batch precision and accuracy across four quality control levels met established criteria of US Food and Drug Administration guidelines. The assay is suitable for measuring accurate esomeprazole and naproxen plasma concentrations in human bioequivalence study following combined administration. Copyright © 2013 John Wiley & Sons, Ltd.
UPLC‐MS/MS assay for the simultaneous quantification of carvedilol and its active metabolite 4′‐hydroxyphenyl carvedilol in human plasma to support a bioequivalence study in healthy volunteers
Authors: Patel Daxesh P. , Sharma Primal , Sanyal Mallika , Singhal Puran , Shrivastav Pranav S.
Published: March 2013

An ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method has been developed for the simultaneous determination of carvedilol and its pharmacologically active metabolite 4′‐hydroxyphenyl carvedilol in human plasma using their deuterated internal standards (IS). Samples were prepared by solid‐phase extraction using 100 μL human plasma. Chromatographic separation of analytes was achieved on UPLC C18 (50 × 2.1 mm, 1.7 µm) column using acetonitrile‐4.0 mm ammonium formate, pH 3.0 adjusted with 0.1% formic acid (78:22, v/v) as the mobile phase. The multiple reaction monitoring transitions for both the analytes and IS were monitored in the positive electrospray ionization mode. The method was validated over a concentration range of 0.05–50 ng/mL for carvedilol and 0.01‐10 ng/mL for 4′‐hydroxyphenyl carvedilol. Intra‐ and inter‐batch precision (% CV) and accuracy for the analytes varied from 0.74 to 3.88 and 96.4 to 103.3% respectively. Matrix effect was assessed by post‐column analyte infusion and by calculation of precision values (coefficient of variation) in the measurement of the slope of calibration curves from eight plasma batches. The assay recovery was within 94–99% for both the analytes and IS. The method was successfully applied to support a bioequivalence study of 12.5 mg carvedilol tablets in 34 healthy subjects. Copyright © 2013 John Wiley & Sons, Ltd.
A Designed Three‐Stranded β‐Sheet in an α/β Hybrid Peptide
Authors: Sonti Rajesh , Gopi Hosahudya N. , Muddegowda Umashankara , Ragothama Srinivasarao , Balaram Padmanabhan
Published: March 2013

The incorporation of β‐amino acid residues into the antiparallel β‐strand segments of a multi‐stranded β‐sheet peptide is demonstrated for a 19‐residue peptide, Boc‐LVβFVDPGLβFVVLDPGLVLβFVV‐OMe (BBH19). Two centrally positioned DPro–Gly segments facilitate formation of a stable three‐stranded β‐sheet, in which β‐phenylalanine (βPhe) residues occur at facing positions 3, 8 and 17. Structure determination in methanol solution is accomplished by using NMR‐derived restraints obtained from NOEs, temperature dependence of amide NH chemical shifts, rates of H/D exchange of amide protons and vicinal coupling constants. The data are consistent with a conformationally well‐defined three‐stranded β‐sheet structure in solution. Cross‐strand interactions between βPhe3/βPhe17 and βPhe3/Val15 residues define orientations of these side‐chains. The observation of close contact distances between the side‐chains on the N‐ and C‐terminal strands of the three‐stranded β‐sheet provides strong support for the designed structure. Evidence is presented for multiple side‐chain conformations from an analysis of NOE data. An unusual observation of the disappearance of the Gly NH resonances upon prolonged storage in methanol is rationalised on the basis of a slow aggregation step, resulting in stacking of three‐stranded β‐sheet structures, which in turn influences the conformational interconversion between type I′ and type II′ β‐turns at the two DPro–Gly segments. Experimental evidence for these processes is presented. The decapeptide fragment Boc‐LVβFVDPGLβFVV‐OMe (BBH10), which has been previously characterized as a type I′ β‐turn nucleated hairpin, is shown to favour a type II′ β‐turn conformation in solution, supporting the occurrence of conformational interconversion at the turn segments in these hairpin and sheet structures.
Removal of Organic Dyes in Environmental Water onto Magnetic‐Sulfonic Graphene Nanocomposite
Authors: Wang Sui , Wei Jing , Lv Shasha , Guo Zhiyong , Jiang Feng
Published: March 2013

A magnetic‐sulfonic graphene nanocomposite (G‐SO3H/Fe3O4) was synthesized and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and X‐ray diffraction. It was used for removal of three cationic dyes: safranine T (ST), neutral red (NR), victoria blue (VB), and three anionic dyes: methyl orange, brilliant yellow, and alizarin red, from environmental water. The experimental conditions were optimized, including pH, amount of adsorbent, adsorption kinetics, adsorption isotherms, ionic strength, etc. The results show that G‐SO3H/Fe3O4 can adsorb cationic dyes more efficiently and selectively than anionic dyes at pH 6.0. In the first 10 min of adsorption time, more than 93% of the cationic dyes were removed by the sorbent. Adsorption kinetics follow the pseudo‐second‐order kinetic model well. The adsorption isotherm coincided with Langmuir and Freundlich adsorption models. The maximum adsorption capacities of G‐SO3H/Fe3O4 for ST, NR, and VB dyes were 199.3, 216.8, and 200.6 mg g−1. The adsorbed cationic dyes were eluted by using different pH values of ethanol as the solvent. The established method was simple, sensitive, and rapid, and was suitable for the adsorption of cationic dyes in environmental water.
Development of Bench‐Scale Bio‐Packed Column for Wastewater Treatment from Optical Emission Spectrometry
Authors: Vijayaraghavan Kuppusamy , Segovia Elvagris
Published: March 2013

An eco‐friendly and inexpensive technique for wastewater treatment originated from inductively coupled plasma‐optical emission spectrometry (ICP‐OES) is presented within this paper. The proposed process comprised of loading waste crab shells in packed column for adsorption of heavy metal ions, followed by desorption using 0.01 M HCl. An exhaustive physical and chemical characterization of ICP‐OES wastewater revealed the complex nature of effluent, including the presence of 15 different metals and metalloid under strong acidic condition (pH 1.3). Based on the preliminary batch experiments, it was identified that solution pH played a major role in metal sequestration by crab shell with pH 3.5 identified as optimum pH. Rapid metal biosorption kinetics along with complete desorption and subsequent reuse for three cycles was possible with crab shell‐based treatment process. Continuous flow‐through column experiments confirmed the high performance of crab shell towards multiple metal ions with the column able to operate for 22 h at a flow rate of 10 mL/min before outlet concentration of arsenic reached 0.25 times of its inlet concentration. Other metal ions such as Cu, Cd, Co, Cr, Pb, Ni, Zn, Mn, Al, and Fe were only in trace levels in the treated water until 22 h. The performance of the treatment process was compared with trade effluent discharge standards, and the process flow diagram along with cost analysis was suggested.
Preparation of Fluorescent Tubulin Binders
Authors: Riva Elena , Mattarella Martin , Borrelli Stella , Christodoulou Michael S. , Cartelli Daniele , Main Marcus , Faulkner Stephen , Sykes Daniel , Cappelletti Graziella , Snaith John S. , Passarella Daniele
Published: March 2013

Invited for this month’s cover are the groups of Prof. Daniele Passarella, Prof. Graziella Cappelletti, Dr. Stephen Faulkner and Prof. John S. Snaith based at the Universities of Milano, Oxford and Birmingham. The image shows that a fluorescent tubulin binder could evidence the tubulin/microtubule network.
Emulsion‐Templated Macroporous Carbons Synthesized By Hydrothermal Carbonization and their Application for the Enzymatic Oxidation of Glucose
Authors: Brun Nicolas , Edembe Lise , Gounel Sébastien , Mano Nicolas , Titirici Magdalena M.
Published: March 2013

Carbon‐based monoliths have been designed using a simple synthetic pathway based on using high internal phase emulsion (HIPE) as a soft template to confine the polymerization and hydrothermal carbonization of saccharide derivatives (furfural) and phenolic compounds (phloroglucinol). Monosaccharides can be isolated from the cellulosic fraction of lignocellulosic biomass and phloroglucinol can be extracted from the bark of fruit trees; however, this approach constitutes an interesting sustainable synthetic route. The macroscopic characteristics can be easily modulated; a high macroporosity and total pore volume of up to 98 % and 18 cm3 g−1 have been obtained, respectively. After further thermal treatment under inert atmosphere, the as‐synthesized macroporous carbonized HIPEs (carbo‐HIPEs) have shaping capabilities relating to interesting mechanical properties as well as a high electrical conductivity of up to 300 S m−1. These conductive foams exhibit a hierarchical structure associated with the presence of both meso‐ and micropores that exhibit specific Brunauer–Emmett–Teller (BET) surface areas and DFT total pore volumes up to 730 m2 g−1 and 0.313 cm3 g−1, respectively. Because of their attractive structural characteristics and intrinsic properties, these macroporous monoliths have been incorporated as a proof of principle within electrochemical devices as modified thin carbon disc electrodes. A promising two‐fold improvement in the catalytic current is observed for the electrooxidation of glucose after the immobilization of a glucose oxidase‐based biocatalytic mixture onto the carbo‐HIPE electrodes compared to that observed if using commercial glassy carbon electrodes.
Solid‐State NMR Spectroscopic Studies of Propylphosphonic Acid Functionalized SBA‐15 Mesoporous Silica: Characterization of Hydrogen‐Bonding Interactions
Authors: Bibent Nicolas , Charpentier Thibault , Devautour‐Vinot Sabine , Mehdi Ahmad , Gaveau Philippe , Henn François , Silly Gilles
Published: March 2013

This work aims to investigate the local structure of mesoporous silica of the type SBA‐15 functionalized with propylphosphonic acid groups by means of an extensive solid‐state NMR spectroscopic study. Here, the functionalized SBA‐15 samples are obtained by a one‐step synthetic method that allowed us better control over the loading and the distribution of the surface functions. In addition to NMR spectroscopy, the materials are characterized by X‐ray diffraction, nitrogen adsorption–desorption and transmission electron microscopy. The 29Si, 13C, 31P and 1H one‐dimensional NMR spectroscopic results are discussed according to the nature of the functional groups in dry and wet materials. This paper proposes a rigorous approach that shows possible hydrogen bonding between adjacent phosphonic acid groups in dry SBA‐15, from the comparative study with an alkylphosphonic acid material. This outcome was demonstrated by two‐dimensional NMR spectroscopic solid–state experiments, including the use of 1H–1H spin‐diffusion exchange experiments, 31P–31P double quanta and an original pulse sequence that corresponds to 31P–1H–1H–31P correlation experiments.
Synthesis of Coordinatively Unsaturated Half‐Sandwich Iron–Silyl Complexes with an N‐Heterocyclic Carbene Ligand and Their Reactions with H2
Authors: Hatanaka Tsubasa , Ohki Yasuhiro , Tatsumi Kazuyuki
Published: March 2013

A half‐sandwich, coordinatively unsaturated N‐heterocyclic carbene complex of iron with a metallacycle was found to cleave the Si–H bonds of hydrosilanes to give 16‐electron iron–silyl complexes. The reactions of silyl complexes with H2 led to the formation of dihydride complexes, in which hydride ligands weakly interact with the silicon atom. The molecular structures of these new complexes have been determined by means of X‐ray crystallography.
Recent Developments in Low‐Dimensional Copper(II) Molecular Magnets
Authors: Landee Christopher P. , Turnbull Mark M.
Published: March 2013

The literature of low‐dimensional CuII molecular magnetic systems in which superexchange pathways involve halide ions and/or cyclic 1,4‐diazines is reviewed. Compounds are organized by lattice type between 1D systems (including uniform and alternating chains, and ladders) and 2D systems (including square and rectangular layers).
Interactomic approach for evaluating nucleophosmin‐binding proteins as biomarkers for Ewing's sarcoma
Authors: Haga Ayako , Ogawara Yoko , Kubota Daisuke , Kitabayashi Issay , Murakami Yasufumi , Kondo Tadashi
Published: March 2013

Nucleophosmin (NPM) is a novel prognostic biomarker for Ewing's sarcoma. To evaluate the prognostic utility of NPM, we conducted an interactomic approach to characterize the NPM protein complex in Ewing's sarcoma cells. A gene suppression assay revealed that NPM promoted cell proliferation and the invasive properties of Ewing's sarcoma cells. FLAG‐tag‐based affinity purification coupled with liquid chromatography‐tandem mass spectrometry identified 106 proteins in the NPM protein complex. The functional classification suggested that the NPM complex participates in critical biological events, including ribosome biogenesis, regulation of transcription and translation, and protein folding, that are mediated by these proteins. In addition to JAK1, a candidate prognostic biomarker for Ewing's sarcoma, the NPM complex, includes 11 proteins known as prognostic biomarkers for other malignancies. Meta‐analysis of gene expression profiles of 32 patients with Ewing's sarcoma revealed that 6 of 106 were significantly and independently associated with survival period. These observations suggest a functional role as well as prognostic value of these NPM complex proteins in Ewing's sarcoma. Further, our study suggests the potential applications of interactomics in conjunction with meta‐analysis for biomarker discovery.
Carbon evasion/accumulation ratio in boreal lakes is linked to nitrogen
Authors: Kortelainen Pirkko , Rantakari Miitta , Pajunen Hannu , Huttunen Jari T. , Mattsson Tuija , Juutinen Sari , Larmola Tuula , Alm Jukka , Silvola Jouko , Martikainen Pertti J.
Published: March 2013

The role of lakes in landscape carbon (C) cycling and primary drivers behind freshwater C balance have remained poorly known, although lakes are an important landscape component and cover 10% of Finland's total area. We studied CO2 evasion and average Holocene C accumulation in 82 boreal lakes (0.04–1540 km2; max depth 1–93 m) located between the latitudes 60°N and 69°N. Both CO2 evasion and C accumulation correlated with numerous drivers and were closely linked to lake area and maximum depth. The total aquatic C retention (C evasion + C accumulation) was largely determined by lake area (r2 = 0.96, p < 0.0001). Carbon in boreal lakes is mostly terrestrially fixed and our data demonstrate that boreal lakes are important conduits for transferring terrestrially fixed C to the atmosphere. C evasion/accumulation ratio (Cev/Cacc) ranged from 4 to 86 (on average 30) and correlated positively only with lake water NO3‐N concentration and maximum depth, and negatively with sediment N pool. Numerous possible important drivers like land use and climate as well as lake physical and chemical characteristics were compared to C balances. Our study might thus be valuable in trying to understand links between aquatic and terrestrial C cycling over boreal landscapes. Although climatic drivers generally play a key role in short‐term C balance fluctuations, our data indicate nitrogen/fertility to be a key contributing factor to long term C balance—increasing Cev/Cacc and thus decreasing the role of lakes in landscape C sequestration in boreal zone.
A Unified Mixed‐Effects Model for Rare‐Variant Association in Sequencing Studies
Authors: Sun Jianping , Zheng Yingye , Hsu Li
Published: March 2013

For rare‐variant association analysis, due to extreme low frequencies of these variants, it is necessary to aggregate them by a prior set (e.g., genes and pathways) in order to achieve adequate power. In this paper, we consider hierarchical models to relate a set of rare variants to phenotype by modeling the effects of variants as a function of variant characteristics while allowing for variant‐specific effect (heterogeneity). We derive a set of two score statistics, testing the group effect by variant characteristics and the heterogeneity effect. We make a novel modification to these score statistics so that they are independent under the null hypothesis and their asymptotic distributions can be derived. As a result, the computational burden is greatly reduced compared with permutation‐based tests. Our approach provides a general testing framework for rare variants association, which includes many commonly used tests, such as the burden test [Li and Leal, 2008] and the sequence kernel association test [Wu et al., 2011], as special cases. Furthermore, in contrast to these tests, our proposed test has an added capacity to identify which components of variant characteristics and heterogeneity contribute to the association. Simulations under a wide range of scenarios show that the proposed test is valid, robust, and powerful. An application to the Dallas Heart Study illustrates that apart from identifying genes with significant associations, the new method also provides additional information regarding the source of the association. Such information may be useful for generating hypothesis in future studies.
Modeling errors in daily precipitation measurements: Additive or multiplicative?
Authors: Tian Yudong , Huffman George J. , Adler Robert F. , Tang Ling , Sapiano Mathew , Maggioni Viviana , Wu Huan
Published: March 2013

The definition and quantification of uncertainty depend on the error model used. For uncertainties in precipitation measurements, two types of error models have been widely adopted: the additive error model and the multiplicative error model. This leads to incompatible specifications of uncertainties and impedes intercomparison and application. In this letter, we assess the suitability of both models for satellite‐based daily precipitation measurements in an effort to clarify the uncertainty representation. Three criteria were employed to evaluate the applicability of either model: (1) better separation of the systematic and random errors; (2) applicability to the large range of variability in daily precipitation; and (3) better predictive skills. It is found that the multiplicative error model is a much better choice under all three criteria. It extracted the systematic errors more cleanly, was more consistent with the large variability of precipitation measurements, and produced superior predictions of the error characteristics. The additive error model had several weaknesses, such as nonconstant variance resulting from systematic errors leaking into random errors, and the lack of prediction capability. Therefore, the multiplicative error model is a better choice.
HEALTH CARE AND IDEOLOGY: A RECONSIDERATION OF POLITICAL DETERMINANTS OF PUBLIC HEALTHCARE FUNDING IN THE OECD
Authors: Herwartz Helmut , Theilen Bernd
Published: March 2013

In this article, we examined if partisan ideology and electoral motives influence public healthcare expenditure (HCE) in countries of the Organization for Economic Cooperation and Development. We distinguished between the effects on the growth of the expenditures and its adjustment to violations of a long‐run equilibrium linking HCE with macroeconomic and demographic trends. Regarding the influence of partisan ideology, we found that if governments are sufficiently long in power, right‐wing governments spend less on public health than their left‐wing counterparts. Furthermore, if a right‐wing party governs without coalition partners, it responds more strongly to deviations from the long‐run HCE equilibrium than left‐wing governments. With regard to electoral motives, we found that health expenditure increases in years of elections. Independent of their partisan ideology, single‐party (minority) governments induce higher (lower) growth of public HCE. Each of these political factors by its own may increase (decrease) HCE growth by approximately one percentage point. Given an average annual growth of HCE of approximately 4.1%, political factors turn out to be important determinants of trends in public HCE. Copyright © 2013 John Wiley & Sons, Ltd.
A modelling approach to assessing variations of total suspended solids (tss) mass fluxes during storm events
Authors: Piro Patrizia , Carbone Marco
Published: March 2013

Connections between the catchment hydrology and accumulation, washoff and transport of pollutants in wet weather greatly affect the management of urban drainage and its wet‐weather effluents. In recent years, the concept of the first flush has gained on prominence and was further developed for analyzing the interaction between the hydrology and transport of runoff pollutants. One of the most important definitions of the first flush can be derived from the analysis of the m(v) curves (i.e. the curves in which the normalized cumulative pollutant mass is plotted vs the normalized cumulative runoff volume). Indeed the m(v) curves, indicating the distribution of pollutant mass versus volume in wet‐weather flow (WWF) discharges, are commonly used for comparing pollutant discharges for different rainfall events and catchments. In this study, the m(v) curves were used to define the concepts of flow‐limited and mass‐limited WWF events. These two different behaviours have been analysed for rainfall/runoff events observed in the urbanized part of the Liguori catchment in Cosenza (Italy). In order to advance the understanding of the intra‐event variability of m(v) curves, the mathematical rainfall/runoff model Storm Water Management Model of the US Environmental Protection Agency (SWMM) was calibrated for eight observed rainfall/runoff events and the differences between observed and simulated m(v) curves were analysed. The results showed a good correlation between the observed and simulated m(v) curves, and this finding offers further benefits in SWMM model calibration. Copyright © 2013 John Wiley & Sons, Ltd.
Book Reviews
Authors: Scriabine Alexander
Published: March 2013

Book reviewed in this article:

The Emotional Health of Physicians. John C. Duffy and Edward M. Litin.

Russian Drug Index, 2nd Edition. Stanley Jablonski, Ed.

Law for the Physician. Carl Erwin Wasmuth, M.D., LL.B. Lea & Febiger
Drugs Released for Clinical Use
Authors: de HAEN PAUL
Published: March 2013

This listing includes new single chemical entities and preparations, duplicate single products, and combination products that have been made available for clinical use by the U.S. Food and Drug Administration during the period December 21, 1971 to January 20, 1972. This information is taken from the manufacturer's package insert or brochure, which should be consulted for further details on indications, dosage, contraindications, and adverse reactions.
Book Reviews
Authors: PROCITA LEONARD
Published: March 2013

Book reviewed in this article:

Essays in Toxicology. Vol. 3. W. J. Hayes, Jr.

Current Diagnosis and Treatment. N. A. Kropp and M. C. Chatton

Transferable Drug Resistance Factor. R. S. Mitsuhashi.

Studies of Neurotransmitters at the Synaptic Level. Advances in Biochemical Psychopharmacology, Volume 6. E. Costa, L. L. Iversen, and R. Paoletti
Synthesis and Characterization of Process Related Impurities of (±)‐Milnacipran
Authors: Gopal P. Raja , Prabakar A. Christy , Chandrashekar ERR , bhaskar B. Vijaya , Somaiah P. Veera
Published: March 2013

Milnacipran is a cyclopropane derivative, used as an anti depressant drug. During the process development of milnacipran, four process related potential impurities were detected in high performance liquid chromatography. All these impurities were identified, synthesized and subsequently characterized by their respective spectral data (IR, LC‐MS, 1H NMR, and 13C NMR) as described in this article.
A Theoretical Investigation of the Decomposition Reactions of Ethyl Formate in the S1 and T1 States
Authors: Chou Yung‐Ching
Published: March 2013

This study investigates the decomposition reactions of ethyl formate in the S1 and T1 states. The dissociation channels leading to HCOOH + C2H4, CH3CH2O + HCO, CH3CH2OCO + H, and CH3CH2 + HCO2 were studied. The major reactions of ethyl formate in the S1 and T1 states are isomerization to the biradical CH2CH2OC(OH)H and dissociation to CH3CH2O + HCO. All the stationary and intersection points were optimized at the CAS(10,8) level of theory with the 6‐31G(d,p) and 6‐311G(2df,2pd) basis sets. Single‐point CASPT3 energy was calculated for each of the stationary and intersection points. Microcanonical rate constants were also calculated for each of the reactions by using the RRKM theory.
Contrasting CO2 concentration discharge dynamics in headwater streams: A multi‐catchment comparison
Authors: Dinsmore K. J. , Wallin M. B. , Johnson M. S. , Billett M. F. , Bishop K. , Pumpanen J. , Ojala A.
Published: March 2013

Aquatic CO2 concentrations are highly variable and strongly linked to discharge, but until recently, measurements have been largely restricted to low‐frequency manual sampling. Using new in situ CO2 sensors, we present concurrent, high‐frequency (<30 min resolution) CO2 concentration and discharge data collected from five catchments across Canada, UK, and Fennoscandinavia to explore concentration‐discharge dynamics; we also consider the relative importance of high flows to lateral aquatic CO2 export. The catchments encompassed a wide range of mean CO2 concentrations (0.73–3.05 mg C L−1) and hydrological flow regimes from flashy peatland streams to muted outflows within a Finnish lake system. In three of the catchments, CO2 concentrations displayed clear bimodal distributions indicating distinct CO2 sources. Concentration‐discharge relationships were not consistent across sites with three of the catchments displaying a negative relationship and two catchments displaying a positive relationship. When individual high flow events were considered, we found a strong correlation between both the average magnitude of the hydrological and CO2 response peaks, and the average response lag times. An analysis of lateral CO2 export showed that in three of the catchments, the top 30% of flow (i.e., flow that was exceeded only 30% of the time) had the greatest influence on total annual load. This indicates that an increase in precipitation extremes (greater high‐flow contributions) may have a greater influence on the flushing of CO2 from soils to surface waters than a long‐term increase in mean annual precipitation, assuming source limitation does not occur.
Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions
Authors: Guengerich F. Peter
Published: March 2013

Cytochrome P450 (P450) enzymes account for ~75% of the metabolism of drugs. Most of the reactions catalyzed by P450s are mixed‐function oxidations, and a C–H bond is (usually) broken. The rate‐limiting nature of this step can be analyzed using the kinetic isotope effect (KIE) approach. The most relevant type of KIE is one termed intermolecular non‐competitive, indicative of rate‐limiting C–H bond breaking. A plot of KIE versus kcat for several P450s showed a correlation coefficient (r2) of 0.62. Deuterium substitution has been considered as a potential means of slowing drug metabolism or redirecting sites of metabolism in some cases, and several general points can be made regarding the potential for application of deuterium in drug design/development based on what is known about P450 KIEs. Copyright © 2013 John Wiley & Sons, Ltd.
Peptide backbone fragmentation initiated by side‐chain loss at cysteine residue in matrix‐assisted laser desorption/ionization in‐source decay mass spectrometry
Authors: Asakawa Daiki , Smargiasso Nicolas , Quinton Loïc , Pauw Edwin De
Published: March 2013

Matrix‐assisted laser desorption/ionization in‐source decay (MALDI‐ISD) is initiated by hydrogen transfer from matrix molecules to the carbonyl oxygen of peptide backbone with subsequent radical‐induced cleavage leading to c′/z• fragments pair. MALDI‐ISD is a very powerful method to obtain long sequence tags from proteins or to do de novo sequencing of peptides. Besides classical fragmentation, MALDI‐ISD also shows specific fragments for which the mechanism of formation enlightened the MALDI‐ISD process. In this study, the MALDI‐ISD mechanism is reviewed, and a specific mechanism is studied in details: the N‐terminal side of Cys residue (Xxx‐Cys) is described to promote the generation of c′ and w fragments in MALDI‐ISD. Our data suggest that for sequences containing Xxx‐Cys motifs, the N–Cα bond cleavage occurs following the hydrogen attachment to the thiol group of Cys side‐chain. The c•/w fragments pair is formed by side‐chain loss of the Cys residue with subsequent radical‐induced cleavage at the N–Cα bond located at the left side (N‐terminal direction) of the Cys residue. This fragmentation pathway preferentially occurs at free Cys residue and is suppressed when the cysteines are involved in disulfide bonds. Hydrogen attachment to alkylated Cys residues using iodoacetamide gives free Cys residue by the loss of •CH2CONH2 radical. The presence of alkylated Cys residue also suppress the formation of c•/w fragments pair via the (Cβ)‐centered radical, whereas w fragment is still observed as intense signal. In this case, the z• fragment formed by hydrogen attachment of carbonyl oxygen followed side‐chain loss at alkylated Cys leads to a w fragment. Hydrogen attachment on peptide backbone and side‐chain of Cys residue occurs therefore competitively during MALDI‐ISD process. Copyright © 2013 John Wiley & Sons, Ltd.
Diurnal temperature range variation and its causes in a semiarid region from 1957 to 2006
Authors: Wang Fuxing , Zhang Chi , Peng Yong , Zhou Huicheng
Published: March 2013

ABSTRACT

The diurnal temperature range (DTR) is an important indicator of climate change, and it has decreased worldwide since the 1950s, particularly over arid and semiarid regions. This study analyses the effect of meteorological and anthropogenic factors on DTR variation to investigate the possible causes of DTR decreases in semiarid climates. The study region is located in northeast China, and the study period is from 1957 to 2006. There are three main results. First, the rate of decrease in the DTR is −1.24 K per 50 years. This decrease is mainly attributed to the increasing daily minimum temperature rate (Tmin, 2.24 K per 50 years), which is greater than the change in the daily maximum temperature (Tmax, 1.00 K per 50 years). Second, sunshine duration (SD) appears to be the most significant meteorological factor that determines the DTR through downward shortwave radiation (Rsw,d) and surface soil moisture (SM). The effect of Rsw,d is larger for Tmax than for Tmin; therefore, the decrease in Rsw,d results in a smaller increase in Tmax than in Tmin. On the other hand, the increase in SM can strengthen daytime latent heat release, and the increase in Tmax is then slowed because of the cooling effect of evaporation. The precipitation values and the leaf area index show a negative correlation with the DTR, whereas the cloud amount and the relative humidity appear not to be main causes of the DTR decrease in this region. Finally, atmospheric aerosols can reduce the SD by 0.27 h year–1 by decreasing atmospheric transparency, as indicated by an analysis of the Total Ozone Mapping Spectrometer Aerosol Index from 1979 to 2005. The decrease in direct solar radiation is the main cause of decreases in Rsw,d. These findings will provide references for DTR variation studies in similar climates.
An overview of underlying causes and animal models for the study of age‐related degenerative disorders of the spine and synovial joints
Authors: Vo Nam , Niedernhofer Laura J. , Nasto Luigi Aurelio , Jacobs Lloydine , Robbins Paul D. , Kang James , Evans Christopher H.
Published: March 2013

As human lifespan increases so does the incidence of age‐associated degenerative joint diseases, resulting in significant negative socioeconomic consequences. Osteoarthritis (OA) and intervertebral disc degeneration (IDD) are the most common underlying causes of joint‐related chronic disability and debilitating pain in the elderly. Current treatment methods are generally not effective and involve either symptomatic relief with non‐steroidal anti‐inflammatory drugs and physical therapy or surgery when conservative treatments fail. The limitation in treatment options is due to our incomplete knowledge of the molecular mechanism of degeneration of articular cartilage and disc tissue. Basic understanding of the age‐related changes in joint tissue is thus needed to combat the adverse effects of aging on joint health. Aging is caused at least in part by time‐dependent accumulation of damaged organelles and macromolecules, leading to cell death and senescence and the eventual loss of multipotent stem cells and tissue regenerative capacity. Studies over the past decades have uncovered a number of important molecular and cellular changes in joint tissues with age. However, the precise causes of damage, cellular targets of damage, and cellular responses to damage remain poorly understood. The objectives of this review are to provide an overview of the current knowledge about the sources of endogenous and exogenous damaging agents and how they contribute to age‐dependent degenerative joint disease, and highlight animal models of accelerated aging that could potentially be useful for identifying causes of and therapies for degenerative joint diseases. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 831–837, 2013
Simulation‐based look‐ahead release planning for color filter fabs
Authors: Chen James C. , Lee Szu‐Hsien , Chen Chien‐Yu , Chen Chih‐Cheng , Peng Tzu‐Wei
Published: March 2013

This study presents a look‐ahead release planning approach on the basis of AutoMod simulation model for a sixth‐generation thin film transistor liquid crystal display color filter (CF) fab in north Taiwan. The studied CF fab has two identical lines with the processes of black matrix (BM), color layer [red, green, and blue (RGB)], indium tin oxide, and photo spacer (PS). These two lines share two supporting processes, multi‐domain vertical alignment (MVA) and laboratory (LAB). MVA has the capability and flexibility to provide the functions of RGB and PS, whereas LAB can provide the functions of BM and RGB. The production release planning becomes complex because of the equipment flexibility in supporting each other. An AutoMod simulation model is therefore developed and validated using real data from the fab. The AutoMod simulation model is well representative of the real system with less than 10% difference in throughput in all production stations. Using simulation to look ahead, a production controller can predict potential equipment idleness and make adjustment to better utilize equipment capacity. On the basis of simulation with design of experiments, the proposed simulation‐based look‐ahead release plan is demonstrated to be effective in improving system throughput.
Juvenile nasopharyngeal angiofibroma: A Systematic Review and Comparison of Endoscopic, Endoscopic‐Assisted, and Open Resection in 1047 Cases
Authors: Boghani Zain , Husain Qasim , Kanumuri Vivek V. , Khan Mohemmed N. , Sangvhi Saurin , Liu James K. , Eloy Jean Anderson
Published: March 2013

Objectives/Hypothesis:

This study is a review of the treatment outcomes of juvenile nasopharyngeal angiofibroma (JNA) specifically comparing endoscopic, endoscopic‐assisted, and open surgical approaches.

Study Design:

Systematic review of studies using the MEDLINE database.

Methods:

A systematic review of studies on JNA from 1990 to 2012 was conducted. A search for articles related to JNA, along with bibliographies of those articles, was performed. Articles were examined for individual patient data (IPD) and aggregate patient data (APD). Demographics, presenting symptoms, surgical approach, follow‐up, and outcome were analyzed.

Results:

Eighty‐five articles were included, with IPD reported in 57 articles (345 cases) and APD in 28 articles (702 cases). For the IPD cohort, average follow‐up was 33.4 months (range, 0.5–264 months). Average blood loss was 544.0 mL, 490.0 mL, and 1579.5 mL for endoscopic, endoscopic‐assisted, and open surgical cases, respectively (P < .05). Recurrence rate following endoscopic surgery and open surgery were significantly less than endoscopic‐assisted surgery (P < .05). In the APD cohort, the recurrence rate following endoscopic surgery was 4.7% compared to 20.6% in the endoscopic‐assisted group and 22.6% in the open surgery group (P < .05). Among studies that reported Radkowski/Sessions grading, there was no significant difference in recurrence rates for both the IPD and APD cohorts across each stage between open and endoscopic surgery (P > .05).

Conclusions:

In this study, endoscopic resection had a significantly lower intraoperative blood loss and lower recurrence rate when compared to open resection. However, there was no difference in recurrence rate when analyzing the IPD and controlling for Radkowski/Sessions grading. Therefore, further large‐scale studies may be required to fully elucidate treatment options.
Health economic evaluation: Important principles and methodology
Authors: Rudmik Luke , Drummond Michael
Published: March 2013

Objectives/Hypothesis

To discuss health economic evaluation and improve the understanding of common methodology.

Results

This article discusses the methodology for the following types of economic evaluations: cost‐minimization, cost‐effectiveness, cost‐utility, cost‐benefit, and economic modeling. Topics include health‐state utility measures, the quality‐adjusted life year (QALY), uncertainty analysis, discounting, decision tree analysis, and Markov modeling.

Conclusion

Economic evaluation is the comparative analysis of alternative courses of action in terms of both their costs and consequences. With increasing health care expenditure and limited resources, it is important for physicians to consider the economic impact of their interventions. Understanding common methodology involved in health economic evaluation will improve critical appraisal of the literature and optimize future economic evaluations.
Laryngotracheal transplantation
Authors: Farwell D. Gregory , Birchall Martin A. , Macchiarini Paolo , Luu Quang C. , de Mattos Angelo M. , Gallay Brian J. , Perez Richard V. , Grow Matthew P. , Ramsamooj Rajen , Salgado Moses D. , Brodie Hilary A. , Belafsky Peter C.
Published: March 2013

Objectives/Hypothesis

Laryngeal transplantation offers the potential for patients without a larynx to recover their voice, which is critical in our communication age. We report clinical and functional outcomes from a laryngotracheal transplant. Widespread adoption of this technique has been slowed due to the ethical concerns of life‐long immunosuppression after a nonvital organ transplant. Our patient was already on immunosuppressive medication from prior kidney–pancreas transplantation, and therefore was not exposed to added long‐term risk. We describe the unique technical advances, clinical course, and rehabilitation of this patient and the implications for future laryngeal transplantation.

Study Design

Case report.

Methods

A laryngotracheal transplantation was performed in a 51‐year‐old prior kidney–pancreas transplant recipient presenting with complete laryngotracheal stenosis. Surgical modifications were made in the previously described technique related to retrieval, vascular supply, and reinnervation. This resulted in a robustly vascularized organ with well‐perfused long‐segment tracheal transplant and early return of motor reinnervation.

Results

A multidisciplinary approach resulted in a successful transplant without evidence of rejection to date. Postoperatively, the patient continues to rely on a tracheotomy but has had the return of an oral and nasal airway, vocalization, smell, and taste, all experienced for the first time in 11 years.

Conclusions

We have demonstrated that our methods may result in a successful laryngotracheal transplant. We describe the preparation, surgical technique, rehabilitation, and interventions employed in achieving optimal outcomes. This report contributes valuable information on this rarely performed composite transplant. Laryngoscope, 123:2502–2508, 2013
Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease
Authors: Mizuno Yoshikuni , Kondo Tomoyoshi ,   the Japanese Istradefylline Study Group
Published: March 2013

Background

We evaluated the efficacy and safety of istradefylline, a selective adenosine A2A receptor antagonist administered as adjunctive treatment to levodopa for 12 weeks in a double‐blind manner in Parkinson's disease patients with motor complications in Japan.

Methods

A total of 373 subjects were randomized to receive placebo (n = 126), istradefylline 20 mg/day (n = 123), or istradefylline 40 mg/day (n = 124). The primary efficacy variable was the change in daily OFF time. Other secondary variables were also evaluated.

Results

The change in daily OFF time was significantly reduced in the istradefylline 20 mg/day (−0.99 hours, P = .003) and istradefylline 40 mg/day (−0.96 hours, P = .003) groups compared with the placebo group (−0.23 hours). The most common adverse event was dyskinesia (placebo, 4.0%; istradefylline 20 mg/day, 13.0%; istradefylline 40 mg/day, 12.1%).

Conclusions

Istradefylline reduced daily OFF time and was well tolerated in Japanese PD patients with motor complications on levodopa treatment. © 2013 Movement Disorder Society
Is cardiac function impaired in premotor Parkinson's disease? A retrospective cohort study
Authors: Palma Jose‐Alberto , Carmona‐Abellan Maria‐Mar , Barriobero Noelia , Trevino-Peinado Cristina , Garcia‐Lopez Martin , Fernandez‐Jarne Elena , Luquin Maria R.
Published: March 2013

The objective of this study was to assess cardiovascular response during cardiac stress testing in neurologically asymptomatic individuals who developed motor features of Parkinson's disease several years after the cardiac stress testing. This was a retrospective cohort study of patients who underwent cardiac stress testing between January 2001 and December 2010. Patients were followed until May 2012 to select those who developed Parkinson's disease. Heart rate and blood pressure both at rest and at peak exercise and heart rate variability at rest were recorded. For each patient who developed Parkinson's disease, 2 matched controls who did not develop Parkinson's disease at the end of the follow‐up period were selected. Patients who were diagnosed with Parkinson's disease the same day of cardiac stress testing also were selected for comparison purposes. After excluding participants who were lost to follow‐up, 2739 patients remained. From this cohort, 18 (11 men) had developed Parkinson's disease 4.27 ± 2.56 years after the cardiac stress test. Thirty‐six matched controls were selected. At peak exercise, the maximum heart rate and the percentage of theoretical maximum heart rate were significantly lower in patients who developed Parkinson's disease after cardiac stress testing compared with controls. The sensitivity of a maximum heart rate ≤ 143 beats per minute to predict a diagnosis of Parkinson's disease after a mean of 4.27 years was 83%, and the specificity was 62%. The results from this exploratory study demonstrate that chronotropic insufficiency may constitute an early sign of Parkinson's disease during the premotor phase, serving as potential risk factor for its diagnosis. Further investigations are needed in larger populations. © 2013 Movement Disorder Society