bluuebunny/crossref_metadata_2025 huggingface dataset:
Gestational Hypoxia Induces White Matter Damage in Neonatal Rats: A New Model of Periventricular Leukomalacia
Authors: Baud Olivier , Daire Jean‐Luc , Dalmaz Yvette , Fontaine Romain H , Krueger Richard C. , Sebag Guy , Evrard Philippe , Gressens Pierre , Verney Catherine
Published: July 2010

In the premature infant, periventricular leukomalacia, usually related to hypoxic‐ischemic white matter damage, is the main cause of neurological impairment. We hypothesized that protracted prenatal hypoxia might induce white matter damage during the perinatal period. Pregnant Sparague‐Dawley rats were placed in a chamber supplied with hypoxic gas (10% O2 ‐90% N2) from embryonic day 5(E5) to E20. Neonatal rat brains were investigated by histology, immunocytochemistry, western blotting, in situ hybridization, DNA fragmentation analysis, and in vivo magnetic resonance imaging (MRI).

Body weight of pups subjected to prenatal hypoxia was 10 to 30% lower from p0 to P14 than in controls. Specific white matter cysts wear detected between p0 and p7 in pups subjected to prenatal hypoxia, in addition to abnormal extra‐cellular matrix, increased lipid peroxidation, white matter cell death detected by TUNEL and increased activated macrophage counts in white matter. Subsequently, gliotic scars and delayed myelination primarily involving immature oligodendrocytes were seen In vivo MRI with T1, T2, and diffusion sequences disclosed similar findings immediately after birth, showing strong correlations with histological abnormalities. We speculate that protracted prenatal hypoxia in rat induces abnormalities. We speculate that protracted prenatal hypoxia in rat induces white matter damage occurring through local inflammatory response and oxidative stress linked to re‐oxygenation during the perinatal period.
Angiogenesis in Gliomas: Biology and Molecular Pathophysiology
Authors: Fischer Ingeborg , Gagner Jean‐Pierre , Law Meng , Newcomb Elizabeth W. , Zagzag David
Published: July 2010

Glioblastoma multiforme (GBM) is characterized by exuberant angiogenesis, a key event in tumor growth and progression. The pathologic mechanisms driving this change and the biological behavior of gliomas remain unclear. One mechanism may involve cooption of native blood vessels by glioma cells inducing expression of angio‐poietin‐2 by endothelial cells. Subsequently, vascular apoptosis and involution leads to necrosis and hypoxia. This in turn induces angiogenesis that is associated with expression of hypoxia‐inducible factor (HIF)‐1 a and vascular endothelial growth factor (VEGF) in perinecrotic pseudopalisading glioma cells. Here we review the molecular and cellular mechanisms implicated in HIF‐1 ‐dependent and HIF‐1 ‐independent glioma‐associated angiogenesis. In GBMs, both tumor hypoxia and genetic alterations commonly occur and act together to induce the expression of HIF‐1. The angiogenic response of the tumor to HIF‐1 is mediated by HIF‐1‐regulated target genes leading to the upregulation of several proangiogenic factors such as VEGF and other adaptive response molecules. Understanding the roles of these regulatory processes in tumor neovascularization, tumor growth and progression, and resistance to therapy will ultimately lead to the development of improved antiangiogenic therapies for GBMs.
Angiogenesis in Gliomas: Imaging and Experimental Therapeutics
Authors: Gagner Jean‐Pierre , Law Meng , Fischer Ingeborg , Newcomb Elizabeth W. , Zagzag David
Published: July 2010

Much of the interest in angiogenesis and hypoxia has led to investigating diagnostic imaging methodologies and developing efficacious agents against angiogenesis in gliomas. In many ways, because of the cytostatic effects of these agents on tumor growth and tumor‐associated endothelial cells, the effects of therapy are not immediately evident. Hence finding clinically applicable imaging tools and pathologic surrogate markers is an important step in translating glioma biology to therapeutics. There are a variety of strategies in the approach to experimental therapeutics that target the hypoxia‐inducible factor pathway, the endogenous antiangiogenic and proangiogenic factors and their receptors, adhesion molecules, matrix proteases and cytokines, and the existing vasculature. We discuss the rationale for antiangiogenesis as a treatment strategy, the preclinical and clinical assessment of antiangiogenic interventions and finally focus on the various treatment strategies, including combining antiangiogenic drugs with radiation and chemotherapy.
Multiple Sclerosis Pathology: Evolution of Pathogenetic Concepts
Authors: Lassmann Hans
Published: July 2010

This historical review describes the evolution of pathogenetic concepts of multiple sclerosis (MS) from the viewpoint of pathology. MS research is based on studies of descriptive neuropathology, performed during the 19th and early‐20th century, which defined the basic nature of the inflammatory demyelinating lesions. Advances in basic immunology and neurobiology, performed during the second half of the 20th century, paved the way for the understanding of the molecular mechanims involved in inflammation and well as tissue destruction in this disease. However, recent clinical and neuroradiological studies on the evolution of the disease and its brain lesions as well as ongoing attempts to define the genetic basis of the disease indicate that our current pathogenetic concepts may be too simple and that essential aspects of MS pathology have to be redefined.
A 15‐YEAR‐OLD FEMALE WITH PROGRESSIVE MYELOPATHY
Authors: Siami‐Namini Koushan , Shuey‐Drake Rhonda , Wilson Don , Francel Paul , Perry Arie , Fung Kar‐Ming
Published: July 2010

March 2005. A 15‐year‐old female presented with urinary retention, inability to walk and low back pain. MRI disclosed an elongated epidural mass in the thoracic spine with cord compression and invasion into the surrounding bone and soft tissue. Cytologic preparation at intraoperative consultation disclosed a rather monotonous small tumor cells with hyperchromatic nuclei and vacuolated cytoplasm. These vacuoles were best visualized with DiffQuick stain. Pathologic studies revealed an Ewing sarcoma/peripheral primitive neuroectodermal tumor (EWS/pPNET) with typical features including periodic acid Schiff positive diastase sensitive cytoplasmic substance; strong membranous pattern of immunoreactivity for CD99, and a reciprocal translocation of t(11;22)(q24;q12) that was demonstrated by fluorescent in situ hybridization (FISH). The vacuolated cytoplasm was produced by glycogen as demonstrated by electron microscopy. Although primary vertebral EWS/pPNETs are uncommon, they should be considered in the differential diagnoses of extradural/epidural mass of the spine in young patients.
Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity
Authors: Medina David X. , Caccamo Antonella , Oddo Salvatore
Published: July 2010

Promising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg‐AD) that develops age‐dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg‐AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin‐ and trypsin‐like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD‐like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action.
Restauration, reconstitution et copie des instruments de musique
Authors: Koster John
Published: July 2010

Vaut‐il mieuxjouer sur un instrument ancien on sur une copie d'ancien? La question fait l'objet de vives polémiques, aussi bien parmi les muséologues que chez les musiciens. John Koster expose le point de vue du Shrine to Music Museum de Vermillion (Dakota du Sud, États‐Unis d'Amérique), où il est conservateur et professeur associé de muséologie. Auteur d'un ouvrage, Keyboard, musical instruments in the Museum of Fine Arts, Boston [Les instruments à clavier du Musée des beaux‐arts de Boston], 1994, il a été titulaire, en 1990–1991, d'une bourse Andrew W. Mellon au Metropolitan Museum of Art de New York.
Alkane degradation under anoxic conditions by a nitrate‐reducing bacterium with possible involvement of the electron acceptor in substrate activation
Authors: Zedelius Johannes , Rabus Ralf , Grundmann Olav , Werner Insa , Brodkorb Danny , Schreiber Frank , Ehrenreich Petra , Behrends Astrid , Wilkes Heinz , Kube Michael , Reinhardt Richard , Widdel Friedrich
Published: July 2010

Microorganisms can degrade saturated hydrocarbons (alkanes) not only under oxic but also under anoxic conditions. Three denitrifying isolates (strains HxN1, OcN1, HdN1) able to grow under anoxic conditions by coupling alkane oxidation to CO2 with NO3‐ reduction to N2 were compared with respect to their alkane metabolism. Strains HxN1 and OcN1, which are both Betaproteobacteria, utilized n‐alkanes from C6 to C8 and C8 to C12 respectively. Both activate alkanes anaerobically in a fumarate‐dependent reaction yielding alkylsuccinates, as suggested by present and previous metabolite and gene analyses. However, strain HdN1 was unique in several respects. It belongs to the Gammaproteobacteria and was more versatile towards alkanes, utilizing the range from C6 to C30. Neither analysis of metabolites nor analysis of genes in the complete genome sequence of strain HdN1 hinted at fumarate‐dependent alkane activation. Moreover, whereas strains HxN1 and OcN1 grew with alkanes and NO3‐, NO2‐ or N2O added to the medium, strain HdN1 oxidized alkanes only with NO3‐ or NO2‐ but not with added N2O; but N2O was readily used for growth with long‐chain alcohols or fatty acids. Results suggest that NO2‐ or a subsequently formed nitrogen compound other than N2O is needed for alkane activation in strain HdN1. From an energetic point of view, nitrogen–oxygen species are generally rather strong oxidants. They may enable enzymatic mechanisms that are not possible under conditions of sulfate reduction or methanogenesis and thus allow a special mode of alkane activation.
TRACKING PRODUCT‐PROCESS INTERACTIONS: A RESEARCH PARADIGM*
Authors: CHAKRAVARTY AMIYA K. , GHOSE SANJOY
Published: July 2010

To design (or redesign) a competitive product, it is imperative that both the sales and manufacturing cost implications are assessed in a structured way. That is, the interactive (multidimensional) aspects of manufacturing and marketing variables need to be positioned in a proper perspective so that the system impact of variation in one or more variables may be ascertained quickly. In this paper we show how some of the system‐related paradigms can be used as foundations for developing quantitative and qualitative models for tracking such interactive ímpacts. The emphasis is not on building complex mathematical models to solve specific problems but on providing a framework where system properties expressed as simple postulates can be used in an intelligent way to assess the impact of improvements in specific product‐process scenarios.
THE VALIDITY OF THE INDEPENDENT INCREMENTS ASSUMPTION FOR PRODUCTION: AN EMPIRICAL STUDY OF AN AUTOMOTIVE ASSEMBLY PLANT
Authors: INMAN ROBERT R. , LEON MAURICIO
Published: July 2010

In assembly plants, random line stoppages cause production variability. For analytic tractability and data availability, researchers commonly assume that the production process possesses the independent increments property (necessary for a process to be Poisson). If the production process has independent increments, then the production in any interval is independent of the production in any other nonoverlapping interval. This property means, for one thing, that the current period's production is never influenced by previous production periods. Intuition, however, suggests that current production could be correlated to past production‐violating this assumption of independence. If production problems persist from one period to the next, then one would expect the production in adjacent time periods to be correlated. Although the independent increments property is oflen assumed, its validity has not been demonstrated in practice. We analyze data from an automotive assembly plant to assess the validity of the independent increments assumption for its production.
COMPETITION IN REMANUFACTURING
Authors: MAJUMDER PRANAB , GROENEVELT HARRY
Published: July 2010

We present a two‐period model of remanufacturing in the face of competition. In our model, an original equipment manufacturer (OEM) competes with a local remanufacturer (L) under many reverse logistics configurations for the returned items. After establishing the Nash Equilibrium in the second period sub‐game, we use numerical experiments for comparative statics. OEM wants to increase L'S remanufacturing cost. Surprisingly, while L competes in the sales market, she has incentives to reduce oem's remanufacturing cost. A social planner who wants to increase remanufacturing can give incentives to the OEM to increase the fraction available for remanufacturing, or reduce his remanufacturing costs.
INTERNATIONAL DIFFUSION OF ISO 14000 CERTIFICATION
Authors: CORBETT CHARLES J. , KIRSCH DAVID A.
Published: July 2010

The ISO 9000 series of quality management systems standards and the more recent ISO 14000 environmental management systems standards have generated much controversy among practitioners. Although ISO 9000 has become a de facto requirement for many firms, its effects are poorly understood, and similarly the value and domain of applicability of ISO 14000 have been questioned. This paper reports on an exploratory study into the global spread of ISO 14000. We interviewed practitioners worldwide to identify factors that they believe explain differences between national ISO 14000 certification counts. We then collected quantititive data for these factors and, using regression analysis, we found that exports, environmental attitudes (combined with economic development), and ISO 9000 certification count were significant. The fact that ISO 9000 appears as an important factor explaining diffusion of ISO 14000 certifications suggests that the drivers behind the two have significant overlap. This indicates that, although ISO 14000 is an environmental standard, many of the factors driving national certification patterns are not at all environmental in nature, and that ISO 14000 therefore needs to be studied from a broader perspective than from a purely environmental point of view.
Setup Time Reduction for Electronics Assembly: Combining Simple (SMED) and IT‐Based Methods
Authors: Trovinger Sheri Coble , Bohn Roger E.
Published: July 2010

As much as 50% of effective capacity can be lost to setups in printed circuit board assembly. Shigeo Shingo showed that radical reductions in setup times are possible in metal fabrication using an approach he called “Single Minute Exchange of Dies” (SMED). We applied SMED to setups of high speed circuit board assembly tools. Its key concepts were valid in this very different industry, but while SMED typically emphasizes process simplification, we had to add modern information technology tools including wireless terminals, barcodes, and a relational database. These tools shield operators from the inherent complexity of managing thousands of unique parts and feeders.

The economic value of setup reduction is rarely calculated. We estimate a reduction of key setup times by more than 80%, and direct benefits of $1.8 million per year. Total cost of the changes was approximately $350,000.
The Impact of Outsourced Manufacturing on Timing of Entry in Uncertain Markets
Authors: Ülkü Sezer , Toktay L. Beril , Yücesan Enver
Published: July 2010

Several firms are interested in manufacturing and selling new products based on a new process technology. Before manufacturing can begin, either these Original Equipment Manufacturers (OEMs), or a Contract Manufacturer (CM) needs to adopt the process technology, i. e., make a capacity investment in it. Due to market uncertainty, the timing of capacity investment is crucial. In such a setting, we investigate how the timing of process adoption, an important determinant of time‐to‐market, is impacted by the make/buy decision. We first characterize the optimal time for process adoption and show that this delay depends on competitive intensity, cost structure and the rate of forecast improvement. Due to differing cost structures, incentives and risks, an OEM and a CM may invest in a new process technology at different times. We show that while there are conditions where outsourced manufacturing can be advantageous for the OEM from a time‐to‐market perspective, there are also cases where the OEM would be disadvantaged. In these cases, the OEM can accelerate process adoption by risk sharing through joint investment. Finally, the right choice of CM is extremely important for an OEM that faces a short time window for product introduction: An efficient CM not only provides low costs but also rapid access to new process technologies, and therefore higher revenues.
Economic Evaluation of Systems that Expedite Inventory Information
Authors: Bensoussan Alain , Çakanyildirim Metin , Sethi Suresh P.
Published: July 2010

Information delays exist when the most recent inventory information available to the Inventory Manager (IM) is dated. Such situations arise when it takes a while to process the demand data, count the inventory, and pass the results to the IM. We show that the optimal total inventory‐related cost decreases when the length of the information delay decreases. The amount of the decrease is an important datum for an IM interested in considering whether or not to invest in reducing the delay. The investment is required to finance design and acquisition of an information (collection and dissemination) system that can reduce the information delay. Such systems include phone calls, business meetings, and the use of information collection mechanisms such as radiofrequency identification tags.
Dynamic Pricing in e‐Services under Demand Uncertainty
Authors: Xia Cathy H. , Dube Parijat
Published: July 2010

High volatility of the e‐services market, due to increasing competition, low life cycle of products, and easy availability of information about competing service offerings to customers, makes the demand for service offerings quite uncertain. Revenue management in such markets calls for real‐time techniques to learn the demand and its dependence on both the price and the service level associated with the service offering. We assume firms reply on exploratory approaches for demand estimation, in which firms experiment with different service offerings in order to simultaneously learn the demand while doing business. Such exploration and learning process can be costly without supervision. As reported by Rothschild (Journal of Economic Theory, 9 185‐202, 1974), traditional Bayesian dynamic control approaches may conclude with suboptimal offerings. We propose a novel demand learning approach that is guaranteed to converge to the optimal offering. The approach combines simulated annealing algorithm with Bayesian learning. We further present intelligent techniques that adaptively reduce the effort of exploration on suboptimal service offerings so as to improve the long‐run average profit.
Costs of Bloodstream Infections Caused by
Escherichia coli
and Influence of Extended-Spectrum-β-Lactamase Production and Inadequate Initial Antibiotic Therapy
Authors: Tumbarello Mario , Spanu Teresa , Di Bidino Rossella , Marchetti Marco , Ruggeri Matteo , Trecarichi Enrico Maria , De Pascale Gennaro , Proli Enrica Maria , Cauda Roberto , Cicchetti Americo , Fadda Giovanni
Published: July 2010

Escherichia coli
is the leading cause of bloodstream infections (BSIs) caused by Gram-negative bacteria. The increasing prevalence of antibiotic-resistant
E. coli
strains, particularly those producing extended-spectrum β-lactamases (ESBLs), increases the odds that empirically prescribed antimicrobial therapy for these infections will be inadequate, but the economic impact of this risk has not been fully evaluated. In the present retrospective 1-year analysis of 134 consecutive
E. coli
BSIs in our hospital, we explored the clinical and economic impacts of (i) inadequate initial antimicrobial treatment (IIAT) (i.e., empirical treatment with drugs to which the isolate had displayed
in vitro
resistance) of these infections and (ii) ESBL production by the bloodstream isolate. Cost data were obtained from the hospital accounting system. Compared with the 107 (79.8%) adequately treated patients, the 27 (20.1%) who received IIAT had a higher proportion of ESBL BSIs (74.0% versus 15.8%), longer (+6 days) and more costly (+EUR 4,322.00) post-BSI-onset hospital stays, and higher 21-day mortality rates (40.7% versus 5.6%). Compared with the 97 non-ESBL infections, the 37 (27.6%) ESBL BSIs were also associated with longer (+7 days) and more costly (+EUR 5,026.00) post-BSI-onset hospital stays and increased 21-day mortality (29.7% versus 6.1%). These findings confirm that the hospital costs and mortality associated with
E. coli
BSIs are significantly increased by ESBL production and by IIAT.
Lysyl-Phosphatidylglycerol Attenuates Membrane Perturbation Rather than Surface Association of the Cationic Antimicrobial Peptide 6W-RP-1 in a Model Membrane System: Implications for Daptomycin Resistance
Authors: Kilelee Erin , Pokorny Antje , Yeaman Michael R. , Bayer Arnold S.
Published: July 2010

The presence of the cationic phospholipid lysyl-phosphatidylglycerol (lysyl-PG) in staphylococcal cytoplasmic membranes has been linked to increased resistance to cationic compounds, including antibiotics such as daptomycin as well as host defense antimicrobial peptides. We investigated the effects of lysyl-PG on binding of 6W-RP-1, a synthetic antimicrobial peptide, to lipid vesicles and on peptide-induced membrane permeabilization. Unexpectedly, physiological lysyl-PG concentrations only minimally reduced membrane binding of 6W-RP-1. In contrast, 6W-RP-1-induced dye leakage was severely inhibited by lysyl-PG, suggesting that lysyl-PG primarily impacts membrane defect formation.
Effects of Tuberculosis, Race, and Human Gene
SLCO1B1
Polymorphisms on Rifampin Concentrations
Authors: Weiner Marc , Peloquin Charles , Burman William , Luo Chi-Cheng , Engle Melissa , Prihoda Thomas J. , Mac Kenzie William R. , Bliven-Sizemore Erin , Johnson John L. , Vernon Andrew
Published: July 2010

Rifampin has concentration-dependent activity against
Mycobacterium tuberculosis
. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes
SLCO1B1
,
SLCO1B3
, and
MDR1
. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC
0-24
] of 40.2 versus 40.9 μg·h/ml;
P
= 0.9). However, in multivariable analyses, the rifampin AUC
0-24
was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the
SLCO1B1
gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC
0-24
was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC
0-24
was also 36% lower among participants with
SLCO1B1
genotype c.463CA than that among participants with
SLCO1B1
genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml;
P
= 0.001). Polymorphisms in the
SLCO1B1
gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC
0-24
values was observed, but the mean values of the AUC
0-24
did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the
SLCO1B1
c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.
Discovery of Novel Orally Bioavailable Oxaborole 6-Carboxamides That Demonstrate Cure in a Murine Model of Late-Stage Central Nervous System African Trypanosomiasis
Authors: Nare Bakela , Wring Stephen , Bacchi Cyrus , Beaudet Beth , Bowling Tana , Brun Reto , Chen Daitao , Ding Charles , Freund Yvonne , Gaukel Eric , Hussain Ali , Jarnagin Kurt , Jenks Matthew , Kaiser Marcel , Mercer Luke , Mejia Elena , Noe Andy , Orr Matt , Parham Robin , Plattner Jacob , Randolph Ryan , Rattendi Donna , Rewerts Cindy , Sligar Jessica , Yarlett Nigel , Don Robert , Jacobs Robert
Published: July 2010

We report the discovery of novel boron-containing molecules, exemplified byN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (AN3520) and 4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds againstTrypanosoma brucei in vitro, including the two subspecies responsible for human diseaseT. b. rhodesienseandT. b. gambiense.These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to 10 mg/kg of body weight for 4 consecutive days. In stage 2 disease (central nervous system [CNS] involvement), mice infected withT. b. bruceiwere cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole-treated animals did not exhibit gross signs of compound-related acute or subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman primates, demonstrate that both SCYX-6759 and AN3520 are low-clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated the ability to cross the blood-brain barrier with no evidence of interaction with the P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against allT. bruceisubspecies, excellent physicochemical profiles,in vitrometabolic stability, a low potential for CYP450 inhibition, a lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for the development of new and effective orally administered treatments for human African trypanosomiasis.
Rapid and Sensitive Liquid Chromatography/Mass Spectrometry Assay for Caspofungin in Human Aqueous Humor
Authors: Neoh Chin Fen , He Hui , Li Jian , Fullinfaw Robert O. , Leung Lok , Misra Anant , Vajpayee Rasik B. , Davies Geoffrey E. , Stewart Kay , Kong David C. M.
Published: July 2010

A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra- and interday accuracies (percent bias) were within 11%, while the intra- and interday precisions were within 6%.
HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance
Authors: Rhee Soo-Yon , Taylor Jonathan , Fessel W. Jeffrey , Kaufman David , Towner William , Troia Paolo , Ruane Peter , Hellinger James , Shirvani Vivian , Zolopa Andrew , Shafer Robert W.
Published: July 2010

The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzedin vitrosusceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.
Colistin Dosing and Nephrotoxicity in a Large Community Teaching Hospital
Authors: DeRyke C. Andrew , Crawford Amanda J. , Uddin Nizam , Wallace Mark R.
Published: July 2010

Thirty adult patients who received intravenous colistin (5.1 ± 2.4 mg/kg/day) were reviewed to evaluate dosing with respect to nephrotoxicity, which occurred in 10 (33%) patients within the first 5 days of treatment. Excessive colistin dosing was frequent (47%), often (71%) resulted from the use of actual body weight in obese patients, and was associated with higher rates of nephrotoxicity (80% versus 30%,
P
= 0.019).
CD4+T Cells and Antibody Are Required for Optimal Major Outer Membrane Protein Vaccine-Induced Immunity toChlamydia muridarumGenital Infection
Authors: Farris Christina M. , Morrison Sandra G. , Morrison Richard P.
Published: July 2010

Despite effective antimicrobial chemotherapy, control ofChlamydia trachomatisurogenital infection will likely require a vaccine. We have assessed the protective effect of an outer membrane protein-based vaccine by using a murine model of chlamydial genital infection. Female mice were first vaccinated withChlamydia muridarummajor outer membrane protein (MOMP) plus the adjuvants CpG-1826 and Montanide ISA 720; then they were challenged withC. muridarum. Vaccinated mice shed 2 log10to 3 log10fewer inclusion-forming units (IFU) than ovalbumin-vaccinated or naïve animals, resolved infection sooner, and had a lower incidence of hydrosalpinx. To determine the relative contribution of T cells to vaccine-induced protection, mice were vaccinated, depleted of CD4+or CD8+T cells, and then challenged vaginally withC. muridarum. Depletion of CD4+T cells, but not depletion of CD8+T cells, diminished vaccine-induced protection, with CD4-depleted mice shedding 2 log10to 4 log10more IFU than CD8-depleted or nondepleted mice. The contribution of antibodies to vaccine-induced protection was demonstrated by the absence of protective immunity in vaccinated B-cell-deficient mice and by a 2 log10to 3 log10decrease in bacterial shedding by mice passively administered an anti-MOMP serum. Thus, optimal protective immunity in this model of vaccine-induced protection depends on contributions from both CD4+T cells and antibody.
Irish views on death and dying: a national survey
Authors: McCarthy J , Weafer J , Loughrey M
Published: July 2010

Objective

To determine the public's understanding of and views about a range of ethical issues in relation to death and dying.

Design

Random, digit-dialling, telephone interview

Setting

Ireland.

Participants

667 adult individuals.

Results

The general public are unfamiliar with terms associated with end-of-life care. Although most want to be informed if they have a terminal illness, they also value family support in this regard. Most of the respondents believe that competent patients have the right to refuse life-saving treatment. Most also (mistakenly) believe that families, either alone or with physicians, have the authority to make decisions about starting or stopping treatment for incompetent patients. Most Irish people are more concerned about the quality of their dying than death itself. Religious commitment is important to most Irish people, and this impacts on their views about medical treatment and care at the end of life.

Conclusions

The study paints a picture of a general public that is not very comfortable with or informed about the processes of dying and death. Great sensitivity is required of health professionals who must negotiate the timing and the context of breaking of bad news with patients and families. Educational interventions, public and organisational policies and legislation need to address the uncertainty that surrounds the role of professionals and families in making decisions for dying patients.
Defending human enhancement technologies: unveiling normativity
Authors: de Melo-Martín Inmaculada
Published: July 2010

Recent advances in biotechnologies have led to speculations about enhancing human beings. Many of the moral arguments presented to defend human enhancement technologies have been limited to discussions of their risks and benefits. The author argues that in so far as ethical arguments focus primarily on risks and benefits of human enhancement technologies, these arguments will be insufficient to provide a robust defence of these technologies. This is so because the belief that an assessment of risks and benefits is a sufficient ethical evaluation of these technologies incorrectly presupposes that risk assessments do not involve value judgements. Second, it presupposes a reductionist conception of ethics as merely a risk management instrument. Each of these assumptions separates ethical evaluation from discussion and appraisal of ends and means and thus leaves important—indeed, essential—ethical considerations out of view. Once these problematic assumptions are rejected, it becomes clear that an adequate defence of human enhancement technologies requires more than a simple balance of their risks and benefits.
Memory models
Authors: Adve Sarita V. , Boehm Hans-J.
Published: July 2010

Solving the memory model problem will require an ambitious and cross-disciplinary research direction.
Judging the Credibility of Information Gathered from Face-to-Face Interactions
Authors: Jensen Matthew L. , Burgoon Judee K. , Nunamaker Jay F.
Published: July 2010

One of the most pernicious threats to information quality comes through perpetration of deception by information suppliers. Deception undermines many critical dimensions of information quality, such as accuracy, completeness, and believability. Despite this threat, information gatherers are ill equipped to assess the credibility of information suppliers. This work presents a prototype system that examines messages gathered during direct, face-to-face information gathering. The system unobtrusively identifies kinesic and linguistic features that may indicate deception in information suppliers’ messages. System use was found to significantly improve assessment ability in between-subjects and within-subjects tests. The improved ability to accurately assess credibility during face-to-face interactions should yield higher information quality.
A Quality Model for Conceptual Models of MDD Environments
Authors: Marín Beatriz , Giachetti Giovanni , Pastor Oscar , Abran Alain
Published: July 2010

In Model-Driven Development (MDD) processes, models are key artifacts that are used as input for code generation. Therefore, it is very important to evaluate the quality of these input models in order to obtain high-quality software products. The detection of defects is a promising technique to evaluate software quality, which is emerging as a suitable alternative for MDD processes. The detection of defects in conceptual models is usually manually performed. However, since current MDD standards and technologies allow both the specification of metamodels to represent conceptual models and the implementation of model transformations to automate the generation of final software products, it is possible to automate defect detection from the defined conceptual models. This paper presents a quality model that not only encapsulates defect types that are related to conceptual models but also takes advantage of current standards in order to automate defect detection in MDD environments.
Biliary Innate Immunity: Function and Modulation
Authors: Harada Kenichi , Nakanuma Yasuni
Published: July 2010

Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor-γ(PPARγ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARγligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA.
Technological Innovations in Surgical Approach for Thyroid Cancer
Authors: Lang Brian Hung-Hin , Lo Chung-Yau
Published: July 2010

Over the last decade, surgeons have witnessed dramatic changes in surgical practice as a result of the introduction of new technological advancement. Some of these changes include refinement of techniques in thyroid cancer surgery. The development of various endoscopic thyroidectomy techniques, the addition of the da Vinci robot, and the use of operative adjuncts in thyroid surgery, such as intraoperative neuromonitoring and quick intraoperative parathyroid hormone, have made thyroid cancer surgery not only safer and better accepted by patients with thyroid cancer but also offer them more surgical treatment options.
Linear Robust Output Regulation in a Class of Switched Power Converters
Authors: Olm Josep M. , Biel Domingo
Published: July 2010

This article addresses the robust output regulation problem for a class of nonlinear switched power converters after its linearization by means of a change of the control vector variable. The methodology employs a dynamic state feedback control law and considers parametric uncertainty due to unknown values of resistive loads. Restrictions arising from the fact that the control gains exhibit fixed values are taken into account. The proposed technique is exemplified with the output voltage regulation of a Noninverting Buck‐Boost converter and tested through realistic numerical simulations.
Difficult Airway Management Algorithm in Emergency Medicine: Do Not Struggle against the Patient, Just Skip to Next Step
Authors: Sudrial Jérôme , Birlouez Caroline , Guillerm Anne-Laurette , Sebbah Jean-Luc , Amathieu Roland , Dhonneur Gilles
Published: July 2010

We report a case of prehospital “cannot intubate” and “cannot ventilate” scenarios successfully managed by strictly following a difficult airway management algorithm. Five airway devices were used: the Macintosh laryngoscope, the gum elastic Eschmann bougie, the LMA Fastrach, the Melker cricothyrotomy cannula, and the flexible fiberscope. Although several airway devices were used, overall airway management duration was relatively short, at 20 min, because for each scenario, failed primary and secondary backup devices were quickly abandoned after 2 failed attempts, each attempt of no more than 2 min in duration, in favor of the tertiary rescue device. Equally, all three of these rescue devices failed, an uncuffed cricothyroidotomy cannula was inserted to restore optimal arterial oxygenation until a definitive airway was secured in the ICU using a flexible fiberscope. Our case reinforces the need to strictly follow a difficult airway management algorithm that employs a limited number of effective devices and techniques, and highlights the imperative for early activation of successive preplanned steps of the algorithm.
The Initial Immune Reaction to a New Tumor Antigen Is Always Stimulatory and Probably Necessary for the Tumor′s Growth
Authors: Prehn Richmond T.
Published: July 2010

All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse‐skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin.
Influence of Tillage and Daily Manure Application on the Survival of Bacterial Pathogens Indicators in Soil and on Radish
Authors: Entry James A. , Bjorneberg David L. , Verwey Sheryl
Published: July 2010

We measuredEscherichia coli, andEnterococcussp. numbers in soil and on fresh radish (Raphanus sativusL.) at 1, 7, 14, 28, 54, and 84 days after the addition of high and low amounts of solid dairy manure in combination with chisel tillage to a 20 cm depth (deep) or roller tillage to a 10 cm depth (shallow). When the high or low amount of solid dairy manure was added to the soil,E. colipopulations in soil were higher in the 54 days following manure addition compared to the control treatment. Dairy manure addition increasedEnterococcussp. in soils compared to the control treatment for the entire 84 days sampling period. At harvest, which was 84 days after application, we did not detectE. coliin radish in rhizosphere soil or on radish roots. Addition of solid dairy manure increasedEnterococcussp. numbers in radish rhizosphere soil and on radish roots. We suggest that fresh animal manure be applied to soil at least 120 days prior to planting to allow die-off of human pathogenic bacteria and reduce the incidence of bacterial adhesion on or bacterial colonization of ready to eat vegetables.
Periodic and Chaotic Motions of a Two‐Bar Linkage with OPCL Controller
Authors: Han Qingkai , Zhao Xueyan , Yang Xiaoguang , Wen Bangchun
Published: July 2010

A two‐bar linkage, which is described in differential dynamical equations, can perform nonlinear behaviors due to system parameters or external input. As a basic component of robot system, the investigation of its behavior can improve robot performance, control strategy, and system parameters. An open‐plus‐close‐loop (OPCL) control method therefore is developed and applied to reveal and classify the complicated behaviors of a two‐bar linkage. In this paper, the conception and stability of OPCL are addressed firstly. Then it is applied to the dynamical equations of two‐bar linkage. Different motions including single‐periodic, multiple‐periodic, quasiperiodic, and chaotic motions are unfolded by numerical simulations when changing the controller parameters. Furthermore, the obtained chaotic motions are sorted out for qualitative and quantificational study using Lyapunov exponents and hypothetic possibilities of surrogate data method.
Preclinical and Clinical Evidence that Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography with Computed Tomography Is a Reliable Tool for the Detection of Early Molecular Responses to Erlotinib in Head and Neck Cancer
Authors: Vergez Sébastien , Delord Jean-Pierre , Thomas Fabienne , Rochaix Philippe , Caselles Olivier , Filleron Thomas , Brillouet Séverine , Canal Pierre , Courbon Frédéric , Allal Ben C.
Published: July 2010

Purpose: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[18F]fluoro-d-glucose positron emission tomography with computed tomography (18FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity.

Experimental Design: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in 18FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the 18FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed.

Results: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in 18FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses.

Conclusion: These results show that the 18FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma. Clin Cancer Res; 16(17); 4434–45. ©2010 AACR.