bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracorporeal Liver Support Therapy With Prometheus in Patients With Liver Failure in the Intensive Care Unit
Authors: Oppert Michael , Rademacher Sibylle , Petrasch Kathrin , Jörres Achim
Published: September 2009

Acute liver failure (ALF) and acute‐on‐chronic liver failure (AoCLF) are associated with a high mortality. In these patients an accumulation of both water‐soluble and water‐insoluble, protein‐bound, metabolic waste products occurs. Conventional extracorporeal blood purification techniques based on diffusion and/or convection such as hemodialysis or hemofiltration may only eliminate small molecular weight, water‐soluble compounds. In recent years, fractionated plasma separation and adsorption (FPSA) with the Prometheus system has been introduced for extracorporeal liver support therapy. To date, however, only limited data is available regarding the effect of this treatment on mortality and outcome of patients with advanced liver disease. Here we report on our experience with 23 patients with severe liver failure who were treated with Prometheus in our medical intensive care unit. Fourteen patients had AoCLF, and nine patients experienced ALF. The median bilirubin level at the start of Prometheus therapy was 30.5 mg/dL and the median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 26. During 40 individual treatment sessions lasting 5–6 h, Prometheus therapy reduced serum bilirubin levels from 23.7 mg/dL to 15.0 mg/dL (median values) (P < 0.001), and the overall survival was 26%. ALF patients had a better survival compared to AoCLF patients (44% vs. 22%; P = 0.022). Apart from one patient who developed hemodynamic instability during a treatment session, Prometheus therapy was well tolerated without relevant side‐effects. In conclusion, extracorporeal liver support therapy with Prometheus is a novel and safe treatment option in patients with severe liver failure. In this series, patients with ALF showed a significantly better outcome with Prometheus therapy compared to AoCLF patients.
Effect of Extracorporeal Liver Support by Molecular Adsorbents Recirculating System and Prometheus on Redox State of Albumin in Acute‐on‐Chronic Liver Failure
Authors: Oettl Karl , Stadlbauer Vanessa , Krisper Peter , Stauber Rudolf E
Published: September 2009

Oxidative stress is believed to play an important role in acute‐on‐chronic liver failure (AoCLF). Albumin, an important transport vehicle, was found to be severely oxidized in AoCLF patients. Extracorporeal liver support systems may exert beneficial effects in AoCLF via removal of albumin‐bound toxins. At present, two systems are commercially available, the molecular adsorbents recirculating system (MARS) and fractionated plasma separation, adsorption and dialysis (FPAD, also known as Prometheus). The aim of this study was to compare the effect of MARS and Prometheus treatments on the redox state of human serum albumin. Eight patients with AoCLF underwent alternating treatments with either MARS or Prometheus in a randomized cross‐over design. Sixteen treatments (eight MARS and eight Prometheus) were available for analysis. The fraction of human mercaptalbumin (HMA), human nonmercaptalbumin‐1 (HNA1), and human nonmercaptalbumin‐2 (HNA2) were measured before and after single MARS and Prometheus treatments and during follow‐up. In AoCLF patients the oxidized fractions of albumin, HNA1, and HNA2 were markedly increased. Both MARS and Prometheus treatments resulted in a shift of HNA1 to HMA, while HNA2 was not significantly affected. This shift in albumin fractions was transient and disappeared within 24 h after treatment. There were no significant differences between MARS and Prometheus treatments with respect to the redox state of albumin. Both MARS and Prometheus treatments lead to transient improvements of the redox state of albumin, which could be beneficial in the treatment of AoCLF.
EFFECT OF ARTISANAL PARBOILING METHODS ON MILLING YIELD AND COOKED RICE TEXTURAL CHARACTERISTICS
Authors: MANFUL JOHN T. , ABBEY LAWRENCE D. , COKER RAYMOND D.
Published: September 2009

One of the main objectives of artisanal rice parboiling is to reduce the levels of broken grains (brokens) on milling. Rice samples that had been parboiled using different regimes of soaking temperatures and steaming times were analyzed for their physical properties and cooked rice textures. It was established that inappropriate soaking and steaming regimes resulted in greater levels of brokens than raw‐milled paddy. Consequently, in artisanal parboiling, the initial soaking temperature should be about 90C and the steaming time should be more than 8 min, ideally, about 12 min. On cooking, more severely parboiled rice samples had firmer textures than mildly parboiled samples. The commercially parboiled sample and the more severely laboratory‐parboiled samples required a rice‐to‐water ratio of 1:3, while the raw‐milled sample and the mildly parboiled ones required a 1:2½ rice‐to‐water ratio for optimum cooking.

PRACTICAL APPLICATIONS

Artisanal rice parboiling is carried out mainly to reduce the levels of broken grains and increase the yield of milled rice in many countries. If this is carried out very well, there are economic benefits as more rice of better quality is available to be sold. This study provides information on optimum processing conditions, i.e., initial soaking temperature of about 90C and a steaming time of about 12 min. The study also provides recommendations on optimum cooking conditions, i.e., rice‐to‐water ratio, for the variably parboiled rice samples.
EFFECT OF WAX APPLICATION ON THE QUALITY, LYCOPENE CONTENT AND CHILLING INJURY OF TOMATO FRUIT
Authors: MEJÍA‐TORRES SILVIA , VEGA‐GARCÍA MISAEL , VALVERDE‐JUÁREZ JAVIER , LÓPEZ‐VALENZUELA JOSÉ , CARO‐CORRALES JOSÉ
Published: September 2009

Waxed and nonwaxed mature green tomato fruits were stored at 12C (nonchilled) or 5C (chilled) for 5, 10, 15 and 20 days before being transferred to 22C for 3, 6, 9 and 12 days, were evaluated for weight loss, chemical composition, skin color, chilling injury (CI) index and pigment content. Waxed fruits showed a delay in weight loss, color development and ripening. The sensitivity of tomato fruit to CI was reduced in waxed fruits, which showed a delay in the appearance of symptoms. A delay in chlorophyll degradation and lycopene synthesis was observed as a result of the use of wax and low temperature. Waxing of tomato fruits allowed their storage at temperatures below critical reducing CI sensitivity and maintaining quality giving more time for marketing.

PRACTICAL APPLICATIONS

Nowadays, local tomato producers use wax on fruits as an everyday practice to carry postharvest fungicides and to improve brightness. They store tomato fruits at nonchilling temperature (12C) because lower temperatures would cause chilling injury and irregular ripening. In this way, it is interesting that waxing tomato fruits allow reducing their storage temperature, protecting them from chilling injury and maintaining their quality and correct color change and ripening; thereby producers and sellers have more days to position their fruits with no extra cost.
Constraints to Watershed Planning: Group Structure and Process1
Authors: Floress Kristin , Mangun Jean C. , Davenport Mae A. , Williard Karl W.J.
Published: September 2009

Floress, Kristin, Jean C. Mangun, Mae A. Davenport, and Karl W.J. Williard, 2009. Constraints to Watershed Planning: Group Structure and Process. Journal of the American Water Resources Association (JAWRA) 45(6):1352‐1360.

Abstract:  The roles that agencies and other partners play in collaborative watershed management are not always clearly identified. Key factors contributing to group‐level outcomes in watershed groups include both structural and procedural elements. Structural elements include membership systems, project partners, and funding, while procedural elements include leadership, shared vision, and mission development. The current research reports on a case study conducted with a Midwestern watershed group that received Clean Water Act Section 319 funds to undertake a watershed planning process. Data come from focus groups, interviews, public comments, and meeting observation, and were analyzed using grounded theory. Findings of this study indicate that homogenous skill set, discord over group and partner roles, and failed problem identification contributed to the organizational inertia experienced by the watershed group. Implications of this research for groups receiving 319 funds are provided.
sofsog: a suite of programs to avoid inbreeding in plantation designs
Authors: FERNÁNDEZ J. , GONZÁLEZ‐MARTÍNEZ S. C.
Published: September 2009

Cost‐effective ways of controlling inbreeding in conservation or productive plantations imply the allocation of individuals reducing the possibility of close relatives’ mating and, consequently, limiting inbreeding. sofsog is a suite of programs, which helps to design plantation sites. First, if the plantation scheme involves several plots, it allows distribution of individuals available among different sites minimizing within‐site global coancestry. Then, it yields a plantation design for each site, either following the classical permutated neighbourhood strategy or the recently developed method by Fernández and González‐Martínez. This new method allows the implementation of different pollen dispersion kernels, and to include in the designing strategy any available information on individual relationships, reproductive success, differences in phenology, etc., via weighting or penalization matrices. Additionally, the package includes a tool for calculating the molecular coancestry (Identity By State) from codominant marker data.
Critiquing the General Theory of Crime's Empirical Evidence: Does the Evidence Support the Theory?
Authors: Crosswhite Jennifer M. , Kerpelman Jennifer L.
Published: September 2009

Gottfredson and Hirschi's general theory of crime proposes that low self‐control leads to engagement in deviant behaviors, parents must properly socialize self‐control in their children, and self‐control fully mediates the parenting‐deviance association. A critical analysis of the empirical evidence generated suggests a number of unresolved issues regarding the theory that remain to be investigated. Some of the specific issues addressed include determining which aspects of parenting influence the etiology of self‐control and to what extent self‐control mediates the parenting‐deviance association.
A New Subject-Specific Skin Correction Factor for Three-Dimensional Kinematic Analysis of the Scapula
Authors: Bourne Douglas A. , Choo Anthony M. , Regan William D. , MacIntyre Donna L. , Oxland Thomas R.
Published: September 2009

Noninvasive measurement of scapular kinematics using skin surface markers presents technical challenges due to the relative movement between the scapula and the overlying skin. The objectives of this study were to develop a noninvasive subject-specific skin correction factor that would enable a more accurate measurement of scapular kinematics and evaluate this new technique via comparison with a gold standard for scapular movement. Scapular kinematics were directly measured using bone pins instrumented with optoelectronic marker carriers in eight healthy volunteers while skin motion was measured simultaneously with optoelectronic markers attached to the skin surface overlying the scapula. The relative motion between the skin markers and the underlying scapula was estimated over a range of humeral orientations by palpating and digitizing bony landmarks on the scapula and then used to calculate correction factors that were weighted by humeral orientation. The scapular kinematics using these correction factors were compared with the kinematics measured via the bone pins during four arm movements in the volunteers: abduction, forward reaching, hand behind back, and horizontal adduction. The root-mean-square (rms) errors for the kinematics determined from skin markers without the skin correction factors ranged from 5.1 deg to 9.5 deg while the rms errors with the skin correction factors ranged from 1.4 deg to 3.0 deg. This technique appeared to perform well for different movements and could possibly be extended to other applications.
A Three-Dimensional Human Trunk Model for the Analysis of Respiratory Mechanics
Authors: Behr Michel , Pérès Jeremie , Llari Maxime , Godio Yves , Jammes Yves , Brunet Christian
Published: September 2009

Over the past decade, road safety research and impact biomechanics have strongly stimulated the development of anatomical human numerical models using the finite element (FE) approach. The good accuracy of these models, in terms of geometric definition and mechanical response, should now find new areas of application. We focus here on the use of such a model to investigate its potential when studying respiratory mechanics. The human body FE model used in this study was derived from the RADIOSS® HUMOS model. Modifications first concerned the integration and interfacing of a user-controlled respiratory muscular system including intercostal muscles, scalene muscles, the sternocleidomastoid muscle, and the diaphragm and abdominal wall muscles. Volumetric and pressure measurement procedures for the lungs and both the thoracic and abdominal chambers were also implemented. Validation of the respiratory module was assessed by comparing a simulated maximum inspiration maneuver to volunteer studies in the literature. Validation parameters included lung volume changes, rib rotations, diaphragm shape and vertical deflexion, and intra-abdominal pressure variation. The HUMOS model, initially dedicated to road safety research, could be turned into a promising, realistic 3D model of respiration with only minor modifications.
Time-multiplexed, inductively coupled plasma process with separate SiCl4 and O2 steps for etching of GaAs with high selectivity
Authors: Golka S. , Arens M. , Reetz M. , Kwapien T. , Bouchoule S. , Patriarche G.
Published: September 2009

The authors present the results and the optimization procedure for a time-multiplexed dry etching process to etch GaAs in an inductively coupled plasma reactive ion etching system. The gas feed chopping sequence employed a SiCl4 etch phase and an O2 passivation phase. Care is taken not to intermix O2 with SiCl4. The investigated structures consist of pillars, trenches, stripes, and holes, all with lateral structure size of 1 μm or less. This feature size is interesting for diffractive elements and cavities in integrated mid-IR optoelectronics. They achieve an aspect ratio of 10 for holes, 17 for trenches, and 30 for stripes with a selectivity of 200:1 on open areas. The improvements in the sidewall morphology are related to the O2 passivation step investigated by optical emission spectroscopy and energy dispersive x-ray analysis that reveals a Si-rich SiOX sidewall.
Numerical approach for the theory of harmonic self-heating technique to measure thermophysical properties of suspended thin samples
Authors: Feng Bo , Li Zhixin , Zhang Xing , Peterson G. P.
Published: September 2009

3ω technique is effective for the thermophysical property measurement of micro- and nanosized samples. In the present study, a new theoretical approach for the harmonic self-heating technique is presented to simultaneously measure the specific heat and thermal conductivity of thin samples. The numerical analysis of transient heat-conduction equation and a virtual lock-in amplifier are combined to substitute the traditional analytical expression. This approach is capable of providing a more general insight into the harmonic signals at different desired frequencies such as 2ω signals, which are also informative to extract thermophysical properties such as the traditional 3ω technique, as well as to be readily extended to more complicated experimental configurations in terms of the advantage of numerical calculation. A suspended microsized platinum wire is first studied to confirm this theoretical approach. In further, 2ω and 3ω techniques based on the present theoretical approach are also used to measure the thermal conductivity and specific heat of a single carbon fiber.
Introduction of Ertapenem into a Hospital Formulary: Effect on Antimicrobial Usage and Improved In Vitro Susceptibility of
Pseudomonas aeruginosa
Authors: Goldstein Ellie J. C. , Citron Diane M. , Peraino Victoria , Elgourt Tanya , Meibohm Anne R. , Lu Shuang
Published: September 2009

After ertapenem was added to the formulary of a 344-bed community teaching hospital, we retrospectively studied its effect on antimicrobial utilization and on the in vitro susceptibility of various antimicrobial agents against
Pseudomonas aeruginosa
. Three study periods were defined as preintroduction (months 1 to 9), postintroduction but before the autosubstitution of ertapenem for ampicillin-sulbactam (months 10 to 18), and after the policy of autosubstitution (months 19 to 48) was initiated. Ertapenem usage rose slowly from introduction to a range of 36 to 48 defined daily doses/1,000 patient days (DDD) with a resultant decrease in ampicillin-sulbactam usage due to autosubstitution. Imipenem usage peaked 6 months after the introduction of ertapenem and started to decline coincidently with the increased use of ertapenem. During the second period, imipenem usage decreased (slope = −1.28;
P
= 0.002). Prior to the introduction of ertapenem, the susceptibility of
P. aeruginosa
to imipenem increased from 61 to 81% at month 7 but then decreased slightly to 67% at month 9. After the introduction of ertapenem, susceptibility continued to increase; the increasing trend was significant (slope = 1.74;
P
< 0.001). In the third period, the median susceptibility (interquartile range) was 88% (82 to 95%). This change appeared related to decreased imipenem usage. For every unit decrease in the monthly DDD of imipenem, there was an increase of 0.38% (
P
= 0.008) in the susceptibility of
P. aeruginosa
to imipenem in the same month. Ertapenem was effective in our antimicrobial stewardship program and may have helped improve the
P. aeruginosa
antimicrobial susceptibility to imipenem by decreasing the unnecessary usage and selective pressure of antipseudomonal agents.
Fmt Bypass in
Pseudomonas aeruginosa
Causes Induction of MexXY Efflux Pump Expression
Authors: Caughlan Ruth E. , Sriram Shubha , Daigle Denis M. , Woods Angela L. , Buco Jennifer , Peterson Ron L. , Dzink-Fox JoAnn , Walker Susan , Dean Charles R.
Published: September 2009

The intrinsic resistance of
P. aeruginosa
PAO1 to the peptide deformylase inhibitor (PDF-I) LBM415 was mediated by the MexAB-OprM and MexXY-OprM efflux pumps, the latter of which was strongly induced by LBM415. Single-step exposure of PAO1 deleted for
mexAB-oprM
(therefore lacking both MexAB-OprM and MexXY-OprM functions) to PDF-Is selected for
nfxB
mutants, which express the MexCD-OprJ efflux pump, indicating that these compounds are also substrates for this pump. Selection of resistant mutants by use of levels of LBM415 greater than that accommodated by efflux yielded two additional groups of mutations, in the methionyl-tRNA
fmet
formyltransferase (
fmt
) and
folD
genes. Both mechanisms are known to impose an in vitro growth deficit (also observed here), presumably due to impairment of protein synthesis. We surmised that this inherent impairment of protein synthesis would upregulate expression of
mexXY
in a fashion similar to upregulation by LBM415 or by ribosome inhibitory compounds. Transcriptional profiling and/or
mexX
::
lux
promoter fusion analysis revealed that
fmt
and
folD
mutants were strongly upregulated for
mexXY
and another gene known to be required for upregulation of the pump, PA5471. Complementation of the
fmt
mutation in
trans
reversed this constitutive expression. This supports the notion that MexXY has a natural physiological function responding to impairment of ribosome function or protein synthesis and that
fmt
mutation (Fmt bypass) and
folD
mutation generate the intracellular
mexXY
-inducing signal.
In Vivo Investigations of Selected Diamidine Compounds againstTrypanosoma evansiUsing a Mouse Model
Authors: Gillingwater Kirsten , Kumar Arvind , Anbazhagan Mariappan , Boykin David W. , Tidwell Richard R. , Brun Reto
Published: September 2009

Surra is an animal pathogenic protozoan infection, caused byTrypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introduction of novel aromatic diamidines, a new category of antitrypanosomal drugs was discovered. Nevertheless, their efficacy within aT. evansi-infected mouse model was not known. In total, 30 compounds previously selected based on their in vitro activity were tested in aT. evansimouse model of infection. Six of the compounds were capable of curingT. evansi-infected mice at drug doses as low as 0.5 and 0.25 mg/kg of body weight administered for 4 consecutive days, and they were more effective than the standard drugs suramin, diminazene, and quinapyramine. After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates againstT. evansiinfection.
Susceptibilities of 23
Desulfovibrio
Isolates from Humans
Authors: Nakao Ken-ichi , Tanaka Kaori , Ichiishi Suguru , Mikamo Hiroshige , Shibata Toshiyuki , Watanabe Kunitomo
Published: September 2009

Antimicrobial susceptibilities of 23 strains of
Desulfovibrio
spp. were tested by Etest. Generally,
Desulfovibrio
spp. were highly susceptible to sulbactam-ampicillin, meropenem, clindamycin, metronidazole, and chloramphenicol: MIC
90
s of 6, 4, 0.19, 0.25, and 8 μg/ml, respectively. In addition, these strains generally showed high MICs to piperacillin and piperacillin-tazobactam.
D
esulfovibrio fairfieldensis
(eight strains) was the species least susceptible to most agents, especially β-lactams, and was the only species resistant to fluoroquinolones.
D
esulfovibrio desulfuricans
strain Essex 6 isolates were less susceptible to β-lactams than
D. desulfuricans
strain MB isolates.
Pharmacokinetic-Pharmacodynamic Modeling of the In Vitro Activities of Oxazolidinone Antimicrobial Agents against Methicillin-ResistantStaphylococcus aureus
Authors: Schmidt Stephan , Sabarinath Sreedharan Nair , Barbour April , Abbanat Darren , Manitpisitkul Prasarn , Sha Sue , Derendorf Hartmut
Published: September 2009

Linezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin)-resistantStaphylococcus aureus(MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined in time-kill curve experiments, against MRSA. The in vitro activities of RWJ-416457 and the first-in-class representative, linezolid, against MRSA OC2878 were determined in static and dynamic time-kill curve experiments over a wide range of concentrations: 0.125 to 8 μg/ml (MIC, 0.5 μg/ml) and 0.25 to 16 μg/ml (MIC, 1 μg/ml), respectively. After correction for drug degradation during the time-kill curve experiments, a two-subpopulation model was simultaneously fitted to all data in the NONMEM VI program. The robustness of the model and the precision of the parameter estimates were evaluated by internal model validation by nonparametric bootstrap analysis. A two-subpopulation model, consisting of a self-replicating, oxazolidinone-susceptible and a persistent, oxazolidinone-insusceptible pool of bacteria was appropriate for the characterization of the time-kill curve data. The PK-PD model identified was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The simultaneous fit of the proposed indirect-response, maximum-effect model to the data resulted in concentrations that produced a half-maximum killing effect that were significantly (P< 0.05) lower for RWJ-416457 (0.41 μg/ml) than for linezolid (1.39 μg/ml). In combination with the appropriate PK data, the susceptibility-based two-subpopulation model identified may provide valuable guidance for the selection of oxazolidinone doses or dose regimens for use in clinical studies.
ADS-J1 Inhibits Human Immunodeficiency Virus Type 1 Entry by Interacting with the gp41 Pocket Region and Blocking Fusion-Active gp41 Core Formation
Authors: Wang Hongtao , Qi Zhi , Guo Angi , Mao Qinchao , Lu Hong , An Xiuli , Xia Chenglai , Li Xiaojuan , Debnath Asim K. , Wu Shuguang , Liu Shuwen , Jiang Shibo
Published: September 2009

We previously identified a small-molecule anti-human immunodeficiency virus type 1 (anti-HIV-1) compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme-linked immunosorbent assay (ELISA) as a secondary screening method. In the present study, we demonstrated that ADS-J1 is an HIV-1 entry inhibitor, as determined by a time-of-addition assay and an HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 does not block gp120-CD4 binding and exhibits a marginal interaction with the HIV-1 coreceptor CXCR4. However, ADS-J1 inhibited the fusion-active gp41 core formation mimicked by peptides derived from the viral gp41 N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, using a surface plasmon resonance assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing the gp41 pocket region, resulting in the conformational change of IQN17 and the blockage of its interaction with a short D peptide, PIE7. The positively charged residue (K574) located in the gp41 pocket region is critical for the binding of ADS-J1 to NHR. These results suggest that ADS-J1 may bind to the viral gp41 NHR region through its hydrophobic and ionic interactions with the hydrophobic and positively charged resides located in the pocket region, subsequently blocking the association between the gp41 NHR and CHR regions to form the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry.
Modifying Culture Conditions in Chemical Library Screening Identifies Alternative Inhibitors of Mycobacteria
Authors: Miller Christopher H. , Nisa Shahista , Dempsey Sandi , Jack Cameron , O'Toole Ronan
Published: September 2009

In this study, application of a dual absorbance/fluorescence assay to a chemical library screen identified several previously unknown inhibitors of mycobacteria. In addition, growth conditions had a significant effect on the activity profile of the library. Some inhibitors such as Se-methylselenocysteine were detected only when screening was performed under nutrient-limited culture conditions as opposed to nutrient-rich culture conditions. We propose that multiple culture condition library screening is required for complete inhibitory profiling and for maximal antimycobacterial compound detection.
Susceptibilities of Human Cytomegalovirus Clinical Isolates and Other Herpesviruses to New Acetylated, Tetrahalogenated Benzimidazole
d
-Ribonucleosides
Authors: Hwang Jae-Seon , Schilf Rita , Drach John C. , Townsend Leroy B. , Bogner Elke
Published: September 2009

Recently we characterized two inhibitors targeting the human cytomegalovirus (HCMV) terminase, 2-bromo-4,5,6-trichloro-1-(2,3,5-tri-
O
-acetyl-β-
d
-ribofuranosyl) benzimidazole (BTCRB) and 2,4,5,6-tetrachloro-1-(2,3,5-tri-
O
-acetyl-β-
d
-ribofuranosyl) benzimidazole (Cl
4
RB). The terminase consists of the ATP-hydrolyzing subunit pUL56 and the subunit pUL89 required for duplex nicking. Because mammalian cell DNA replication does not involve cleavage of concatemeric DNA by a terminase, these compounds represent attractive alternative HCMV antivirals. We now have tested these previously identified benzimidazole ribonucleosides in order to determine if they are active against HCMV clinical isolates as well as those of herpes simplex virus type 1, mouse cytomegalovirus, rat cytomegalovirus (RCMV), and varicella-zoster virus (VZV). Antiviral activity was quantified by measurement of viral plaque formation (plaque reduction) and by viral growth kinetics. Interestingly, both BTCRB and Cl
4
RB had an inhibitory effect in ganciclovir (GCV)-sensitive and GCV-resistant clinical isolates, with the best effect produced by Cl
4
RB. Electron microscopy revealed that in cells infected with GCV-sensitive or GCV-resistant isolates, B capsids and dense bodies were formed mainly. Furthermore, pulsed-field gel electrophoresis showed that cleavage of concatenated DNA was inhibited in clinical isolates. In addition, the antiviral effect on other herpesviruses was determined. Interestingly, in plaque reduction assays, BTCRB was active against all tested herpesviruses. The best effects were observed on VZV- and RCMV-infected cells. These results demonstrate that the new compounds are highly active against GCV-resistant and GCV-sensitive clinical isolates and slightly active against other herpesviruses.
Paradoxical Growth of
Candida dubliniensis
Does Not Preclude In Vivo Response to Echinocandin Therapy
Authors: Mariné Marçal , Pastor F. Javier , Sahand Ismail H. , Pontón José , Quindós Guillermo , Guarro Josep
Published: September 2009

Candida dubliniensis
commonly shows paradoxical or trailing growth effects in vitro in the presence of echinocandins. We tested the in vitro activities of anidulafungin, caspofungin, and micafungin against clinical isolates of
C. dubliniensis
and evaluated the efficacy of these drugs in two murine models of systemic infection. The three echinocandins were similarly effective in the treatment of experimental disseminated infections with
C. dubliniensis
strains showing or not showing abnormal growth in vitro.
Bacterial Toxins Induce Sustained mRNA Expression of the Silencing Transcription Factor
klf2
via Inactivation of RhoA and Rhophilin 1
Authors: Dach Kristina , Zovko Josip , Hogardt Michael , Koch Isabel , van Erp Katrin , Heesemann Jürgen , Hoffmann Reinhard
Published: September 2009

Yersiniae bearing the
Yersinia
virulence plasmid pYV impact the transcriptome of J774A.1 macrophage-like cells in two distinct ways: (i) by suppressing, in a
Yersinia
outer protein P (YopP)-dependent manner, the induction of inflammatory response genes and (ii) by mRNA induction of the silencing transcription factor
klf2
. Here we show that
klf2
induction by
Yersinia enterocolitica
occurs in several cell lines of macrophage and squamous and upper gastrointestinal epithelial origin as well as in bone marrow-derived dendritic cells. Several strains of
Pseudomonas aeruginosa
and
Staphylococcus aureus
are equally effective as
Y. enterocolitica
in inducing
klf2
expression. Screening of mutant strains or incubation with recombinant toxins identified the rho-inactivating toxins YopT from
Yersinia
spp., ExoS from
Pseudomonas aeruginosa
, EDIN-B from
Staphylococcus aureus
, and C3bot from
Clostridium botulinum
as bacterial inducers of
klf2
mRNA.
klf2
mRNA induction by these toxins does not require de novo protein synthesis. Serum response factor or actin depolymerization does not seem to be involved in regulating
klf2
expression in response to bacterial infection. Instead, short hairpin RNA-mediated inactivation of RhoA and its effector rhophilin 1 is sufficient to induce long-term
klf2
expression. Thus, bacteria exploit the RhoA-rhophilin signaling cascade to mediate sustained expression of the immunosuppressive transcription factor
klf2
.
Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated
Plasmodium falciparum
Protein PFF0165c
Authors: Olugbile S. , Kulangara C. , Bang G. , Bertholet S. , Suzarte E. , Villard V. , Frank G. , Audran R. , Razaname A. , Nebie I. , Awobusuyi O. , Spertini F. , Kajava A. V. , Felger I. , Druilhe P. , Corradin G.
Published: September 2009

We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the
Plasmodium falciparum
genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of
P. falciparum
hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in
P. falciparum
-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate.
oxyR
, a LysR-Type Regulator Involved in
Klebsiella pneumoniae
Mucosal and Abiotic Colonization
Authors: Hennequin Claire , Forestier Christiane
Published: September 2009

Colonization of the gastrointestinal tract is the first event in
Klebsiella pneumoniae
nosocomial infections, followed by colonization of the bladder or respiratory tract or entry into the bloodstream. To survive in the host, bacteria must harbor specific traits and overcome multiple stresses. OxyR is a conserved bacterial transcription factor with a key role both in the upregulation of defense mechanisms against oxidative stress and in pathogenesis by enhancing biofilm formation, fimbrial expression, and mucosal colonization. A homolog of
oxyR
was detected in silico in the
K. pneumoniae
sequenced genome and amplified from the LM21 wild-type strain. To determine the role of
oxyR
in
K. pneumoniae
host-interaction processes, an
oxyR
isogenic mutant was constructed, and its behavior was assessed. At concentrations lower than 10
7
ml
−1
,
oxyR
-deficient organisms were easily killed by micromolar concentrations of H
2
O
2
and exhibited typical aerobic phenotypes. The
oxyR
mutant was impaired in biofilm formation and types 1 and 3 fimbrial gene expression. In addition, the
oxyR
mutant was unable to colonize the murine gastrointestinal tract, and in vitro assays showed that it was defective in adhesion to Int-407 and HT-29 intestinal epithelial cells. The behavior of the
oxyR
mutant was also determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment: deletion of
oxyR
resulted in higher sensitivity to bile and acid stresses but not to osmotic stress. These results show the pleiotropic role of
oxyR
in
K. pneumoniae
gastrointestinal colonization.
The Enteropathogenic
Escherichia coli
Effector Cif Induces Delayed Apoptosis in Epithelial Cells
Authors: Samba-Louaka Ascel , Nougayrède Jean-Philippe , Watrin Claude , Oswald Eric , Taieb Frédéric
Published: September 2009

The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic
Escherichia coli
(EPEC), Cif induces both G
2
and G
1
cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21
waf1
and p27
kip1
proteins that inhibit CDK-cyclin complexes, whose activation is required for G
1
/S and G
2
/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer.
Efficacy of low dose dexamethasone in severe thrombocytopenia caused by dengue fever: a placebo controlled study
Authors: Kularatne S A M , Walathara C , Mahindawansa S I , Wijesinghe S , Pathirage M M K , Kumarasiri P V R , Dissanayake A M S D M
Published: September 2009

Background

The use of corticosteroids in the management of thrombocytopenia in dengue fever remains untested.

Objectives

To test whether intravenous low dose dexamethasone is efficacious in increasing platelet count in acute severe thrombocytopenia in dengue infection.

Methods

We undertook a placebo controlled study at the Teaching Hospital, Peradeniya, Sri Lanka in July 2004. Patients with thrombocytopenia (platelet count <50×109/l) were allocated to the treatment and placebo groups using the sealed envelop method. The treatment group received an initial intravenous dose of 4 mg dexamethasone, followed by 2 mg doses every 8 h for 24 h, and the placebo group received normal saline. The primary outcome was the degree of mean platelet count rise.

Results

Each group comprised 100 patients and their baseline data and other variables (headaches, nausea, flush, temperature, pulse, blood pressure, haematocrit, white cell count and haemoglobin) were similar. The primary outcome—mean platelet count (×109/l)—increased steadily in both groups from day 1 to 4 and showed no significant difference between the two groups (p>0.05): day 1, 35 vs 35 (p = 0.70); day 2, 47 vs 43 (p = 0.19); day 3, 64 vs 59 (p = 0.31); day 4, 72 vs 78 (p = 0.55). Analysis of variance (ANOVA) statistics showed a significant linear association of mean platelet counts by days in either group (p<0.001). Regression analysis identified the day of the illness and patient age as the independent predictors of platelet count change.

Conclusion

At a low dose regimen, dexamethasone was not effective in achieving a higher rise of platelet count in dengue infection.
Narrow complex (supraventricular) tachycardias
Authors: Linton N W F , Dubrey S W
Published: September 2009

Patients experiencing a narrow complex tachycardia are usually at a lower risk than those in whom a broad complex tachycardia occurs. Therefore, in the UK cardiologists are frequently involved in broad complex dysrhythmias at an early stage, while general physicians and general practitioners will often have greater involvement in the management of patients with narrow complex arrhythmias. We describe the management of narrow complex arrhythmias likely to be encountered, including the ubiquitous atrial fibrillation.
The ethical imperative to scale up health care services for people with severe mental disorders in low and middle income countries
Authors: Patel V , Bloch S
Published: September 2009

Most mentally ill people in low and middle income countries, where clinical services are typically scarce and mental health legal provisions often inadequate, do not receive requisite evidence based treatment. The unfortunate consequence is compromised health and well-being and lack of social integration in the community. Recent initiatives, such as the Movement for Global Mental Health, aim to improve the situation and, in so doing, take into account ethical factors that play a role in the face of inadequate care and mental health legislative frameworks. Two composite case vignettes based on the narratives of actual patients living in India are used to show how family carers resort to measures like deception, coercion and physical restraint in order to deal with challenging behaviours stemming from severe and enduring mental disorders. These actions, while violating patients’ fundamental human rights, are also the consequence of the utter frustration and despair experienced by families. Scaling up mental health care based on the principle of cost effectiveness is not only a clinical imperative, but also a pivotal means to ensure that the severely mentally ill are accorded the same universal rights as those enjoyed by others.
Modulatory action of potassium channel openers on field potential and histamine release from rat peritoneal mast cells
Authors: Yeung Chi-Kong , Law Jessica Ka-Yan , Sam Sze-Wing , Ingebrandt Sven , Lau Hang-Yung Alaster , Rudd John Anthony , Chan Mansun
Published: September 2009

To determine whether changes in membrane potential affect the extent of mast cell degranulation, compound 48/80 was added to rat peritoneal mast cell suspensions in the absence or presence of potassium channel openers (KCOs). Changes were compared between the field potential (FP) and the amount of histamine released. The results demonstrated that (i) the onset and duration of FP, which reflects the hyperpolarizing nature of the response, increased as the concentration of compound 48/80 increased; (ii) both FP and the amount of histamine released increased as the concentration of compound 48/80 increased; (iii) although both KCOs (SDZ PCO400, a benzopyran derivative, and P1060, a cyanoguanidine derivative) potentiated compound 48/80-induced increases in FP and histamine release, without compound 48/80, they had no effect on either parameter; (iv) both glibenclamide and charybdotoxin significantly attenuated the compound 48/80-induced increase in FP; and (v) glibenclamide was able to attenuate the KCO-induced potentiation of FP. The results show that drugs presumably causing hyperpolarization can affect histamine release from rat peritoneal mast cells. The effect of KCOs on compound 48/80-induced response appears to be potentiation in nature rather than synergism. It is possible that KCO hyperpolarizes the cell membrane, enhances Ca2+ influx, and thus increases histamine release. As such, selective blockers of K+ channels may be useful for the treatment of immunological disorders.
Cardioprotective roles of aged garlic extract, grape seed proanthocyanidin, and hazelnut on doxorubicin-induced cardiotoxicity
Authors: Demirkaya Erkan , Avci Aslıhan , Kesik Vural , Karslioglu Yıldırım , Oztas Emin , Kismet Erol , Gokcay Erdal , Durak Ilker , Koseoglu Vedat
Published: September 2009

Doxorubicin (DXR) is a chemotherapeutic agent used effectively in the treatment of several childhood malignancies. During treatment, cardiotoxicity caused by cell damage due to the free oxygen radicals that are generated is a major limiting factor. This study was undertaken to determine whether DXR-induced cardiotoxicity could be prevented by natural foods with antioxidant properties such as aged garlic extract (AGEX), grape seed proanthocyanidin (PA), and hazelnut. Wistar albino male rats were assigned randomly to 9 groups each consisting of 15 rats. AGEX, PA, and hazelnut groups received these antioxidants in addition to their standard rat diet. They were also treated with cumulative intraperitoneal (i.p.) injections according to 2 different regimens: either a high-dose of 15 mg/kg DXR (3.75 mg/kg per week for 4 weeks) or a low-dose of 7.5 mg/kg DXR (1.875 mg/kg per week for 4 weeks). The control group received i.p. 0.9% saline. AGEX, PA, or hazelnut supplements were given orally to the groups for a 6-week period starting 1 week before the DXR treatment and ending 1 week after the treatment. One week after the last DXR injection, heart tissue samples were analyzed to determine malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and xanthine oxidase (XO) levels, and serum samples were taken for creatine kinase (CK). There were no significant changes in MDA levels among the control, DXR-treated groups, or supplemented groups that received additional natural antioxidant foods. SOD enzyme levels were decreased in rats treated with DXR. PA prevented the decrease at low doses of DXR. DXR treatment decreased CAT enzyme levels, but additional PA and hazelnut consumption increased these levels at low cumulative doses. XO enzyme levels were decreased in AGEX and hazelnut groups, but PA prevented the decrease. CK levels were elevated after DXR administration, indicating myocardial injury, but PA significantly reversed this. Although there were no differences histopathologically between AGEX, PA, and hazelnut groups, the protective effects of AGEX and PA were evident in electron microscopy. In conclusion, the positive effects of natural antioxidant foods on the prevention of DXR-induced cardiac injury could not be clearly shown on the basis of antioxidant enzymes. However, the electron microscopic changes clearly demonstrated the protective effects of AGEX and PA. The supplementation of these antioxidant foods over longer periods may show more definitive results. Human studies with different doses are needed to evaluate the effects of these foods on the human heart.
COLLISION THERMALIZATION OF NUCLEONS IN RELATIVISTIC HEAVY-ION COLLISIONS
Authors: ANCHISHKIN D. , MUSKEYEV A. , YEZHOV S.
Published: September 2009

We consider a possible mechanism of thermalization of nucleons in relativistic heavy-ion collisions. Our model belongs, to a certain degree, to the transport ones; we investigate the evolution of the system created in nucleus–nucleus collision, but we parametrize this development by the number of collisions of every particle during evolution rather than by the time variable. We based on the assumption that the nucleon momentum transfer after several nucleon–nucleon (–hadron) elastic and inelastic collisions becomes a random quantity driven by a proper distribution. This randomization results in a smearing of the nucleon momenta about their initial values and, as a consequence, in their partial isotropization and thermalization. The trial evaluation is made in the framework of a toy model. We show that the proposed scheme can be used for extraction of the physical information from experimental data on nucleon rapidity distribution.
EMERGENT GRAVITY FROM NONCOMMUTATIVE SPACE–TIME
Authors: YANG HYUN SEOK
Published: September 2009

We showed before that self-dual electromagnetism in noncommutative (NC) space–time is equivalent to self-dual Einstein gravity. This result implies a striking picture about gravity: gravity can emerge from electromagnetism in NC space–time. Gravity is then a collective phenomenon emerging from gauge fields living in fuzzy space–time. We elucidate in some detail why electromagnetism in NC space–time should be a theory of gravity. In particular, we show that NC electromagnetism is realized through the Darboux theorem as a diffeomorphism symmetry G which is spontaneously broken to symplectomorphism H due to a background symplectic two-form Bμν = (1/θ)μν, giving rise to NC space–time. This leads to a natural speculation that the emergent gravity from NC electromagnetism corresponds to a nonlinear realization G/H of the diffeomorphism group, more generally its NC deformation. We also find some evidences that the emergent gravity contains the structures of generalized complex geometry and NC gravity. To illuminate the emergent gravity, we illustrate how self-dual NC electromagnetism nicely fits with the twistor space describing curved self-dual space–time. We also discuss derivative corrections of Seiberg–Witten map which give rise to higher-order gravity.