bluuebunny/crossref_metadata_2025 huggingface dataset:
Values in Translation: How Asking the Right Questions Can Move Translational Science Toward Greater Health Impact
Authors: Kelley Maureen , Edwards Kelly , Starks Helene , Fullerton Stephanie M. , James Rosalina , Goering Sara , Holland Suzanne , Disis Mary L. , Burke Wylie
Published: August 2012

The speed and effectiveness of current approaches to research translation are widely viewed as disappointing given small gains in real population health outcomes despite huge investments in basic and translational science. We identify critical value questions—ethical, social, economic, and cultural—that arise at moments throughout the research pathway. By making these questions visible, and promoting discussion of them with diverse stakeholders, we can facilitate handoffs along the translational pathway and increase uptake of effective interventions. Who is involved with those discussions will determine which research projects, populations, and methods get prioritized. We argue that some upfront investment in community and interdisciplinary engagement, shaped by familiar questions in ethics, social justice, and cultural knowledge, can save time and resources in the long run because interventions and strategies will be aimed in the right direction, that is, toward health improvements for all. Clin Trans Sci 2012; Volume 5: 445–451
Effects of Oral Rho Kinase Inhibitor Fasudil on Detrusor Overactivity after Bladder Outlet Obstruction in Rats
Authors: KIM Ji‐Yoon , HAN Ji‐Yeon , KWON Tae Gyun , CHOO Myung‐Soo
Published: August 2012

Objectives: Bladder outlet obstruction (BOO)‐related detrusor hypertrophy is associated with upregulation of Rho‐kinase (ROCK) activity in an experimental animal model, and has been implicated in BOO‐induced bladder dysfunction. The aim of this study was to test whether chronic oral administration of an oral ROCK inhibitor, fasudil (HA1077, 5‐isoquinolinesulfonyl homopiperazine), could prevent the development of both detrusor hypertrophy and detrusor overactivity in rat model.

Methods: Thirty five‐week‐old male Sprague‐Dawley rats were divided into three groups (n = 10 per group): control (sham surgical) with no treatment (group 1); 6‐week obstructed rats (group 2); and 6‐week obstructed rats treated for 6 weeks with fasudil (group 3).

Results: The BOO group showed increased detrusor overactivity. Treatment with fasudil partly but significantly ameliorated the development of detrusor overactivity. The expression of RhoA protein in detrusor muscle was significantly greater in the BOO group than in the control group and subsequently decreased with fasudil treatment in the BOO‐induced rat.

Conclusion: These findings suggest that fasudil, a specific inhibitor of Rho‐kinase, ameliorates BOO‐induced detrusor overactivity in a rat model. Thus, ROCK inhibitor might be used as a novel agent to treat overactive bladder symptoms.
First two cases of adult‐onset type II citrullinemia successfully treated by deceased‐donor liver transplantation in Japan
Authors: Yazaki Masahide , Hineno Akiyo , Matsushima Akira , Ozawa Kazuki , Kishida Dai , Tazawa Ko‐ichi , Fukushima Kazuhiro , Urata Koichi , Ikegami Toshihiko , Miyagawa Shinichi , Ikeda Shu‐ichi
Published: August 2012

We report the first two cases of adult‐onset type II citrullinemia (CTLN2) successfully treated by liver transplantation from deceased donors in Japan. One patient was a 34‐year‐old female, who had suffered from depression since the age of 28 years and developed consciousness disturbance at 34 years old. The other patient was a 41‐year‐old man who began to experience consciousness disturbance with abnormal behavior at 37 years old. Both patients were first treated with non‐surgical therapies, including low‐carbohydrate diet, arginine granules and sodium pyruvate. However, their therapeutic efficacy was limited and attacks of encephalopathy occurred frequently with elevation of plasma ammonia despite treatment. While both patients and their families desired liver transplantation, no candidate donors for live‐donor liver transplantation were available. Fortunately, within a relatively short period after enrollment for liver transplant from deceased donors in Japan (13 and 43 days, respectively), they underwent cadaveric liver transplantation. The clinical courses after the operation were uneventful in both cases and no attacks of hepatic encephalopathy have occurred. Although there have been no reports of good therapies for CTLN2 patients with resistance to non‐surgical therapies and no live‐donor candidates, our observations indicate that cadaveric liver transplantation can be a promising therapeutic option for CTLN2 patients.
Churg–Strauss syndrome manifesting as cholestasis and diagnosed by liver biopsy
Authors: Harada Masaru , Oe Shinji , Shibata Michihiko , Taguchi Masashi , Matsuhashi Toru , Hiura Masaaki , Abe Shintaro , Harada Riko , Shimajiri Shohei
Published: August 2012

A 56‐year‐old woman was referred to our hospital due to fever and cholestatic liver dysfunction. Her eosinophil count was normal and she had no abdominal pain or neurological manifestations. We performed a liver biopsy and found fibrinoid necrosis of the hepatic artery with granulomatous reaction and eosinophilic infiltration in the portal area in the liver. Later, sensory abnormalities of the arms and legs appeared and the eosinophil count increased. Serum immunoglobulin E and immunoglobulin G4 were elevated and rheumatoid factor was strongly positive. Endoscopic retrograde cholangiopancreatography revealed no abnormality of the bile duct and pancreatic duct. We made a diagnosis of Churg–Strauss syndrome and began corticosteroid treatment. Fever and liver function immediately improved. In the present patient, Churg–Strauss syndrome manifested first in the liver, before hypereosinophilia and neural manifestations. We believe that Churg–Strauss syndrome is an autoimmune liver disease, and it is important to recognize that the liver may be involved in Churg–Strauss syndrome.
A Survey on Practitioner Attitudes toward Research in Interior Design Education
Authors: Dickinson Joan I. , Anthony Lori , Marsden John P.
Published: August 2012

The purpose of this study was to investigate interior design practitioners’ perceived attitudes toward the inclusion of research at the undergraduate and graduate levels, minimum degree requirements for practice and teaching, and the value of the graduate degree in the field of interior design. Interior design practitioners who are members of the American Society of Interior Designers (ASID) were surveyed ( n = 250) using an online questionnaire based on several existing scales. The questionnaire was distributed through a primary contact with ASID as an e–mail blast to all members within the organization. As a whole, the participants in this investigation believed that undergraduate and graduate students should have an understanding of research and be able to apply findings to design projects. However, practitioners did not respond positively to positioning the Master of Interior Design (MID) as the first professional degree or to a graduate degree in general as a minimum credential to practice. Some practitioners valued the graduate degree to increase marketability, enhance the prestige of the profession, and provide specialization. Others placed more emphasis on practical experience, continuing education, and innate talent rather than a graduate degree. More educated individuals with advanced degrees who were younger than 40 and were practicing commercial design were significantly more likely to value research. The fact that some educators have been advocating for the MID as the first professional degree for the discipline shows a disconnect between practice and academia.
Autologous Peripheral Blood Hematopoietic Cell Transplantation in Dogs with B‐cell Lymphoma
Authors: Willcox J.L. , Pruitt A. , Suter S.E.
Published: August 2012

Background

Peripheral blood CD34+ hematopoietic cell transplantation (PBHCT) is commonly used to treat human patients with relapsed non‐Hodgkin diffuse, large B‐cell lymphoma with cure rates approaching 50%.

Objective

To determine the safety and feasibility of performing PBHCT to treat canine B‐cell lymphoma (LSA) patients in a clinical academic setting.

Animals

Twenty‐four client‐owned dogs diagnosed with B‐cell LSA.

Methods

After high‐dose cyclophosphamide and rhG‐colony‐stimulating factor treatment, peripheral blood mononuclear cells were collected using cell separator machines. The harvested cells then were infused after a 10 Gy dose of total body irradiation (TBI). Post‐irradiation adverse effects were managed symptomatically and dogs were discharged upon evidence of engraftment.

Results

More than 2 × 106 CD34+ cells/kg were harvested in 23/24 dogs. Preapheresis peripheral blood monocyte count was correlated with the number of CD34+ cells/kg harvested. Twenty‐one of 24 (87.5%) dogs engrafted appropriately, whereas 2 dogs (8.3%) died in the hospital. One (5%) dog exhibited delayed engraftment and died 45 days after PBHCT. One dog developed presumed TBI‐induced pulmonary fibrosis approximately 8 months after PBHCT. The median disease‐free interval and overall survival (OS) of all dogs from the time of PBHCT was 271 and 463 days, respectively. Five of 15 (33%) dogs transplanted before they relapsed remain in clinical remission for their disease at a median OS of 524 days (range, 361–665 days).

Conclusions and Clinical Importance

In most cases, PBHCT led to complete hematologic reconstitution. Therefore, PBHCT may be considered as a treatment option for dogs with B‐cell lymphoma.
Acute Azotemia as a Predictor of Mortality in Dogs and Cats
Authors: Harison E. , Langston C. , Palma D. , Lamb K.
Published: August 2012

Background

Acute kidney injury (AKI) has been shown to be a predictor of mortality in human medicine. Published studies in the veterinary literature evaluating relative changes in serum creatinine concentration as a prognostic factor are limited.

Objective

To evaluate anAKIgrading system based on serum creatinine concentration to determine if it correlates with outcome prediction in dogs and cats.

Animals

Six hundred forty‐five dogs and 209 cats that had at least 2 serum creatinine concentration measurements measured within 7 days.

Methods

Retrospective study. Dogs and cats with an initial serum creatinine concentrations of ≤1.6 mg/dL and that had more than 1 concentration measured within 2, 3, and 7 days were placed into levels (0–2) based on absolute changes. Mortality then was determined at 30 and 90 days.

Results

Based on odds ratios calculated with a 95% confidence interval, dogs placed in level 1 within 2 days were approximately 3 times more likely to die within 90 days. Dogs placed in level 2 within 2, 3, or 7 days were approximately 3 times more likely to die within 30 or 90 days. Cats placed in level 2 within 3 or 7 days were approximately 3 times more likely to die at 30 days and 4 times more likely to die if placed in this level within 7 days. If placed in level 2 within 2 or 3 days, cats were approximately 3 times more likely to die within 90 days.

Conclusions and Clinical Importance

Detecting increasing severity of azotemia helps predict mortality in dogs and cats.
Motivations for Self‐Injury, Affect, and Impulsivity: A Comparison of Individuals with Current Self‐Injury to Individuals with a History of Self‐Injury
Authors: Taylor Julia , Peterson Claire M. , Fischer Sarah
Published: August 2012

Individuals who report nonsuicidal self‐injury (NSSI) are characterized by the tendency to act rashly while experiencing distress (negative urgency), the tendency to act without thinking, and endorsement of both social and affect regulation motives for the behavior. However, very little research has identified characteristics that distinguish current self‐injurers from those with a history of the behavior. The purpose of this study was to compare individuals with current self‐injury to a history of self‐injury on impulsivity‐related personality traits, motives for self‐injury, and distress. Among a sample of 429 undergraduates, 120 reported self‐injury. Among these 120 individuals, 33 endorsed self‐injury within the past month, with a mean frequency of 4.77 acts of NSSI. Within the self‐injury group, current self‐injurers reported higher endorsement of affect regulation motives for NSSI, and higher levels of current negative affect than individuals with a history of self‐injury. There were no differences between current and former self‐injurers on measures of impulsivity, endorsement of social motives for NSSI, or positive affect. We propose that individuals who use NSSI to regulate negative affect may be more likely to repeatedly engage in this behavior over time.
Promoting Multilateralism or Searching for a New Hegemony: A Chinese Vision of Multipolarity
Authors: Courmont Barthélémy
Published: August 2012

The rise of China and its bigger implications within the international system raise the questions of Beijing's vision of multipolarity. Alongside its growing economic power, China tries to address its own definition of the new world order by officially strongly promoting a multilateralism that makes China an important actor, but limits the responsibilities that come with such a status. At the same time, Beijing is keener to impose its views towards its partners, mostly in its vicinity, at the risk of being tempted by a new form of hegemony. This article explores the Chinese attitude in a multipolar world, and asserts that China's grand strategy is both pragmatic and proactive, by constantly keeping a balance between its opportunities and its duties.
Oral lichenoid contact lesions induced by areca nut and betel quid chewing: a mini review
Authors: Reichart Peter A. , Warnakulasuriya Saman
Published: August 2012

Betel quid (BQ) and areca nut chewing is widely prevalent in many parts of Asia and Asian‐migrant communities throughout the world. Global reports estimate 600 million users. Sufficient evidence of carcinogenicity has been found for BQ and its main ingredient, areca nut. BQ areca nut users have an increased risk of potentially malignant disorders. Among chewers, BQ remains in contact with the oral mucosa for prolonged periods. This review examines the clinical and pathological aspects of lichenoid lesions caused by areca nut and BQ, a condition that has received little attention in the published literature.
The pharmacology of neuroplasticity induced by non‐invasive brain stimulation: building models for the clinical use of CNS active drugs
Authors: Nitsche Michael A. , Müller‐Dahlhaus Florian , Paulus Walter , Ziemann Ulf
Published: August 2012

Abstract  The term neuroplasticity encompasses structural and functional modifications of neuronal connectivity. Abnormal neuroplasticity is involved in various neuropsychiatric diseases, such as dystonia, epilepsy, migraine, Alzheimer's disease, fronto‐temporal degeneration, schizophrenia, and post cerebral stroke. Drugs affecting neuroplasticity are increasingly used as therapeutics in these conditions. Neuroplasticity was first discovered and explored in animal experimentation. However, non‐invasive brain stimulation (NIBS) has enabled researchers recently to induce and study similar processes in the intact human brain. Plasticity induced by NIBS can be modulated by pharmacological interventions, targeting ion channels, or neurotransmitters. Importantly, abnormalities of plasticity as studied by NIBS are directly related to clinical symptoms in neuropsychiatric diseases. Therefore, a core theme of this review is the hypothesis that NIBS‐induced plasticity can explore and potentially predict the therapeutic efficacy of CNS‐acting drugs in neuropsychiatric diseases. We will (a) review the basics of neuroplasticity, as explored in animal experimentation, and relate these to our knowledge about neuroplasticity induced in humans by NIBS techniques. We will then (b) discuss pharmacological modulation of plasticity in animals and humans. Finally, we will (c) review abnormalities of plasticity in neuropsychiatric diseases, and discuss how the combination of NIBS with pharmacological intervention may improve our understanding of the pathophysiology of abnormal plasticity in these diseases and their purposeful pharmacological treatment.
Exact Solution of Unsteady Conductive Heat Transfer in Cylindrical Composite Laminates
Authors: Norouzi M. , Rezaei Niya S. M. , Kayhani M. H. , Shariati M. , Karimi Demneh M. , Naghavi M. S.
Published: August 2012

This paper presents an exact analytical solution for unsteady conductive heat transfer in a cylindrical multilayer composite laminate. Here, it is supposed that fibers have been wound around the cylinder in each lamina. In order to find the exact solution, the Laplace transformation is applied on anisotropic heat conduction equation to convert the time scale of problem to frequency scale and the separation of variable method is used to solve the resulted partial differential equations. The effect of fibers arrangements of multilayer cylindrical laminates and thermal boundary conditions on unsteady conductive heat transfer of these orthotropic materials is studied based on the exact solution that is presented in the current investigation. The analytical results illustrated that the unsteady temperature distribution in any multilayer composite laminates is in a state between the temperature distribution in single layer laminates with fibers’ angle equal to 0 deg and 90 deg.
Specification of Micro-Nanoscale Radiative Patterns Using Inverse Analysis for Increasing Solar Panel Efficiency
Authors: Hajimirza Shima , El Hitti Georges , Heltzel Alex , Howell John
Published: August 2012

This work proposes a comprehensive and efficient optimization approach for designing surface patterning for increasing solar panel absorption efficiency using near-field radiation effects. Global and local optimization methods, such as the Broyden–Fletcher–Goldfarb–Shanno quasi-Newton (BFGS-QN) and simulated annealing (SA), are employed for solving the inverse near-field radiation problem. In particular, a thin amorphous silicon (a-Si) solar panel with periodic silver nanowire patterning is considered. The design of the silver patterned solar panel is optimized to yield maximum enhancement in photon absorption. The optimization methods reproduce results found in the previous literature but with reduced computational expense. Additional geometric parameters, which are not discussed in previous work, are included in the optimization analysis, further allowing for increased absorption enhancement. Both the BFGS-QN and the SA methods give efficient results, providing designs with enhanced absorption.
Effect of Magnetic Field on Heat Transfer in Non-Newtonian Nanofluids Over a Nonisothermal Stretching Wall
Authors: Khan Waqar A. , Gorla Rama Subba Reddy
Published: August 2012

In this study, the effects of magnetic field on combined heat and mass transfer in non-Newtonian nanofluids over a stretching surface with prescribed wall temperature and uniform surface nanoparticle concentration are investigated numerically. A power-law model is used for non-Newtonian fluids, whereas Brownian motion and thermophoresis effects are incorporated in the nanofluid model. A set of similarity transformation is used to reduce mass, momentum, thermal energy, and nanoparticles concentration equations into nonlinear ordinary differential equations, which are solved numerically by using a fourth–fifth order Runge–Kutta–Fehlberg method. Effects of nanofluid parameters, suction/injection and temperature parameters, and generalized Pr and Le numbers on dimensionless functions, skin friction, local Nusselt, and Sherwood numbers are investigated in the presence of magnetic field and are shown graphically. The quantitative comparison of skin friction and heat transfer rates with the published results for special cases is shown in tabular form and is found in good agreement.
Numerical Simulation of Microdroplet Impact and Evaporation on a Solid Surface
Authors: Son Gihun
Published: August 2012

Microdroplet impact and evaporation on a solid surface, which is an integral part of an inkjet printing process, is studied numerically by solving the equations governing the conservation of mass, momentum, energy, and mass fraction in the liquid and gas phases. The deformed droplet shape is tracked by a sharp-interface level-set method, which is extended to include the effects of evaporation at the liquid–gas interface and dynamic contact angle at the liquid–gas–solid interline. The numerical results show that the droplet impact and evaporation pattern depends significantly on the advancing and receding contact angles. Also, the effect of cavity sidewall on the droplet motion is investigated.
Analytical Solution of the Graetz Problem Extended to Slip-Flow in Microtube
Authors: Xu Fayao , Ma Hugen
Published: August 2012

The original Graetz problem is extended to slip-flow in microtube. The extended Graetz problem in slip-flow with the isothermal boundary condition on the wall was solved using conventional energy equation with both the velocity slip and the temperature jump condition of slip-flow. The analytical solution was obtained by solving the energy equation with the method of separation of variables. The accurate eigenvalues were obtained by solving the eigenfunction with the method of power series expansion. In the end, temperature distributions, local Nusselt number Nux, and dimensionless temperature jump θs were obtained. In addition, the influences of Knudsen number Kn on Nux, Nu∞, and θs were discussed.
Residence Time and Heat Transfer When Water Droplets Hit a Scalding Surface
Authors: Yong Park Ji , Min Chang-Ki , Granick Steve , Cahill David G.
Published: August 2012

We study, using pump-probe optical methods with a time resolution of 1 ms, heat transfer when a series of water droplets impact a smooth surface whose temperature exceeds the boiling point. The volume of the individual water droplets is ≈10 nl, the time between droplets is ≈0.3 ms, and the number of water droplets in the series of droplets is 3, 20, or 100. In the temperature range 100 °C < T < 150 °C, our measurements of the heat transfer, and the residence time of water in contact with the surface, show that nearly all of the dispensed water vaporizes, but more rapidly, the higher the temperature. At higher temperatures, 150 °C < T < 220 °C, droplet shattering plays an increasingly important role in limiting heat transfer and, as a result, the volume of water evaporated and residence time decrease strongly with increasing temperature.
Enhanced Thermal Transport in Microchannel Using Oblique Fins
Authors: Lee Y. J. , Lee P. S. , Chou S. K.
Published: August 2012

Sectional oblique fins are employed, in contrast to continuous fins in order to modulate the flow in microchannel heat sinks. The breakage of a continuous fin into oblique sections leads to the reinitialization of the thermal boundary layer at the leading edge of each oblique fin, effectively reducing the boundary layer thickness. This regeneration of entrance effects causes the flow to always be in a developing state, thus resulting in better heat transfer. In addition, the presence of smaller oblique channels diverts a small fraction of the flow into adjacent main channels. The secondary flows created improve fluid mixing, which serves to further enhance heat transfer. Both numerical simulations and experimental investigations of copper-based oblique finned microchannel heat sinks demonstrated that a highly augmented and uniform heat transfer performance, relative to the conventional microchannel, is achievable with such a passive technique. The average Nusselt number, Nuave, for the copper microchannel heat sink which uses water as the working fluid can increase as much as 103%, from 11.3 to 22.9. Besides, the augmented convective heat transfer leads to a reduction in maximum temperature rise by 12.6 °C. The associated pressure drop penalty is much smaller than the achieved heat transfer enhancement, rendering it as an effective heat transfer enhancement scheme for a single-phase microchannel heat sink.
Nonlinear Thermal Instability in a Rotating Viscous Fluid Layer Under Temperature/Gravity Modulation
Authors: Bhadauria B. S. , Siddheshwar P. G. , Suthar Om P.
Published: August 2012

In the present paper, the effect of time-periodic temperature/gravity modulation on the thermal instability in a rotating viscous fluid layer has been investigated by performing a weakly nonlinear stability analysis. The disturbances are expanded in terms of power series of amplitude of modulation, which has been assumed to be small. The amplitude equation, viz., the Ginzburg–Landau equation, for the stationary mode of convection is obtained and using the same, the effect of temperature/gravity modulation on heat transport has been investigated. The stability of the system is studied and the stream lines are plotted at different slow times as a function of the amplitude of modulation, Rossby number, and Prandtl number. It is found that the temperature/gravity modulation can be used as an external means to augment/diminish heat transport in a rotating system. Further, it is shown that rotation can be effectively used in regulating heat transport.
Visualization of beams from ionic liquid ion sources for focused ion beam applications
Authors: Perez-Martinez Carla S. , Lozano Paulo C.
Published: August 2012

Ionic liquid ion sources (ILIS) share qualities with liquid metal ion sources necessary for focused ion beams (FIB) operation, such as pure ion emission and low energy spreads. These sources work at lower currents, room temperature, and are able to produce both positive and negative ions from a large number of ionic liquids. The influence of the applied voltage on the beam emitted from the ILIS based on the liquid EMI-BF4 (1-ethyl 3-methyl imidazolium tetrafluoroborate) is characterized by using a beam visualization system. As the applied voltage is increased, the source transitions from single to multiple beam emission. The visualization tool is also used to determine the spatial distribution of the neutral particle population contained within the beam emitted from ILIS. Cluster ions can break during flight, yielding a new ion and neutral particles. This neutral population can be highly energetic, and might be of interest for material treatment applications where charging of targets is undesirable. For FIB applications, these neutrals could lead to undesired effects in the sample, and so it is necessary to know the distribution of the neutrals within the beam in order to specify the filtering and optics required to implement an ILIS-based FIB. It is found that 20% of the ion beam results from fragmentation events, and that the neutral population is concentrated at the center of the beam.
First-principles calculations and XPS measurements of gold segregation at the Cu3Au(111) surface
Authors: Dionízio Moreira Marcos , Fontes Giselle N. , Niehus Horst , Achete Carlos A. , Capaz Rodrigo B.
Published: August 2012

A combination of first-principles calculations based on density-functional theory, pseudopotentials, and x-ray photoelectron spectroscopy (XPS) measurements is used in order to study Au segregation in Cu3Au(111) surfaces. Our theoretical results suggest Au compositions from 50% to 75% in the topmost layer, depending on the chemical potentials of the atomic species. This strong Au segregation is restricted to the topmost surface plane and it is supported by the XPS measurements in a semiquantitative manner.
Seasonal presence of cetaceans and ambient noise levels in polar waters of the North Atlantic
Authors: Klinck Holger , Nieukirk Sharon L. , Mellinger David K. , Klinck Karolin , Matsumoto Haruyoshi , Dziak Robert P.
Published: August 2012

In 2009 two calibrated acoustic recorders were deployed in polar waters of the North Atlantic to study the seasonal occurrence of blue, fin, and sperm whales and to assess current ambient noise levels. Sounds from these cetaceans were recorded at both locations in most months of the year. During the summer months, seismic airguns associated with oil and gas exploration were audible for weeks at a time and dominated low frequency noise levels. Noise levels might further increase in the future as the receding sea ice enables extended human use of the area.
Adaptive Sleep Loss in Polygynous Pectoral Sandpipers
Authors: Lesku John A. , Rattenborg Niels C. , Valcu Mihai , Vyssotski Alexei L. , Kuhn Sylvia , Kuemmeth Franz , Heidrich Wolfgang , Kempenaers Bart
Published: August 2012

You Snooze, You Lose

Sleep serves restorative and memory functions, but it does not always operate analogously across species. Deferral of sleep may be possible when selection strongly favors the awake.

Lesku
et al.

(p.
1654
; see the Perspective by

Siegel

) show that sleep may be deferred without cost or impairment in pectoral sandpipers. These birds breed collectively in the high Arctic, and male competition is intense. Competing for, and displaying to, females are both physically and cognitively demanding, yet birds who slept the least showed no decrease in their ability to perform these activities. Indeed, those males who slept the least obtained the most matings and sired the most offspring.
Nucleolar Localization of a Netrin-1 Isoform Enhances Tumor Cell Proliferation
Authors: Delloye-Bourgeois Céline , Goldschneider David , Paradisi Andrea , Therizols Gabriel , Belin Stéphane , Hacot Sabine , Rosa-Calatrava Manuel , Scoazec Jean-Yves , Diaz Jean-Jacques , Bernet Agnès , Mehlen Patrick
Published: August 2012

A nuclear-localized isoform of netrin may enhance ribosome biogenesis to promote cancer growth.
Science Signaling
Podcast: 7 August 2012
Authors: Ward Christopher W. , Khairallah Ramzi J. , Hoffman Eric P. , VanHook Annalisa M.
Published: August 2012

Drugs that reduce microtubule density or prevent the production of reactive oxygen species in skeletal muscle might slow the progression of Duchenne muscular dystrophy.
Is Winter Past?
Authors: Hines Pamela J.
Published: August 2012

Arabidopsis
adjusts the onset of flowering to the length of winters via an epigenetic mechanism.
SIRT-ain to Become Brown Fat
Authors: Wong Wei
Published: August 2012

SIRT-1–mediated deacetylation promotes the ability of PPARγ to induce the browning of white adipose tissue.
In Vitro
and
In Vivo
Activities of the Novel Ketolide RBx 14255 against Clostridium difficile
Authors: Kumar Manoj , Mathur Tarun , Barman Tarani K. , Ramkumar G. , Bhati Ashish , Shukla Gunjan , Kalia Vandana , Pandya Manisha , Raj V. Samuel , Upadhyay Dilip J. , Vaishnavi Chetana , Chakrabarti Anjan , Das Biswajit , Bhatnagar Pradip K.
Published: August 2012

The MIC
90
of RBx 14255, a novel ketolide, against
Clostridium difficile
was 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An
in vitro
time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for
C. difficile
. Furthermore, in the hamster model of
C. difficile
infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for
C. difficile
treatment.
In Vitro
Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New
In Vitro
Dynamic Model
Authors: Al-Saigh R. , Elefanti A. , Velegraki A. , Zerva L. , Meletiadis J.
Published: August 2012

The pharmacodynamics (PD) of voriconazole activity against
Aspergillus
spp. were studied using a new
in vitro
dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three
Aspergillus
clinical isolates (1
A. fumigatus
, 1
A. flavus
, and 1
A. terreus
isolate) with CLSI MICs of 0.5 mg/liter were tested in an
in vitro
model simulating voriconazole PK in human plasma with
C
max
values of 7, 3.5, and 1.75 mg/liter and a
t
1/2
of 6 h. The area under the galactomannan index-time curve (AUC
GI
) was used as the PD parameter.
In vitro
PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The
in vitro
PK-PD relationship of
f
AUC
0-24
-AUC
GI
followed a sigmoid pattern (global
R
2
= 0.97), with near-maximum activities (10% fungal growth) observed at an
f
AUC
0-24
(95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against
A. fumigatus
, 26.6 (21.1 to 32.9) mg · h/liter against
A. flavus
, and 36.2 (27.8 to 45.7) mg · h/liter against
A. terreus
(F test;
P
< 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for
A. fumigatus
, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for
A. flavus
, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for
A. terreus
. Based on the
in vitro
exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with
A. fumigatus
but not
A. flavus
and
A. terreus
infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage.
Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience
Authors: Nikanjam Mina , Kabamba Desiré , Cressey Tim R. , Burger David , Aweeka Francesca T. , Acosta Edward P. , Spector Stephen A. , Capparelli Edmund V.
Published: August 2012

Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings.
The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans
Authors: Duan Jianmin , Bolger Gordon , Garneau Michel , Amad Ma'an , Batonga Joëlle , Montpetit Hélène , Otis François , Jutras Martin , Lapeyre Nicole , Rhéaume Manon , Kukolj George , White Peter W. , Bethell Richard C. , Cordingley Michael G.
Published: August 2012

Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kpliver) were calculated from liver to plasma exposure ratios.In vitrohepatocyte partition coefficients (Kphep) were determined by the ratio of cellular to medium drug concentrations. Human Kpliverwas predicted using anin vitro-in vivoproportionality method: the species-averaged animal Kplivermultiplied by the ratio of human Kphepover those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kpliver. Our results demonstrated that thein vitro-in vivoproportionality approach provided the best human Kpliverprediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r2of 0.48) with maximum viral load reduction and led to a corresponding 50% effective dose (ED50) IQ of 42, with a 95% confidence interval (CI) of 0.1 to 148534. In contrast, the LCIQ-maximum VLR relationship fit into a typical sigmoidal curve with anr2value of 0.95 and an ED50LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kpliverprediction model, and the LCIQ correlated well with the viral load reductions observed in short-term HCV monotherapy of different DAAs and provides a valuable tool to guide HCV drug discovery.
γ-Glutamyl Spermine Synthetase PauA2 as a Potential Target of Antibiotic Development against Pseudomonas aeruginosa
Authors: Yao Xiangyu , Li Congran , Zhang Jianmei , Lu Chung-Dar
Published: August 2012

Polyamines are absolute requirements for cell growth. When in excess,
Pseudomonas aeruginosa
possesses six γ-glutamylpolyamine synthetases (GPSs) encoded by the
pauA1-pauA7
genes to initiate polyamine catabolism. Recently, the
pauA2
mutant was reported to lose the capability to grow on spermine (Spm) and spermidine (Spd) as sole carbon and nitrogen sources. Although this mutant grew normally in defined minimal medium and LB broth, growth was completely abolished by the addition of Spm or Spd. These two compounds exert a bactericidal effect (Spm > Spd) on the mutants as demonstrated by MIC measurements (over 500-fold reduction) and time-killing curves. Spm toxicity in the
pauA2
mutant was attenuated when the major uptake system was further deleted from the strain, suggesting cytoplasmic targets of toxicity. In addition, the synergistic effect of Spm and carbenicillin in the wild-type strain PAO1 was diminished in mutants without functional PauA2. Furthermore, Spm MIC was reduced by 8-fold when the Spm uptake system was deleted from the wild-type strain, suggesting a second target of Spm toxicity in the periplasm. Experiments were also conducted to test the hypothesis that native Spm and Spd in human serum may be sufficient to kill the
pauA2
mutant. Growth of the mutant was completely inhibited by 40% (vol/vol) human serum, whereas the parental strain required 80%. Colony counts indicated that the mutant but not the parent was in fact killed by human plasma. In addition, carbenicillin MIC against the mutant was reduced by 16-fold in the presence of 20% human serum while that of the parental strain remained unchanged. Taking PauA2 as the template, sequence comparison indicates that putative PauA2 homologues are widespread in a variety of Gram-negative bacteria. In summary, this study reveals the importance of GPS in alleviation of polyamine toxicity when in excess, and it provides strong support to the feasibility of GPS as a molecular target for new antibiotic development.
Isolation and Quantitation of Topoisomerase Complexes Accumulated on Escherichia coli Chromosomal DNA
Authors: Aedo Sandra , Tse-Dinh Yuk-Ching
Published: August 2012

DNA topoisomerases are important targets in anticancer and antibacterial therapy because drugs can initiate cell death by stabilizing the transient covalent topoisomerase-DNA complex. In this study, we employed a method that uses CsCl density gradient centrifugation to separate unbound from DNA-bound GyrA/ParC in
Escherichia coli
cell lysates after quinolone treatment, allowing antibody detection and quantitation of the covalent complexes on slot blots. Using these procedures modified from the
in vivo
complexes of enzyme (ICE) bioassay, we found a correlation between gyrase-DNA complex formation and DNA replication inhibition at bacteriostatic (1× MIC) norfloxacin concentrations. Quantitation of the number of gyrase-DNA complexes per
E. coli
cell permitted an association between cell death and chromosomal gyrase-DNA complex accumulation at norfloxacin concentrations greater than 1× MIC. When comparing levels of gyrase-DNA complexes to topoisomerase IV-DNA complexes in the absence of drug, we observed that the gyrase-DNA complex level was higher (∼150-fold) than that of the topoisomerase IV-DNA complex. In addition, levels of gyrase and topoisomerase IV complexes reached a significant increase after 30 min of treatment at 1× and 1.7× MIC, respectively. These results are in agreement with gyrase being the primary target for quinolones in
E. coli
. We further validated the utility of this method for the study of topoisomerase-drug interactions in bacteria by showing the gyrase covalent complex reversibility after removal of the drug from the medium, and the resistant effect of the Ser83Leu
gyrA
mutation on accumulation of gyrase covalent complexes on chromosomal DNA.
DNA Microarray Profiling of a Diverse Collection of Nosocomial Methicillin-Resistant Staphylococcus aureus Isolates Assigns the Majority to the Correct Sequence Type and Staphylococcal Cassette Chromosome
mec
(SCC
mec
) Type and Results in the Subsequent Identification and Characterization of Novel SCC
mec
-SCC
M1
Composite Islands
Authors: Shore Anna C. , Brennan Orla M. , Deasy Emily C. , Rossney Angela S. , Kinnevey Peter M. , Ehricht Ralf , Monecke Stefan , Coleman David C.
Published: August 2012

One hundred seventy-five isolates representative of methicillin-resistant
Staphylococcus aureus
(MRSA) clones that predominated in Irish hospitals between 1971 and 2004 and that previously underwent multilocus sequence typing (MLST) and staphylococcal cassette chromosome
mec
(SCC
mec
) typing were characterized by
spa
typing (175 isolates) and DNA microarray profiling (107 isolates). The isolates belonged to 26 sequence type (ST)-SCC
mec
types and subtypes and 35
spa
types. The array assigned all isolates to the correct MLST clonal complex (CC), and 94% (100/107) were assigned an ST, with 98% (98/100) correlating with MLST. The array assigned all isolates to the correct SCC
mec
type, but subtyping of only some SCC
mec
elements was possible. Additional SCC
mec/
SCC genes or DNA sequence variation not detected by SCC
mec
typing was detected by array profiling, including the SCC-fusidic acid resistance determinant Q6GD50/
fusC
. Novel SCC
mec
/SCC composite islands (CIs) were detected among CC8 isolates and comprised SCC
mec
IIA-IIE, IVE, IVF, or IVg and a
ccrAB4
-SCC element with 99% DNA sequence identity to SCC
M1
from ST8/t024-MRSA, SCC
mec
VIII, and SCC-CI in
Staphylococcus epidermidis
. The array showed that the majority of isolates harbored one or more superantigen (94%; 100/107) and immune evasion cluster (91%; 97/107) genes. Apart from fusidic acid and trimethoprim resistance, the correlation between isolate antimicrobial resistance phenotype and the presence of specific resistance genes was ≥97%. Array profiling allowed high-throughput, accurate assignment of MRSA to CCs/STs and SCC
mec
types and provided further evidence of the diversity of SCC
mec
/SCC. In most cases, array profiling can accurately predict the resistance phenotype of an isolate.
Efficient Replication of Genotype 3a and 4a Hepatitis C Virus Replicons in Human Hepatoma Cells
Authors: Saeed Mohsan , Scheel Troels K. H. , Gottwein Judith M. , Marukian Svetlana , Dustin Lynn B. , Bukh Jens , Rice Charles M.
Published: August 2012

Despite recent advances in the treatment of hepatitis C, the quest for pan-genotype, effective, and well-tolerated inhibitors continues. To facilitate these efforts, it is desirable to have
in vitro
replication systems for all major HCV genotypes. However, cell culture replication systems exist for only genotypes 1a, 1b, and 2a. In this study, we generated G418-selectable subgenomic replicons for prototype strains of genotypes 3a (S52) and 4a (ED43). Production of G418-resistant colonies by S52 and ED43 in Huh-7.5 cells required the amino acid substitutions S2210I and R2882G, respectively, cell culture adaptive mutations originally reported for genotype 1b replicons. RNA replication was confirmed by quantitative reverse transcription-PCR and detection of viral protein. Sequencing of multiple independent replicon clones revealed the presence of additional nonsynonymous mutations. Interestingly, all potentially adaptive mutations mapped to the NS3 protein. These mutations, when introduced back into original constructs, substantially increased colony formation efficiency. To make these replicons useful for high-throughput screening and evaluation of antiviral compounds, they were modified to express a chimeric fusion protein of firefly luciferase and neomycin phosphotransferase to yield stable replicon-expressing cells. Using these constructs, the inhibitory effects of beta interferon (IFN-β), an NS3 protease inhibitor, and an NS5B nucleoside polymerase inhibitor were readily detected by monitoring luciferase activity. In conclusion, we have established functional replicons for HCV genotypes 3a and 4a, important new additions to the armamentarium required to develop inhibitors with a pan-genotype activity.
Hemophagocytic Macrophages in Murine Typhoid Fever Have an Anti-Inflammatory Phenotype
Authors: McCoy Melissa W. , Moreland Sarah M. , Detweiler Corrella S.
Published: August 2012

Histiocytes are white blood cells of the monocytic lineage and include macrophages and dendritic cells. In patients with a variety of infectious and noninfectious inflammatory disorders, histiocytes can engulf nonapoptotic leukocytes and nonsenescent erythrocytes and thus become hemophagocytes. We report here the identification and characterization of splenic hemophagocytes in a natural model of murine typhoid fever. The development of a flow-cytometric method allowed us to identify hemophagocytes based on their greater than 6N (termed 6N+) DNA content. Characterization of the 6N+ population from infected mice showed that these cells consist primarily of macrophages rather than dendritic cells and contain T lymphocytes, consistent with hemophagocytosis. Most 6N+ macrophages fromSalmonella entericaserovar Typhimurium-infected mice contain intact DNA, consistent with hemophagocytosis. In contrast, most 6N+ macrophages from control mice or mice infected with a different bacterial pathogen,Yersinia pseudotuberculosis, contain damaged DNA. Finally, 6N+ splenic macrophages fromS. Typhimurium-infected mice express markers consistent with an anti-inflammatory M2 activation state rather than a classical M1 activation state. We conclude that macrophages are the predominant splenic hemophagocyte in this disease model but not inY. pseudotuberculosis-infected mice. The anti-inflammatory phenotype of hemophagocytic macrophages suggests that these cells contribute to the shift from acute to chronic infection.