bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanics-Based Interactive Modeling for Medical Flexible Needle Insertion in Consideration of Nonlinear Factors
Authors: Jiang Shan , Wang Xingji
Published: June 2015

A mechanics-based model of flexible needle insertion into soft tissue is presented in this paper. Different from the existing kinematic model, a new model has been established based on the quasi-static principle, which also incorporates the dynamics of needle motions. In order to increase the accuracy of the model, nonlinear characteristics of the flexible needle and the soft tissue are both taken into account. The nonlinear Winkler foundation model and the modified Euler–Bernoulli theory are applied in this study, providing a theoretical framework to study insertion and deformation of needles. Galerkin method and iteration cycle analysis are applied in solving a series of deformation control equations to obtain the needle deflection. The parameters used in the mechanics-based model are obtained from the needle force and needle insertion experiment. Sensitivity studies show that the model can respond reasonably to changes in response to variations in different parameters. A 50 mm needle insertion simulation and a 50 mm corresponding needle insertion experiment are conducted to prove the validity of the model. At last, a study on different needle tip bevel demonstrates that the mechanics-based model can precisely predict the needle deflection when more than one parameter is changed. The solution can also be used in optimizing trajectory of the needle tip, enabling the needle to reach the target without touching important physiological structures such as blood vessels with the help of dynamic trajectory planning.
Peg-in-Hole Revisited: A Generic Force Model for Haptic Assembly
Authors: Behandish Morad , Ilieş Horea T.
Published: June 2015

The development of a generic and effective force model for semi-automatic or manual virtual assembly with haptic support is not a trivial task, especially when the assembly constraints involve complex features of arbitrary shape. The primary challenge lies in a proper formulation of the guidance forces and torques that effectively assist the user in the exploration of the virtual environment (VE), from repulsing collisions to attracting proper contact. The secondary difficulty is that of efficient implementation that maintains the standard 1 kHz haptic refresh rate. We propose a purely geometric model for an artificial energy field that favors spatial relations leading to proper assembly, differentiated to obtain forces and torques for general motions. The energy function is expressed in terms of a cross-correlation of shape-dependent affinity fields, precomputed offline separately for each object. We test the effectiveness of the method using familiar peg-in-hole examples. We show that the proposed technique unifies the two phases of free motion and precise insertion into a single interaction mode and provides a generic model to replace the ad hoc mating constraints or virtual fixtures, with no restrictive assumption on the types of the involved assembly features.
Evaluation of Lubricants for Stamping of Al 5182-O Aluminum Sheet Using Cup Drawing Test
Authors: Ju Long , Mao Tingting , Malpica Julio , Altan Taylan
Published: June 2015

Lubricants are necessary to avoid adhesion, galling, and scratching in aluminum stamping processes. In this study, various lubricants, including dry lubes and wet lubes, were evaluated using cup drawing test (CDT) for stamping of Al 5182-O aluminum sheets. The effects of surface texturing, with electro-discharge texturing (EDT) and mill finish (MF), on the friction behavior were also investigated. Furthermore, the methodology to evaluate the performance of lubricants was established based on (a) maximum applicable blank holder force (BHF) and (b) draw-in length in flange or flange perimeter of formed cups. Finite element (FE) simulations were carried out to determine the coefficient of friction (CoF) at tool–workpiece interface during deep drawing under different lubrication conditions. Flow stress data of Al 5182-O material were obtained using viscous pressure bulge (VPB) and tensile tests. In this study, it was confirmed that, in forming Al 5182-O, dry film lubricants have better lubricity than wet lubricants. A better lubrication condition was found with EDT surface texture.
Learning Approach to Cycle-Time-Minimization of Wood Milling Using Adaptive Force Control
Authors: Sörnmo Olof , Olofsson Björn , Robertsson Anders , Johansson Rolf
Published: June 2015

A majority of the machining processes in the industry of today are performed using position-controlled machine tools, where conservative feed rates have to be used in order to avoid excessive process forces. Instead of controlling the process forces, the feed rate, and consequently the material removal rate, can be maximized. In turn, this leads to decreased cycle times and cost savings. Furthermore, path planning with respect to time-minimization for milling processes, especially in nonisotropic materials, is not straightforward. This paper presents a model-based adaptive force controller that achieves optimal feed rates, in combination with a learning algorithm to obtain the optimal machining path, in terms of minimizing the milling duration. The proposed solution is evaluated in both simulation and experiments, where an industrial robot is used to perform rough-cut wood milling. Cycle-time reductions of 14% using force control compared to position control were achieved and on average an additional 28% cycle-time reduction with the proposed learning algorithm.
Modified Shallow Water Equations With Application for Horizontal Centrifugal Casting of Rolls
Authors: Kharicha Abdellah , Bohacek Jan , Ludwig Andreas , Wu Menghuai
Published: June 2015

A numerical model based on the shallow water equations (SWE) was proposed to simulate the two-dimensional (2D) average flow dynamics of the liquid metal spreading inside a horizontally rotating mold. The SWE were modified to account for the forces, such as the centrifugal force, Coriolis force, shear force with the mold wall, and gravity. In addition, inherent vibrations caused by a poor roundness of the mold and the mold deformation due to temperature gradients were applied explicitly by perturbing the gravity and the axis bending, respectively. Several cases were studied with the following initial conditions: a constant average height of the liquid metal (5, 10, 20, 30, and 40 mm) patched as a flat or a perturbed surface. The angular frequency Ω of the mold (∅1150–3200) was 71.2 (or 30) rad/s. Results showed various wave patterns propagating on the free surface. In early stages, a single longitudinal wave moved around the circumference. As the time proceeded, it slowly diminished and waves traveled mainly in the axial direction. It was found that the mean amplitude of the oscillations grows with the increasing liquid height.
A Model Constraint for Polydisperse Solids in Multifluid Flows
Authors: Kinzel Michael P. , Peltier Leonard Joel , Rosendall Brigette , Elbert Mallory , Rizhakov Andri , Berkoe Jonathan , Knight Kelly
Published: June 2015

A method to assess computational fluid dynamics (CFD) models for polydisperse granular solids in a multifluid flow is developed. The proposed method evaluates a consistency constraint, or a condition that an Eulerian multiphase solution for a monodisperse material in a single carrier fluid is invariant to an arbitrary decomposition into a pseudo-polydisperse mixture of multiple, identical fluid phases. The intent of this condition is to develop tests to assist model development and testing for multiphase fluid flows. When applied to two common momentum exchange models, the constraint highlights model failures for polydisperse solids interacting with a multifluid flow. It is found that when inconsistency occurs at the algebraic level, model failure clearly extends to application. When the models are reformulated to satisfy the consistency constraint, simple tests and application-scale simulations no longer display consistency failure.
A Pediatric Perspective on Sport-Related Concussion
Authors: McLeod Tamara C. Valovich , Houston Megan N. , Welch Cailee E.
Published: June 2015

Concussions resulting from sports and recreational activities are a significant concern in the pediatric population. The number of children and adolescents sustaining sport-related concussions is increasing and, as a result, legislation has been passed in all 50 states to ensure appropriate recognition and referral of pediatric athletes following concussion. The developing brain may make the diagnosis, assessment, and management of concussion more challenging for health care providers and requires the use of specific age-appropriate assessment tools. Concussion management must also include considerations for cognitive and physical rest, a collaborative concussion management team that includes medical and school personnel, and more conservative stepwise progressions for returning to school and to physical activity.
Determining the Appropriate Model for Concussion Health Care in the College or University Setting
Authors: Thompson Charles R.
Published: June 2015

The incidence of concussions and potential for long-term health effects has captured the attention of the media, general public, medical professionals, parents, and obviously the athletes themselves. Concussions have been blamed for a variety of mental and physical health issues. The athletic trainer is at the forefront of the concussion management team, as they are typically on the scene when the concussion occurs and are often the first medical personnel to evaluate and, hopefully, remove the athlete from activity. There has been controversy of late regarding the influence of coaches in the care of concussed athletes. Therefore, a move to the “medical model” of sports medicine management can go a long way in resolving conflict of interest issues regarding the care of concussed athletes. A comprehensive concussion team and protocol are also essential to providing the highest level of care. This article takes a closer look at concussion management in the collegiate arena, with a particular focus on Princeton University.
Clinical Management of Sport-Related Concussion: Developing a Roadmap to a Successful Outcome
Authors: Guskiewicz Kevin , Teel Elizabeth
Published: June 2015

In order to promote the most successful outcomes following concussion, a multifaceted team of individuals is required for appropriate injury diagnosis and management. This review explores the primary roles of sports medicine personnel in the concussion diagnosis and management process. We will discuss the psychometric properties, including sensitivity, specificity, and clinical utility, of on-field/sideline, laboratory, and neurophysiological assessment tools. Additionally, we will discuss the roles of other kinesiology experts in concussion management and recovery, and their importance to concussion research. By developing a thorough and consistent roadmap for concussion management, clinicians and researchers will be capable of providing athletes with the most successful outcomes.
Tuning friction atom-by-atom in an ion-crystal simulator
Authors: Bylinskii Alexei , Gangloff Dorian , Vuletić Vladan
Published: June 2015

A frigid simulator for friction

Friction can be a friend or a foe, depending on whether we are trying to brake on a slippery road or to protect moving parts in industrial equipment. It results from the forces between atoms on the two surfaces in contact, but the details of the process are not well understood. Bylinskii
et al.
constructed a tunable friction simulator out of a handful of cold trapped ions that move in the potential of an optical lattice (see the Perspective by Meyer). They could vary the friction force experienced by the ions from maximal to nearly zero simply by changing the spatial arrangement of the ion array with respect to the optical lattice.

Science
, this issue p.
1115
; see also p.
1089
Making contact
Authors: Lawler Andrew
Published: June 2015

Some of the last isolated tribes are emerging from Peru's rainforests.
In peril
Authors: Pringle Heather
Published: June 2015

As contacts spike, critics fear that Brazil's once-vaunted protection of isolated tribes is crumbling.
Targeting DnaN for tuberculosis therapy using novel griselimycins
Authors: Kling Angela , Lukat Peer , Almeida Deepak V. , Bauer Armin , Fontaine Evelyne , Sordello Sylvie , Zaburannyi Nestor , Herrmann Jennifer , Wenzel Silke C. , König Claudia , Ammerman Nicole C. , Barrio María Belén , Borchers Kai , Bordon-Pallier Florence , Brönstrup Mark , Courtemanche Gilles , Gerlitz Martin , Geslin Michel , Hammann Peter , Heinz Dirk W. , Hoffmann Holger , Klieber Sylvie , Kohlmann Markus , Kurz Michael , Lair Christine , Matter Hans , Nuermberger Eric , Tyagi Sandeep , Fraisse Laurent , Grosset Jacques H. , Lagrange Sophie , Müller Rolf
Published: June 2015

New for old—TB drug development

Tuberculosis (TB) is a global health threat for which there is only lengthy drug treatment. Patients need to consume multiple tablets over several months and frequently fail to complete their treatment. Consequently, drug-resistant strains of the pathogen have emerged, which add to the threat. Kling
et al.
revisited a natural product called griselimycin, extracted from the same organism that produced the prototype anti-TB drug, streptomycin. Unmodified griselimycin has poor pharmacological properties. However, one synthetic derivative had improved oral uptake and penetrated cells of the immune system that harbor the TB mycobacterium. In combination with other drugs, the griselimycin derivative showed high potency in mice with TB.

Science
, this issue p.
1106
Comment on “Human-like hand use in
Australopithecus africanus
”
Authors: Almécija Sergio , Wallace Ian J. , Judex Stefan , Alba David M. , Moyà-Solà Salvador
Published: June 2015

Skinner and colleagues (Research Article, 23 January 2015, p. 395), based on metacarpal trabecular bone structure, argue that
Australopithecus africanus
employed human-like dexterity for stone tool making and use 3 million years ago. However, their evolutionary and biological assumptions are misinformed, failing to refute the previously existing hypothesis that human-like manipulation preceded systematized stone tool manufacture, as indicated by the fossil record.
Irrational actors
Misbehaving The Making of Behavioral Economics
Richard H. Thaler
Norton, 2015. 431 pp.
Authors: Oswald Andrew J.
Published: June 2015

Embracing the mystifying choices that flummox the field of economics
Cytokine Profiles from Antigen-Stimulated Whole-Blood Samples among Patients with Pulmonary or Nonmeningeal Disseminated Coccidioidomycosis
Authors: Ampel Neil M. , Nesbit Lance A. , Nguyen Chinh T. , Chavez Suzette , Knox Kenneth S. , Johnson Suzanne M. , Pappagianis Demosthenes
Published: June 2015

The outcome of coccidioidomycosis depends on a robust specific cellular immune response. A T-helper type 1 (Th1) cellular immune response has been previously associated with resolution of clinical illness. However, the precise elements of this response and whether cytokines not involved with the Th1 response play a role in coccidioidomycosis are not known. Whole-blood samples were obtained from subjects with active coccidioidomycosis and controls and incubated for 18 h with T27K, a coccidioidal antigen preparation. The supernatant was then assayed for gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, IL-10, and IL-17A. A total of 43 subjects, 16 with acute pneumonia, 9 with pulmonary sequelae of nodules and cavities, and 18 with nonmeningeal disseminated coccidioidomycosis, were studied. Compared to concentrations in healthy immune and nonimmune donors, the median concentration of IL-17A was significantly higher in those with active coccidioidomycosis (for both,
P
< 0.01). In addition, IL-6 concentrations were higher while IL-2 and IFN-γ concentrations were significantly lower in those with nonmeningeal disseminated disease diagnosed within 12 months than in those with acute pneumonia (for all,
P
< 0.05). The cytokine profile among patients with active coccidioidomycosis is distinct in that IL-17A is persistently present. In addition, those with nonmeningeal disseminated disease have an increased inflammatory cytokine response and diminished Th1 responses that modulate over time.
Performance of a Noninvasive Test for Detecting Mycobacterium bovis Shedding in European Badger (Meles meles) Populations
Authors: King Hayley C. , Murphy Andrew , James Phillip , Travis Emma , Porter David , Sawyer Jason , Cork Jennifer , Delahay Richard J. , Gaze William , Courtenay Orin , Wellington Elizabeth M.
Published: June 2015

The incidence of
Mycobacterium bovis
, the causative agent of bovine tuberculosis, in cattle herds in the United Kingdom is increasing, resulting in substantial economic losses. The European badger (
Meles meles
) is implicated as a wildlife reservoir and is the subject of control measures aimed at reducing the incidence of infection in cattle populations. Understanding the epidemiology of
M. bovis
in badger populations is essential for directing control interventions and understanding disease spread; however, accurate diagnosis in live animals is challenging and currently uses invasive methods. Here we present a noninvasive diagnostic procedure and sampling regimen using field sampling of latrines and detection of
M. bovis
with quantitative PCR tests, the results of which strongly correlate with the results of immunoassays in the field at the social group level. This method allows
M. bovis
infections in badger populations to be monitored without trapping and provides additional information on the quantities of bacterial DNA shed. Therefore, our approach may provide valuable insights into the epidemiology of bovine tuberculosis in badger populations and inform disease control interventions.
Assessment of African Swine Fever Diagnostic Techniques as a Response to the Epidemic Outbreaks in Eastern European Union Countries: How To Improve Surveillance and Control Programs
Authors: Gallardo C. , Nieto R. , Soler A. , Pelayo V. , Fernández-Pinero J. , Markowska-Daniel I. , Pridotkas G. , Nurmoja I. , Granta R. , Simón A. , Pérez C. , Martín E. , Fernández-Pacheco P. , Arias M.
Published: June 2015

This study represents a complete comparative analysis of the most widely used African swine fever (ASF) diagnostic techniques in the European Union (EU) using field and experimental samples from animals infected with genotype II ASF virus (ASFV) isolates circulating in Europe. To detect ASFV, three different PCRs were evaluated in parallel using 785 field and experimental samples. The results showed almost perfect agreement between the Universal ProbeLibrary (UPL-PCR) and the real-time (κ = 0.94 [95% confidence interval {CI}, 0.91 to 0.97]) and conventional (κ = 0.88 [95% CI, 0.83 to 0.92]) World Organisation for Animal Health (OIE)-prescribed PCRs. The UPL-PCR had greater diagnostic sensitivity for detecting survivors and allows earlier detection of the disease. Compared to the commercial antigen enzyme-linked immunosorbent assay (ELISA), good-to-moderate agreement (κ = 0.67 [95% CI, 0.58 to 0.76]) was obtained, with a sensitivity of 77.2% in the commercial test. For ASF antibody detection, five serological methods were tested, including three commercial ELISAs, the OIE-ELISA, and the confirmatory immunoperoxidase test (IPT). Greater sensitivity was obtained with the IPT than with the ELISAs, since the IPT was able to detect ASF antibodies at an earlier point in the serological response, when few antibodies are present. The analysis of the exudate tissues from dead wild boars showed that IPT might be a useful serological tool for determining whether or not animals had been exposed to virus infection, regardless of whether antibodies were present. In conclusion, the UPL-PCR in combination with the IPT was the most trustworthy method for detecting ASF during the epidemic outbreaks affecting EU countries in 2014. The use of the most appropriate diagnostic tools is critical when implementing effective control programs.
Distinct Immune Responses in Resistant and Susceptible Strains of Mice during Neurovirulent Alphavirus Encephalomyelitis
Authors: Kulcsar Kirsten A. , Baxter Victoria K. , Abraham Rachy , Nelson Ashley , Griffin Diane E.
Published: June 2015

Susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. Neuroadapted Sindbis virus (NSV) causes uniformly fatal disease in adult C57BL/6 (B6) mice, but adult BALB/c (Bc) mice recover from infection. In B6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. To identify the immunological determinants of host susceptibility to fatal NSV-induced encephalomyelitis, we compared virus titers and immune responses in adult B6 and Bc mice infected intranasally with NSV. B6 mice had higher levels of virus replication, higher levels of type I interferon (IFN), and slower virus clearance than did Bc mice. B6 mice had more neuronal apoptosis, more severe neurologic disease, and higher mortality than Bc mice. B6 mice had more infiltration of inflammatory cells and higher levels ofIL1b,IL-6,TNFa,Csf2, andCCL2mRNAs and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IFN-γ, and C-C motif ligand 2 (CCL2) protein in brains than Bc mice. However, Bc mice had more brain antibody at day 7 and a higher percentage of CD4+T cells. CD4+T cells in the brains of Bc mice included fewer Th17 cells and more regulatory T cells (Tregs) producing IL-10 than B6 mice, accompanied by higher levels ofIl2andCxcl10mRNAs. In the absence of IL-10, resistant Bc mice became susceptible to fatal encephalomyelitis after NSV infection. These studies demonstrate the importance of the immune response and its regulation in determining host survival during alphavirus encephalomyelitis.

IMPORTANCEMosquito-borne alphavirus infections are an important cause of encephalomyelitis in humans. The severity of disease is dependent both on the strain of the virus and on the age and genetic background of the host. A neurovirulent strain of Sindbis virus causes immune-mediated fatal encephalomyelitis in adult C57BL/6 mice but not in BALB/c mice. To determine the host-dependent immunological mechanisms underlying the differences in susceptibility between these two strains of mice, we compared their immune responses to infection. Resistance to fatal disease in BALB/c mice was associated with better antibody responses, more-rapid virus clearance, fewer Th17 cells, and more-potent regulatory T cell responses than occurred in susceptible C57BL/6 mice. In the absence of interleukin-10, a component of the regulatory immune response, resistant mice became susceptible to lethal disease. This study demonstrates the importance of the immune response and its regulation for host survival during alphavirus encephalomyelitis.
New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A
Authors: Fénéant Lucie , Potel Julie , François Catherine , Sané Famara , Douam Florian , Belouzard Sandrine , Calland Noémie , Vausselin Thibaut , Rouillé Yves , Descamps Véronique , Baumert Thomas F. , Duverlie Gilles , Lavillette Dimitri , Hober Didier , Dubuisson Jean , Wychowski Czeslaw , Cocquerel Laurence
Published: June 2015

In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatitis C virus (HCV) life cycle. We showed that monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Using the selective pressure of monensin, we selected a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces an N-glycosylation site within HVR1 and increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (anti-ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In summary, we identified a mutation in HVR1 that overcomes the vesicular pH dependence, modifies the biophysical properties of particles, and drastically reduces cell-to-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH dependence of cell-free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation.

IMPORTANCE
Although several cell surface proteins have been identified as entry factors for hepatitis C virus (HCV), the precise mechanisms regulating its transmission to hepatic cells are still unclear. In our study, we used monensin A, an ionophore that is known to raise the intracellular pH, and demonstrated that cell-free and cell-to-cell transmission pathways are both pH-dependent processes. We generated monensin-resistant viruses that displayed different entry routes and biophysical properties. Thanks to these mutants, we highlighted the importance of hypervariable region 1 (HVR1) of the E2 envelope protein for the association of particles with apolipoprotein E, which in turn might control the pH dependency of cell-free and cell-to-cell transmission.
Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease
Authors: Lee Sungseok , Ives Angela M. , Bertke Andrea S.
Published: June 2015

Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in sensory and autonomic neurons after ocular or genital infection, but their recurrence patterns differ. HSV-1 reactivates from latency to cause recurrent orofacial disease, and while HSV-1 also causes genital lesions, HSV-2 recurs more efficiently in the genital region and rarely causes ocular disease. The mechanisms regulating these anatomical preferences are unclear. To determine whether differences in latent infection and reactivation in autonomic ganglia contribute to differences in HSV-1 and HSV-2 anatomical preferences for recurrent disease, we compared HSV-1 and HSV-2 clinical disease, acute and latent viral loads, and viral gene expression in sensory trigeminal and autonomic superior cervical and ciliary ganglia in a guinea pig ocular infection model. HSV-2 produced more severe acute disease, correlating with higher viral DNA loads in sensory and autonomic ganglia, as well as higher levels of thymidine kinase expression, a marker of productive infection, in autonomic ganglia. HSV-1 reactivated in ciliary ganglia, independently from trigeminal ganglia, to cause more frequent recurrent symptoms, while HSV-2 replicated simultaneously in autonomic and sensory ganglia to cause more persistent disease. While both HSV-1 and HSV-2 expressed the latency-associated transcript (LAT) in the trigeminal and superior cervical ganglia, only HSV-1 expressed LAT in ciliary ganglia, suggesting that HSV-2 is not reactivation competent or does not fully establish latency in ciliary ganglia. Thus, differences in replication and viral gene expression in autonomic ganglia may contribute to differences in HSV-1 and HSV-2 acute and recurrent clinical disease.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) and HSV-2 establish latent infections, from which the viruses reactivate to cause recurrent disease throughout the life of the host. However, the viruses exhibit different manifestations and frequencies of recurrent disease. HSV-1 and HSV-2 establish latency in both sensory and autonomic ganglia. Autonomic ganglia are more responsive than sensory ganglia to stimuli associated with recurrent disease in humans, such as stress and hormone fluctuations, suggesting that autonomic ganglia may play an important role in recurrent disease. We show that HSV-1 can reactivate from autonomic ganglia, independently from sensory ganglia, to cause recurrent ocular disease. We found no evidence that HSV-2 could reactivate from autonomic ganglia independently from sensory ganglia after ocular infection, but HSV-2 did replicate in both ganglia simultaneously to cause persistent disease. Thus, viral replication and reactivation in autonomic ganglia contribute to different clinical disease manifestations of HSV-1 and HSV-2 after ocular infection.
Early Steps of Jaagsiekte Sheep Retrovirus-Mediated Cell Transformation Involve the Interaction between Env and the RALBP1 Cellular Protein
Authors: Monot Margaux , Erny Alexandra , Gineys Barbara , Desloire Sophie , Dolmazon Christine , Aublin-Gex Anne , Lotteau Vincent , Archer Fabienne , Leroux Caroline
Published: June 2015

Ovine pulmonary adenocarcinoma is a naturally occurring lung cancer in sheep induced by the Jaagsiekte sheep retrovirus (JSRV). Its envelope glycoprotein (Env) carries oncogenic properties, and its expression is sufficient to induce
in vitro
cell transformation and
in vivo
lung adenocarcinoma. The identification of cellular partners of the JSRV envelope remains crucial for deciphering mechanisms leading to cell transformation. We initially identified RALBP1 (
Ral
A
b
inding
p
rotein
1
; also known as RLIP76 or RIP), a cellular protein implicated in the
ras
pathway, as a partner of JSRV Env by yeast two-hybrid screening and confirmed formation of RALBP1/Env complexes in mammalian cells. Expression of the RALBP1 protein was repressed in tumoral lungs and in tumor-derived alveolar type II cells. Through its inhibition using specific small interfering RNA (siRNA), we showed that RALBP1 was involved in envelope-induced cell transformation and in modulation of the mTOR (mammalian target of rapamycin)/p70S6K pathway by the retroviral envelope.

IMPORTANCE
JSRV-induced lung adenocarcinoma is of importance for the sheep industry. While the envelope has been reported as the oncogenic determinant of the virus, the cellular proteins directly interacting with Env are still not known. Our report on the formation of RALBP/Env complexes and the role of this interaction in cell transformation opens up a new hypothesis for the dysregulation observed upon virus infection in sheep.
Poxvirus Protein MC132 from Molluscum Contagiosum Virus Inhibits NF-κB Activation by Targeting p65 for Degradation
Authors: Brady Gareth , Haas Darya A. , Farrell Paul J. , Pichlmair Andreas , Bowie Andrew G.
Published: June 2015

Molluscum contagiosum virus (MCV) is unique in being the only known extant, human-adapted poxvirus, yet to date, it is very poorly characterized in terms of host-pathogen interactions. MCV causes persistent skin lesions filled with live virus, but these are generally immunologically silent, suggesting the presence of potent inhibitors of human antiviral immunity and inflammation. Fewer than five MCV immunomodulatory genes have been characterized in detail, but it is likely that many more remain to be discovered given the density of such sequences in all well-characterized poxviruses. Following virus infection, NF-κB activation occurs in response to both pattern recognition receptor (PRR) signaling and cellular activation by virus-elicited proinflammatory cytokines, such as tumor necrosis factor (TNF). As such, NF-κB activation is required for virus detection, antiviral signaling, inflammation, and clearance of viral infection. Hence, we screened a library of MCV genes for effects on TNF-stimulated NF-κB activation. This revealed MC132, a unique protein with no orthologs in other poxviral genomes, as a novel inhibitor of NF-κB. Interestingly, MC132 also inhibited PRR- and virus-activated NF-κB, since MC132 interacted with the NF-κB subunit p65 and caused p65 degradation. Unbiased affinity purification to identify host targets of MC132 revealed that MC132 acted by targeting NF-κB p65 for ubiquitin-dependent proteasomal degradation by recruiting p65 to a host Cullin-5/Elongin B/Elongin C complex. These data reveal a novel mechanism for poxviral inhibition of human innate immunity and further clarify how the human-adapted poxvirus MCV can so effectively evade antiviral immunity to persist in skin lesions.

IMPORTANCE
How human cells detect and respond to viruses is incompletely understood, but great leaps in our understanding have been made by studying both the early innate immune response and the ways that viruses evade it. Poxviruses adapt to specific hosts over time by evolving elegantly precise inhibitors targeting the rate-limiting steps of immunity. These inhibitors reveal new features of the antiviral response while also offering potent new tools for approaching therapeutic intervention in autoimmunity. Molluscum contagiosum virus (MCV) is the only known extant poxvirus specifically adapted to human infection, yet it remains poorly characterized. In this study, we report the identification of the MCV protein MC132 as a potent inhibitor of NF-κB, an essential regulatory crux of innate immunity. Furthermore, identification of the mechanism of inhibition of NF-κB by MC132 reveals an elegant example of convergent evolution with human herpesviruses. This discovery greatly expands our understanding of how MCV so effectively evades human immunity.
Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection
Authors: Saunders Kevin O. , Wang Lingshu , Joyce M. Gordon , Yang Zhi-Yong , Balazs Alejandro B. , Cheng Cheng , Ko Sung-Youl , Kong Wing-Pui , Rudicell Rebecca S. , Georgiev Ivelin S. , Duan Lijie , Foulds Kathryn E. , Donaldson Mitzi , Xu Ling , Schmidt Stephen D. , Todd John-Paul , Baltimore David , Roederer Mario , Haase Ashley T. , Kwong Peter D. , Rao Srinivas S. , Mascola John R. , Nabel Gary J.
Published: June 2015

Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 μg/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled.

IMPORTANCE
Sustained interventions that can prevent HIV-1 infection are needed to halt the spread of the HIV-1 pandemic. The protective capacity of anti-HIV antibody gene therapy has been established in mouse models of HIV-1 infection but has not been established for primates. We show here a proof-of-concept that gene transfer of anti-HIV antibody genes can protect against infection by viruses that cause AIDS in primates when host immune responses are controlled.
Oomycete Interactions with Plants: Infection Strategies and Resistance Principles
Authors: Fawke Stuart , Doumane Mehdi , Schornack Sebastian
Published: June 2015

The Oomycota include many economically significant microbial pathogens of crop species. Understanding the mechanisms by which oomycetes infect plants and identifying methods to provide durable resistance are major research goals. Over the last few years, many elicitors that trigger plant immunity have been identified, as well as host genes that mediate susceptibility to oomycete pathogens. The mechanisms behind these processes have subsequently been investigated and many new discoveries made, marking a period of exciting research in the oomycete pathology field. This review provides an introduction to our current knowledge of the pathogenic mechanisms used by oomycetes, including elicitors and effectors, plus an overview of the major principles of host resistance: the established R gene hypothesis and the more recently defined susceptibility (S) gene model. Future directions for development of oomycete-resistant plants are discussed, along with ways that recent discoveries in the field of oomycete-plant interactions are generating novel means of studying how pathogen and symbiont colonizations overlap.
Effects of Electroacupuncture on Overactive Bladder Refractory to Anticholinergics: A Single-Blind Randomised Controlled Trial
Authors: Zhang Jie , Cheng Wei , Cai Mingming
Published: June 2015

Objective

To investigate the clinical effects and safety of electroacupuncture (EA) in the treatment of overactive bladder (OAB) refractory to first-line anticholinergic treatment.

Methods

Women diagnosed with OAB who were refractory to first-line anticholinergic treatment were referred for EA therapy. 50 women enrolled in this single-blind randomised controlled trial and were randomised 1:1 to EA or sham EA (SEA). The EA and SEA groups were treated with 30 sessions (5 sessions a week for 6 weeks), and each session lasted 30 min. OAB symptom scores (OABSS), King's Health Questionnaire scores (KHQ) and urodynamic parameters were used to assess treatment effects. Safety was also evaluated.

Results

45 women completed all aspects of the study (23 in the EA group and 22 in the SEA group). The OABSS and KHQ showed statistically significant improvements in the EA group compared with the SEA group after 6 weeks of treatment (p<0.05). There were no statistical differences in the maximum flow rate and postvoid residual (p>0.05), but there were statistical improvements in the first sensation of bladder filling, first urge to void and maximum cystometric capacity (p<0.05) in the EA group compared with the SEA group. No serious adverse events occurred in either group.

Conclusions

EA appears to be an effective, safe and minimally invasive treatment for women with OAB. Further studies with longer follow-up are needed to evaluate whether it could be a therapeutic option for OAB refractory to treatment with anticholinergics.
Thoracic outlet syndrome secondary to a mid-clavicle malunion
Authors: Beliaev Andrei M , Fougere Christopher
Published: June 2015

A 22-year-old man presented with a painful ‘clunking’ sensation in the right mid-clavicle, and pain and dysaesthesia along the medial aspect of his right arm and hand. Three months earlier, he had been involved in a vehicle accident and sustained a right clavicle fracture. He had a large step off of the right clavicle with a medialisation of the right shoulder. At 90° abduction in external rotation of both shoulders he developed pain, paraesthesia and disappearance of the right radial artery pulsation. CT of the right shoulder in the neutral position demonstrated the clavicle-to-first rib distance of 5.5 mm, MRI showed the clavicular bone callus had a mass effect with effacement of anterior fat adjacent to the brachial plexus cords. He was diagnosed with thoracic outlet syndrome and underwent a corrective right clavicle osteotomy with the use of an AcuMed superior clavicle plate.
Unusual association of keratoconus with situs inversus and micronystagmus
Authors: Jain Pooja , Agarwal Richa , Arora Ritu , Goyal Jawaharlal
Published: June 2015

Keratoconus is a bilateral non-inflammatory ectasia of the cornea and the presentation is usually as an isolated condition. A few ocular and a number of systemic associations have been described. Situs inversus of retinal vessels is a rare developmental anomaly due to anomalous insertion of optic stalk into the optic vesicle. In this case report, we describe an unusual association of keratoconus with situs inversus and micronystagmus in a young man. An additional feature, a blue dot cataract, was also present. To the best of our knowledge, such a conglomeration of multiple ocular features has not been described previously.
Ameloblastic fibro-odontoma
Authors: Gantala Ramlal , Gotoor Srikanth Goud , Kumar R Vijaya , Munisekhar MS
Published: June 2015

Ameloblastic fibro-odontoma is a slow growing, benign, expansile epithelial odontogenic tumour with odontogenic mesenchyme, accounting for 0.3–1.7% of jaw tumours, signifying its rarity. The WHO defines it as “a neoplasm composed of proliferating odontogenic epithelium in a cellular ectomesenchymal tissue with varying degrees of inductive changes and dental hard tissue formation”. We report a case of an 11-year-old girl who presented to the Department of Maxillo-Facial Medicine and Radiology for the evaluation of a swelling in the left posterior mandible. Her clinical chart and investigations unveiled it as ameloblastic fibro-odontoma. After a promising presurgical evaluation, the lesion was enucleated using an intraoral approach followed by osteoplasty. Osteogenesis was attained despite of any definitive techniques to promote bone regeneration. Immediate postoperative inter-maxillary fixation was performed to prevent pathological fractures for a period of 3 weeks. In an 8-month follow-up, no untoward complications were noticed.
Presumed latent ocular tuberculosis diagnosed with the positive quantiFERON–TB Gold In-Tube Test in a HLA-A29-positive patient
Authors: Rangel Carlos Mario , Atencia Cesar , Merayo-Lloves Jesus , Fernandez-Vega Sanz Alvaro
Published: June 2015

A 59-year-old Hispanic woman presented with a 3-year history of floaters associated with bilateral reduced visual acuity. Her best-corrected visual acuity (BCVA) was 20/40. Both anterior segments were without inflammation, but fundoscopy showed mild vitreous inflammation and multiple inflammatory choroidal lesions. Tests for inflammatory and infectious diseases were negative except for human leucocyte antigen A29. The patient was diagnosed with birdshot choroidoretinopathy, and treatment was initiated with cyclosporine A 2.5 mg/kg/day. One year after treatment, the patient reported systemic symptoms with no improvement in visual acuity. Fundus findings remained with vitreal inflammation. QuantiFERON-TB Gold In-Tube Test was positive, and a diagnosis of presumed latent ocular tuberculosis (TB) was made. We initiated anti-TB treatment for 9 months. At 6 months of anti-TB therapy, there was no active inflammation. The patient was followed for 2 years with no medications and no active inflammation. Her final BCVA was 20/25.
A long-term, observational cohort study on the safety of low-dose glucocorticoids in ankylosing spondylitis: adverse events and effects on bone mineral density, blood lipid and glucose levels and body mass index
Authors: Zhang Yu-Ping , Gong Yao , Zeng Qing Yu , Hou Zhi-Duo , Xiao Zheng-Yu
Published: June 2015

Objectives

This study aimed to investigate the risk of adverse events and effects on bone mineral density (BMD), blood lipid and glucose levels and body mass index (BMI) of low-dose glucocorticoid (GC) treatment in ankylosing spondylitis.

Design

We performed a retrospective, observational cohort study. Adverse effects were compared between GC users and non-GC users, and we analysed differences in the duration of GC exposure (no GC exposure, <6 months, 6 months to 2 years and >2 years).

Setting

Outpatient clinic in a tertiary general hospital in China, rheumatology follow-up visits over the past 30 years.

Participants

We included 830 patients with ankylosing spondylitis who were followed up for at least 6 months without a previous history or current complications of active gastrointestinal problems, hypertension, psychiatric or mental problems, diabetes mellitus, tuberculosis and hepatitis. The median follow-up time was 1.6 years (range 0.5–15 years, a total of 1801 patient-years).

Results

A total of 555 (66.9%) patients were treated with low-dose GCs, and the median cumulative duration of GC therapy was 1.3 years (range 0.1–8.5 years). Dermatological incidents, including acne, bruisability and cutaneous infections, were the most common adverse events, with a cumulative incidence rate of 5.4% (22.2 events per 1000 patient-years), followed by a puffy and rounded face (1.6%), symptoms of weight gain (1.1%) and serious infections (1.0%). The rates of all other types of adverse events were less than 1%. The GC groups (GC users and non-GC users) and the duration of GC therapy were not associated with the frequency of low BMD, dyslipidaemia, hyperglycaemia or obesity (p<0.05).

Conclusions

Adverse events during long-term treatment of low-dose GCs are limited. Low-dose GCs do not have an adverse effect on BMD, blood lipid and glucose levels and BMI.
Exploiting altered patterns of choline kinase-alpha expression on human prostate tissue to prognosticate prostate cancer
Authors: Challapalli Amarnath , Trousil Sebastian , Hazell Steve , Kozlowski Kasia , Gudi Mihir , Aboagye Eric O , Mangar Stephen
Published: June 2015

Aims

Malignant transformation results in overexpression of choline-kinase (CHK) and altered choline metabolism, which is potentially detectable by immunohistochemistry (IHC). We investigated the utility of CHK-alpha (CHKA) IHC as a complement to current diagnostic investigation of prostate cancer by analysing expression patterns in normal (no evidence of malignancy) and malignant human prostate tissue samples.

Methods

As an initial validation, paraffin-embedded prostatectomy specimen blocks with both normal and malignant prostate tissue were analysed for CHKA protein and mRNA expression by western blot and quantitative reverse transcriptase PCR (qRT-PCR), respectively. Subsequently, 100 paraffin-embedded malignant prostate tumour and 25 normal prostate cores were stained for both Ki67 (labelling-index: LI) and CHKA expression.

Results

The validity of CHKA-antibody was verified using CHKA-transfected cells and siRNA knockdown. Immunoblotting of tissues showed good resolution of CHKA protein in malignant prostate, verifying use of the antibody for IHC. There was minimal qRT-PCR detectable CHKA mRNA in normal tissue, and conversely high expression in malignant prostate tissues. IHC of normal prostate cores showed mild (intensity) CHKA expression in only 28% (7/25) of samples with no Ki67 expression. In contrast, CHKA was expressed in all malignant prostate cores along with characteristically low proliferation (median 2% Ki67-LI; range 1–17%). Stratification of survival according to CHK intensity showed a trend towards lower progression-free survival with CHK score of 3.

Conclusions

Increased expression of CHKA, detectable by IHC, is seen in malignant lesions. This relatively simple cost-effective technique (IHC) could complement current diagnostic procedures for prostate cancer and, therefore, warrants further investigation.