Anti-inflammatory IL-10 is upregulated in both hemispheres after experimental ischemic stroke: Hypertension blunts the response.
Exogenous administration of the anti-inflammatory cytokine, interleukin 10 (IL-10), is known to promote neuroprotection and mitigate neuroinflammation after ischemia. However, endogenous expression and localization of IL-10 and its receptor (IL-10R) in the post-ischemic brain are still to be elucidated. In this investigation we aimed at determining the temporospatial expression of IL-10 in the rat brain relative to its systemic levels after ischemic stroke. Wistar rats were subjected to either permanent (pMCAO) or 3-h temporary (tMCAO) middle cerebral artery occlusion and euthanized at either 24 or 72 h. IL-10/IL-10R levels were quantified in ischemic and contralesional hemispheres and compared to shams using multiplex bead array and Western blotting, respectively. Localization of IL-10/IL-10R with markers for neurons, microglia, astrocytes & endothelial cells were examined using double labeling immunofluorescence. IL-10 was also quantified in the brain tissue of spontaneously hypertensive rats (SHRs) at 24 h after tMCAO. After both pMCAO and tMCAO in Wistars, IL-10 was significantly upregulated in both hemispheres by ≈ 50% at 24 h while IL-10R expression was significantly decreased only at 72 h in the ischemic hemisphere. IL-10 and IL-10R expression highly co-localized with viable neurons in the ischemic penumbra and contralesional hemisphere. In hypertensive rats, IL-10 showed no significant contralesional upregulation and declined significantly in the ischemic side at 24 h post-ischemia. Our data highlights the involvement of the ischemic and contralesional neurons in the endogenous anti-inflammatory response after ischemic stroke through increased production of IL-10. This increase in IL-10 is blunted in hypertensive animals and may contribute to worse outcomes.


Performance optimization of 193 nm antireflective coatings with wide incident angle ranges on strongly curved spherical substrates.
A method to optimize the spectral performance of 193 nm antireflective (AR) coating with a broad range of angle of incidence (AOI) on strongly curved spherical substrates is described. In this method, the actual film thickness on test plates for single-layer LaF3 and MgF2 films are corrected by measuring the relationship between the film thickness on test plates and that on quartz crystal microbalance. Interface roughness in multi-layer AR coating is obtained from atomic force microscopy measurements and its effect on the spectrum of the multi-layer is taken into account in this method by being simulated as a homogeneous sublayer. Porosities of the sublayers in AR coatings are obtained by reversely engineering the residual reflectance of the coatings/substrate/coating stacks. The obtained refractive indices and thicknesses in the multilayer are then used for analysis and optimization of the spectrum of 193 nm AR coatings. For strongly curved spherical surfaces, spectrum uniformity of the AR coating is optimized by taking into consideration simultaneously the merit functions at different positions of spherical substrates. This work provides a general solution to the performance optimization of 193 nm AR coatings with broad AOI range and on strongly curved spherical substrates.


A FDTD solution of scattering of laser beam with orbital angular momentum by dielectric particles: Far-field characteristics.
Electromagnetic (EM) beams with orbital angular momentum (OAM) may have great potential applications in communication technology and in remote sensing of the Earth- atmosphere system and outer planets. Study of their interaction with optical lenses and dielectric or metallic objects, or scattering of them by particles in the Earth-atmosphere system, is a necessary step to explore the advantage of the OAM EM beams. In this study, the 3-dimensional (3D) scattered-field (SF) finite-difference time domain (FDTD) technique with the convolutional perfectly matched layer (CPML) absorbing boundary conditions (ABC) is applied to calculate the scattering of the purely azimuthal (the radial mode number is assumed to be zero) Laguerre-Gaussian (LG) beams with the OAM by dielectric particles. We found that for OAM beam's interaction with dielectric particles, the forward-scattering peak in the conventional phase function (P11) disappears, and light scattering peak occurs at a scattering angle of ~ 15° to 45°. The disappearance of forward-scattering peak means that, in laser communications most of the particle-scattered noise cannot enter the receiver, thus the received light is optimally the original OAM-encoded signal. This feature of the OAM beam also implies that in lidar remote sensing of the atmospheric particulates, most of the multiple-scattering energy will be off lidar sensors, and this may result in an accurate profiling of particle layers in the atmosphere or in the oceans by lidar, or even in the ground when a ground penetration radar (GPR) with the OAM is applied. This far-field characteristics of the scattered OAM light also imply that the optical theorem, which is derived from plane-parallel wave scattering case and relates the forward scattering amplitude to the total cross section of the scatterer, is invalid for the scattering of OAM beams by dielectric particles.


Organisational culture and post-merger integration in an academic health centre: a mixed-methods study.
Around the world, the last two decades have been characterised by an increase in the numbers of mergers between healthcare providers, including some of the most prestigious university hospitals and academic health centres. However, many mergers fail to bring the anticipated benefits, and successful post-merger integration in university hospitals and academic health centres is even harder to achieve. An increasing body of literature suggests that organisational culture affects the success of post-merger integration and academic-clinical collaboration. This paper reports findings from a mixed-methods single-site study to examine 1) the perceptions of organisational culture in academic and clinical enterprises at one National Health Service (NHS) trust, and 2) the major cultural issues for its post-merger integration with another NHS trust and strategic partnership with a university. From the entire population of 72 clinician-scientists at one of the legacy NHS trusts, 38 (53%) completed a quantitative Competing Values Framework survey and 24 (33%) also provided qualitative responses. The survey was followed up by semi-structured interviews with six clinician-scientists and a group discussion including five senior managers. The cultures of two legacy NHS trusts differed and were primarily distinct from the culture of the academic enterprise. Major cultural issues were related to the relative size, influence, and history of the legacy NHS trusts, and the implications of these for respective identities, clinical services, and finances. Strategic partnership with a university served as an important ameliorating consideration in reaching trust merger. However, some aspects of university entrepreneurial culture are difficult to reconcile with the NHS service delivery model and may create tension. There are challenges in preserving a more desirable culture at one of the legacy NHS trusts, enhancing cultures in both legacy NHS trusts during their post-merger integration, and in aligning academic and clinical cultures following strategic partnership with a university. The seeds of success may be found in current best practice, good will, and a near identical ideal of the future preferred culture. Strong, fair leadership will be required both nationally and locally for the success of mergers and post-merger integration in university hospitals and academic health centres.


Evidence-Based Digital Tools for Weight Loss Maintenance: The NoHoW Project.
Effective interventions and commercial programmes for weight loss (WL) are widely available, but most people regain weight. Few effective WL maintenance (WLM) solutions exist. The most promising evidence-based behaviour change techniques for WLM are self-monitoring, goal setting, action planning and control, building self-efficacy, and techniques that promote autonomous motivation (e.g., provide choice). Stress management and emotion regulation techniques show potential for prevention of relapse and weight regain. Digital technologies (including networked-wireless tracking technologies, online tools and smartphone apps, multimedia resources, and internet-based support) offer attractive tools for teaching and supporting long-term behaviour change techniques. However, many digital offerings for weight management tend not to include evidence-based content and the evidence base is still limited. The Project: First, the project examined why, when, and how many European citizens make WL and WLM attempts and how successful they are. Second, the project employed the most up-to-date behavioural science research to develop a digital toolkit for WLM based on 2 key conditions, i.e., self-management (self-regulation and motivation) of behaviour and self-management of emotional responses for WLM. Then, the NoHoW trial tested the efficacy of this digital toolkit in adults who achieved clinically significant (≥5%) WL in the previous 12 months (initial BMI ≥25). The primary outcome was change in weight (kg) at 12 months from baseline. Secondary outcomes included biological, psychological, and behavioural moderators and mediators of long-term energy balance (EB) behaviours, and user experience, acceptability, and cost-effectiveness. The project will directly feed results from studies on European consumer behaviour, design and evaluation of digital toolkits self-management of EB behaviours into development of new products and services for WLM and digital health. The project has developed a framework and digital architecture for interventions in the context of EB tracking and will generate results that will help inform the next generation of personalised interventions for effective self-management of weight and health.


Optical and thermal modeling of an optrode microdevice for infrared neural stimulation.
Infrared neural stimulation is a promising medical technique using pulsed infrared light for generating temperature-controlled firing of neurons. A combined optical and thermal model of a stimulating microtool-or so-called optrode-has been developed to investigate the amount, the spatial distribution, and the temporal behavior of the thermal excitation. Ray tracing and Fourier optics were used to describe the propagation and scattering of light in the optrode, and the finite element method was applied to model heat transfer. The scattered intensity distribution profiles were calculated based on measured surface roughness of the device and were integrated into the ray optics model. As a validation of the optical model, the simulated and measured values of the light efficiency of the microoptical system are compared. The temperature rise of the brain tissue during the infrared stimulation was estimated using the combined model. Using 30 mW total power and a single 100 ms pulse, the excitation resulted in a temperature rise of 3°C of the brain tissue. The spatial and temporal distributions of the tissue temperature are discussed in the paper. The proposed combined model is an efficient tool for the investigation and optimization of the stimulation process and for further development of the optrode configuration.


Presynaptic rat Kv1.2 channels suppress synaptic terminal hyperexcitability following action potential invasion.
Voltage-gated K+ channels activating close to resting membrane potentials are widely expressed and differentially located in axons, presynaptic terminals and cell bodies. There is extensive evidence for localisation of Kv1 subunits at many central synaptic terminals but few clues to their presynaptic function. We have used the calyx of Held to investigate the role of presynaptic Kv1 channels in the rat by selectively blocking Kv1.1 and Kv1.2 containing channels with dendrotoxin-K (DTX-K) and tityustoxin-Kalpha (TsTX-Kalpha) respectively. We show that Kv1.2 homomers are responsible for two-thirds of presynaptic low threshold current, whilst Kv1.1/Kv1.2 heteromers contribute the remaining current. These channels are located in the transition zone between the axon and synaptic terminal, contrasting with the high threshold K+ channel subunit Kv3.1 which is located on the synaptic terminal itself. Kv1 homomers were absent from bushy cell somata (from which the calyx axons arise); instead somatic low threshold channels consisted of heteromers containing Kv1.1, Kv1.2 and Kv1.6 subunits. Current-clamp recording from the calyx showed that each presynaptic action potential (AP) was followed by a depolarising after-potential (DAP) lasting around 50 ms. Kv1.1/Kv1.2 heteromers had little influence on terminal excitability, since DTX-K did not alter AP firing. However TsTX-Kalpha increased DAP amplitude, bringing the terminal closer to threshold for generating an additional AP. Paired pre- and postsynaptic recordings confirmed that this aberrant AP evoked an excitatory postsynaptic current (EPSC). We conclude that Kv1.2 channels have a general presynaptic function in suppressing terminal hyperexcitability during the depolarising after-potential.


Steroid receptor expression in the fish inner ear varies with sex, social status, and reproductive state.
Gonadal and stress-related steroid hormones are known to influence auditory function across vertebrates but the cellular and molecular mechanisms responsible for steroid-mediated auditory plasticity at the level of the inner ear remain unknown. The presence of steroid receptors in the ear suggests a direct pathway for hormones to act on the peripheral auditory system, but little is known about which receptors are expressed in the ear or whether their expression levels change with internal physiological state or external social cues. We used qRT-PCR to measure mRNA expression levels of multiple steroid receptor subtypes (estrogen receptors: ERalpha, ERbetaa, ERbetab; androgen receptors: ARalpha, ARbeta; corticosteroid receptors: GR2, GR1a/b, MR) and aromatase in the main hearing organ of the inner ear (saccule) in the highly social African cichlid fish Astatotilapia burtoni, and tested whether these receptor levels were correlated with circulating steroid concentrations. We show that multiple steroid receptor subtypes are expressed within the main hearing organ of a single vertebrate species, and that expression levels differ between the sexes. We also show that steroid receptor subtype-specific changes in mRNA expression are associated with reproductive phase in females and social status in males. Sex-steroid receptor mRNA levels were negatively correlated with circulating estradiol and androgens in both males and females, suggesting possible ligand down-regulation of receptors in the inner ear. In contrast, saccular changes in corticosteroid receptor mRNA levels were not related to serum cortisol levels. Circulating steroid levels and receptor subtype mRNA levels were not as tightly correlated in males as compared to females, suggesting different regulatory mechanisms between sexes. This is the most comprehensive study of sex-, social-, and reproductive-related steroid receptor mRNA expression in the peripheral auditory system of any single vertebrate. Our data suggest that changes in steroid receptor mRNA expression in the inner ear could be a regulatory mechanism for physiological state-dependent auditory plasticity across vertebrates.


Phylogenetic relationships of the genus Phanerochaete inferred from the internal transcribed spacer region.
Phanerochaete is a genus of resupinate homobasidiomycetes that are saprophytic on woody debris and logs. Morphological studies in the past indicated that Phanerochaete is a heterogeneous assemblage of species. In this study the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA was used to test the monophyly of the genus Phanerocthaete and to infer phylogenetic relationships of the 24 taxa studied. Maximum parsimony, maximum likelihood, and Bayesian analyses do not support the monophyly of the genus. However, a core group of species represented by Phanerochaete velutina, P. chrysosporium, P. sordida, P. sanguinea and others are closely related and group together in a clade. Other common Phanerochaete species including Phanerochaete rimosa, P. chrysorhiza, P. omnivora, P. avellanea, P. tiberculata, P. flava, and P. allantospora, however, do not cluster with the core Phanerochaete group.


Physical activity levels after hip and knee joint replacement surgery: an observational study.
Usual care after hip or knee joint replacement does not adequately address the problem of low physical activity levels. We aimed to determine whether exercise delivered in a group setting in the early stage of outpatient rehabilitation influenced self-reported physical activity levels after hip or knee joint replacement. A case series of 79 participants referred to a 6-week outpatient orthopaedic exercise group after total hip or knee replacement were evaluated using the International Physical Activity Questionnaire (IPAQ) short form. Physical function was evaluated using Osteoarthritis Research Society International (OARSI) recommended performance-based tests (30 s Chair Stand Test, 40 m Fast Pace Walk Test, Stair Climb Test, Timed Up and Go Test, 6 Minute Walk Test). Measures were assessed at admission, discharge and 6 weeks after group discharge. Non-parametric analysis was conducted for IPAQ scores. Analysis of functional measures was conducted with linear mixed models with time modelled as a repeated measure. Standard multiple regression and correlation analysis were conducted. Fifty-four participants completed the study. Self-reported activity levels improved significantly at program discharge but not at 6-week follow-up. All performance-based measures improved significantly at program discharge. Fast-paced walking and 6 Minute Walk Test measures continued to improve at 6-week follow-up. Group dynamics present in an outpatient rehabilitation exercise program may increase physical activity levels during group participation but not after group cessation. Performance in all functional measures improved at group discharge.


Application of pulsed buffer gas jets for the signal enhancement of laser-induced breakdown spectroscopy.
We report a new simple method for the signal enhancement of laser-induced breakdown spectroscopy using a pulsed buffer gas jet. The signal is enhanced up to more than 10 fold by using argon gas jets, which are injected through a pulsed nozzle onto the sample area to be analyzed. By synchronizing the buffer gas pulse with the laser pulse and optimizing the spatial arrangements between the gas jet and the sample surface, we have successfully exploited the useful properties of the buffer gas in open atmosphere. The signal-enhancement mechanism in our buffer gas jet has been discussed. Also, applications to various samples (metal, glass, and paper) have been demonstrated.


Implementing Silicon Nanoribbon Field-Effect Transistors as Arrays for Multiple Ion Detection.
Ionic gradients play a crucial role in the physiology of the human body, ranging from metabolism in cells to muscle contractions or brain activities. To monitor these ions, inexpensive, label-free chemical sensing devices are needed. Field-effect transistors (FETs) based on silicon (Si) nanowires or nanoribbons (NRs) have a great potential as future biochemical sensors as they allow for the integration in microscopic devices at low production costs. Integrating NRs in dense arrays on a single chip expands the field of applications to implantable electrodes or multifunctional chemical sensing platforms. Ideally, such a platform is capable of detecting numerous species in a complex analyte. Here, we demonstrate the basis for simultaneous sodium and fluoride ion detection with a single sensor chip consisting of arrays of gold-coated SiNR FETs. A microfluidic system with individual channels allows modifying the NR surfaces with self-assembled monolayers of two types of ion receptors sensitive to sodium and fluoride ions. The functionalization procedure results in a differential setup having active fluoride- and sodium-sensitive NRs together with bare gold control NRs on the same chip. Comparing functionalized NRs with control NRs allows the compensation of non-specific contributions from changes in the background electrolyte concentration and reveals the response to the targeted species.


Subaortic fibrous ridge and ventricular septal defect: role of septal malalignment.
The purpose of this study was to test the hypothesis that the presence of a subaortic ridge associated with a ventricular septal defect (VSD) is related to a malaligned ventricular septum caused by anterior or posterior deviation of the infundibular septum with or without obstructive lesions of the aortic arch. Thirty-two of 295 patients in whom a diagnosis of VSD was made by two-dimensional echocardiography and who were studied from June 1983 to April 1985 presented with a subaortic shelf. Every patient (p less than .00001) had a malalignment type of defect; the defect was produced by anterior deviation of the outlet septum (without compromise of the right ventricular outflow tract) in 28 and by posterior deviation of the infundibular septum in four. The prevalence of a subaortic shelf in the malalignment VSD group was 82% (32/39). Among the 28 patients with a subaortic ridge and anterior deviation of the outlet septum only three had aortic coarctation, but all four patients with subaortic stenosis and posterior infundibular malalignment had obstructive lesions of the aortic arch--coarctation in three and interruption of the aortic arch in one (p less than .001). We conclude that a malalignment type of VSD may be a consistent feature in patients with VSD and associated discrete subaortic stenosis. We also noted a high prevalence of subaortic ridge in the presence of a malalignment VSD and therefore speculate that there may be a common morphogenesis for malalignment VSD, subaortic shelf, and obstructive lesions of the aortic arch.


CROW bottles.
A coupled resonator optical waveguide (CROW) bottle is a bottle-shaped nonuniform distribution of resonator and coupling parameters. This Letter solves the inverse problem for a CROW bottle, i.e., develops a simple analytical method that determines a CROW with the required group delay and dispersion characteristics. In particular, the parameters of CROWs exhibiting the group delay with zero dispersion (constant group delay) and constant dispersion (linear group delay) are found.


Communication and team situation awareness in the OR: Implications for augmentative information display.
Team Situation Awareness (TSA) is one of the critical factors in effective Operating Room (OR) teamwork and can impact patient safety and quality of care. While previous research showed a relationship between situation awareness, as measured by communication events, and team performance, the implications for developing technology to augment and facilitate TSA were not examined. This research aims to further study situation-related communications in the cardiac OR in order to uncover potential degradation in TSA which may lead to adverse events. The communication loop construct-the full cycle of information flow between the participants in the sequence-was used to assess susceptibility to breakdown. Previous research and the findings here suggest that communication loops that are open, non-directed, or with delayed closure, can be susceptible to information loss. These were quantitatively related to communication indicators of TSA such as questions, replies, and announcements. Taken together, both qualitative and quantitative analyses suggest that a high proportion of TSA-related communication (63%) can be characterized as susceptible to information loss. The findings were then used to derive requirements and design a TSA augmentative display. The design principles and potential benefits of such a display are outlined and discussed.


Validation of the OMNI-cycle scale of perceived exertion in the elderly.
This study examined the concurrent and construct validity of the OMNI-Cycle Rating of Perceived Exertion (RPE) Scale, using elderly men and women. Seventy-six participants performed a load-incremented cycle-ergometer exercise test. Concurrent validity was determined by correlating OMNI-RPE responses with oxygen uptake, relative peak oxygen uptake, pulmonary ventilation, heart rate, respiratory rate, and respiratory-exchange ratio during a load-incremented cycle-ergometer protocol. Construct validity was established by correlating RPE derived from the OMNI-Cycle Scale with RPE from the Borg (6-20) Scale. Multilevel, mixed linear-regression models indicated that OMNI-RPE distributed as a significant (p < .05) positive linear function (r = .81-.92) for all physiological measures. OMNI-RPE was positively (p < .01) and linearly related to Borg-RPE in elderly men (r = .97) and women (r = .96). This study demonstrates both concurrent and construct validity of the OMNI-Cycle RPE Scale. These findings support the use of this scaling metric with elderly men and women to estimate RPE during cycle-ergometer exercise.


Non-viraemic transmission of Thogoto virus: influence of time and distance.
Previous studies have demonstrated that Thogoto virus is transmitted from infected to uninfected ticks when co-feeding on uninfected guinea-pigs, even though the guinea-pigs do not develop detectable viraemia. The dynamics of this 'non-viraemic transmission' were investigated. The percentage of nymphs (recipients) that acquired virus increased from zero, when co-feeding with infected adults (donors) for 3 d, to 80% for a co-feeding period of 5 d. No statistically significant difference was detected when infected donors and uninfected recipients were separated physically up to a maximum distance of approximately 160 mm. These results indicate that the temporal, but not the spatial, relationship affects the number of recipient ticks that become infected.


A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion.
Cervical cancer is caused by persistent infection with human papillomavirus (HPV). Most infections and associated lesions clear spontaneously. It is important to define the determinants and timing of clearance, so that viral persistence can be recognized and managed. We investigated HPV natural history among 4504 subjects from ALTS (Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study). A discrete-time Markov model was used to simultaneously describe the prevalence, incidence, and persistence of type-specific HPV infection over 24 months in women with equivocal or mildly abnormal cytological results. Interactions between multiple HPV types infecting the same woman were examined for incidence of new infection (after an HPV-16 infection) and persistence of a current infection within groups defined by phylogenetic relatedness or by carcinogenicity. Ninety-one percent (95% credible interval [CI], 90%-92%) of prevalent HPV infections at enrollment cleared within 24 months. The probability that an infection would persist for a further 6 months increased with the duration of infection, from 37% (95% CI, 35%-39%) for a newly observed infection to 65% (95% CI, 61%-70%) for an infection that had already persisted for > or =18 months. No consistent evidence of interactions was found between multiple HPV types regarding the incidence of new infection after an HPV-16 infection or regarding persistence of current HPV infection. Although virtually all HPV infections clear within 2 years, the remaining infections have a high potential for persistence and, by implication, progression to precancer and cancer. Once biological and behavioral determinants are controlled for, HPV infections with different types seem to be independent of each other.


Pathophysiology of NASH in endocrine diseases.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. NAFLD encompasses a whole spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The latter can lead to hepatocellular carcinoma. Furthermore, NASH is the most rapidly increasing indication for liver transplantation in western countries and therefore represents a global health issue. The pathophysiology of NASH is complex and includes multiple parallel hits. NASH is notably characterized by steatosis as well as evidence of hepatocyte injury and inflammation, with or without fibrosis. NASH is frequently associated with type 2 diabetes and conditions associated with insulin resistance. Moreover, NASH may also be found in many other endocrine diseases such as polycystic ovary syndrome, hypothyroidism, male hypogonadism, growth hormone deficiency or glucocorticoid excess, for example. In this review, we will discuss the pathophysiology of NASH associated with different endocrinopathies.


Pontine mechanisms of respiratory control.
Pontine respiratory nuclei provide synaptic input to medullary rhythmogenic circuits to shape and adapt the breathing pattern. An understanding of this statement depends on appreciating breathing as a behavior, rather than a stereotypic rhythm. In this review, we focus on the pontine-mediated inspiratory off-switch (IOS) associated with postinspiratory glottal constriction. Further, IOS is examined in the context of pontine regulation of glottal resistance in response to multimodal sensory inputs and higher commands, which in turn rules timing, duration, and patterning of respiratory airflow. In addition, network plasticity in respiratory control emerges during the development of the pons. Synaptic plasticity is required for dynamic and efficient modulation of the expiratory breathing pattern to cope with rapid changes from eupneic to adaptive breathing linked to exploratory (foraging and sniffing) and expulsive (vocalizing, coughing, sneezing, and retching) behaviors, as well as conveyance of basic emotions. The speed and complexity of changes in the breathing pattern of behaving animals implies that "learning to breathe" is necessary to adjust to changing internal and external states to maintain homeostasis and survival.


Cultural Adaptation of a Scalable World Health Organization E-Mental Health Program for Overseas Filipino Workers.
Electronic mental (e-mental) health interventions can address mental health needs of different populations. Cultural adaptation of these interventions is crucial to establish a better fit with the cultural group and to achieve better treatment outcomes. This study aimed to describe the cultural adaptation of the World Health Organization's e-mental health program Step-by-Step for overseas Filipino workers. We used a framework which posits that cultural adaptation should enhance (1) relevance, wherein the cultural group can relate with the content; (2) acceptability, where the cultural group will not find any element offensive; (3) comprehensibility, where the program is understandable; and (4) completeness, wherein the adapted version covers the same concepts and constructs as the original program. We aimed to have English and Filipino and male and female versions. Overall, 3 experienced Filipino psychologists provided their perspectives on the program and how it might be adapted for overseas Filipino workers. We then adapted the program and obtained feedback from 28 overseas Filipino workers from diverse industries through focus group discussions. We conducted 7 and 9 focus group discussions with male and female participants, respectively. Per discussion, cognitive interviewing was used to probe for relevance, acceptability, comprehensibility, and completeness of illustrations and text. Participant feedback guided iterative program adaptations, which were again shown to participants for validation and improvement. Several issues were raised by participants about the generic version of Step-by-Step. There were elements deemed irrelevant, like unfitting characters, lack of Filipino values, and unsuitable problems and activities. There were unacceptable components that were stigmatizing, political, inappropriate to context or subgroups, and too feminine for male users. Some elements were incomprehensible, unclear, or complicated. To address these issues, we made key adaptations. To enhance relevance, we adapted the narrative to match the experiences of overseas Filipino workers, incorporated Filipino values, and illustrated familiar problems and activities. To increase acceptability, our main characters were changed to wise elders rather than health professionals (reducing mental health and help-seeking stigma), political or unacceptable content was removed, and the program was made suitable for overseas Filipino workers from different sectors. To increase comprehension, we used English and Filipino languages, simplified the text to ease interpretation of abstract terms, and ensured that text and illustrations matched. We also used Taglish (ie, merged English and Filipino) when participants deemed pure Filipino translations sounded odd or incomprehensible. Finally, we retained the core elements and concepts included in the original Step-by-Step program to maintain completeness. This study showed the utility of a 4-point framework that focuses on acceptance, relevance, comprehensibility, and completeness in cultural adaptation. Moreover, we achieved a culturally appropriate adapted version of the Step-by-Step program for overseas Filipino workers. We discuss lessons learned in the process to guide future cultural adaptation projects of e-mental health interventions.


Finding Matrix Product State Representations of Highly Excited Eigenstates of Many-Body Localized Hamiltonians.
A key property of many-body localized Hamiltonians is the area law entanglement of even highly excited eigenstates. Matrix product states (MPS) can be used to efficiently represent low entanglement (area law) wave functions in one dimension. An important application of MPS is the widely used density matrix renormalization group (DMRG) algorithm for finding ground states of one-dimensional Hamiltonians. Here, we develop two algorithms, the shift-and-invert MPS (SIMPS) and excited state DMRG which find highly excited eigenstates of many-body localized Hamiltonians. Excited state DMRG uses a modified sweeping procedure to identify eigenstates, whereas SIMPS applies the inverse of the shifted Hamiltonian to a MPS multiple times to project out the targeted eigenstate. To demonstrate the power of these methods, we verify the breakdown of the eigenstate thermalization hypothesis in the many-body localized phase of the random field Heisenberg model, show the saturation of entanglement in the many-body localized phase, and generate local excitations.


Monitoring women's experiences during three rounds of breast cancer screening: results from a longitudinal study.
(a) To monitor experiences of women during three successive rounds of breast screening; (b) to examine the impact of previous experiences (obtained either immediately after the latest mammogram or shortly before the subsequent one) on reattendance; and (c) to examine which factors are associated with the experience of pain and distress during screening. The Dutch Breast Cancer Screening Programme 2657 women completed a baseline measurement (response rate 67%) about 8 weeks after they had been invited for an initial mammogram (T(1)). Actual participation data of these women in the second and third rounds of screening were collected. Follow up questionnaires were sent to subgroups of the sample at different times: shortly before the second screening (T(2); response rate 86%), shortly after the second screening (T(3); response rate 85%), shortly before the third screening (T(4); response rate 80%), and shortly after the third screening (T(5); response rate 78%). Most women were satisfied with the first screening round and remained positive about subsequent screens. Although pain and anxiety were not uncommon, only a few (10%-15%) experienced moderate or severe levels of distress or pain. Experiences were relatively stable: women who experienced pain in the first screen were more likely to experience pain in subsequent screens (r values from 0.39 to 0.50). Fear of breast cancer was associated with increased distress related to mammography and, to a lesser extent, with increased pain during the mammography. Evidence was found for a relief effect: women were more positive about their previous screen when asked shortly after this screen, than when asked just before the subsequent one. Previous experiences (obtained either proximally or distally) were only slightly predictive for future attendance. Experiences during mammography are fairly stable. Negative experiences were generally not a reason to drop out of the programme.


Unusual variations of gastrointestinal smooth muscle abnormalities associated with chronic intestinal pseudo-obstruction.
The clinicopathological spectrum of gastrointestinal (GI) smooth-muscle abnormalities associated with chronic intestinal pseudo-obstruction (CIPO) includes numerous heterogeneous conditions that are often ill-defined and poorly understood. Primary GI smooth-muscle abnormalities include familial and sporadic forms. Secondary involvement of GI smooth-muscle may result from associated GI and systemic conditions, but is less frequent than in adults. This study documents the clinicopathological findings observed in 12 South African patients with unusual forms of visceral smooth-muscle abnormalities not conforming to the diagnostic criteria of known primary visceral myopathies at the Tygerberg and Red Cross Childrens' Hospitals over a 14-year period (July 1985 through January 1999). Congenital muscle defects occurred in 5 patients where layers of bowel-wall muscle were absent or attenuated. Idiopathic fibrosis and ultrastructural features of perinuclear and mitochondrial vacuolisation were noted in 2 patients. A 21-year-old female with long-standing pseudo-obstruction demonstrated diminished immunohistochemical expression of enteric alpha-smooth-muscle actin without associated muscular degeneration or fibrosis. A secondary complication of dermatomyositis (bowel perforation) occurred twice in 1 patient. In 3 further patients (1 each with anorectal malformation, long-segment Hirschsprung's disease, and intestinal neuronal dysplasia), muscle fibrosis appeared during progression of the pre-existing disease. Visceral myopathies are poorly understood conditions that may present with CIPO. Unusual variations occur that do not conform to the usual recognised histological patterns. Secondary involvement may also be more common than anticipated in children. The challenge to further understanding these uncommon conditions lies in timely diagnosis and identification of early, subtle signs. Optimal and extensive application of various diagnostic modalities, including the development of new diagnostic tools, is of considerable importance in identifying hitherto unexplained CIPO due to GI smooth-muscle abnormalities.


Magnesium transport in Salmonella typhimurium: mgtA encodes a P-type ATPase and is regulated by Mg2+ in a manner similar to that of the mgtB P-type ATPase.
Salmonella typhimurium has three distinct Mg2+ transport systems: CorA, MgtA, and MgtB, each encoded by its respective gene. corA and mgtB have been previously sequenced and characterized. This report details the sequence and properties of mgtA. Like mgtB, mgtA encodes a P-type ATPase. The mgtA gene encodes a slightly smaller protein than does mgtB, with a predicted molecular mass of about 95 kDa, running at 91 kDa on protein gels, which compares with values of 101 and 102 kDa, respectively, for the MgtB protein. The deduced amino acid sequence of MgtA is only 50% identical to that of MgtB, with a further 25% conservative amino acid substitutions, surprisingly low for such otherwise functionally similar proteins from the same organism. Codon usage for each gene is normal for S. typhimurium, however, indicating that neither gene is the result of a recent acquisition from another organism. A single open reading frame at mgtA encodes MgtA, in contrast to mgtB, which is shown to be an operon encoding (5' to 3') the 22.5-kDa MgtC and the MgtB proteins. Genetic constructs were used to show that deletion of MgtC does not alter the expression or transport properties of MgtB, making the role of the companion MgtC protein unclear. (The S. typhimurium homolog of treR, which encodes a putative repressor for trehalose uptake, is encoded by a gene adjacent to mgtA, and its sequence is also reported. Finally, exteremely strong Mg(2+) regulation of the mgtA and mgtB promoters but not of the corA or treR promoters was demonstrated by cloning the appropriate DNA sequences with luxAB and measuring enhancement of light production as a function of extracellular Mg(2+) concentration. Lowering the extracellular Mg(2+) concentration from 10 mM to 1 or 10 microM elicited a transcriptional response of several thousandfold from both the mgtA and mgtB promoters.


Global reprogramming of transcription and metabolism in Medicago truncatula during progressive drought and after rewatering.
Medicago truncatula is a model legume forage crop native to the arid and semi-arid environments of the Mediterranean. Given its drought-adapted nature, it is an ideal candidate to study the molecular and biochemical mechanisms conferring drought resistance in plants. Medicago plants were subjected to a progressive drought stress over 14 d of water withholding followed by rewatering under controlled environmental conditions. Based on physiological measurements of plant water status and changes in morphology, plants experienced mild, moderate and severe water stress before rehydration. Transcriptome analysis of roots and shoots from control, mildly, moderately and severely stressed, and rewatered plants, identified many thousands of genes that were altered in expression in response to drought. Many genes with expression tightly coupled to the plant water potential (i.e. drought intensity) were identified suggesting an involvement in Medicago drought adaptation responses. Metabolite profiling of drought-stressed plants revealed the presence of 135 polar and 165 non-polar compounds in roots and shoots. Combining Medicago metabolomic data with transcriptomic data yielded insight into the regulation of metabolic pathways operating under drought stress. Among the metabolites detected in drought-stressed Medicago plants, myo-inositol and proline had striking regulatory profiles indicating involvement in Medicago drought tolerance.


Wayfinding as a Social Activity.
We discuss the important, but greatly under-researched, topic of the social aspects of human wayfinding during navigation. Wayfinding represents the planning and decision-making component of navigation and is arguably among the most common, real-world domains of both individual and group-level decision making. We highlight the myriad ways that wayfinding by people is not a solitary psychological process but is influenced by the actions of other people, even by their mere presence. We also present a novel and comprehensive framework for classifying wayfinding in complex environments that incorporates the influence of other people. This classification builds upon the premises of previous wayfinding taxonomies and is further structured into four parts based upon (1) the nature of the interaction between the actors and (2) the time frame in which the interaction takes place. We highlight gaps in our current understanding of social wayfinding and outline future research opportunities.


Eating disorders and associated psychiatric comorbidity in elderly Canadian women.
This study examined the prevalence of disordered eating symptomatology and their associations with socio-demographic characteristics and health indicators in a nationally representative sample of Canadian women aged 50 years and older. The study also examined associations of disordered eating symptomatology with comorbid mood disorders, anxiety disorders and alcohol dependence. The study was based on secondary data analysis of the Canadian Community Health Survey, cycle 1.2. About 2.6% of women 50-64 years old and 1.8% of women 65 years or older reported disordered eating symptomatology. These women exhibited elevated frequencies of dieting behaviors and preoccupation with food intake and body shape. Disordered eating symptomatology was positively associated with stress level and negatively associated with physical health. Similar to findings in younger women, risk of eating disorders was strongly associated with mood and anxiety disorders. Results indicate that the risk of having eating disorders is a lifelong concern. Hence, older women should be screened for symptoms of disordered eating and associated psychiatric comorbidity.


The influence of social preferences and reputational concerns on intergroup prosocial behaviour in gains and losses contexts.
To what extent do people help ingroup members based on a social preference to improve ingroup members' outcomes, versus strategic concerns about preserving their reputation within their group? And do these motives manifest differently when a prosocial behaviour occurs in the context of helping another gain a positive outcome (study 1), versus helping another to avoid losing a positive outcome (study 2)? In both contexts, we find that participants are more prosocial towards ingroup (versus outgroup members) and more prosocial when decisions are public (versus private) but find no interaction between group membership and either anonymity of the decision or expected economic value of helping. Therefore, consistent with a preference-based account of ingroup favouritism, people appear to prefer to help ingroup members more than outgroup members, regardless of whether helping can improve their reputation within their group. Moreover, this preference to help ingroup members appears to take the form of an intuitive social heuristic to help ingroup members, regardless of the economic incentives or possibility of reputation management. Theoretical and practical implications for the study of intergroup prosocial behaviour are discussed.


Consequences of the addition of nitrous oxide to anesthesia during pneumoperitoneum in videolaparoscopic surgeries.
The use of pneumoperitoneum during videolaparoscopic surgeries activates neuroendocrine mechanisms, and causes cardiovascular and hormonal changes. The aim of this study was to evaluate the effects of the addition of nitrous oxide, to maintain adequate anesthetic levels, on the cardiovascular sympathetic response and in the expired concentration of sevoflurane (ECsevo) during pneumoperitoneum, by evaluating hemodynamic parameters, BIS, and SEF95%, during videolaparoscopic cholecystectomies. Thirty-one patients, physical status ASA I and II, ages 19 to 76 years, were included in the study. Anesthetic induction was accomplished with sufentanyl 0.3 microg kg(-1)), propofol (2.5 mg kg(-1)), and cisatracurium (0.15 mg kg(-1)). During the maintenance phase of anesthesia, the dose of ECsevo was adjusted to maintain BIS between 40 and 60. The administration of increasing concentrations of nitrous oxide, 20%, 40%, and 60%, was initiated after inducing pneumoperitoneum. The bispectral index, SEF95%, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were evaluated at M1 - 5 minutes after the pneumoperitoneum; M2 - when the expired concentration of N2O = 20% (ECN2O = 20%); M3 - ECN2O = 40%; M4 - ECN2O = 60%. There were no significant differences among SBP, DBP, MAP, and HR in the moments studied. There was a significant difference in ECsevo in those same moments, with a 35% reduction when M1 and M4 were compared. When nitrous oxide is administered in association with sevoflurane during pneumoperitoneum in videolaparoscopic cholecystectomy, it provides for hemodynamic stability and reduces the amount of sevoflurane needed while, at the same time, maintaining electroencephalographic parameters compatible with adequate anesthesia.


Assessing the delivery efficacy and internalization route of cell-penetrating peptides.
Developing efficient delivery vectors for bioactive molecules is of great importance within both traditional and novel drug development, such as oligonucleotide (ON)-based therapeutics. To address delivery efficiency using cell-penetrating peptides (CPPs), we here present a protocol based on splice correction utilizing both neutral and anionic antisense ONs, either covalently conjugated via a disulfide bridge or non-covalently complexed, respectively, that generates positive readout in the form of luciferase expression. The decisive advantage of using splice correction for evaluation of CPPs is that the ON induces a biological response in contrast to traditionally used methods, for example, fluorescently labeled peptides. An emerging number of studies emphasize the role of endocytosis in translocation of CPPs, and this protocol is also utilized to determine the relative contribution of different endocytic pathways in the uptake of CPPs, which provides valuable information for future design of novel, more potent CPPs for bioactive cargoes.


Involvement of integrin alphavbeta3 in cell adhesion, motility, and liver metastasis of murine RAW117 large cell lymphoma.
The molecules that mediate metastatic cell homing to specific organ sites remain largely unidentified. As a target organ for metastasis, the liver is a unique environment characterized by fenestrated sinusoidal endothelium, lack of a complete basement membrane, and production of serum components, including fibronectin and vitronectin. We examined a series of marine RAW117 large cell lymphoma variants selected in vivo for liver-colonizing properties (H10 >> L17 > P). Compared with L17 or P cells, the highly liver-colonizing H1O cells expressed much higher levels of surface integrin alphavbeta3, as shown by affinity chromatography, immunoprecipitation, and flow cytometry. H10 cells adhered at higher rates to vitronectin and fibronectin than to fibrinogen, fibrin, laminin, and type I collagen. Among the RGD peptides, H10 cells adhered at significantly higher rates to the polymeric RGD peptide (glycyl-arginyl-glycyl-aspartyl-serine)4 than to monomeric RGD peptides. H10 cells were able to spread on immobilized vitronectin with highly polarized morphology but not on fibronectin. In contrast, the poorly liver-metastatic P and L17 cells did not adhere or spread well on vitronectin or fibronectin. H10 cells also migrated toward vitronectin concentration gradients. Blocking cell surface alphavbeta3 molecules with specific anti-beta3 monoclonal antibodies resulted in significant decreases in the adhesion of H10 cells to vitronectin and (glycyl-arginyl-glycyl-aspartyl-serine)4 and significant inhibition of the formation of experimental liver metastases. These data suggest an important role of integrin alphavbeta3 in the metastasis of RAW117 cells to the liver.


Control of DNA replication licensing in a cell cycle.
To maintain genome integrity in eukaryotes, DNA must be duplicated precisely once before cell division occurs. A process called replication licensing ensures that chromosomes are replicated only once per cell cycle. Its control has been uncovered by the discovery of the CDKs (cyclin dependent kinases) as master regulators of the cell cycle and the initiator proteins of DNA replication, such as the Origin Recognition Complex (ORC), Cdc6/18, Cdt1 and the MCM complex. At the end of mitosis, the MCM complex is loaded on to chromatin with the aid of ORC, Cdc6/18 and Cdt1, and chromatin becomes licensed for replication. CDKs, together with the Cdc7 kinase, trigger the initiation of replication, recruiting the DNA replicating enzymes on sites of replication. The activated MCM complex appears to play a key role in the DNA unwinding step, acting as a replicating helicase and moves along with the replication fork, at the same time bringing the origins to the unlicensed state. The cycling of CDK activity in the cell cycle separates the two states of replication origins, the licensed state in G1-phase and the unlicensed state for the rest of the cell cycle. Only when CDK drops at the completion of mitosis, is the restriction on licensing relieved and a new round of replication is allowed. Such a CDK-regulated licensing control is conserved from yeast to higher eukaryotes, and ensures that DNA replication takes place only once in a cycle. Xenopus laevis and mammalian cells have an additional system to control licensing. Geminin, whose degradation at the end of mitosis is essential for a new round of licensing, has been shown to bind Cdt1 and negatively regulate it, providing a new insight into the regulation of DNA replication in higher eukaryotes.


Top-down computerized cognitive remediation in schizophrenia: a case study of an individual with impairment in verbal fluency.
The objective of this case study was to assess the specific effect of cognitive remediation for schizophrenia on the pattern of cognitive impairments. Case A is a 33-year-old man with a schizophrenia diagnosis and impairments in visual memory, inhibition, problem solving, and verbal fluency. He was provided with a therapist delivered cognitive remediation program involving practice and strategy which was designed to train attention, memory, executive functioning, visual-perceptual processing, and metacognitive skills. Neuropsychological and clinical assessments were administered at baseline and after three months of treatment. At posttest assessment, Case A had improved significantly on targeted (visual memory and problem solving) and nontargeted (verbal fluency) cognitive processes. The results of the current case study suggest that (1) it is possible to improve specific cognitive processes with targeted exercises, as seen by the improvement in visual memory due to training exercises targeting this cognitive domain; (2) cognitive remediation can produce improvements in cognitive processes not targeted during remediation since verbal fluency was improved while there was no training exercise on this specific cognitive process; and (3) including learning strategies in cognitive remediation increases the value of the approach and enhances participant improvement, possibly because strategies using verbalization can lead to improvement in verbal fluency even if it was not practiced.


Preparation and application of a molecularly imprinted polymer for the determination of trace metolcarb in food matrices by high performance liquid chromatography.
In this article, for the first time, a molecularly imprinted polymer (MIP) for the metolcarb was prepared by bulk polymerization using metolcarb as the template, methacrylic acid as the functional monomer and ethylene glycol dimethacrylate as the cross-linker. The prepared polymer was characterized by FT-IR, static and kinetic adsorption experiments, and the results showed that it has been successfully synthesized and had good selective ability for metolcarb. The MIP was applied as a sorbent in molecularly imprinted SPE coupled with HPLC-UV for separation and determination of trace metolcarb in three kinds of food matrices at three concentration levels. Under the optimal conditions, the LODs (S/N=3) of cabbage, cucumber and pear were 7.622, 6.455 and 13.52 microg/kg, respectively, and recoveries were in the range of 68.80-101.31% with RSD (n=3) below 3.78% in all cases. To demonstrate further the selectivity of the MIP obtained, a comparison with commercially available C(18) SPE was performed. The results indicated that molecularly imprinted SPE showed better chromatography, better selectivity and higher recoveries for metolcarb than commercially available C(18) SPE.


The role of particulate size and chemistry in the association between summertime ambient air pollution and hospitalization for cardiorespiratory diseases.
In order to address the role that the ambient air pollution mix, comprised of gaseous pollutants and various physical and chemical measures of particulate matter, plays in exacerbating cardiorespiratory disease, daily measures of fine and coarse particulate mass, aerosol chemistry (sulfates and acidity), and gaseous pollution (ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide) were collected in Toronto, Ontario, Canada, in the summers of 1992, 1993, and 1994. These time series were then compared with concurrent data on the number of daily admissions to hospitals for either cardiac diseases (ischemic heart disease, heart failure, and dysthymias) or respiratory diseases (tracheobronchitis, chronic obstructive long disease, asthma, and pneumonia). After adjusting the admission time series for long-term temporal trends, seasonal variations, the effects of short-term epidemics, day of the week effects, and ambient temperature and dew point temperature, positive associations were observed for all ambient air pollutants for both respiratory and cardiac diseases. Ozone was least sensitive to adjustment for the gaseous and particulate pollution measures. However, the association between the health outcomes and carbon monoxide, fine and coarse mass, sulfate levels and aerosol acidity could be explained by adjustment for exposure to gaseous pollutants. Increases in ozone, nitrogen dioxide, and sulfur dioxide equivalent to their interquartile ranges corresponded to an 11% and 13% increase in daily hospitalizations for respiratory and cardiac diseases, respectively. The inclusion of any one of the particulate air pollutants in multiple regression models did not increase these percentages. Particle mass and chemistry could not be identified as an independent risk factor for the exacerbation of cardiorespiratory diseases in this study beyond that attributable to climate and gaseous air pollution. We recommend that effects of particulate matter on health be assessed in conjunction with temporally covarying gaseous air pollutants.


Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients.


High rates of homologous recombination in the mite endosymbiont and opportunistic human pathogen Orientia tsutsugamushi.
Orientia tsutsugamushi is an intracellular alpha-proteobacterium which resides in trombiculid mites, and is the causative agent of scrub typhus in East Asia. The genome sequence of this species has revealed an unprecedented number of repeat sequences, most notably of the genes encoding the conjugative properties of a type IV secretion system (T4SS). Although this observation is consistent with frequent intragenomic recombination, the extent of homologous recombination (gene conversion) in this species is unknown. To address this question, and to provide a protocol for the epidemiological surveillance of this important pathogen, we have developed a multilocus sequence typing (MLST) scheme based on 7 housekeeping genes (gpsA, mdh, nrdB, nuoF, ppdK, sucD, sucB). We applied this scheme to the two published genomes, and to DNA extracted from blood taken from 84 Thai scrub typhus patients, from 20 cultured Thai patient isolates, 1 Australian patient sample, and from 3 cultured type strains. These data demonstrated that the O. tsutsugamushi population was both highly diverse [Simpson's index (95% CI) = 0.95 (0.92-0.98)], and highly recombinogenic. These results are surprising given the intracellular life-style of this species, but are broadly consistent with results obtained for Wolbachia, which is an alpha-proteobacterial reproductive parasite of arthropods. We also compared the MLST data with ompA sequence data and noted low levels of consistency and much higher discrimination by MLST. Finally, twenty-five percent of patients in this study were simultaneously infected with multiple sequence types, suggesting multiple infection caused by either multiple mite bites, or multiple strains co-existing within individual mites.


Behind Closed Doors: The Priorities of the Alcohol Industry as Communicated in a Trade Magazine.
Background: Efforts to reduce alcohol-related harm face strong resistance from the alcohol industry. It is important to monitor industry actions over time to assist in developing appropriate responses to this resistance. Monitoring can enable public health to identify industry positions on alcohol policy issues, stay abreast of current and emerging marketing tactics, and inform the development of possible counter-actions. One form of monitoring is the examination of industry trade publications where the industry converses with itself. The aim of this study was to assess industry strategic approaches as communicated in articles published in a leading Australian alcohol trade magazine to provide insights for policy makers and advocacy groups. Methods: Thematic analysis of 362 articles published in a trade magazine over a one-year period. Results: Three primary themes were evident in the articles: (1) the legitimization of alcohol as an important social and economic product, (2) the portrayal of the industry as trustworthy and benign, and (3) the strategic embedding of alcohol in various facets of everyday life. Conclusions: There was a general failure to acknowledge the substantial burden of disease caused by alcohol products, and instead much effort was expended on legitimizing the product and the companies responsible for its production, distribution, and promotion. The level of denial exhibited shows that additional regulation of the industry and its tactics will need to proceed without industry acceptance. Clear resistance to increasing consumer protections also points to the futility of inviting industry members to the policy table.


Geographical spread of bacterial and fungal diseases of crustaceans.
The author discusses the way in which bacterial and fungal diseases of crustaceans can be and have been transmitted via commercial movements of stocks. Two classic examples of such diseases are presented, namely gaffkaemia (a bacterial disease of marine lobsters) and crayfish plague (a fungal disease of freshwater crayfish). In both cases, there is ample evidence that much of the disease spread can be linked to the commercial movement of infected animals caught from infected wild stocks and transported over large distances for wholesale and retail. In the case of crayfish plague, much of the relentless spread of this disease through Europe for nearly 140 years can also be liked to the movement of contaminated fishing equipment without disinfection.


Reduced glomerular filtration rate and its association with clinical outcome in older patients at risk of vascular events: secondary analysis.
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20-40], [40-50], [50-60]) >or= 60 ml/min/1.73 m(2). Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m(2) relative to eGFR >or= 60 ml/min/1.73m(2) respectively 2.04 (1.48-2.80), 2.37 (1.53-3.67), 3.52 (1.78-6.96), 1.64 (1.18-2.27), 3.31 (2.03-5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs. We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.


Human-on-Leaf-Chip: A Biomimetic Vascular System Integrated with Chamber-Specific Organs.
The vascular network is a central component of the organ-on-a-chip system to build a 3D physiological microenvironment with controlled physical and biochemical variables. Inspired by ubiquitous biological systems such as leaf venation and circulatory systems, a fabrication strategy is devised to develop a biomimetic vascular system integrated with freely designed chambers, which function as niches for chamber-specific vascularized organs. As a proof of concept, a human-on-leaf-chip system with biomimetic multiscale vasculature systems connecting the self-assembled 3D vasculatures in chambers is fabricated, mimicking the in vivo complex architectures of the human cardiovascular system connecting vascularized organs. Besides, two types of vascularized organs are built independently within the two halves of the system to verify its feasibility for conducting comparative experiments for organ-specific metastasis studies in a single chip. Successful culturing of human hepatoma G2 cells (HepG2s) and mesenchymal stem cells (MSCs) with human umbilical vein endothelial cells (HUVECs) shows good vasculature formation, and organ-specific metastasis is simulated through perfusion of pancreatic cancer cells and shows distinct cancer encapsulation by MSCs, which is absent in HepG2s. Given good culture efficacy, study design flexibility, and ease of modification, these results show that the bioinspired human-on-leaf-chip possesses great potential in comparative and metastasis studies while retaining organ-to-organ crosstalk.


Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma.
Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.


Progressive Stochastic Reconstruction Technique (PSRT) for cryo electron tomography.
Cryo Electron Tomography (cryoET) plays an essential role in Structural Biology, as it is the only technique that allows to study the structure of large macromolecular complexes in their close to native environment in situ. The reconstruction methods currently in use, such as Weighted Back Projection (WBP) or Simultaneous Iterative Reconstruction Technique (SIRT), deliver noisy and low-contrast reconstructions, which complicates the application of high-resolution protocols, such as Subtomogram Averaging (SA). We propose a Progressive Stochastic Reconstruction Technique (PSRT) - a novel iterative approach to tomographic reconstruction in cryoET based on Monte Carlo random walks guided by Metropolis-Hastings sampling strategy. We design a progressive reconstruction scheme to suit the conditions present in cryoET and apply it successfully to reconstructions of macromolecular complexes from both synthetic and experimental datasets. We show how to integrate PSRT into SA, where it provides an elegant solution to the region-of-interest problem and delivers high-contrast reconstructions that significantly improve template-based localization without any loss of high-resolution structural information. Furthermore, the locality of SA is exploited to design an importance sampling scheme which significantly speeds up the otherwise slow Monte Carlo approach. Finally, we design a new memory efficient solution for the specimen-level interior problem of cryoET, removing all associated artifacts.


Establishment of feline in-house reference intervals for hematologic and biochemical parameters and potential age-related differences.
Reference intervals (RIs) are one of the essential elements in the procedure of disease diagnosis. This is especially true for feline species in which RI is less available than in canine species. RIs are affected by biological, geographical and instrumental factors, yet published RIs with incomplete background are popularly used. Inappropriate interpretations of RIs may affect classification of disease and subsequent treatment. In this study, we demonstrated the step-by-step establishment of feline RIs following the American Society for Veterinary Clinical Pathology (ASVCP) reference interval guideline. A total of 51 parameters were examined, including 20 hematology and 31 biochemistry parameters, and the results were compared to one local RI and two foreign RIs. Overall, about 29% (10/35) of tested parameters were different form local RIs and 60% (30/50) were different from the two foreign RIs, highlighting geographical variations. A higher upper reference limit (URL) in red blood cell count (RBC), hematocrit (Hct), Hemoglobin (Hgb), albumin, creatinine and lower URL in potassium and white blood cell count (WBC) were identified, which may impact the interpretation. In addition, statistical analysis of age and gender were factored separately and indicated that 10 parameters were significantly higher in the adult group. For the impact of gender, percentage of basophil and total iron-binding capacity (TIBC) were lower in female and male cats, respectively. In conclusion, we have demonstrated that it is desirable to establish in-house RIs or RIs of local sources. An age specific RI for the geriatric feline population is advisable for better diagnosis and monitoring the disease.


Effects of double filtration plasmapheresis, leflunomide, and methotrexate on inflammatory changes found through magnetic resonance imaging in early rheumatoid arthritis.
To evaluate the effects of double filtration plasmapheresis (DFPP) in combination with leflunomide and methotrexate (MTX) on magnetic resonance imaging (MRI)-detected inflammatory changes (synovitis and bone edema) in patients with early rheumatoid arthritis (RA) with high disease activity. Sixty RA patients with highly active disease of 6 months' to 3 years' duration were randomized to receive DFPP in combination with leflunomide and MTX (DFPP group), and leflunomide plus MTX (no-DFPP group). The primary endpoint was the improvement in MRI-detected synovitis from baseline over 6 months. Secondary endpoint variables included DAS28 remission and American College of Rheumatology (ACR) criteria responses for 6 consecutive months. The study achieved significant improvement in synovitis and bone edema, with significantly lower synovitis and bone edema scores in the DFPP group compared with the no-DFPP group (p < 0.001). Synovitis scores in 48.39% of patients (15/31) in the DFPP group were 0 at Month 6. Bone edema scores in 32.26% of patients (10/31) in the DFPP group were 0 at Month 6. We observed significantly greater ACR20, ACR50, ACR70, and ACR90 responses and DAS28 remission rates in the DFPP group than in the no-DFPP group (p < 0.001). Sustained DAS28 remission and ACR90 response for at least 6 months were achieved in 100% of patients receiving DFPP therapy. The combination of DFPP and disease-modifying antirheumatic drugs (DMARD) was superior to DMARD alone for reducing MRI-detected signs of synovitis and bone edema in patients with early highly active RA. DFPP therapy enabled rapid and more complete suppression of inflammation in patients with highly active RA. Nearly half the patients (48.39%) who had received DFPP therapy achieved both clinical remission and imaging remission, a state characterized as true remission.