Association of a protease (plasminogen activator) with a specific membrane fraction isolated from transformed cells.
The intracellular distribution of specific protease, plasminogen activator (PA), has been examined in Rous sarcoma virus-transformed chick embryo fibroblasts (RSV-CEF). Cellular homogenates were fractionated by differential centrifugation followed by sucrose gradient centrifugation. The activities and the percent distribution of a series of marker enzymes, specific for different subcellular organelles, were compared to those of PA. Normal CEF have been similarly fractionated and the relatively low amount of PA activity present in these cells has been analyzed in terms of its subcellular distribution. A membrane fraction was isolated from the RSV-CEF that contained the bulk of the PA activity and less than 8% of the total cellular protein. The specific activity of the PA in this fraction is 40-fold higher than that of a comparable fraction isolated from companion cultures of normal cells. This fraction contains little or no nuclear and cytoplasmic material and is contaminated only to a relatively small degree with mitochondria, lysosomes, endoplasmic reticulum. Significant amounts of a putative Golgi membrane marker are present in this fraction. The relatively high specific activities of Na+,K+-ATPase, 5'-nucleotidase, and [3H]fucose indicate that the fraction is enriched in surface membrane. Further purification of the fraction by equilibrium centrifugation on shallow sucrose gradients reduces further the contaminating activities and results in a PA distribution that closely parallels the distribution of the membrane enzyme, 5'-nucleotidase. PA was not released from its membrane association by hypotonic and hypertonic extraction and ultrasonication, while granule-bound enzymes were released by these treatments. The PA activity from hamster SV40 cells fractionated the same way as that of RSV-CEF. These results suggest that a protease that is dramatically enhanced upon malignant transformation is associated with "plasma membrane-like" elements of the cell and may serve as an intrinsic modifier of cell surface proteins after malignant transformation.


FHL1 is a major host factor for chikungunya virus infection.
Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1)3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o'nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblasts and muscle cells derived from patients with Emery-Dreifuss muscular dystrophy that lack functional FHL15 are resistant to CHIKV infection. Furthermore, CHIKV infection is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies.


KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment.
Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients.Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression.


Using ambient ozone for assignment of double bond position in unsaturated lipids.
Unsaturated lipids deposited onto a range of materials are observed to react with the low concentrations of ozone present in normal laboratory air. Parent lipids and ozonolysis cleavage products are both detected directly from surfaces by desorption electrospray ionisation mass spectrometry (DESI-MS) with the resulting mass spectra providing clear evidence of the double bond position within these molecules. This serendipitous process has been coupled with thin-layer chromatography (TLC) to provide a simple but powerful approach for the detailed structural elucidation of lipids present in complex biological extracts. Lipid extracts from human lens were deposited onto normal phase TLC plates and then developed to separate components according to lipid class. Exposure of the developed plates to laboratory air for ca. 1 h prior to DESI-MS analysis gave rise to ozonolysis products allowing for the unambiguous identification of double bond positions in even low abundant, unsaturated lipids. In particular, the co-localization of intact unsaturated lactosylceramides (LacCer) with products from their oxidative cleavage provide the first evidence for the presence of three isomeric LacCer (d18:0/24:1) species in the ocular lens lipidome, i.e., variants with double bonds at the n-9, n-7 and n-5 positions.


Follow-up after primary treatment for breast cancer.
Follow-up after primary treatment for breast cancer is a routine practice aiming at early detection and management of local recurrences and/or distant metastases of the disease or of new primaries. Breast self-examination and periodic physical examination, mammography, and pelvic examination are the most important methods in following-up these patients. The, at one time, more popular intensive routine diagnostic evaluation (including head, chest, abdominal, and pelvic computerized tomography and/or magnetic resonance imaging, liver ultrasonography, bone scans, tumor markers, etc.) is not currently considered appropriate and cost-effective. However, flexibility, based on clinical judgement, is required on the part of medical staff involved in the follow-up in order appropriately to adapt the general guidelines and meet the specific needs of the individual patients. Non-specialist or non-physician models of follow-up care have been proposed as interesting and cost-effective alternatives in the follow-up of breast cancer patients.


An fNIRS Investigation of Discrete and Continuous Cognitive Demands During Dual-Task Walking in Young Adults.
Introduction: Dual-task studies have demonstrated that walking is attention-demanding for younger adults. However, numerous studies have attributed this to task type rather than the amount of required to accomplish the task. This study examined four tasks: two discrete (i.e., short intervals of attention) and two continuous (i.e., sustained attention) to determine whether greater attentional demands result in greater dual-task costs due to an overloaded processing capacity. Methods: Nineteen young adults (21.5 ± 3.6 years, 13 females) completed simple reaction time (SRT) and go/no-go (GNG) discrete cognitive tasks and n-back (NBK) and double number sequence (DNS) continuous cognitive tasks with or without self-paced walking. Prefrontal cerebral hemodynamics were measured using functional near-infrared spectroscopy (fNIRS) and performance was measured using response time, accuracy, and gait speed. Results: Repeated measures ANOVAs revealed decreased accuracy with increasing cognitive demands (p = 0.001) and increased dual-task accuracy costs (p < 0.001). Response times were faster during the single compared to dual-tasks during the SRT (p = 0.005) and NBK (p = 0.004). DNS gait speed was also slower in the dual compared to single task (p < 0.001). Neural findings revealed marginally significant interactions between dual-task walking and walking alone in the DNS (p = 0.06) and dual -task walking compared to the NBK cognitive task alone (p = 0.05). Conclusion: Neural findings suggest a trend towards increased PFC activation during continuous tasks. Cognitive and motor measures revealed worse performance during the discrete compared to continuous tasks. Future studies should consider examining different attentional demands of motor tasks.


A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes.
Rates of esophageal adenocarcinoma and gastric cardia adenocarcinoma have increased, while rates of esophageal squamous cell carcinoma (ESCC) and gastric noncardia adenocarcinoma have decreased, suggesting distinct etiologies. The authors prospectively investigated the associations of alcohol and tobacco with these cancers in 474,606 US participants using Cox models adjusted for potential confounders. Between 1995/1996 and 2000, 97 incident cases of ESCC, 205 of esophageal adenocarcinoma, 188 of gastric cardia, and 187 of gastric noncardia cancer occurred. Compared with nonsmokers, current smokers were at increased risk for ESCC (hazard ratio (HR) = 9.27, 95% confidence interval (CI): 4.04, 21.29), esophageal adenocarcinoma (HR = 3.70, 95% CI: 2.20, 6.22), gastric cardia (HR = 2.86, 95% CI: 1.73, 4.70), and gastric noncardia (HR = 2.04, 95% CI: 1.32, 3.16). Assuming causality, ever smoking had population attributable risks of 77% (95% CI: 0.55, 0.89) for ESCC, 58% (95% CI: 0.38, 0.72) for esophageal adenocarcinoma, 47% (95% CI: 0.27, 0.63) for gastric cardia, and 19% (95% CI: 0.00, 0.37) for gastric noncardia. For drinkers of more than three alcoholic beverages per day, compared with those whose intake was up to one drink per day, the authors found significant associations between alcohol intake and ESCC risk (HR = 4.93, 95% CI: 2.69, 9.03) but not risk for esophageal, gastric cardia, or gastric noncardia adenocarcinoma.


Physical activity, exercise, depression and anxiety disorders.
There is a general belief that physical activity and exercise have positive effects on mood and anxiety and a great number of studies describe an association of physical activity and general well-being, mood and anxiety. In line, intervention studies describe an anxiolytic and antidepressive activity of exercise in healthy subjects and patients. However, the majority of published studies have substantial methodological shortcomings. The aim of this paper is to critically review the currently available literature with respect to (1) the association of physical activity, exercise and the prevalence and incidence of depression and anxiety disorders and (2) the potential therapeutic activity of exercise training in patients with depression or anxiety disorders. Although the association of physical activity and the prevalence of mental disorders, including depression and anxiety disorders have been repeatedly described, only few studies examined the association of physical activity and mental disorders prospectively. Reduced incidence rates of depression and (some) anxiety disorders in exercising subjects raise the question whether exercise may be used in the prevention of some mental disorders. Besides case series and small uncontrolled studies, recent well controlled studies suggest that exercise training may be clinically effective, at least in major depression and panic disorder. Although, the evidence for positive effects of exercise and exercise training on depression and anxiety is growing, the clinical use, at least as an adjunct to established treatment approaches like psychotherapy or pharmacotherapy, is still at the beginning. Further studies on the clinical effects of exercise, interaction with standard treatment approaches and details on the optimal type, intensity, frequency and duration may further support the clinical administration in patients. Furthermore, there is a lack of knowledge on how to best deal with depression and anxiety related symptoms which hinder patients to participate and benefit from exercise training.


Primary mental health care for survivors of collective sexual violence in Rwanda.
This paper draws attention to the obligation and opportunity to respond to the mental health impacts of collective sexual violence (CSV) among genocide-rape survivors in post-genocide Rwanda. Qualitative data gathered from CSV survivors who were members of Rwandan women's genocide survivor associations are presented to illustrate how they strive to overcome adversity while seeking access to quality mental health care and using informal community mental health services. The results reveal that a system of high quality, holistic health and mental health care is yet needed to meet Rwandan CSV survivors' complex and serious health and mental health needs. Given that a rural health system, modelled on community-based, comprehensive HIV/AIDS care and treatment, is currently being implemented in Rwanda, we recommend enhancements to this model that would contribute to meeting the mental health care needs of CSV survivors while benefiting the health and mental health system as a whole within Rwanda.


Dynamics of a paired optical vortex generated by second-harmonic generation.
We study the dynamics of a paired optical vortex (OV) generated by second-harmonic generation (SHG) using sub-picosecond pulses. By changing the position of a thin nonlinear crystal along the propagation direction, we observe a rotation of two vortices with changing separation distance. The dynamics is well explained by SHG with a beam walk-off, which introduces a contamination of zero-order Laguerre-Gaussian beam (LG(0)) together with topological charge doubling. The quantitative analysis indicates that the rotation angle of the OVs manifests the Gouy phase while the splitting provides the walk-off angle of the crystal. We also show that the subtraction of LG(0) is realized by the superposition of LG(0) with an anti-balanced phase in the pump.


Strategies for efficient and fast wave optics simulation of coded-aperture and other x-ray phase-contrast imaging methods.
We derive a Fourier formulation of coded-aperture x-ray phase-contrast imaging, based on the wave theory of optics in the Fresnel approximation. We use this model to develop a flexible, efficient, and general simulation algorithm that can be easily adapted to other implementations of x-ray phase contrast imaging. Likewise, the algorithm enables a simple extension to 2D aperture designs, different acquisition schemes, etc. Problems related to numerical implementation of the algorithm are analyzed in detail, and simple rules are derived that enable us to avoid or at least mitigate them. Finally, comparisons with experimental data and data obtained with a different simulation algorithm are presented to validate the model and demonstrate its advantages in practical implementations. This also enabled us to demonstrate an increase in computational speed of more than one order of magnitude over a previous algorithm.


The Unique Phylogenetic Position of a Novel Tick-Borne Phlebovirus Ensures an Ixodid Origin of the Genus Phlebovirus.
The recent emergence of novel tick-borne RNA viruses has complicated the epidemiological landscape of tick-borne infectious diseases, posing a significant challenge to public health systems that seek to counteract tick-borne diseases. The identification of two novel tick-borne phleboviruses (TBPVs), severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV), as causative agents of severe illness in humans has accelerated the investigation and discoveries of novel TBPVs. In the present study, we isolated a novel TBPV designated Mukawa virus (MKWV) from host-questing Ixodes persulcatus females captured in Japan. Genetic characterization revealed that MKWV is a member of the genus Phlebovirus in the family Phenuiviridae Interestingly, MKWV is genetically distinct from other known TBPVs and shares a most recent common ancestor with mosquito/sandfly-borne (insect-borne) phleboviruses. Despite its genetic similarity to insect-borne phleboviruses, the molecular footprints of its viral proteins and its biological characteristics define MKWV as a tick-borne virus that can be transmitted to mammals. A phylogenetic ancestral-state reconstruction for arthropod vectors of phleboviruses including MKWV based on viral L segment sequences indicated that ticks likely harbored ancestral phleboviruses that evolved into both the tick-borne and MKWV/insect-borne phlebovirus lineages. Overall, our findings suggest that most of the phlebovirus evolution has occurred in hard ticks to generate divergent viruses, which may provide a seminal foundation for understanding the mechanisms underlying the evolution and emergence of pathogenic phleboviruses, such as Rift Valley fever virus and SFTSV/HRTV.IMPORTANCE The emergence of novel tick-borne RNA viruses causing severe illness in humans has complicated the epidemiological landscape of tick-borne diseases, requiring further investigation to safeguard public health. In the present study, we discovered a novel tick-borne phlebovirus from Ixodes persulcatus ticks in Japan. While its viral RNA genome sequences were similar to those of mosquito/sandfly-borne viruses, molecular and biological footprints confirmed that this is a tick-borne virus. The unique evolutionary position of the virus allowed us to estimate the ancestral phlebovirus vector, which was likely a hard tick. Our findings may provide a better understanding of the evolution and emergence of phleboviruses associated with emerging infectious diseases, such as severe fever with thrombocytopenia syndrome (SFTS) and Heartland virus disease.


Interaction kinetics of oximes with native, phosphylated and aged human acetylcholinesterase.
Oximes are commonly used nucleophilic reactivators of alkyl phosphorylated and alkyl methylphosphonylated acetylcholinesterase (AChE) and butyrylcholinesterase. Covalent inhibition of these enzymes by organophosphate (OP) pesticides results typically in phosphorylated enzymes, while covalent inhibition by nerve agent OPs results in methyl phosphonylated cholinesterases. In this study we determined kinetic constants for interaction of three triazole containing oximes with native human AChE, enzyme diethylphosphorylated by paraoxon, enzyme phosphonylated by VX and cyclosarin as well as enzyme aged upon phosphonylation by soman. Stopped-flow kinetics of oxime interaction was monitored using quenching of intrinsic tryptophan fluorescence of AChE as an indicator of oxime binding. Triazole oximes were efficiently synthesized using copper catalyzed cycloaddition between azide and alkyne building blocks ("Click chemistry"). Equilibrium dissociation constants determined for both native enzymes were in low micromolar range for all three oximes, while dissociation constants for phosphylated (phosphorylated and phosphonylated) enzymes were typically one to two orders of magnitude larger. Dissociation constants for interaction with aged enzymes were similar or smaller than those determined for native enzymes. Similar results were obtained with reference oximes, 2PAM and HI6. Association rate constants for formation of oxime complexes were similar for both native, phosphylated and aged enzymes. In summary our data suggest that modification of active site gorge in AChEs by phosphylation of the active serine compromises oxime binding. Dealkylation of phosphonylated enzyme, however opens space in the gorge allowing oximes to bind tighter.


Physician practices in response to intimate partner violence in southern India: insights from a qualitative study.
Health care providers in India are often the only institutional contact for women experiencing intimate partner violence, a pervasive public health problem with adverse health outcomes. This qualitative study was among the first to examine Indian primary care physicians' intimate partner violence practices. Between July 2007 and January 2008, 30 in-depth interviews were conducted with physicians serving low-to-middle income women aged 18-30 in southern India. A modified grounded theory approach was used for data collection and analysis. Study findings revealed a distinct subset of 'physician champions' who responded to intimate partner violence more consistently, informed women of their rights, and facilitated their utilization of support services. Findings also offered insights into physicians' ability to identify indications of intimate partner violence and use of potentially culturally appropriate practices to respond to intimate partner violence, even without training. However, physician practices were mediated by individual attitudes. Although not generalizable, findings offer some useful lessons which may be transferable for adaptation to other settings. A potential starting point is to study physicians' current practices, focusing on their safety and efficacy, as well as enhancing these practices through appropriate training. Further research is also needed on women's perspectives on the appropriateness of physicians' practices, and women's recommendations for intimate partner violence intervention strategies.


Experimentally evoking nonbelieved memories for childhood events.
We report on the 1st experimental elicitation of nonbelieved memories for childhood events in adults (Study 1) and children (Study 2) using a modified false memory implantation paradigm. Participants received true (trip to a theme park) and false (hot air balloon ride) narratives and recalled these events during 2 interviews. After debriefing, 13% of adults and 15% of children reported nonbelieved memories. While phenomenal ratings were higher for true than for nonbelieved memories immediately after the debriefing, after a month nonbelieved memories behaved as true memories. Also following debriefing, 23% of adults and 15% of children retracted their false memory claims. Prior to debriefing, participants with nonbelieved memories were most likely to indicate remembering the event, whereas participants with false memories who retracted their claim were most likely to endorse believing but not remembering the event. This research suggests that debriefings in previous false memory studies can lead to the development of nonbelieved memories. Additional findings regarding the correspondence between subjective belief, subjective memory, and objective memory judgments prior to and following debriefing are discussed.


Reassessing the cost-effectiveness of meningococcal serogroup C conjugate (MCC) vaccines using a transmission dynamic model.
The meningococcal serogroup C conjugate (MCC) vaccination program has successfully reduced morbidity and mortality from serogroup C disease in England and Wales, owing to high short-term vaccine effectiveness and substantial herd immunity. The latter effect was not accounted for in the previous economic analysis of the MCC program. The authors applied a transmission dynamic model, which accounts for herd immunity, to reevaluate the cost-effectiveness of MCC vaccination. The direct and indirect benefits of the MCC vaccine strategy implemented in England and Wales were compared. The cost-effectiveness of alternative MCC vaccine strategies, including future changes to the current schedule, were evaluated. The authors found that including herd immunity improved the average cost-effectiveness ratio in all cases, although the extent depended on the vaccine strategy considered. Incremental analysis showed that those strategies that offered 1 dose early in the 2nd year of life dominated strategies that offered 3 doses of vaccine in infancy and that catch-up vaccination up to the age of 18 years was also highly attractive. Furthermore, the authors analyzed the effect of future changes to the routine vaccine schedule and predicted that shifting the age at routine vaccination from 2, 3, and 4 months (3 doses) to 12 months (1 dose) resulted in a net gain in the total number of cases prevented with only a few extra cases occurring in children under 1 year of age. This program dominated the current strategy. Models that do not include the indirect effects of vaccination will underestimate the impact of MCC vaccination and may lead to distorted decision making.


Joint Pairing and Structured Mapping of Convolutional Brain Morphological Multiplexes for Early Dementia Diagnosis.
Diagnosis of brain dementia, particularly early mild cognitive impairment (eMCI), is critical for early intervention to prevent the onset of Alzheimer's disease, where cognitive decline is severe and irreversible. There is a large body of machine-learning-based research investigating how dementia alters brain connectivity, mainly using structural (derived from diffusion magnetic resonance imaging [MRI]) and functional (derived from resting-state functional MRI) brain connectomic data. However, how early dementia affects cortical brain connections in morphology remains largely unexplored. To fill this gap, we propose a joint morphological brain multiplexes pairing and mapping strategy for eMCI detection, where a brain multiplex not only encodes the relationship in morphology between pairs of brain regions but also a pair of brain morphological networks. Experimental results confirm that the proposed framework outperforms in classification accuracy several state-of-the-art methods. More importantly, we unprecedentedly identified most discriminative brain morphological networks between eMCI and normal control (NC), which included the paired views derived from maximum principal curvature and the sulcal depth for the left hemisphere, and sulcal depth and the average curvature for the right hemisphere. We also identified the most highly correlated morphological brain connections in our cohort, which included the pericalcarine cortex and insula cortex on the maximum principal curvature view, entorhinal cortex and insula cortex on the mean sulcal depth view, and entorhinal cortex and pericalcarine cortex on the mean average curvature view for both hemispheres. These highly correlated morphological connections might serve as biomarkers for eMCI diagnosis.


Near-surface processing on AlGaN/GaN heterostructures: a nanoscale electrical and structural characterization.
The effects of near-surface processing on the properties of AlGaN/GaN heterostructures were studied, combining conventional electrical characterization on high-electron mobility transistors (HEMTs), with advanced characterization techniques with nanometer scale resolution, i.e., transmission electron microscopy, atomic force microscopy (AFM) and conductive atomic force microscopy (C-AFM). In particular, a CHF3-based plasma process in the gate region resulted in a shift of the threshold voltage in HEMT devices towards less negative values. Two-dimensional current maps acquired by C-AFM on the sample surface allowed us to monitor the local electrical modifications induced by the plasma fluorine incorporated in the material.The results are compared with a recently introduced gate control processing: the local rapid thermal oxidation process of the AlGaN layer. By this process, a controlled thin oxide layer on surface of AlGaN can be reliably introduced while the resistance of the layer below increase locally.


'Prior entry' for pain: attention speeds the perceptual processing of painful stimuli.
We investigated whether the perception of simultaneity for pairs of nociceptive and visual stimuli was dependent upon the focus of participants' attention to a particular sensory modality (either pain or vision). Two stimuli (one painful and the other visual) were presented randomly at different stimulus onset asynchronies (SOAs) using the method of constant stimuli. Participants made unspeeded verbal responses as to which stimulus they perceived as having been presented first, or else responded that the two stimuli were presented simultaneously. This temporal discrimination task was repeated under three different attention conditions (blocks): divided attention, attend pain, and attend vision. The results showed that under conditions of divided attention, nociceptive stimuli had to be presented before visual stimuli in order for the two to be perceived as simultaneous. A comparison of the two focused attention conditions revealed that the painful stimulus was perceived as occurring earlier in time (relative to the visual stimulus) when attention was directed toward pain than when it was directed toward vision. These results provide the first empirical demonstration that attention can modulate the temporal perception of painful stimuli.


Behavior of extraordinary rays in uniaxial crystals.
We have experimentally investigated the behavior of extraordinary rays (E rays) in uniaxial crystals for two cases: that in which optical axes are parallel to the surfaces and that in which they are inclined. The E ray always rotates around the ordinary ray (O ray) in the same direction that the crystal rotates around its surface normal. For the case when the axes are parallel to the surface, we discovered that the E ray rotates up to α = 2π as the crystal rotates to ? = π. The E ray traces a series of ellipses as the angle of incidence is varied. Snell's law is valid for the E ray only when the optical axes are perpendicular to the plane of incidence. For the case in which the optical axes are incident, the E ray and the crystal rotate at different speeds except for the case of normal incidence. The speed of rotation increases with the incidence angle. The ray traces a curve known as the Pascal worm, which is described by the equation (x(2) + z(2) - mx)(2) = n(2)(x(2) + z(2)). When the optical axes coincide with the plane of incidence, the space between the rays in the plane is not related to the angle of incidence.


Monte Carlo based method for fluorescence tomographic imaging with lifetime multiplexing using time gates.
Time-resolved fluorescence optical tomography allows 3-dimensional localization of multiple fluorophores based on lifetime contrast while providing a unique data set for improved resolution. However, to employ the full fluorescence time measurements, a light propagation model that accurately simulates weakly diffused and multiple scattered photons is required. In this article, we derive a computationally efficient Monte Carlo based method to compute time-gated fluorescence Jacobians for the simultaneous imaging of two fluorophores with lifetime contrast. The Monte Carlo based formulation is validated on a synthetic murine model simulating the uptake in the kidneys of two distinct fluorophores with lifetime contrast. Experimentally, the method is validated using capillaries filled with 2.5nmol of ICG and IRDye™800CW respectively embedded in a diffuse media mimicking the average optical properties of mice. Combining multiple time gates in one inverse problem allows the simultaneous reconstruction of multiple fluorophores with increased resolution and minimal crosstalk using the proposed formulation.


Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance.
We examined effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 1145 h, on sleep latency and duration, mood, performance, oral temperature, and changes in serum melatonin levels in 20 healthy male volunteers. A repeated-measure double-blind Latin square design was used. Subjects completed a battery of tests designed to assess mood and performance between 0930 and 1730 h. The sedative-like effects of melatonin were assessed by a simple sleep test: at 1330 h subjects were asked to hold a positive pressure switch in each hand and to relax with eyes closed while reclining in a quiet darkened room. Latency and duration of switch release, indicators of sleep, were measured. Areas under the time-melatonin concentration curve varied in proportion to the different melatonin doses ingested, and the 0.1- and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatonin doses tested significantly increased sleep duration, as well as self-reported sleepiness and fatigue, relative to placebo. Moreover, all of the doses significantly decreased sleep-onset latency, oral temperature, and the number of correct responses on the Wilkinson auditory vigilance task. These data indicate that orally administered melatonin can be a highly potent hypnotic agent; they also suggest that the physiological increase in serum melatonin levels, which occurs around 2100 h daily, may constitute a signal initiating normal sleep onset.


The stress system in the human brain in depression and neurodegeneration.
Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.


Characterization of pro-inflammatory flagellin proteins produced by Lactobacillus ruminis and related motile Lactobacilli.
Lactobacillus ruminis is one of at least twelve motile but poorly characterized species found in the genus Lactobacillus. Of these, only L. ruminis has been isolated from mammals, and this species may be considered as an autochthonous member of the gastrointestinal microbiota of humans, pigs and cows. Nine L. ruminis strains were investigated here to elucidate the biochemistry and genetics of Lactobacillus motility. Six strains isolated from humans were non-motile while three bovine isolates were motile. A complete set of flagellum biogenesis genes was annotated in the sequenced genomes of two strains, ATCC25644 (human isolate) and ATCC27782 (bovine isolate), but only the latter strain produced flagella. Comparison of the L. ruminis and L. mali DSM20444(T) motility loci showed that their genetic content and gene-order were broadly similar, although the L. mali motility locus was interrupted by an 11.8 Kb region encoding rhamnose utilization genes that is absent from the L. ruminis motility locus. Phylogenetic analysis of 39 motile bacteria indicated that Lactobacillus motility genes were most closely related to those of motile carnobacteria and enterococci. Transcriptome analysis revealed that motility genes were transcribed at a significantly higher level in motile L. ruminis ATCC27782 than in non-motile ATCC25644. Flagellin proteins were isolated from L. ruminis ATCC27782 and from three other Lactobacillus species, while recombinant flagellin of aflagellate L. ruminis ATCC25644 was expressed and purified from E. coli. These native and recombinant Lactobacillus flagellins, and also flagellate L. ruminis cells, triggered interleukin-8 production in cultured human intestinal epithelial cells in a manner suppressed by short interfering RNA directed against Toll-Like Receptor 5. This study provides genetic, transcriptomic, phylogenetic and immunological insights into the trait of flagellum-mediated motility in the lactobacilli.


Decoding go/no-go decisions from eye movements.
Neural activity in brain areas involved in the planning and execution of eye movements predicts the outcome of an upcoming perceptual decision. Many real-world decisions, such as whether to swing at a baseball pitch, are accompanied by characteristic eye-movement behavior. Here we ask whether human eye-movement kinematics can sensitively predict decision outcomes in a go/no-go task requiring rapid interceptive hand movements. Observers (n = 45) viewed a moving target that passed through or missed a designated strike box. Critically, the target disappeared briefly after launch, and observers had to predict the target's trajectory, withholding a hand movement if it missed (no-go) or intercepting inside the strike box (go). We found that go/no-go decisions were reflected in distinct eye-movement responses on a trial-by-trial basis: Eye-position error and targeting-saccade dynamics predicted decision outcome with 76% accuracy across conditions. Model prediction accuracy was related to observers' decision accuracy across different levels of task difficulty and sensory-signal strength. Our findings suggest that eye movements provide a sensitive and continuous readout of internal neural decision-making processes and reflect decision-task requirements in human observers.


Role of Rubia cordifolia Linn. in radiation protection.
The radioprotective potential of alcoholic extract of root of R. cordifolia, was studied by survival, hemopoietic cell protection and micronucleus assay. The LD50 value for the alcoholic root extract was found to be 1200 mg/kg body weight at 72 hr post irradiation. A significant radiation protection (67%) as assessed by increased animal survival was observed when R. cordifolia (RC) extract was administered intraperitoneally, 90 min. before the radiation exposure. Besides, the extract also inhibited radiation induced lipid peroxidation measured by the inhibition of thiobarbituric acid reactive substance (TBARS). The RC extract at a selected dose of 460 mg/kg body weight was effective in protecting the radiation induced suppression of endogenous colony forming units in spleen. A significant inhibition of radiation (2 Gy) induced micronuclei formation was observed when RC extract was administered 90 min prior to irradiation. Thus, it appears that the alcoholic root extract of R. cordifolia provides significant protection against radiation induced lipid peroxidation, hemopoietic injury and genotoxicity. The mechanism of action of RC extract appears to be through its anti-oxidant, metal chelation and anti-inflammatory property.


Distribution and diversity of mycoplasma plasmids: lessons from cryptic genetic elements.
The evolution of mycoplasmas from a common ancestor with Firmicutes has been characterized not only by genome down-sizing but also by horizontal gene transfer between mycoplasma species sharing a common host. The mechanisms of these gene transfers remain unclear because our knowledge of the mycoplasma mobile genetic elements is limited. In particular, only a few plasmids have been described within the Mycoplasma genus. We have shown that several species of ruminant mycoplasmas carry plasmids that are members of a large family of elements and replicate via a rolling-circle mechanism. All plasmids were isolated from species that either belonged or were closely related to the Mycoplasma mycoides cluster; none was from the Mycoplasma bovis-Mycoplasma agalactiae group. Twenty one plasmids were completely sequenced, named and compared with each other and with the five mycoplasma plasmids previously reported. All plasmids share similar size and genetic organization, and present a mosaic structure. A peculiar case is that of the plasmid pMyBK1 from M. yeatsii; it is larger in size and is predicted to be mobilizable. Its origin of replication and replication protein were identified. In addition, pMyBK1 derivatives were shown to replicate in various species of the M. mycoides cluster, and therefore hold considerable promise for developing gene vectors. The phylogenetic analysis of these plasmids confirms the uniqueness of pMyBK1 and indicates that the other mycoplasma plasmids cluster together, apart from the related replicons found in phytoplasmas and in species of the clade Firmicutes. Our results unraveled a totally new picture of mycoplasma plasmids. Although they probably play a limited role in the gene exchanges that participate in mycoplasma evolution, they are abundant in some species. Evidence for the occurrence of frequent genetic recombination strongly suggests they are transmitted between species sharing a common host or niche.


Conjunctival melanoma treatment outcomes in 288 patients: a multicentre international data-sharing study.
To relate conjunctival melanoma characteristics to local control. Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. 288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.


Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers.
The treatment of obesity is an increasing global health priority, yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. The aim of this study was to examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. Using a between-subjects, double-blind, placebo-controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15- or 30-mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate, and the participants completed the P1vital® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. mCPP reduced appetite and, in women, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs.


Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling.
Many tumors have chronically elevated activity of PI 3-kinase-dependent signaling pathways, caused largely by oncogenic mutation of PI 3-kinase itself or loss of the opposing tumor suppressor lipid phosphatase, PTEN. Several PI 3-kinase-dependent feedback mechanisms have been identified that may affect the sensitivity of upstream receptor signaling, but the events required to initiate an inhibited state have not been addressed. We show that in a variety of cell types, loss of PTEN via experimental knockdown or in tumor cell lines correlates with a block in insulin-like growth factor 1 (IGF1)/insulin signaling, without affecting the sensitivity of platelet-derived growth factor or epidermal growth factor signaling. These effects on IGF/insulin signaling include a reduction of up to five- to tenfold in IGF-stimulated PI 3-kinase activation, a failure to activate the ERK kinases and, in some cells, reduced expression of insulin receptor substrate 1, and both IGF1 and insulin receptors. These data indicate that chronically elevated PI 3-kinase-dependent signaling to the degree seen in many tumors causes a selective loss of sensitivity in IGF1/insulin signaling that could significantly reduce the selective advantage of deregulated activation of IGF1/IGF1-R signaling in tumor development.


Traditional medical uses of Drimia species in terms of phytochemistry, pharmacology and toxicology.
Drimia genus includes plants that used from ancient time for various ailments such as dropsy, respiratory ailment, bone and joint complications, skin disorders, epilepsy and cancer. Toxic properties of some Drimia species also were noted by ancient scientists and these plants have been traditionally used for rat control. Bufadienolides have been identified as the main constituents in the genus of Drimia. Phenolics, sterols, protein and some of other phytochemicals have been also isolated from these plants. Pharmacological and clinical studies have strongly approved their effect on cardiovascular system. Extracts and compounds isolated from Drimia species showed biological activities such as antibacterial, antifungal, antiviral, antioxidant, anti-inflammatory and insecticidal effects through several in vivo and in vitro studies. Moreover, cytotoxic and antitumor activities which may be related to bufadienolide content of these plants have been considered by many researchers. Traditional therapeutic values of these plants for treating respiratory and rheumatic ailments as well as skin disorders are needed to be validated through more researches. Toxic effects of these plants and isolated compounds have been investigated through several in vivo studies. Drimia plants and their isolated compounds have narrow therapeutic index, so patients should be prohibited from applying these plants without medical supervision and should be informed about the main intoxication symptoms before starting treatment. Moreover, interaction of Drimia plants with other constituents of traditional herbal mixtures as well as chemical and biological modalities for reducing toxicity of bufadienolide compounds can be subjected for future studies.


Music Tuned to 440 Hz Versus 432 Hz and the Health Effects: A Double-blind Cross-over Pilot Study.
The current reference frequency for tuning musical instruments is 440 Hz. Some theorists and musicians claim that the 432 Hz tuning has better effects on the human body, but there are no scientific studies that support this hypothesis. To identify differences in vital parameters and perceptions after listening to music at different frequencies, 440 Hz versus 432 Hz. Cross-over pilot study. A room dedicated to listening to music, in an Italian city. 33 volunteers, not suffering from acute and/or chronic diseases. Two sessions of music listening on different days. Both sessions used the same music (movie soundtracks) but tuned to 440 Hz on one day and 432 Hz on the other. Each session consisted of 20 min' listening. Vital parameters (blood pressure, heart rate, respiratory rate, oxygen saturation), perceptions (physical and emotional sensations, for example fatigue and stress), levels of concentration during the listening session, and general satisfaction with the experience. 432 Hz tuned music was associated with a slight decrease of mean (systolic and diastolic) blood pressure values (although not significant), a marked decrease in the mean of heart rate (-4.79 bpm, p = 0.05) and a slight decrease of the mean respiratory rate values (1 r.a., p = 0.06), compared to 440 Hz. The subjects were more focused about listening to music and more generally satisfied after the sessions in which they listened to 432 Hz tuned music. The data suggests that 432 Hz tuned music can decrease heart rate more than 440 Hz tuned music. The study results suggest repeating the experiment with a larger sample pool and introducing randomized controlled trials covering more clinical parameters.


Exon-trapping mediated by the human retrotransposon SVA.
Although most human retrotransposons are inactive, both inactive and active retrotransposons drive genome evolution and may influence transcription through various mechanisms. In humans, three retrotransposon families are still active, but one of these, SVA, remains mysterious. Here we report the identification of a new subfamily of SVA, which apparently formed after an alternative splicing event where the first exon of the MAST2 gene spliced into an intronic SVA and subsequently retrotransposed. Additional examples of SVA retrotransposing upstream exons due to splicing into SVA were also identified in other primate genomes. After molecular and computational experiments, we found a number of functional 3' splice sites within many different transcribed SVAs across the human and chimpanzee genomes. Using a minigene splicing construct containing an SVA, we observed splicing in cell culture, along with SVA exonization events that introduced premature termination codons (PTCs). These data imply that an SVA residing within an intron in the same orientation as the gene may alter normal gene transcription either by gene-trapping or by introducing PTCs through exonization, possibly creating differences within and across species.


Locally-referenced ultrasonic--LPS for localization and navigation.
This paper presents a flexible deployment of ultrasonic position sensors and a novel positioning algorithm suitable for the navigation of mobile robots (MRs) in extensive indoor environments. Our proposal uses several independently-referenced local positioning systems (LPS), which means that each one of them operates within its own local reference system. In a typical layout, an indoor extensive area can be covered using just a reduced set of globally-referenced LPS (GRLPS), whose beacon positions are known to the global reference system, while the rest of the space can be covered using locally-referenced LPSs (LRLPS) that can be distributed arbitrarily. The number of LRLPS and their position can be also changed at any moment. The algorithm is composed of several Bayesian filters running in parallel, so that when an MR is under the GRLPS coverage area, its position is updated by a global filter, whereas when the MR is inside the LRLPS area, its position is updated using position increments within a local filter. The navigation algorithm has been tested by simulation and with actual data obtained using a real set of ultrasonic LPSs.


Development and validation of the Speech Reception in Noise (SPRINT) Test.
Since 1992, the Speech Recognition in Noise Test, or SPRINT, has been the standard speech-in-noise test for assessing auditory fitness-for-duty of US Army Soldiers with hearing loss. The original SPRINT test consisted of 200 monosyllabic words presented at a Signal-to-Noise Ratio (SNR) of +9 dB in the presence of a six-talker babble noise. Normative data for the test was collected on 319 hearing impaired Soldiers, and a procedure for making recommendations about the disposition of military personnel on the basis of their SPRINT score and their years of experience was developed and implemented as part of US Army policy. In 2013, a new 100-word version of the test was developed that eliminated words that were either too easy or too hard to make meaningful distinctions among hearing impaired listeners. This paper describes the development of the original 200-word SPRINT test, along with a description of the procedure used to reduce the 200-word test to 100 words and the results of a validation study conducted to evaluate how well the shortened 100-word test is able to capture the results from the full 200-word version of the SPRINT.


ROCO kinase activity is controlled by internal GTPase function.
Small guanosine triphosphatases (GTPases) have long been known to control the activities of downstream protein kinases. Some members of a rather new multidomain protein family contain not only a GTPase domain of the ROC (Ras of complex protein) subtype but also a protein kinase domain, and both domains seem to cooperate with each other in the same polypeptide. Data now show that the kinase activity of one of these ROCO proteins depends on whether guanosine diphosphate or guanosine triphosphate (GTP) is bound and that the activity is controlled by the adjacent GTPase, which suggests a novel mechanism of intrinsic control. This ROCO family member, leucine-rich repeat kinase 2 (LRRK2), is of special interest because mutations within both its protein kinase and its GTPase domains are associated with Parkinson's disease (PD). These mutations lead to abnormally enhanced protein kinase activity, which is believed to cause or at least contribute to neuronal damage. The crystal structure of the GTPase domain of LRRK2 has now been resolved and shows that the ROC GTPase domain is responsible for LRRK2 homodimerization in a surprising way. The structure not only offers insights into the molecular effects of some of the PD-associated mutations of LRRK2, but may also help to improve our understanding of the intrinsic control mechanism between a GTPase and a protein kinase within the same protein.


Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence.
Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novoEGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.


To Serve or Not to Serve: Ethical and Policy Implications.
The Institute of Medicine (IOM) is one of the nation's more influential health-related non-profit organizations. It plays a large role in shaping health policy by commissioning panels to develop "white papers" describing research and recommendations on a variety of health topics. These white paper publications are often used to help make policy decisions at the legislative and executive levels. Such a prominent institution might seem like a natural ally for policy-related collaborative efforts. As community psychologists, we strongly endorse efforts to positively influence public policy at the national level. However, while serving on influential panels and commissions like the IOM might seem to be very much part of the ethos of our discipline, there are occasions when such institutions are pursuing a mission that inadvertently has the potential to instigate divisive friction among community activists and organizations. A case study is presented whereby I describe my decision not to accept an invitation to serve on a controversial IOM panel. I explore the ethical challenges regarding maintaining my independence from this institution and its attempt to redefine chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), as well as the process of searching for alternative avenues for collaborating with community activists to influence policy related to these debilitating illnesses.


Comparison of microscopy, culture, and conventional polymerase chain reaction for detection of blastocystis sp. in clinical stool samples.
We tested 513 stool samples from patients in Sydney, Australia for Blastocystis by using five diagnostic techniques: microscopy of a permanently stained smear using a modified iron-hematoxylin stain, two xenic culture systems (a modified Boeck and Drbohlav's medium and tryptone, yeast extract, glucose, methionine-9 medium), and two published conventional polymerase chain reaction methods specific for the small subunit ribosomal DNA. Ninety-eight (19%) samples were positive for Blastocystis in one or more of the diagnostic techniques. The PCR 2 method was the most sensitive at detecting Blastocystis with a sensitivity of 94%, and the least sensitive was microscopy of the permanent stain (48%). Subtype 3 was the most predominant subtype (present in 43% of samples assigned to this group). This study highlights the low sensitivity of microscopy when used as the sole diagnostic modality for detection of Blastocystis sp.


Attitudes of patients and care providers to enhanced recovery after surgery programs after major abdominal surgery.
Enhanced recovery after surgery (ERAS) is a well-established pathway of perioperative care in surgery in an increasing number of specialties. To implement protocols and maintain high levels of compliance, continued support from care providers and patients is vital. This survey aimed to assess the perceptions of care providers and patients of the relevance and importance of the ERAS targets and strategies. Pre- and post-operative surveys were completed by patients who underwent major hepatic, colorectal, or oesophagogastric surgery in three major centers in Scotland, Norway, and The Netherlands. Anonymous web-based and article surveys were also sent to surgeons, anesthetists, and nurses experienced in delivering enhanced recovery protocols. Each questionnaire asked the responder to rate a selection of enhanced recovery targets and strategies in terms of perceived importance. One hundred nine patients and 57 care providers completed the preoperative survey. Overall, both patients and care providers rated the majority of items as important and supported ERAS principles. Freedom from nausea (median, 10; interquartile range [IQR], 8-10) and pain at rest (median, 10; IQR, 8-10) were the care components rated the highest by both patients and care providers. Early return of bowel function (median, 7; IQR, 5-8) and avoiding preanesthetic sedation (median, 6; IQR, 3.75-8) were scored the lowest by care providers. ERAS principles are supported by both patients and care providers. This is important when attempting to implement and maintain an ERAS program. Controversies still remain regarding the relative importance of individual ERAS components.


Consumer estimation of recommended and actual calories at fast food restaurants.
Recently, localities across the United States have passed laws requiring the mandatory labeling of calories in all chain restaurants, including fast food restaurants. This policy is set to be implemented at the federal level. Early studies have found these policies to be at best minimally effective in altering food choice at a population level. This paper uses receipt and survey data collected from consumers outside fast food restaurants in low-income communities in New York City (NYC) (which implemented labeling) and a comparison community (which did not) to examine two fundamental assumptions necessary (though not sufficient) for calorie labeling to be effective: that consumers know how many calories they should be eating throughout the course of a day and that currently customers improperly estimate the number of calories in their fast food order. Then, we examine whether mandatory menu labeling influences either of these assumptions. We find that approximately one-third of consumers properly estimate that the number of calories an adult should consume daily. Few (8% on average) believe adults should be eating over 2,500 calories daily, and approximately one-third believe adults should eat lesser than 1,500 calories daily. Mandatory labeling in NYC did not change these findings. However, labeling did increase the number of low-income consumers who correctly estimated (within 100 calories) the number of calories in their fast food meal, from 15% before labeling in NYC increasing to 24% after labeling. Overall knowledge remains low even with labeling. Additional public policies likely need to be considered to influence obesity on a large scale.


Antileishmanial Activity and Synergistic Effects of Amphotericin B Deoxycholate with Allicin and Andrographolide against Leishmania martiniquensis In Vitro.
Leishmania (Mundinia) martiniquensis is a causative agent of visceral leishmaniasis, but in HIV-infected patients both visceral and disseminated cutaneous leishmaniasis are presented. Recurrence of the disease after treatment has been reported in some cases indicating that improved chemotherapy is required. In this study, the susceptibility of L. martiniquensis to Amphotericin B deoxycholate (AmB), allicin, and andrographolide was evaluated and the synergistic effects of allicin or andrographolide combined with AmB against L. martiniquensis intracellular amastigotes in mouse peritoneal exudate macrophages (PEMs) were investigated in vitro for the first time. The results showed that L. martiniquensis was highly susceptible to AmB as expected, but allicin and andrographolide had selectivity index (SI) values greater than 10, indicating promise in both compounds for treatment of host cells infected with L. martiniquensis. Four AmB/allicin combinations presented combination index (CI) values less than 1 (0.58-0.68) for intracellular amastigotes indicating synergistic effects. The combination with the highest dose reduction index (DRI) allowed an approximately four-fold reduction of AmB use in that combination. No synergistic effects were observed in AmB/andrographolide combinations. The data provided in this study leads for further study to develop novel therapeutic agents and improve the treatment outcome for leishmaniasis caused by this Leishmania species.


Induction of c-fos expression in hypothalamic magnocellular neurons requires synaptic activation and not simply increased spike activity.
Magnocellular neurons of the hypothalamic supraoptic nucleus have been shown to express the immediate-early gene c-fos in a number of experimental and physiological circumstances. In each case the induction of the immediate-early gene followed the increase in the spike activity of the cells. Since an increase in the intracellular concentration of calcium following influx through voltage-sensitive calcium channels is a known stimulus for c-fos expression and since the action potentials of these neurons have a large calcium component, we hypothesized that c-fos induction in these neurons could be attributed to calcium influx during spike activity. In the present experiments we use extracellular recording and immunocytochemistry for Fos, the protein product of c-fos, to demonstrate the activation of the cells following intracerebroventricular administration of the muscarinic agonist, carbachol. Fos expression following carbachol injection was then compared with that induced by a similar number of antidromically evoked action potentials. Antidromic activation, unlike the activation induced by carbachol, did not lead to the induction of Fos. We conclude that Fos induction in these neurons requires receptor activation rather than spike activity.


Comparison of non-directive counselling and cognitive behaviour therapy for patients presenting in general practice with an ICD-10 depressive episode: a randomized control trial.
Most evidence in the UK on the effectiveness of brief therapy for depression concerns cognitive behaviour therapy (CBT). In a trial published in 2000, we showed that non-directive counselling and CBT were equally effective in general practice for patients with depression and mixed anxiety and depression. Our results were criticized for including patients not meeting diagnostic criteria for a depressive disorder. In this reanalysis we aimed to compare the effectiveness of the two therapies for patients with an ICD-10 depressive episode. Patients with an ICD-10 depressive episode or mixed anxiety and depression were randomized to counselling, CBT or usual general practitioner (GP) care. Counsellors provided nondirective, interpersonal counselling following a manual that we developed based on the work of Carl Rogers. Cognitive behaviour therapists provided CBT also guided by a manual. Modelling was carried out using generalized estimating equations with the multiply imputed datasets. Outcomes were mean scores on the Beck Depression Inventory, Brief Symptom Inventory, and Social Adjustment Scale at 4 and 12 months. A total of 134 participants were randomized to CBT, 126 to counselling and 67 to usual GP care. We undertook (1) an interaction analysis using all 316 patients who were assigned a diagnosis and (2) a head-to-head comparison using only those 130 (41%) participants who had an ICD-10 depressive episode at baseline. CBT and counselling were both superior to GP care at 4 months but not at 12 months. There was no difference in the effectiveness of the two psychological therapies. We recommend that national clinical guidelines take our findings into consideration in recommending effective alternatives to CBT.


Structure and regulation of a complex locus: the cut gene of Drosophila.
The cut locus encodes a homeobox protein that is localized in the nuclei of a variety of tissues and is required for proper morphogenesis of those tissues. Cut protein is required in embryonic and adult external sensory organs, where its absence results in conversion of the organs to chordotonal organs. Expression of cut also occurs in the Malpighian tubules, spiracles, central nervous system, and a number of other tissues. Gypsy transposon insertions upstream of the cut promoter block expression in subsets of these tissues. The effect of the gypsy insertions is polar, with those farthest from the promoter affecting the fewest tissues. The hypothesis that gypsy insertions block a series of tissue-specific enhancer elements that are distributed over a region of 80 kb upstream of the promoter predicts the location of the enhancers for cut expression in each of the tissues in which it is active in embryos. DNA fragments from this region drive expression of a reporter gene in each of the embryonic tissues in which endogenous cut gene is expressed. Each tissue has its own enhancer, and none of the enhancers require the activity of the endogenous cut gene to function.


Challenges to a molecular approach to prey identification in the Burmese python, Python molurus bivittatus.
Molecular approaches to prey identification are increasingly useful in elucidating predator-prey relationships, and we aimed to investigate the feasibility of these methods to document the species identities of prey consumed by invasive Burmese pythons in Florida. We were particularly interested in the diet of young snakes, because visual identification of prey from this size class has proven difficult. We successfully extracted DNA from the gastrointestinal contents of 43 young pythons, as well as from several control samples, and attempted amplification of DNA mini-barcodes, a 130-bp region of COX1. Using a PNA clamp to exclude python DNA, we found that prey DNA was not present in sufficient quality for amplification of this locus in 86% of our samples. All samples from the GI tracts of young pythons contained only hair, and the six samples we were able to identify to species were hispid cotton rats. This suggests that young Burmese pythons prey predominantly on small mammals and that prey diversity among snakes of this size class is low. We discuss prolonged gastrointestinal transit times and extreme gastric breakdown as possible causes of DNA degradation that limit the success of a molecular approach to prey identification in Burmese pythons.


Social capital and self-rated health: a contextual analysis.
Social capital consists of features of social organization--such as trust between citizens, norms of reciprocity, and group membership--that facilitate collective action. This article reports a contextual analysis of social capital and individual self-rated health, with adjustment for individual household income, health behaviors, and other covariates. Self-rated health ("Is your overall health excellent, very good, good, fair, or poor?") was assessed among 167,259 individuals residing in 39 US states, sampled by the Behavioral Risk Factor Surveillance System. Social capital indicators, aggregated to the state level, were obtained from the General Social Surveys. Individual-level factors (e.g., low income, low education, smoking) were strongly associated with self-rated poor health. However, even after adjustment for these proximal variables, a contextual effect of low social capital on risk of self-rated poor health was found. For example, the odds ratio for fair or poor health associated with living in areas with the lowest levels of social trust was 1.41 (95% confidence interval = 1.33, 1.50) compared with living in high-trust states. These results extend previous findings on the health advantages stemming from social capital.


Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis.
Several scoring systems have been used to predict mortality in patients with community-acquired pneumonia. The properties of commonly used risk stratification scales were systematically reviewed. MEDLINE and EMBASE (January 1999-October 2009) were searched for prospective studies that reported mortality at 4-8 weeks in patients with radiographically-confirmed community-acquired pneumonia. The search focused on the Pneumonia Severity Index (PSI) and the three main iterations of the CURB (confusion, urea nitrogen, respiratory rate, blood pressure) scale (CURB-65, CURB, CRB-65), and test performance was evaluated based on 'higher risk' categories as follows: PSI class IV/V, CURB-65 (score ≥ 3), CURB (score ≥ 2) and CRB-65 (score ≥ 2). Random effects meta-analysis was used to generate summary statistics of test performance and receiver operating characteristic curves were used for predicting mortality. 402 articles were screened and 23 studies involving 22,753 participants (average mortality 7.4%) were retrieved. The respective diagnostic odds ratios for mortality were 10.77 (PSI), 6.40 (CURB-65), 5.97 (CRB-65) and 5.75 (CURB). Overall, PSI had the highest sensitivity and lowest specificity for mortality, CRB-65 was the most specific (but least sensitive) test and CURB-65/CURB were between the two. Negative predictive values for mortality were similar among the tests, ranging from 0.94 (CRB-65) to 0.98 (PSI), whereas positive predictive values ranged from 0.14 (PSI) to 0.28 (CRB-65). The current risk stratification scales (PSI, CURB-65, CRB-65 and CURB) have different strengths and weaknesses. All four scales had good negative predictive values for mortality in populations with a low prevalence of death but were less useful with regard to positive predictive values.


Ethical decision-making in newborn infants.
One ethical dilemma which neonatologists are faced with on a regular basis is selective non-treatment, that is, clinical decisions made after the birth of a liveborn infant to withhold or to withdraw treatment in certain circumstances. Although the outcome of extremely preterm of critically ill infants has significantly improved over the last decade, many are often left to die at birth by withholding resuscitation or neonatal intensive care. Criteria for initiating life-sustaining treatment must be developed with proper ethical considerations. There are other infants whose clinical course after initiation of intensive care will suggest that further curative efforts are futile or lack compensating benefit. Criteria for withdrawing life-sustaining treatment must also be developed, and palliative care measures defined. Clinical situations in which selective non-treatment is taking place in neonatal medicine are: (1) when death is considered to be inevitable whatever treatment is provided, (2) even when death is not inevitable, there is a significantly high risk of severe physical and mental disability should the infant survive, and (3) when survival with moderate disability is possible, but the infant is likely to experience ongoing pain and suffering, repeated hospitalisation and invasive treatment, and early death in childhood. The decision-making process of selective non-treatment should involve less medical paternalism and more informed parental involvement. The process is built on trust between the neonatal staff and parents, and requires time, information, honesty and empathy. Ethical issues must be approached with extreme responsibility, extraordinary sensitivity and heroic compassion.


Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).


Acute pancreatitis in aging animals: loss of pancreatitis-associated protein protection?
To investigate the effect of age on severity of acute pancreatitis (AP) using biochemical markers, histology and expression of the protective pancreatitis-associated proteins (PAPs). AP was induced via intraductal injection of 4% sodium taurocholate in young and old rats. Sera and pancreata were assayed at 24 h for the parameters listed above; we also employed a novel molecular technique to assess bacterial infiltration using polymerase chain reaction to measure bacterial genomic ribosomal RNA. At 24 h after induction of AP, the pancreata of older animals had less edema (mean ± SE histologic score of young vs old: 3.11 ± 0.16 vs 2.50 ± -0.11, P < 0.05), decreased local inflammatory response (histologic score of stromal infiltrate: 3.11 ± 0.27 vs 2.00 ± 0.17, P < 0.05) and increased bacterial infiltration (174% ± 52% increase from sham vs 377% ± 4%, P < 0.05). A decreased expression of PAP1 and PAP2 was demonstrated by Western blotting analysis and immunohistochemical staining. There were no differences in serum amylase and lipase activity, or tissue myeloperoxidase or monocyte chemotactic protein-1 levels. However, in the most-aged group, serum C-reactive protein levels were higher (young vs old: 0.249 ± 0.04 mg/dL vs 2.45 ± 0.68 mg/dL, P < 0.05). In older animals, there is depressed PAP expression related to a blunted inflammatory response in AP which is associated with worsened bacterial infiltration and higher C-reactive protein level; this may explain the more aggressive clinical course.


Evaluation and importance of selected microbiological methods in the diagnosis of human brucellosis.
Brucellosis is an important public health problem in Bosnia and Herzegovina. The diagnosis of brucellosis in the country without any experiences with this kind of infection may be very difficult. The aim of this study was to evaluate diagnostic methods: Rose Bengal test, blood cultures and ELISA IgM and IgG in the patients with brucellosis. The study included 91 brucellosis patients in the period 2004 to 2007. All the patients were treated at the Clinic for Infectious Diseases, University of Sarajevo Clinics Centre. Blood cultures were positive in 28/91 (30, 8%) patients. This method often needs a long period of incubation and specimens need to be obtained early. These limitations make serology the most useful tool for the laboratory diagnosis of Brucella infection. Rose Bengal is a rapid plate agglutination test, very sensitive irrespective of the stage of the disease. In our study, Rose Bengal test was positive in all patients 91/91 (100, 0%). Brucella IgM antibodies with ELISA were positive in 59/91 (64, 8%). Brucella IgG antibodies with ELISA were positive in 51/91 (56%). In order to determine the diagnostic value of the different tests, we compared the sensitivity among test-methods: Rose Bengal test-100.0%, blood culture-30.8%, ELISA IgM-64.8% and ELISA IgG-56.1%. Sensitivity of test methods was different in the different stages of illness. It is necessary to use combination of different tests such are blood culture, Rose Bengal test and ELISA in order to ensure the diagnosis. Rose Bengal test is excellent for the screening. Blood culture is a method of choice for the diagnosis acute infection. ELISA is a very good method for the diagnostic chronic disease and relapse.


A pathogenesis-related 10 protein catalyzes the final step in thebaine biosynthesis.
The ultimate step in the formation of thebaine, a pentacyclic opiate alkaloid readily converted to the narcotic analgesics codeine and morphine in the opium poppy, has long been presumed to be a spontaneous reaction. We have detected and purified a novel enzyme from opium poppy latex that is capable of the efficient formation of thebaine from (7S)-salutaridinol 7-O-acetate at the expense of labile hydroxylated byproducts, which are preferentially produced by spontaneous allylic elimination. Remarkably, thebaine synthase (THS), a member of the pathogenesis-related 10 protein (PR10) superfamily, is encoded within a novel gene cluster in the opium poppy genome that also includes genes encoding the four biosynthetic enzymes immediately upstream. THS is a missing component that is crucial to the development of fermentation-based opiate production and dramatically improves thebaine yield in engineered yeast.


It is all about patients' stories: Case-based learning in residents' education.
Background: Problem-based learning (PBL) is an inquiry-based learning strategy which is learner centered and facilitates group discussion and critical thinking. Case-based learning (CBL), which is a more guided approach of PBL, enables students to learn within the context of patients and formulate their knowledge around patients' scenarios. Midweek (MW) activity is an important educational activity in the internal medicine residency program (IMRP). CBL has shown many benefits in postgraduate education. The aim of our study was to describe the implementation of a teaching resident's management of acute medical conditions encountered during their call utilizing the CBL format and to evaluate resident satisfaction with the new teaching style. Methods: This study describes the implementation of CBL in residents' education at the IMRP. CBL was introduced in five of the 10 acute medical sessions taught in the noon activity. A mixed-method study was employed using both a structured questionnaire and a focus group to compare the two methods to evaluate the residents' satisfaction and perception of knowledge acquisition. Results: The focus group discussion showed that sessions conducted in CBL format were more engaging, interactive, and resulted in better knowledge acquisition through sharing and peer-to-peer teaching than the traditional lecture format. Thirty-nine out of 83 (47%) residents ranging from PGY2 to PGY4 responded to the survey. Overall satisfaction with CBL was good. Sixty-four percent preferred it over the lecture format; 87% found that they did improve their knowledge; 84% agreed that they were excellent and more interactive. Seventy-nine percent stated that they would like to have this type of teaching in the MW activity sessions. Conclusion: Based on the present study, we conclude that incorporation of CBL resulted in more engagement, interaction, peer-to-peer education, and overall residents' satisfaction. The key elements for a successful implementation of this format are both instructors' and residents' orientation and careful selection of the case scenarios (problems) that trigger the learning process. Incorporation of various teaching strategies in residents' education is mandatory to enhance learning and create excellent educational experiences.


Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD).
To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently. Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD. The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis. The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters. The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.


Sample Size and Power When Designing a Randomized Trial for the Estimation of Treatment, Selection, and Preference Effects.
A 2-stage randomized trial design, incorporating participant choice, provides unbiased estimates of the effects of the treatment or intervention (treatment effect), the difference between outcomes for participants who prefer one treatment compared with another (selection effect), and the interaction between participants' preferences for treatment and the treatment actually received (preference effect). It is important to ensure that such trials are adequately powered to estimate these effects. This paper presents methods for determining the required sample sizes for estimating treatment, selection, and preference effects. We demonstrate the changes in sample size as various key parameters are changed. In general, approximately twice as many participants (in total) are needed to have equivalent power for detecting both treatment and selection/preference effects compared with a trial of the treatment effect alone. We illustrate their application for the design of a primary screening trial comparing human papillomavirus DNA testing versus cervical screening (by Pap smear). Our example would require 520 participants to have 80% power to detect moderate-sized preference and selection effects and a small to moderate treatment effect. With the growing interest in understanding treatment choices and with the use of decision aids, well-designed and adequately powered 2-stage randomized trial designs offer the opportunity to determine the effects of participants' preferences. Our sample size formulas will help future studies ensure that they have adequate power to detect selection and preference effects.


Self-reported consequences and healthcare costs of falls among elderly women.
Although the falls in elderly people lead to serious health consequences, the economic burden is underestimated. The aim of this study was to calculate the medical costs of fall consequences in elderly women. Women aged 65 years and older were interviewed by phone recording the consequences and healthcare procedures related to every fall sustained during the previous 12 months. The healthcare costs were estimated by calculating the sum of costs for all self-reported contacts with medical care providers: ambulance, emergency department, visits to family doctor and other specialists, hospitalisations, and rehabilitation. The study population consisted of 878 community-dwelling women (mean age 72.2±4.8 years). Falls were reported by 310 (35.3%) women; one in three of them had fallen twice or more. Of all women who fell, 280 (90.3%) reported their fall resulted in an injury, and 77 (15.3%) falls led to bone fractures. Fear of falling was reported by 72.9% of women. Fall-related medical care was provided to 135 women (43.5% of those fallen), and 18 (5.8%) subjects were hospitalised, mostly for the fracture. The mean estimated healthcare cost was 254 EUR per patient receiving fall-related medical care, and 116 EUR per women fallen. The highest mean cost (1289 EUR) was estimated in falls resulted in hip fracture; the lowest (135 EUR), in nonfracture injury. The data on the self-reported consequences of falls in elderly women showed a significant number of fall-related injuries and a high cost of healthcare.


Compassion-focused therapy as guided self-help for enhancing public mental health: A randomized controlled trial.
Despite promising results for compassion-focused therapy (CFT) as self-help, larger-scale trials including long-term follow-up data are needed to establish its effectiveness in the context of public mental health. Empirical evidence supporting its effectiveness in improving well-being is lacking. In a randomized controlled trial, the effects of CFT as guided self-help on well-being were evaluated. Adults (mean age = 52.87, SD = 9.99, 74.8% female) with low to moderate levels of well-being were recruited in the Dutch population and randomized to CFT (n = 120) or a waitlist control group (n = 122). Participants completed the Mental Health Continuum-Short Form (well-being), Hospital Anxiety and Depression Scale (depression and anxiety), Perceived Stress Scale (stress), Self-Compassion Scale-Short Form (self-compassion), Forms of Self-Criticizing/Attacking and Reassurance Scale (self-criticism and self-reassurance), Positive and Negative Affect Schedule (positive/negative affect), and Gratitude questionnaire (gratitude) at baseline, postintervention (3 months), 3- and 9-month follow-up. Compared with the waitlist control group, the CFT group showed superior improvement on well-being at postintervention, d = .51, 95% CI [.25, .77], p < .001, and 3-month follow-up, d = .39, 95% CI [.13, .65], p < .001. No significant moderators were found. On all secondary outcome measures but positive affect, the intervention group showed significantly greater improvements up to 3-month follow-up. At 9-month follow-up, improvements on all measures were retained or amplified among CFT participants. CFT as guided self-help shows promise as a public mental health strategy for enhancing well-being and reducing psychological distress. (PsycINFO Database Record


Silicon photonics plasma-modulators with advanced transmission line design.
We have investigated two novel concepts for the design of transmission lines in travelling wave Mach-Zehnder interferometer based Silicon Photonics depletion modulators overcoming the analog bandwidth limitations arising from cross-talk between signal lines in push-pull modulators and reducing the linear losses of the transmission lines. We experimentally validate the concepts and demonstrate an E/O -3 dBe bandwidth of 16 GHz with a 4V drive voltage (in dual drive configuration) and 8.8 dB on-chip insertion losses. Significant bandwidth improvements result from suppression of cross-talk. An additional bandwidth enhancement of ~11% results from a reduction of resistive transmission line losses. Frequency dependent loss models for loaded transmission lines and E/O bandwidth modeling are fully verified.


Molecular evolution of phytochromes in Cardamine nipponica (Brassicaceae) suggests the involvement of PHYE in local adaptation.
Given that plants are sessile organisms, traits involved in adapting to local environments and/or in monitoring the surrounding environment, such as having photoreceptors, are significant targets of natural selection in plant evolution. To assess the intraspecific adaptive evolution of photoreceptors, we investigated sequence variations in four phytochrome genes (PHYA-C and PHYE) of Cardamine nipponica (Brassicaceae), an endemic Japanese alpine plant. The genealogies of haplotypes and genetic differentiations showed inconsistent patterns of evolution across phytochromes, suggesting that evolutionary forces were distinct in phytochromes of C. nipponica. An overall low level of nucleotide diversity in phytochrome genes suggests that the evolution of phytochromes is constrained by purifying selection within C. nipponica, which is consistent with previous findings on phytochromes. However, PHYE alone exhibited a non-neutral pattern of polymorphisms (Tajima's D = 1.91, P < 0.05) and an accumulation of nonsynonymous substitutions between central and northern Japan. In particular, the PHY domain, which plays an important role in stabilizing the active form (Pfr) of phytochromes, harbored a specific nonsynonymous fixation between regions. Thus, our finding indicates that local adaptation is involved in the evolution of PHYE in C. nipponica and is the first to suggest the involvement of PHYE in local adaptation.