Implications of the Fukushima Nuclear Disaster: Man-Made Hazards, Vulnerability Factors, and Risk to Environmental Health.
The objective of this article was to examine the environmental health implications of the 2011 Fukushima nuclear disaster from an all-hazards perspective. The authors performed a literature review that included Japanese and international nuclear guidance and policy, scientific papers, and reports on the Chernobyl and Three Mile Island disasters while also considering all-hazards preparedness rubrics in the U.S. The examination of the literature resulted in the following: a) the authors' "All-Hazards Planning Reference Model" that distinguishes three planning categories-Disaster Trigger Event, Man-Made Hazards, and Vulnerability Factors; b) the generalization of their model to other countries; and c) advocacy for environmental health end fate to be considered in planning phases to minimize risk to environmental health. This article discusses inconsistencies in disaster planning and nomenclature existing in the studied materials and international guidance and proposes new opportunity for developing predisaster risk assessment, risk communication, and prevention capacity building.


Engineering of a dermal equivalent: seeding and culturing fibroblasts in PEGT/PBT copolymer scaffolds.
The engineering of dermal skin substitutes, using autologous fibroblasts, requires high seeding efficiencies, a homogeneous cell distribution in the scaffolds, and optimal culture conditions. Dynamic seeding in spinner flasks was used to seed and subsequently culture fibroblasts in three-dimensional scaffolds. Several seeding and culture variables were investigated. Simulation of medium movement with microspheres showed that three different regions existed in medium (outer, middle, and inner), where overall particle movement was different. In the middle region the flow was turbulent and scaffolds were best placed in this region. After fibroblast seeding, methylene blue staining and scanning electron microscopy analysis of the scaffolds showed that at a low stirring speed (20 rpm) fibroblasts attached mainly onto the upper part of the scaffold, and at 40 and 60 rpm fibroblasts attached and spread throughout the scaffolds. Measurements of total DNA content per scaffold showed that lower stirring speeds (20 and 40 rpm) resulted in significantly higher cell-seeding efficiencies (20 rpm, 99.8 +/- 11.3%; 40 rpm, 93.8 +/- 10.5%) compared with 60 rpm (85.9 +/- 5.3%). Seeding kinetics were comparable for all three speeds investigated. In subsequent studies, 40 rpm was chosen for seeding. Using initial cell numbers ranging from 0.3 x 10(6) to 1.5 x 10(6) fibroblasts per scaffold, seeding efficiencies higher than 85% were consistently found (n = 4). The culture of fibroblast-seeded scaffolds at different stirring speeds (10-80 rpm) showed that stirring speeds higher than 10 rpm significantly stimulated fibroblast proliferation and glycosaminoglycan and collagen deposition as compared with 10 rpm. After 21 days, scaffolds cultured at 80 rpm showed significantly more collagen deposition as compared with those maintained at lower speeds. In conclusion, to achieve high seeding efficiencies, uniform fibroblast distribution and tissue formation in a three-dimensional scaffold, fibroblasts can be dynamically seeded at 40 rpm and subsequently cultured at a stirring speed of 60-80 rpm in spinner flasks. This flexible system shows that it is feasible to tissue engineer autologous dermal substitutes in a clinically acceptable time frame.


The pore domain of the nicotinic acetylcholine receptor: molecular modeling, pore dimensions, and electrostatics.
The pore domain of the nicotinic acetylcholine receptor has been modeled as a bundle of five kinked M2 helices. Models were generated via molecular dynamics simulations incorporating restraints derived from 9-A resolution cryoelectron microscopy data (Unwin, 1993; 1995), and from mutagenesis data that identify channel-lining side chains. Thus, these models conform to current experimental data but will require revision as higher resolution data become available. Models of the open and closed states of a homopentameric alpha 7 pore are compared. The minimum radius of the closed-state model is less than 2 A; the minimum radius of the open-state models is approximately 6 A. It is suggested that the presence of "bound" water molecules within the pore may reduce the effective minimum radii below these values by up to approximately 3 A. Poisson-Boltzmann calculations are used to obtain a first approximation to the potential energy of a monovalent cation as it moves along the pore axis. The differences in electrostatic potential energy profiles between the open-state models of alpha 7 and of a mutant of alpha 7 are consistent with the experimentally observed change in ion selectivity from cationic to anionic. Models of the open state of the heteropentameric Torpedo nicotinic acetylcholine receptor pore domain are also described. Relatively small differences in pore radius and electrostatic potential energy profiles are seen when the Torpedo and alpha 7 models are compared.


Variability of trauma transfer practices among non-tertiary care hospital emergency departments.
To assess both the variability of interhospital trauma transfer practices and nonclinical factors associated with the transfer of injured patients from emergency departments (EDs) of non-tertiary care hospitals. The authors analyzed a retrospective cohort of trauma patients initially presenting to one of 42 non-tertiary care hospitals (Level 3 or 4 hospitals) and requiring admission or transfer from January 1998 to December 2003. Twenty-one clinical, demographic, and hospital-level variables were included in multivariable logistic regression models (outcome = ED transfer to a tertiary care hospital), with hospital and year included as fixed effects to adjust for clustering. Classification and regression tree analysis was used to determine the importance of different covariates in predicting whether or not a patient was transferred from the ED. Included in the analysis were 10,176 persons, of whom 3,785 (37%) were transferred to a tertiary care hospital from the ED. The hospital of initial presentation was the factor of greatest importance in predicting transfer, and there was substantial variability in transfer practices between hospitals. Several additional nonclinical variables were independently associated with transfer, including type and level of hospital, patient age, increasing distance from the nearest higher-level hospital (a measure of geographic isolation), and the patient's insurance status (particularly among Level 3 hospitals). The non-tertiary care hospital of initial presentation is the strongest predictor for whether an injured patient is transferred to a tertiary center from the ED. There is substantial variability in transfer practices between hospitals after accounting for important clinical factors, and several nonclinical variables are independently associated with transfer.


Characterizing microscale biological samples under tensile loading: stress-strain behavior of cell wall fragment of onion outer epidermis.
The results of published studies investigating the tissue-scale mechanical properties of plant cell walls are confounded by the unknown contributions of the middle lamella and the shape and size of each cell. However, due to their microscale size, cell walls have not yet been characterized at the wall fragment level under tensile loading. It is imperative to understand the stress-strain behavior of cell wall fragments to relate the wall's mechanical properties to its architecture. • This study reports a novel method used to characterize wall fragments under tensile loading. Cell wall fragments from onion outer epidermal peels were cut to the desired size (15 × 5 µm) using the focused ion beam milling technique, and these fragments were manipulated onto a microelectromechanical system (MEMS) tensile testing device. The stress-strain behavior of the wall fragments both in the major and minor growth directions were characterized in vacuo. • The measured mean modulus, fracture strength, and fracture strain in the major growth direction were 3.7 ± 0.8 GPa, 95.5 ± 24.1 MPa, and 3.0 ± 0.5%, respectively. The corresponding properties along the minor growth direction were 4.9 ± 1.2 GPa, 159 ± 48.4 MPa, and 3.8 ± 0.5%, respectively. • The fracture strength and fracture strain were significantly different along the major and minor growth directions, the wall fragment level modulus of elasticity anisotropy for a dehydrated cell wall was 1.23, suggesting a limited anisotropy of the cell wall itself compared with tissue-scale results.


p53 expression in the normal murine eye.
The tumor-suppressor gene p53 encodes a phosphoprotein involved in the control of cell growth. Its expression and function have been documented in malignancy, apoptosis, and other abnormal cell proliferation processes. Recently, expression of p53 has been demonstrated in certain normal tissues, including whole eye. The purpose of the study was to map and to characterize expression of p53 in the normal murine eye. Eyes of adult C57BL/6 mice were enucleated after death by CO2 narcosis. Expression of p53 in frozen sections of whole cryoprotected eyes was mapped by indirect immunofluorescence microscopy using the anti-p53 monoclonal antibodies 248 and 421 and the polyclonal antibody FL-393. Additionally, eyes were freshly dissected to separate the various ocular tissues. In these ocular tissues, expression of p53 was quantitated with ELISA and Western blot analyses. Strong expression of p53 was observed in various normal ocular tissues. The corneal and conjunctival epithelium exhibited very high cytoplasmic p53 protein levels. High nuclear p53 protein staining was seen in the lens epithelial cells of the central and pre-equatorial zones and in the lens fiber nuclear bow, situated posterior to the epithelial germinative zone. Cells of the actual lens germinative zone did not stain for p53 protein. Low levels of p53 protein were expressed in retinal tissue. High levels of p53 protein are found in various normal murine ocular tissues, especially the corneal and conjunctival structures and the lens epithelium. Each of these tissues demonstrate unique patterns of staining.


Caring for the continuum of patients with pancreatic cancer: the importance of survivorship care planning.
Pancreatic cancer is widely recognized as one of the most formidable cancer diagnoses. However, whether aggressive treatment is undertaken or not, it is critical for all care providers to understand the treatment plan. Survivorship care plans are a new trend in improving communication between the providers and the patient. The current article will outline the pathophysiology, risk factors, diagnosis and prognosis, treatment, and potential complications of pancreatic cancer. The importance of survivorship care planning will be demonstrated through a case study presentation and evidence-based discussion. In addition, a general template for a survivorship care plan has been included. Based on a review of current literature and recommendations, it can be concluded that survivorship care planning would be beneficial for all patients with cancer. This simple tool has the potential to improve coordination of care and patient satisfaction.


Actions of exendin-4 therapy on cognitive function and hippocampal synaptic plasticity in mice fed a high-fat diet.
High-calorie diet has been shown to impair learning ability and hippocampal synaptic plasticity in rodents. This study examined effects of daily treatment with the glucagon-like peptide-1 mimetic, exendin-4, on cognitive function and hippocampal synaptic plasticity in a model of diet-induced obesity, which exhibits compromised cognitive performance. Mice fed a high-fat diet were treated with exendin-4 (25 nmol kg(-1) bodyweight; twice daily) or saline vehicle (0.9% (w/v) NaCl) over 21 days. In addition to improving metabolic control, exendin-4-treated mice exhibited a marked increase in recognition index highlighting improved learning and memory. High-fat diet resulted in the elimination of in vivo electrophysiological long-term potentiation, which was rescued following exendin-4 treatment. This study shows that exendin-4 therapy improves cognitive function and ameliorates impaired hippocampal synaptic plasticity in dietary-induced obesity.


Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation.
Although the FMR1 premutation is associated with elevated prevalence of psychiatric disorders, the longitudinal course of symptoms has not been established. The present study followed a sample of women with the FMR1 premutation to characterize the incidence, stability, and predictors of mood and anxiety disorders across a 3-year period. Participants included 83 women with the FMR1 premutation (mean age = 38.35) who completed the Structured Clinical Interview for DSM-IV Axis I Disorders at two time points, 3 years apart. Additional information was obtained regarding demographic, child, and biomedical (e.g., medication, menopause, CGG repeats) factors. We found increased prevalence of major depressive disorder (MDD) and anxiety disorders over time, with adverse outcomes predicted by complex interactions among biological, behavioral, and environmental risk factors. Lifetime MDD increased from 46% to 54% and lifetime anxiety disorders increased from 28% to 35%. Midrange CGG repeats, elevated child problem behaviors, and divorced marital status conveyed elevated risk for psychiatric diagnoses. Primary ovarian insufficiency was highly prevalent (41%) but did not account for elevated rates of psychiatric diagnoses. Medication use was highly reported (41%), particularly in women with MDD or anxiety, with selective serotonin reuptake inhibitors reported as the most commonly used medication across diagnostic groups. The elevated prevalence of depression and anxiety in women with the FMR1 premutation is a clear and pressing concern given the frequent occurrence of the FMR1 premutation in the general community and the adverse outcomes-at both individual and systems levels-associated with psychiatric disorders in this population.


Muscle-spindle histochemistry.
Reduced nicotinamide adenine dinucleotide tatrazolium reductase is abundant in cat intrafusal muscle fibers, whereas in the toad its activity is equal to that in extrafusal fibers. Spindles of both species contain little fat. In sections stained for adenosine triphosphatase bound to myofibrils, two types of intrafusal muscle fibers appear in spindles of both the cat and toad.


Trans-Endplate Pedicle Pillar System in Unstable Spinal Burst Fractures: Design, Technique, and Mechanical Evaluation.
Short-segment pedicle screw instrumentation (SSPI) is used for unstable burst fractures to correct deformity and stabilize the spine for fusion. However, pedicle screw loosening, pullout, or breakage often occurs due to the large moment applied during spine motion, leading to poor outcomes. The purpose of this study was to test the ability of a newly designed device, the Trans-Endplate Pedicle Pillar System (TEPPS), to enhance SSPI rigidity and decrease the screw bending moment with a simple posterior approach. Six human cadaveric spines (T11-L3) were harvested. A burst fracture was created at L1, and the SSPI (Moss Miami System) was used for SSPI fixation. Strain gauge sensors were mounted on upper pedicle screws to measure screw load bearing. Segmental motion (T12-L2) was measured under pure moment of 7.5 Nm. The spine was tested sequentially under 4 conditions: intact; first SSPI alone (SSPI-1); SSPI+TEPPS; and second SSPI alone (SSPI-2). SSPI+TEPPS increased fixation rigidity by 41% in flexion/extension, 28% in lateral bending, and 37% in axial rotation compared with SSPI-1 (P<0.001), and it performed even better compared to SSPI-2 (P<0.001 for all). Importantly, the bending moment on the pedicle screws for SSPI+TEPPS was significantly decreased 63% during spine flexion and 47% in lateral bending (p<0.001). TEPPS provided strong anterior support, enhanced SSPI fixation rigidity, and dramatically decreased the load on the pedicle screws. Its biomechanical benefits could potentially improve fusion rates and decrease SSPI instrumentation failure.


Tracing the footprints of a moving hybrid zone under a demographic history of speciation with gene flow.
A lack of optimal gene combinations, as well as low levels of genetic diversity, is often associated with the formation of species range margins. Conservation efforts rely on predictive modelling using abiotic variables and assessments of genetic diversity to determine target species and populations for controlled breeding, germplasm conservation and assisted migration. Biotic factors such as interspecific competition and hybridization, however, are largely ignored, despite their prevalence across diverse taxa and their role as key evolutionary forces. Hybridization between species with well-developed barriers to reproductive isolation often results in the production of offspring with lower fitness. Generation of novel allelic combinations through hybridization, however, can also generate positive fitness consequences. Despite this possibility, hybridization-mediated introgression is often considered a threat to biodiversity as it can blur species boundaries. The contribution of hybridization towards increasing genetic diversity of populations at range margins has only recently gathered attention in conservation studies. We assessed the extent to which hybridization contributes towards range dynamics by tracking spatio-temporal changes in the central location of a hybrid zone between two recently diverged species of pines: Pinus strobiformis and P. flexilis. By comparing geographic cline centre estimates for global admixture coefficient with morphological traits associated with reproductive output, we demonstrate a northward shift in the hybrid zone. Using a combination of spatially explicit, individual-based simulations and linkage disequilibrium variance partitioning, we note a significant contribution of adaptive introgression towards this northward movement, despite the potential for differences in regional population size to aid hybrid zone movement. Overall, our study demonstrates that hybridization between recently diverged species can increase genetic diversity and generate novel allelic combinations. These novel combinations may allow range margin populations to track favourable climatic conditions or facilitate adaptive evolution to ongoing and future climate change.


The Cellular Processing Capacity Limits the Amounts of Chimeric U7 snRNA Available for Antisense Delivery.
Many genetic diseases are induced by mutations disturbing the maturation of pre-mRNAs, often affecting splicing. Antisense oligoribonucleotides (AONs) have been used to modulate splicing thereby circumventing the deleterious effects of mutations. Stable delivery of antisense sequences is achieved by linking them to small nuclear RNA (snRNAs) delivered by viral vectors, as illustrated by studies where therapeutic exon skipping was obtained in animal models of Duchenne muscular dystrophy (DMD). Yet, clinical translation of these approaches is limited by the amounts of vector to be administered. In this respect, maximizing the amount of snRNA antisense shuttle delivered by the vector is essential. Here, we have used a muscle- and heart-specific enhancer (MHCK) to drive the expression of U7 snRNA shuttles carrying antisense sequences against the human or murine DMD pre-mRNAs. Although antisense delivery and subsequent exon skipping were improved both in tissue culture and in vivo, we observed the formation of additional U7 snRNA by-products following gene transfer. These included aberrantly 3' processed as well as unprocessed species that may arise because of the saturation of the cellular processing capacity. Future efforts to increase the amounts of functional U7 shuttles delivered into a cell will have to take this limitation into account.


Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmission.
Fibroblast-to-myofibroblast differentiation - a key event in the development of fibrocontractive diseases and in wound granulation tissue contraction - is hallmarked by the formation of stress fibers and the neo-expression of alpha-smooth muscle actin. Incorporation of the smooth muscle actin isoform into stress fibers confers to myofibroblasts a high contractile activity which is transmitted to the extracellular matrix at sites of specialized adhesions, termed 'fibronexus' in tissue and 'supermature focal adhesions' in two-dimensional cell culture. Myofibroblast differentiation requires a mechanically restrained environment in conjunction with the action of growth factors like transforming growth factor beta and specialized matrix molecules like the ED-A splice variant of fibronectin. This mini-review discusses the roles of myofibroblast adhesions in sensing matrix stress, in transmitting contractile force to the extracellular environment and in creating the high intracellular tension that is required for myofibroblast development.


Effects of a psychological intervention in a primary health care center for caregivers of dependent relatives: a randomized trial.
To assess, in the context of Primary Health Care (PHC), the effect of a psychological intervention in mental health among caregivers (CGs) of dependent relatives. Randomized multicenter, controlled clinical trial. The 125 CGs included in the trial were receiving health care in PHC. Identifying oneself as principal CG of a dependent relative with dementia or any other disability, and having performed this task for at least 6 months. CGs were randomized to an intervention group (cognitive-behavioral treatment for managing dysfunctional thoughts about caregiving and training in self-help techniques) or to a control group (care as usual). CG mental health (General Health Questionnaire [GHQ-12]), dysfunctional thoughts about caregiving, quality of life, and burden were measured. The intervention group showed improvement in mental health: A mean reduction in GHQ-12 score of -3.33 points was recorded in the intervention group vs. the control group (95% CI: -5.95 to -0.70; p = .01; Cohen d = 0.55). Improvement was also recorded in dysfunctional thoughts about caregiving: (-5.84; 95% CI: -10.60 to -1.09; p = .01; Cohen d = 0.62). Among the CGs that completed the initial and final assessments, a mean of 4.77 (SD 2.68) attended a maximum of 8 sessions. Men attended more often (5.00 sessions with SD 2.68) than women (4.70 sessions with SD 2.45; p < .001). Psychological group intervention in the context of PHC, aimed at the CGs of dependent persons with dementia and other disabilities, has improved mental health condition in CGs.


Foam property tests to evaluate the potential for longwall shield dust control.
Tests were conducted to determine properties of four foam agents for their potential use in longwall mining dust control. Foam has been tried in underground mining in the past for dust control and is currently being reconsidered for use in underground coal longwall operations in order to help those operations comply with the Mine Safety and Health Administration's lower coal mine respirable dust standard of 1.5 mg/m3. Foams were generated using two different methods. One method used compressed air and water pressure to generate foam, while the other method used low-pressure air generated by a blower and water pressure using a foam generator developed by the U.S. National Institute for Occupational Safety and Health. Foam property tests, consisting of a foam expansion ratio test and a water drainage test, were conducted to classify foams. Compressed-air-generated foams tended to have low expansion ratios, from 10 to 19, with high water drainage. Blower-air-generated foams had higher foam expansion ratios, from 30 to 60, with lower water drainage. Foams produced within these ranges of expansion ratios are stable and potentially suitable for dust control. The test results eliminated two foam agents for future testing because they had poor expansion ratios. The remaining two foam agents seem to have properties adequate for dust control. These material property tests can be used to classify foams for their potential use in longwall mining dust control.


Enhancing Early Engagement (E3) in mental health services training for children's advocacy center's victim advocates: feasibility protocol for a randomized controlled trial.
Child maltreatment is a major public issue in the United States, yet most children affected by abuse or neglect never engage in evidence-based practices (EBP) for child mental health. Children's Advocacy Centers (CACs') are uniquely situated to serve as Family Navigators who connect children impacted by maltreatment to appropriate EBPs. In fact, the CAC position of Victim Advocate mirrors the Mental Health Family Navigator national initiative. The feasibility study protocol is to develop, implement, and evaluate web-based and consultative training for Victim Advocates to enhance early engagement in services (E3 training). The interactive web-based training embeds key targets of knowledge and skills related to family engagement, trauma, and EBP services. Participating CACs were randomized to E3 webinar-based training, E3 webinar plus consultation, or delayed training. The project will test the E3 training's impact on key mechanisms of change (e.g., knowledge, skills) to improve rates of screening, referral, and access to EBP services. The feasibility of implementing the training program and differential impact and costs by level of training will be examined. The overarching goal of this project is to test the feasibility of training that is readily implemented through CACs and examine the mechanisms for improving early engagement and, ultimately, child, and adolescent mental health outcomes. Results and cost findings will be used to plan a large-scale comprehensive, mixed-methods hybrid type II effectiveness-implementation and cost-effectiveness trial of family navigator E3 training. If outcomes are positive, considerable infrastructure exists to support the scale-up and sustainability of E3 training nationwide, by embedding the training in national CAC training protocols. NCT04221633 DATE AND VERSION IDENTIFIER: March 25, 2021; Vers. 1.0 (original); September 11, 2021; Vers 2.0 (revision); October 29, 2021; Vers. 3.0 (revision).


Lateral diffusion of an 80,000-dalton glycoprotein in the plasma membrane of murine fibroblasts: relationships to cell structure and function.
The lateral diffusion of an 80,000-dalton major cell surface glycoprotein of murine fibroblasts has been measured. This antigen, identified through the use of monoclonal antibodies, is an integral glycoprotein distributed through the plasma membrane as judged by immunofluorescence and immunoelectron microscopy (see preceding paper). Measurements of fluorescence recovery after photobleaching were performed on the antigen-antibody complex within the plasma membrane of C3H/10T1/2 and NIH/3T3 cells after labeling the monoclonal antibody with fluorescein. Measurements were performed as a function of temperature, for interphase, mitotic, and G0 C3H/10T1/2 cells. The mean lateral diffusion coefficients (D) for the antibody-protein complex in interphase cells were in the range of 0.7-3.5 X 10(-10) cm2/s between 9 degrees and 37 degrees C, while that for the lipid analog probe, dihexadecylindocarbocyanine was about two orders of magnitude greater. This comparison indicates that peripheral interactions other than bilayer fluidity limit the lateral mobility of the antigen. The mobile fraction of mitotic, G0, and interphase cells showed a monotonic increase with temperature with most of the antibody-antigen complexes being free to move about 25 degrees C. Semi-quantitative interpretations of both the slow glycoprotein diffusion and the immobile fraction are offered. Comparison of diffusion coefficients for cells in different phases of the cell cycle does not reveal striking differences. Mobile fractions for G0 cells at 25 degrees C or less are substantially lower than in interphase cells. In all cases, there was a remarkably broad range of the fluorescence recovery data between different cells, resulting in up to a 10-fold variation in diffusion coefficients, which is far greater than the precision limits of the experiment. Diffusion values and mobile fractions were generally well within a factor of two when measured at several arbitrary points on a single cell. The origins of this cellular heterogenity remain to be elucidated. Lateral mobility in cell fragments and specific regions of single cells was also examined. The glycoprotein was mobile in ventral surface cell fragments. Its mobility was not altered in regions of cell-cell underlapping. However, the diffusion coefficient was threefold higher near the leading edge of motile cells compared to the trailing region. This difference may reflect weaker coupling of the glycoprotein to the underlying cytoskeleton in the dynamic leading edge region.


Once daily monotherapy with prolonged-release valproate minitablets given in the evening--a chronopharmacological study.
Chronopharmacological investigations concerning efficacy, side effects and circadian serum concentration are lacking for many antiepileptic drugs. In this study 27 patients with focal or generalized epilepsy receiving a single dosage of prolonged-release valproate given in the evening were included. The valproate serum concentration over a course of 24 hours and their correlation with the value measured at 9:00 am was examined. In approximately 60% of the patients the serum level measured at 9:00 am corresponded to the peak value. In an additional 33% of the patients the peak value was reached at either 12:00 midnight or at 3:00 am. During the course of the day all patients showed on average an additional decline in these values compared to the 9:00 am serum level of 41%. In only a third of the patients did the 24-hour profile exhibit an average increase that exceeded the 9:00 am value by as much as 4%. In the case of the 24-hour serum profile, when the daily dosage was weight-correlated no values for the normal dosage range (18 - 24 mg/kg body weight) gave values that exceeded or fell below the so-called therapeutic serum level range (50 - 100 mg/l). Neither seizures nor new adverse reactions occurred in this group. Therefore, in the case of adults and young adults, therapy with valproate prolonged-release at a dose rate of 24 mg/kg preparation given as a single dosage in the evening will be sufficient for seizure control in most patients. The low-dosage group (10 - 17 mg/kg body weight) exhibited values that fell below this range in the afternoon and early evening. The results are discussed with regards to the treatment in young adults and the elderly.


Geochemical precursors to volcanic activity at Mount St. Helens, USA.
The importance of the interplay between degassing and crystallization before and after the eruption of Mount St. Helens (Washington, USA) in 1980 is well established. Here, we show that degassing occurred over a period of decades to days before eruptions and that the manner of degassing, as deduced from geochemical signatures within the magma, was characteristic of the eruptive style. Trace element (lithium) and short-lived radioactive isotope (lead-210 and radium-226) data show that ascending magma stalled within the conduit, leading to the accumulation of volatiles and the formation of lead-210 excesses, which signals the presence of degassing magma at depth.


Influenza A Virus Infection, Innate Immunity, and Childhood.
Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population.


Indirect Effects of the Fast Track Intervention on Conduct Disorder Symptoms and Callous-Unemotional Traits: Distinct Pathways Involving Discipline and Warmth.
Little is known about intervening processes that explain how prevention programs improve particular youth antisocial outcomes. We examined whether parental harsh discipline and warmth in childhood differentially account for Fast Track intervention effects on conduct disorder (CD) symptoms and callous-unemotional (CU) traits in early adolescence. Participants included 891 high-risk kindergarteners (69% male; 51% African American) from urban and rural United States communities who were randomized into either the Fast Track intervention (n = 445) or non-intervention control (n = 446) groups. The 10-year intervention included parent management training and other services (e.g., social skills training, universal classroom curriculum) targeting various risk factors for the development of conduct problems. Harsh discipline (Grades 1 to 3) and warmth (Grades 1 and 2) were measured using parent responses to vignettes and direct observations of parent-child interaction, respectively. Parents reported on children's CD symptoms in Grade 6 and CU traits in Grade 7. Results demonstrated indirect effects of the Fast Track intervention on reducing risk for youth antisocial outcomes. That is, Fast Track was associated with lower scores on harsh discipline, which in turn predicted decreased levels of CD symptoms. In addition, Fast Track was associated with higher scores on warmth, which in turn predicted reduced levels of CU traits. Our findings inform developmental and intervention models of youth antisocial behavior by providing evidence for the differential role of harsh discipline and warmth in accounting for indirect effects of Fast Track on CD symptoms versus CU traits, respectively.


A pain research agenda for the 21st century.
Chronic pain represents an immense clinical problem. With tens of millions of people in the United States alone suffering from the burden of debilitating chronic pain, there is a moral obligation to reduce this burden by improving the understanding of pain and treatment mechanisms, developing new therapies, optimizing and testing existing therapies, and improving access to evidence-based pain care. Here, we present a goal-oriented research agenda describing the American Pain Society's vision for pain research aimed at tackling the most pressing issues in the field. This article presents the American Pain Society's view of some of the most important research questions that need to be addressed to advance pain science and to improve care of patients with chronic pain.


Commentary on Vul et al.'s (2009) "Puzzlingly High Correlations in fMRI Studies of Emotion, Personality, and Social Cognition".
The article "Puzzlingly High Correlations in fMRI Studies of Emotion, Personality, and Social Cognition" (Vul, Harris, Winkielman, & Pashler, 2009, this issue) makes a broad case that current practice in neuroimaging methodology is deficient. Vul et al. go so far as to demand that authors retract or restate results, which we find wrongly casts suspicion on the confirmatory inference methods that form the foundation of neuroimaging statistics. We contend the authors' argument is overstated and that their work can be distilled down to two points already familiar to the neuroimaging community: that the multiple testing problem must be accounted for, and that reporting of methods and results should be improved. We also illuminate their concerns with standard statistical concepts such as the distinction between estimation and inference and between confirmatory and post hoc inferences, which makes their findings less puzzling.


Optical noise reduction for dc-removed coaxial holographic data storage.
A method of reconstructing positive and negative images from Fourier holograms recorded without the dc components is demonstrated by use of a coaxial holographic storage system. Reconstructed images are obtained by adding a phase-modulated dc component of the signal beam on reading. Contrast reversal of the reconstructed images can be achieved by reversing the readout reference pattern. This method can realize not only optical noise reduction but also less consumption of the dynamic range of the recording medium, potentially contributing to increasing the number of multiplexed holograms.


Prioritisation of wildlife pathogens to be targeted in European surveillance programmes: Expert-based risk analysis focus on ruminants.
This study attempted to develop a list of priority pathogens. It is part of a European Union (EU) project dedicated to the surveillance of emerging or re-emerging pathogens of wildlife. Partners of the consortium established an initial list of 138 pathogens of concern, which was reduced to a smaller list of 65 pathogens likely to affect ruminants (i.e., the most costly animal group in the EU over the last 15 years). These 65 pathogens underwent a two-step, expert-based risk analysis: 92 experts graded them with respect to their global importance for animal welfare, species conservation, trade/economic impacts and public health. In step 2, the top 15 pathogens from step 1 were assessed by 69 experts considering seven weighted epidemiological criteria (pathogen variability, host specificity, potential for contagion, speed of spread, presence in Europe, difficulty of surveillance in wildlife and persistence in the environment) for which four options were possible. The responses concerned a wide geographic coverage. The resulting top-list pathogens were ranked as follows: 1. Salmonella enterica, 2. Coxiella burnetii, 3. foot-and-mouth disease virus, 4. Mycobacterium bovis, 5. bluetongue virus, and 6. European tick-borne encephalitis virus. The influence of the characteristics of the respondents, the importance of the levels of uncertainty/variability and the implication of the results are discussed. This work highlights the relevance of developing such lists for preparedness.


Volumetric breast density from full-field digital mammograms and its association with breast cancer risk factors: a comparison with a threshold method.
Breast density, a strong breast cancer risk factor, is usually measured on the projected breast area from film screen mammograms. This is far from ideal, as breast thickness and technical characteristics are not taken into account. We investigated whether volumetric density measurements on full-field digital mammography (FFDM) are more strongly related to breast cancer risk factors than measurements with a computer-assisted threshold method. Breast density was measured on FFDMs from 370 breast cancer screening participants, using a computer-assisted threshold method and a volumetric method. The distribution of breast cancer risk factors among quintiles of density was compared between both methods. We adjusted for age and body mass index (BMI) with linear regression analysis. High percent density was strongly related to younger age, lower BMI, nulliparity, late age at first delivery and pre/perimenopausal status, to the same extent with both methods (all P < 0.05). Similarly strong relationships were seen for the absolute dense area but to a lesser extent for absolute dense volume. A larger dense volume was only significantly associated with late age at menopause, use of menopausal hormone therapy, and, in contrast to the other methods, high BMI. Both methods related equally well to known breast cancer risk factors. Despite its alleged higher precision, the volumetric method was not more strongly related to breast cancer risk factors. This is in agreement with other studies. The definitive relationship with breast cancer risk still needs to be investigated.


Roles of NtGTBP1 in telomere stability.
Telomeres are protective nucleoprotein structures at the ends of linear eukaryotic chromosomes. In contrast to double-stranded-specific telomere-binding proteins, the cellular roles of single-stranded-specific telomeric proteins are not well understood in higher plants. Three highly conserved tobacco G-strand-specific telomere-binding protein paralogs (NtGTBP1, NtGTBP2, and NtGTBP3) were identified and characterized. All three NtGTBPs were able to bind specifically to the plant single-stranded telomeric repeat elements in vitro with similar affinities. Suppression of NtGTBP1 by means of the RNAi-mediated gene knock-down method resulted in developmental defects in transgenic tobacco plants accompanied by lengthened telomeres, extra-chromosomal telomeric circles, and abnormal anaphase bridges. These results suggest that the down-regulation of NtGTBP1 results in genome instability. NtGTBP1 prevented in vitro strand invasion, a prerequisite process for inter-chromosomal telomeric recombination. Therefore, tobacco NtGTBP1 is one of the essential factors for telomere stability. Because abnormal telomeric elongation and recombination due to the suppression of NtGTBP1 are reminiscent of the recombinational telomere lengthening mechanism that purportedly operates in telomerase negative cancer cells, it is of interest to investigate whether telomeric recombination is associated with cell death in animal systems.


Wnt/β-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction.
Wnt/β-catenin signaling plays an important role in regulating hepatic metabolism. This study is to explore the molecular mechanisms underlying the potential crosstalk between Wnt/β-catenin and mTOR signaling in hepatic steatosis. Transgenic mice (overexpress Wnt1 in hepatocytes, Wnt+) mice and wild-type littermates were given high fat diet (HFD) for 12 weeks to induce hepatic steatosis. Mouse hepatocytes cells (AML12) and those transfected to cause constitutive β-catenin stabilization (S33Y) were treated with oleic acid for lipid accumulation. Wnt+ mice developed more hepatic steatosis in response to HFD. Immunoblot shows a significant increase in the expression of fatty acid synthesis-related genes (SREBP-1 and its downstream targets ACC, AceCS1, and FASN) and a decrease in fatty acid oxidation gene (MCAD) in Wnt+ mice livers under HFD. Wnt+ mice also revealed increased Akt signaling and its downstream target gene mTOR in response to HFD. In vitro, increased lipid accumulation was detected in S33Y cells in response to oleic acid compared to AML12 cells reinforcing the in vivo findings. mTOR inhibition by rapamycin led to a down-regulation of fatty acid synthesis in S33Y cells. In addition, β-catenin has a physical interaction with mTOR as verified by co-immunoprecipitation in hepatocytes. Taken together, our results demonstrate that β-catenin stabilization through Wnt signaling serves a central role in lipid metabolism in the steatotic liver through up-regulation of fatty acid synthesis via Akt/mTOR signaling. These findings suggest hepatic Wnt signaling may represent a therapeutic strategy in hepatic steatosis.


Neuromuscular taping for the upper limb in Cerebral Palsy: A case study in a patient with hemiplegia.
To assess quantitatively the effects of Neuromuscular Taping (NMT) on the upper limb in a female child with left hemiplegia, due to Cerebral Palsy (CP). The patient underwent NMT on cervical level, shoulder and hand only of the plegic upper limb, followed by physical therapy. Kinematic data of upper limbs during reaching task were collected before (PRE) and after 2 weeks of treatment (POST). After the intervention, the affected limb improved in terms of movement duration, Average Jerk and Number of Unit Movements indices, indicating a faster, smoother and less segmented movement. Improvements appeared at the ranges of motion of the upper limb joints, both at shoulder and elbow joints. No significant changes were globally displayed for the unaffected arm. NMT seems to be a promising intervention for improving upper limb movement in patients with CP. Further investigations are certainly needed to assess effectively the effects of the intervention in this pathological state.


Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas.
Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.


Beam profile shaping for laser radars that use detector arrays.
The beam shaper we developed shapes the transmit beam of a CO(2) laser radar that uses a linear detector array. It consists of a diffraction grating and an anamorphic prism beam compressor and produces a stretched profile that efficiently and uniformly illuminates the far-field footprint of the detector array. The diffraction grating phase modulates the near field or the laser beam to generate a far-field flattop intensity profile, whereas the compressor produces the necessary profile eccentricity. We have achieved conversion efficiencies in the 70-90% range.


Accessory mental foramina and nerves: Application to periodontal, periapical, and implant surgery.
Recent studies investigating accessory mental foramina using developments in diagnostic imaging have primarily defined the morphology of the foramina; however, few studies have described the structures passing through them. Additional clinical knowledge of the foramina is therefore required for preoperative diagnosis prior to surgery, including implant, periodontal and periapical surgery. In this study, we investigated the accessory mental foramina and the associated nerves and arteries in donated cadaveric mandibles using anatomical and radiological observation methods. We examined 63 mandibles with overlying soft tissue by cone-beam computed tomography and noted the existence of the accessory mental foramina. Mandibles with accessory mental foramina were subsequently analyzed. Additionally, the neurovascular bundles passing through these foramina were dissected using anatomical methods.The incidence of accessory mental foramina was 14.3%. The larger foramina tended to be located anteriorly or superiorly and proximal to the mental foramen, while the smaller foramina tended to be located posterosuperiorly and distal to the mental foramen. The mental foramen ipsilateral to the accessory mental foramen was smaller than the one contralateral to it. The comparatively distant and large accessory mental foramen included an artery.This study elucidated the relationship between accessory mental foramina and the associated nerves and arteries. We believe that the results will contribute to the clinical dentistry field.


In-flight transmission of foodborne disease: How can airlines improve?
Food contamination during air travel presents unique risks to those affected. Foodborne pathogens can cause serious illness among all on board, and potentially jeopardize flight safety. These risks are likely to increase with current trends of "densification" and a predicted massive expansion of air travel. While aircraft are being equipped with ever newer designs with a focus on efficiency and comfort, regulations remained largely unmodified in terms of basic hygiene requirements. Strict guidelines for food hygiene exist for on-ground food settings and catering kitchens. There is uncertainty about hygiene standards on board commercial aircraft, and little regulatory oversight of what happens to food in-flight. In two hypothetical scenarios we indicate the potential risks associated with poor food handling practice onboard aircraft, with the ultimate aim of bringing aviation food safety in line with on-ground regulations. Changes in cabin design alongside adequate training in safe food handling have the potential to increase public health protection. We urge a review of existing in-flight hygiene protocols to better direct the development of regulation, prevention, and intervention measures for aviation food safety.


Fertility decline and child schooling in urban settings of Burkina Faso.
As evidenced in Western rich countries, Asia, and Latin America, lower fertility allows couples to invest more in each of their children's schooling. This postulate is the key rationale of family planning policies in sub-Saharan Africa. Yet, most studies on Africa have found no correlation or even a positive relationship between the number of children in a family and their educational attainment. These mixed results are usually explained by African family solidarity and resource transfers that might reduce pressures on household resources occasioned by many births as well as methodological problems that have afflicted much research on the region. Our study aims to assess the impact of family size on children's schooling in Ouagadougou (capital of Burkina Faso), using a better measure of household budget constraints and taking into account the simultaneity of fertility and schooling decisions. In contrast to most prior studies on sub-Saharan Africa, we find a net negative effect of sibship size on the level of schooling achieved by children--one that grows stronger as they progress through the educational system.


Presence of Viral RNA and Proteins in Exosomes from Cellular Clones Resistant to Rift Valley Fever Virus Infection.
Rift Valley Fever Virus (RVFV) is a RNA virus that belongs to the genus Phlebovirus, family Bunyaviridae. It infects humans and livestock and causes Rift Valley fever. RVFV is considered an agricultural pathogen by the USDA, as it can cause up to 100% abortion in cattle and extensive death of newborns. In addition, it is designated as Category A pathogen by the CDC and the NIAID. In some human cases of RVFV infection, the virus causes fever, ocular damage, liver damage, hemorrhagic fever, and death. There are currently limited options for vaccine candidates, which include the MP-12 and clone 13 versions of RVFV. Viral infections often deregulate multiple cellular pathways that contribute to replication and host pathology. We have previously shown that latent human immunodeficiency virus-1 (HIV-1) and human T-cell lymphotropic virus-1 (HTLV-1) infected cells secrete exosomes that contain short viral RNAs, limited number of genomic RNAs, and viral proteins. These exosomes largely target neighboring cells and activate the NF-κB pathway, leading to cell proliferation, and overall better viral replication. In this manuscript, we studied the effects of exosome formation from RVFV infected cells and their function on recipient cells. We initially infected cells, isolated resistant clones, and further purified using dilution cloning. We then characterized these cells as resistant to new RVFV infection, but sensitive to other viral infections, including Venezuelan Equine Encephalitis Virus (VEEV). These clones contained normal markers (i.e., CD63) for exosomes and were able to activate the TLR pathway in recipient reporter cells. Interestingly, the exosome rich preparations, much like their host cell, contained viral RNA (L, M, and S genome). The RNAs were detected using qRT-PCR in both parental and exosomal preparations as well as in CD63 immunoprecipitates. Viral proteins such as N and a modified form of NSs were present in some of these exosomes. Finally, treatment of recipient cells (T-cells and monocytic cells) showed drastic rate of apoptosis through PARP cleavage and caspase 3 activation from some but not all exosome enriched preparations. Collectively, these data suggest that exosomes from RVFV infected cells alter the dynamics of the immune cells and may contribute to pathology of the viral infection.


Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans.
The human pathogenic fungus Cryptococcus neoformans secretes a phospholipase enzyme that demonstrates phospholipase B (PLB), lysophospholipase hydrolase and lysophospholipase transacylase activities. This enzyme has been postulated to be a cryptococcal virulence factor. We cloned a phospholipase-encoding gene (PLB1) from C. neoformans and constructed plb1 mutants using targeted gene disruption. All three enzyme activities were markedly reduced in the mutants compared with the wild-type parent. The plb1 strains did not have any defects in the known cryptococcal virulence phenotypes of growth at 37 degrees C, capsule formation, laccase activity and urease activity. The plb1 strains were reconstituted using the wild-type locus and this resulted in restoration of all extracellular PLB activities. In vivo testing demonstrated that the plb1 strain was significantly less virulent than the control strains in both the mouse inhalational model and the rabbit meningitis model. We also found that the plb1 strain exhibited a growth defect in a macrophage-like cell line. These data demonstrate that secretory phospholipase is a virulence factor for C. neoformans.


Regaining equilibrium: Understanding the process of sibling adjustment to pediatric acquired brain injury.
This study developed a comprehensive framework for understanding the process of sibling adjustment to pediatric acquired brain injury (ABI). Grounded theory methodology was employed to inductively explore the issues siblings perceived to be their main concerns and how they managed these concerns. Fifty-three interviews (N = 28) were conducted recursively with 20 child and adolescent siblings of individuals with an ABI, 4 adult siblings of individuals with an ABI, and 4 child and adolescent siblings of individuals with congenital disability. Observational and secondary data from hospital staff and parents were also analyzed. The framework was developed and verified through simultaneous data collection and analysis that continued to the point of data saturation. The main concern for siblings was the loss of equilibrium in their lives as defined by the concepts of vulnerability and emotional turmoil. Losing equilibrium was enduring and threatened siblings' sense of security, safety, predictability and control many years post injury. To manage these concerns, siblings employed a variety of interrelated strategies to regain equilibrium. These strategies were conceptualized by the concepts navigating and sacrificing to restore safety, predictability, and control. Like the nonfinite nature of losing equilibrium, regaining equilibrium was an ongoing cyclical process. Rather than focusing on adjustment outcomes only, this study extends previous research by offering a framework for understanding the process of sibling adjustment, and thus providing a set of integrated categories, concepts, hypotheses, and propositions to inform future research and practice. (PsycINFO Database Record


Characterization of brainstem peptide YY (PYY) neurons.
Peptide YY (PYY), a member of the NPY superfamily of peptides, is predominantly synthesized by the colon and is thought to act on both the gut and brain to modulate energy homeostasis. Although neurons expressing PYY mRNA have also been reported in the brainstem, little is known about their physiological role and study of their projections has been problematic due to crossreactivity of PYY antibodies with NPY. In the present study we examined the localization of central PYY cell bodies in the mouse, rat, and monkey. In addition, efferent projections and afferent inputs of central PYY neurons were examined in rodents. Central PYY projections were examined by immunohistochemistry in the NPY knockout mouse, or with an NPY-preabsorbed PYY antibody in the rat to avoid any crossreactivity with NPY. In all species investigated PYY-immunoreactive (ir) cell bodies were localized exclusively to the gigantocellular reticular nucleus (Gi) of the rostral medulla. The highest density of PYY fibers was present within the solitary tract nucleus, specifically within the dorsal and lateral aspects. PYY fibers were also concentrated within the dorsal motor nucleus of the vagus and the hypoglossal nucleus. In addition, both orexin and melanin-concentrating hormone fibers made numerous close appositions with PYY cell bodies in the Gi. Collectively, the projection pattern and association with orexigenic neuropeptides suggest that brainstem PYY neurons may play a role in energy homeostasis through a coordinated effect on visceral, motor, and sympathetic output targets.


Brown rice and its component, γ-oryzanol, attenuate the preference for high-fat diet by decreasing hypothalamic endoplasmic reticulum stress in mice.
Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.


Nafamostat for Prophylaxis against Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis Compared with Gabexate.
The protease inhibitors, nafamostat and gabexate, have been used to prevent pancreatitis related to endoscopic retrograde cholangiopancreatography (ERCP). In vitro, nafamostat inhibits the pancreatic protease activities 10-100 times more potently than gabexate. We evaluated the efficacy of nafamostat for prophylaxis against post-ERCP pancreatitis in comparison with gabexate. Five hundred patients (208 patients in the nafamostat-treated group and 292 in the gabexate-treated group) were analyzed retrospectively after selective exclusion. The incidences of pancreatitis and hyperamylasemia after the ERCP were compared between the nafamostat and gabexate groups. The incidences of acute pancreatitis and hyperamylasemia were 9.1% and 40.9%, respectively, in the nafamostat-treated group, and 8.6% and 39.4% in the gabexate-treated group. The frequencies of post-ERCP pancreatitis and hyperamylasemia did not differ significantly between the two groups, Post-ERCP pancreatitis in two group did not vary according to the different ERCP procedures. The mean serum amylase level at 6 h after ERCP was significantly lower in the nafamostat-treated group than in the gabexate-treated group (p=0.020). However, the difference in serum amylase level did not persist at 18 h and 36 h post-ERCP. Administration of nafamostat before ERCP was not inferior to gabexate in protecting against the development of pancreatitis.


The reality of at risk mental state services: a response to recent criticisms.
In the 1990s criteria were developed to detect individuals at high and imminent risk of developing a psychotic disorder. These are known as the at risk mental state, ultra high risk or clinical high risk criteria. Individuals meeting these criteria are symptomatic and help-seeking. Services for such individuals are now found worldwide. Recently Psychological Medicine published two articles that criticise these services and suggest that they should be dismantled or restructured. One paper also provides recommendations on how ARMS services should be operate. In this paper we draw on the existing literature in the field and present the perspective of some ARMS clinicians and researchers. Many of the critics' arguments are refuted. Most of the recommendations included in the Moritz et al. paper are already occurring. ARMS services provide management of current problems, treatment to reduce risk of onset of psychotic disorder and monitoring of mental state, including attenuated psychotic symptoms. These symptoms are associated with a range of poor outcomes. It is important to assess them and track their trajectory over time. A new approach to detection of ARMS individuals can be considered that harnesses broad youth mental health services, such as headspace in Australia, Jigsaw in Ireland and ACCESS Open Minds in Canada. Attention should also be paid to the physical health of ARMS individuals. Far from needing to be dismantled we feel that the ARMS approach has much to offer to improve the health of young people.


Stereotypic Movements in Case of Sporadic Creutzfeldt-Jakob Disease: Possible Role of Anti-NMDA Receptor Antibodies.
Sporadic Creutzfeldt-Jakob disease (sCJD) and anti-NMDA receptor antibody encephalitis (NMDAE) can both produce a rapidly progressive dementia with resulting state of catatonia or akinetic mutism. Both are associated with movement disorders. In published case series, myoclonus appears to be the most frequent movement disorder in sCJD, while stereotypic, synchronized, one-cycle-per-second movements such as arm or leg elevation, jaw opening, grimacing, head turning, and eye deviation are seen in NMDAE. We report a case of a 59-year-old woman with rapidly worsening cognitive disturbance leading to a nearly catatonic state interrupted by stereotypic movements. sCJD was diagnosed via periodic sharp wave complexes on EEG as well as cerebrospinal fluid (CSF) 14-3-3 and tau protein elevation. Characteristic movement disorder of NMDAE was present in absence of ovarian mass or CSF pleiocytosis. Given prior case reports of presence of anti-NMDA receptor antibodies in sCJD, we propose that the movement disorder in this case was caused by anti-NMDA receptor antibodies whose formation was secondary to neuronal damage from prion disease. It is important to consider sCJD even in cases that have some clinical features suggestive of NMDAE.


Changes in state prescription contraceptive mandates for insurers: the effect on women's contraceptive use.
Access to effective contraceptives is critical to reducing levels of unintended childbearing in the United States. Since 1998, more than half the states have passed legislation requiring insurers that cover prescription drugs to cover prescription contraceptives approved by the Food and Drug Administration. An assessment of the impact of these laws on women's contraceptive use is needed to determine whether such policies are effective. Information was collected on state contraceptive coverage policies, and contraceptive use data among women at risk of unintended pregnancy were drawn from Behavioral Risk Factor Surveillance System surveys conducted between 1998 and 2010. Logit regression analysis was used to calculate the marginal effects of state contraceptive coverage laws on insured and uninsured women's use of prescription methods. Insured women who lived in a state with a contraceptive coverage law were 5% more likely than their counterparts in states without such laws to use an effective method (i.e., a prescription method, condoms or sterilization). Among women who used such methods, those in contraceptive coverage states were 5% more likely than women in other states to use any prescription method, and 4% more likely to use the pill. No associations were found between contraceptive mandates and method use by uninsured women. Among both users and nonusers, contraceptive coverage was associated with a 5% increase in pill use. Contraceptive coverage mandates appear to play a role in increasing the use of prescription contraceptives among insured women, and hence may help to reduce the numbers of unintended pregnancies.


Markers associated with heading and aftermath heading in perennial ryegrass full-sib families.
Heading and aftermath heading are important traits in perennial ryegrass because they impact forage quality. So far, genome-wide association analyses in this major forage species have only identified a small number of genetic variants associated with heading date that overall explained little of the variation. Some possible reasons include rare alleles with large phenotypic affects, allelic heterogeneity, or insufficient marker density. We established a genome-wide association panel with multiple genotypes from multiple full-sib families. This ensured alleles were present at the frequency needed to have sufficient statistical power to identify associations. We genotyped the panel via partial genome sequencing and performed genome-wide association analyses with multi-year phenotype data collected for heading date, and aftermath heading. Genome wide association using a mixed linear model failed to identify any variants significantly associated with heading date or aftermath heading. Our failure to identify associations for these traits is likely due to the extremely low linkage disequilibrium we observed in this population. However, using single marker analysis within each full-sib family we could identify markers and genomic regions associated with heading and aftermath heading. Using the ryegrass genome we identified putative orthologs of key heading genes, some of which were located in regions of marker-trait associations. Given the very low levels of LD, genome wide association studies in perennial ryegrass populations are going to require very high SNP densities. Single marker analysis within full-sibs enabled us to identify significant marker-trait associations. One of these markers anchored proximal to a putative ortholog of TFL1, homologues of which have been shown to play a key role in continuous heading of some members of the rose family, Rosaceae.


Archaeal aminoacyl-tRNA synthesis: diversity replaces dogma.
Accurate aminoacyl-tRNA synthesis is essential for faithful translation of the genetic code and consequently has been intensively studied for over three decades. Until recently, the study of aminoacyl-tRNA synthesis in archaea had received little attention. However, as in so many areas of molecular biology, the advent of archaeal genome sequencing has now drawn researchers to this field. Investigations with archaea have already led to the discovery of novel pathways and enzymes for the synthesis of numerous aminoacyl-tRNAs. The most surprising of these findings has been a transamidation pathway for the synthesis of asparaginyl-tRNA and a novel lysyl-tRNA synthetase. In addition, seryl- and phenylalanyl-tRNA synthetases that are only marginally related to known examples outside the archaea have been characterized, and the mechanism of cysteinyl-tRNA formation in Methanococcus jannaschii and Methanobacterium thermoautotrophicum is still unknown. These results have revealed completely unexpected levels of complexity and diversity, questioning the notion that aminoacyl-tRNA synthesis is one of the most conserved functions in gene expression. It has now become clear that the distribution of the various mechanisms of aminoacyl-tRNA synthesis in extant organisms has been determined by numerous gene transfer events, indicating that, while the process of protein biosynthesis is orthologous, its constituents are not.


Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson's disease.
Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent multicenter genetic studies have revealed that mutations in the glucocerebrosidase 1 (GBA1) gene, which are responsible for Gaucher's disease, are strong risk factors for PD and DLB. However, the mechanistic link between the functional loss of glucocerebrosidase (GCase) and the toxicity of αSyn in vivo is not fully understood. In this study, we employed Drosophila models to examine the effect of GCase deficiency on the neurotoxicity of αSyn and its molecular mechanism. Behavioral and histological analyses showed that knockdown of the Drosophila homolog of GBA1 (dGBA1) exacerbates the locomotor dysfunction, loss of dopaminergic neurons and retinal degeneration of αSyn-expressing flies. This phenotypic aggravation was associated with the accumulation of proteinase K (PK)-resistant αSyn, rather than with changes in the total amount of αSyn, raising the possibility that glucosylceramide (GlcCer), a substrate of GCase, accelerates the misfolding of αSyn. Indeed, in vitro experiments revealed that GlcCer directly promotes the conversion of recombinant αSyn into the PK-resistant form, representing a toxic conformational change. Similar to dGBA1 knockdown, knockdown of the Drosophila homolog of β-galactosidase (β-Gal) also aggravated locomotor dysfunction of the αSyn flies, and its substrate GM1 ganglioside accelerated the formation of PK-resistant αSyn. Our findings suggest that the functional loss of GCase or β-Gal promotes the toxic conversion of αSyn via aberrant interactions between αSyn and their substrate glycolipids, leading to the aggravation of αSyn-mediated neurodegeneration.


Prevalence of depression in adults with type 2 diabetes in the Basque Country: relationship with glycaemic control and health care costs.
The aim of the study was to estimate the prevalence of depression in the population diagnosed with diabetes type 2 and to test the hypothesis that the presence of depression in such cases was associated with a) worse glycaemic control, and b) higher healthcare costs. We conducted a cross-sectional analysis, from 1st September 2010 to 31st August 2011, among patients with type 2 diabetes aged 35 years and over in the Basque Country. It was identified how many of them had also depression. The database included administrative individual level information on age, sex, healthcare costs, other comorbidities, and values of glycaemic control (HbA1c). Deprivation index variable was used as socioeconomic measure and, to observe the coexistent pathologies, all the patients diagnoses were categorized by Adjusted Clinical Groups. We used a measure of association, a logistic and a linear regression for analysis. 12.392 (9.8%) of type 2 diabetes patients were diagnosed with depression, being the prevalence 5.2% for males and 15.1% for females. This comorbidity was higher among the most deprived population. There was no association between the presence of depression and glycaemic control. We estimated that the comorbidity average cost per patient/year was 516€ higher than in patients with just type 2 diabetes (P < 0.001) adjusted by the other covariates. We did not find any relationship between depression and glycaemic control in patients with type 2 diabetes. However, the comorbidity was associated with significantly high healthcare costs compared to that of type 2 diabetes occurring alone, after adjusting by other illness. Thus, there is a need of more precise recognition, screening and monitoring of depression among diabetic population. Evidence-based treatment for depression should be included in type 2 diabetes clinical guidelines.


Photosynthetic growth despite a broken Q-cycle.
Central in respiration or photosynthesis, the cytochrome bc(1) and b(6)f complexes are regarded as functionally similar quinol oxidoreductases. They both catalyse a redox loop, the Q-cycle, which couples electron and proton transfer. This loop involves a bifurcated electron transfer step considered as being mechanistically mandatory, making the Q-cycle indispensable for growth. Attempts to falsify this paradigm in the case of cytochrome bc(1) have failed. The rapid proteolytic degradation of b(6)f complexes bearing mutations aimed at hindering the Q-cycle has precluded so far the experimental assessment of this model in the photosynthetic chain. Here we combine mutations in Chlamydomonas that inactivate the redox loop but preserve high accumulation levels of b(6)f complexes. The oxidoreductase activity of these crippled complexes is sufficient to sustain photosynthetic growth, which demonstrates that the Q-cycle is dispensable for oxygenic photosynthesis.


Gender-related neuroanatomical differences in alcohol dependence: findings from the ENIGMA Addiction Working Group.
Gender-related differences in the susceptibility, progression and clinical outcomes of alcohol dependence are well-known. However, the neurobiological substrates underlying such differences remain unclear. Therefore, this study aimed to investigate gender differences in the neuroanatomy (i.e. regional brain volumes) of alcohol dependence. We examined the volume of a priori regions of interest (i.e., orbitofrontal cortex, hippocampus, amygdala, nucleus accumbens, caudate, putamen, pallidum, thalamus, corpus callosum, cerebellum) and global brain measures (i.e., total grey matter (GM), total white matter (WM) and cerebrospinal fluid). Volumes were compared between 660 people with alcohol dependence (228 women) and 326 controls (99 women) recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age and education years. Compared to controls, individuals with alcohol dependence on average had (3-9%) smaller volumes of the hippocampus (bilateral), putamen (left), pallidum (left), thalamus (right), corpus callosum, total GM and WM, and cerebellar GM (bilateral), the latter more prominently in women (right). Alcohol-dependent men showed smaller amygdala volume than control men, but this effect was unclear among women. In people with alcohol dependence, more monthly standard drinks predicted smaller amygdala and larger cerebellum GM volumes. The neuroanatomical differences associated with alcohol dependence emerged as gross and widespread, while those associated with a specific gender may be confined to selected brain regions. These findings warrant future neuroscience research to account for gender differences in alcohol dependence to further understand the neurobiological effects of alcohol dependence.


Bicarbonate loading to enhance training and competitive performance.
Bicarbonate loading is a popular ergogenic aid used primarily by athletes in short-duration, high-intensity sporting events and competitions. Controlled experimental trials have shown that small (worthwhile) benefits can obtained from acute doses of bicarbonate taken before exercise. Gastrointestinal problems encountered by some athletes limit the widespread use of this practice, however. The transfer of positive research findings to the competitive environment has proved problematic for some individuals. More recent applications involve serial ingestion of bicarbonate over several days before competition or during high-intensity training sessions over a few weeks. A number of research questions need to be addressed to enhance applications of bicarbonate loading in the elite sport environment. This commentary examines some of research and practical issues of bicarbonate loading used to enhance both training and competitive performance.


Are we there yet? The state of the evidence base for guidelines on breaking bad news to cancer patients.
The way clinicians break bad news to cancer patients has been retrospectively associated with poor psychosocial outcomes for patients. Education and practice in breaking bad news may be ineffective for improving patients' well-being unless it is informed by a sound evidence base. In the health field, research efforts are expected to advance evidence over time to inform evidence-based practice. Key characteristics of an advancing evidence base are a predominance of new data, and rigorous intervention studies which prospectively demonstrate improved outcomes. This review aimed to examine the progress of the evidence base in breaking bad news to cancer patients. Manual and computer-based searches (Medline and PsycINFO) were performed to identify publications on the topic of breaking bad news to cancer patients published between January 1995 and March 2009. Relevant publications were coded in terms of whether they provided new data, examined psychosocial outcomes for patients or tested intervention strategies and whether intervention studies met criteria for design rigour. Of the 245 relevant publications, 55.5% provided new data and 16.7% were intervention studies. Much of the intervention effort was directed towards improving provider skills rather than patient outcomes (9.8% of studies). Less than 2% of publications were rigorous intervention studies which addressed psychosocial outcomes for patients. Rigorous intervention studies which evaluate strategies for improving psychosocial outcomes in relation to breaking bad news to cancer patients are needed. Current practice and training regarding breaking bad news cannot be regarded as evidence-based until further research is completed.


Energy and the food system.
Modern agriculture is heavily dependent on fossil resources. Both direct energy use for crop management and indirect energy use for fertilizers, pesticides and machinery production have contributed to the major increases in food production seen since the 1960s. However, the relationship between energy inputs and yields is not linear. Low-energy inputs can lead to lower yields and perversely to higher energy demands per tonne of harvested product. At the other extreme, increasing energy inputs can lead to ever-smaller yield gains. Although fossil fuels remain the dominant source of energy for agriculture, the mix of fuels used differs owing to the different fertilization and cultivation requirements of individual crops. Nitrogen fertilizer production uses large amounts of natural gas and some coal, and can account for more than 50 per cent of total energy use in commercial agriculture. Oil accounts for between 30 and 75 per cent of energy inputs of UK agriculture, depending on the cropping system. While agriculture remains dependent on fossil sources of energy, food prices will couple to fossil energy prices and food production will remain a significant contributor to anthropogenic greenhouse gas emissions. Technological developments, changes in crop management, and renewable energy will all play important roles in increasing the energy efficiency of agriculture and reducing its reliance of fossil resources.


The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation.
The tumor suppressor p53 plays a key role in regulating apoptosis and cell cycle progression. In addition, p53 is implicated in control of cell differentiation in muscle, the circulatory system, ocular lens and various carcinoma tissues. However, the mechanisms by which p53 controls cell differentiation are not fully understood. Here we present evidence that p53 directly regulates c-Maf and Prox1, two important transcription factors controlling differentiation in the ocular lens. First, human and murine c-Maf and Prox1 gene promoters contain authentic p53 DNA binding sites. Second, p53 directly binds to the p53 binding sites found in the promoter regions. Third, exogenous p53 induces dose-dependent expression of the luciferase report gene driven by both c-Maf and Prox1 promoters, and p53 binds to both promoters in the ChIP assays. Fourth, in the in vitro differentiation model, knockdown of p53 significantly inhibits lens differentiation which is associated with downregulated expression of c-Maf and Prox1. Finally, in p53 knockout mice, the expression of c-Maf and Prox1 are significantly altered. Together, our results reveal that p53 regulates lens differentiation through modulation of two important transcription factors, c-Maf and Prox1, and through them p53 thus controls expression of various differentiation-related downstream crystallin genes.


Knee braces: current evidence and clinical recommendations for their use.
Methods of preventing and treating knee injuries have changed with the rapid development and refinement of knee braces. Prophylactic knee braces are designed to protect uninjured knees from valgus stresses that could damage the medial collateral ligaments. However, no conclusive evidence supports their effectiveness, and they are not recommended for regular use. Functional knee braces are intended to stabilize knees during rotational and anteroposterior forces. They offer a useful adjunct to the treatment and rehabilitation of ligamentous knee injuries. Patellofemoral knee braces have been used to treat anterior knee disorders and offer moderate subjective improvement without significant disadvantages. Additional well-designed studies are needed to demonstrate objectively the benefits of all knee braces. Knee braces should be used in conjunction with a rehabilitation program that incorporates strength training, flexibility, activity modification and technique refinement.


Discovery of novel human and animal cells infected by the severe acute respiratory syndrome coronavirus by replication-specific multiplex reverse transcription-PCR.
The severe acute respiratory syndrome coronavirus (SARS-CoV) is the causative agent of the recent outbreak of severe acute respiratory syndrome. VeroE6 cells, fetal rhesus monkey kidney cells, and human peripheral blood mononuclear cells were the only cells known to be susceptible to SARS-CoV. We developed a multiplex reverse transcription-PCR assay to analyze the susceptibility of cells derived from a variety of tissues and species to SARS-CoV. Additionally, productive infection was determined by titration of cellular supernatants. Cells derived from three species of monkey were susceptible to SARS-CoV. However, the levels of SARS-CoV produced differed by 4 log(10). Mink lung epithelial cells (Mv1Lu) and R-Mix, a mixed monolayer of human lung-derived cells (A549) and mink lung-derived cells (Mv1Lu), are used by diagnostic laboratories to detect respiratory viruses (e.g., influenza virus); they were also infected with SARS-CoV, indicating that the practices of diagnostic laboratories should be examined to ensure appropriate biosafety precautions. Mv1Lu cells produce little SARS-CoV compared to that produced by VeroE6 cells, which indicates that they are a safer alternative for SARS-CoV diagnostics. Evaluation of cells permissive to other coronaviruses indicated that these cell types are not infected by SARS-CoV, providing additional evidence that SARS-CoV binds an alternative receptor. Analysis of human cells derived from lung, kidney, liver, and intestine led to the discovery that human cell lines were productively infected by SARS-CoV. This study identifies new cell lines that may be used for SARS-CoV diagnostics and/or basic research. Our data and other in vivo studies indicate that SARS-CoV has a wide host range, suggesting that the cellular receptor(s) utilized by SARS-CoV is highly conserved and is expressed by a variety of tissues.


Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds.
Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ's exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.


A methodological review of the quality of reporting of surveys in transfusion medicine.
Surveys are a common tool used to gather information about practices across many medical specialties. The quality of survey reporting impacts the strength of any conclusions. Thorough and accurate reporting of survey-based research is critical for evaluation of the validity, reliability, and generalizability of the results. The objective of this study was to appraise the quality of recently reported surveys in transfusion medicine (TM). A systematic review of the literature was performed to identify studies evaluating clinical practices in TM that used a questionnaire as the research tool and were published between January 2001 and November 2017. Manuscripts that met eligible criteria were appraised using a modified Survey Reporting Guideline questionnaire. The search identified 1632 references, from which 54 abstracts met eligibility criteria for analysis. Only seven (13%) manuscripts reported reliability and validity of the survey tool, 26 (48%) provided a description of the survey population and sample frame, and 11 (20%) indicated the representativeness of the underlying population. Additional reporting limitations included 31 (57%) manuscripts reporting the response rate calculation, two (4%) the analysis of nonresponse error, nine (17%) the method description for handling of missing data, 11 (20%) the analysis of responder and nonresponder characteristics, and 23 (43%) explicitly discussed the generalizability of the results. Our findings document quality deficiencies in the reporting of research conducted using surveys in TM. Validated guidelines for the reporting of survey-based clinical research should be developed and applied to improve the quality of survey reporting in TM.


The Snail repressor is required for PMC ingression in the sea urchin embryo.
In metazoans, the epithelial-mesenchymal transition (EMT) is a crucial process for placing the mesoderm beneath the ectoderm. Primary mesenchyme cells (PMCs) at the vegetal pole of the sea urchin embryo ingress into the floor of the blastocoele from the blastula epithelium and later become the skeletogenic mesenchyme. This ingression movement is a classic EMT during which the PMCs penetrate the basal lamina, lose adherens junctions and migrate into the blastocoele. Later, secondary mesenchyme cells (SMCs) also enter the blastocoele via an EMT, but they accompany the invagination of the archenteron initially, in much the same way vertebrate mesenchyme enters the embryo along with endoderm. Here we identify a sea urchin ortholog of the Snail transcription factor, and focus on its roles regulating EMT during PMC ingression. Functional knockdown analyses of Snail in whole embryos and chimeras demonstrate that Snail is required in micromeres for PMC ingression. Snail represses the transcription of cadherin, a repression that appears evolutionarily conserved throughout the animal kingdom. Furthermore, Snail expression is required for endocytosis of cadherin, a cellular activity that accompanies PMC ingression. Perturbation studies position Snail in the sea urchin micromere-PMC gene regulatory network (GRN), downstream of Pmar1 and Alx1, and upstream of several PMC-expressed proteins. Taken together, our findings indicate that Snail plays an essential role in PMCs to control the EMT process, in part through its repression of cadherin expression during PMC ingression, and in part through its role in the endocytosis that helps convert an epithelial cell to a mesenchyme cell.


Coagulation factor activity in units of leukoreduced and nonleukoreduced canine fresh-frozen plasma.
To evaluate coagulation factors in units of leukoreduced (LR) and nonleukoreduced (non-LR) canine fresh-frozen plasma (cFFP). 8 healthy research dogs. In a crossover study, dogs were randomly assigned to 1 of 2 groups from which blood was collected and either did or did not undergo leukoreduction. After a recovery period of ≥ 28 days, the dogs were switched between protocols. After each collection, blood samples were centrifuged, and cFFP was stored frozen for later comparative analysis of coagulation factors, antithrombin, and protein C activities (reported as comparative percentages of the corresponding activities determined in a canine pooled plasma standard); prothrombin and activated partial thromboplastin times; and fibrinogen concentration. There were no significant differences detected between results for LR cFFP, compared with those for non-LR cFFP. Although there was variation among residual activities of coagulation factors in LR and non-LR cFFP, the variations and differences were considered unlikely to impact the efficacy of LR cFFP transfused for coagulation factor replacement in dogs. However, owing to the small sample size and high variability of results in the present study, additional research with a larger sample size is required for definitive conclusions on the effects of leukoreduction on coagulation factors in cFFP and to develop treatment guidelines for LR cFFP use in dogs with congenital and acquired coagulopathies.


Striatal morphology is associated with tobacco cigarette craving.
The striatum has a clear role in addictive disorders and is involved in drug-related craving. Recently, enhanced striatal volume was associated with greater lifetime nicotine exposure, suggesting a bridge between striatal function and structural phenotypes. To assess this link between striatal structure and function, we evaluated the relationship between striatal morphology and this brain region's well-established role in craving. In tobacco smokers, we assessed striatal volume, surface area, and shape using a new segmentation methodology coupled with local shape indices. Striatal morphology was then related with two measures of craving: state-based craving, assessed by the brief questionnaire of smoking urges (QSU), and craving induced by smoking-related images. A positive association was found between left striatal volume and surface area with both measures of craving. A more specific relationship was found between both craving measures and the dorsal, but not in ventral striatum. Evaluating dorsal striatal subregions showed a single relationship between the caudate and QSU. Although cue-induced craving and the QSU were both associated with enlarged striatal volume and surface area, these measures were differentially associated with global or more local striatal volumes. We also report a connection between greater right striatal shape deformations and cue-induced craving. Shape deformations associated with cue-induced craving were specific to striatal subregions involved in habitual responding to rewarding stimuli, which is relevant given the habitual nature of cue-induced craving. The current findings confirm a relationship between striatal function and morphology and suggest that variation in striatal morphology may be a biomarker for craving severity.


ROSE bitumen: Mesoscopic model of bitumen and bituminous mixtures.
We present a mesoscopic model for bitumen and bituminous mixtures. The model, which is based on dissipative particle dynamics, consists of different dynamical entities that represent the different characteristic time scales. Through the stress relaxation function, the mechanical properties of the model are investigated. For pure bitumen, the viscosity features super-Arrhenius behavior in the low-temperature regime in agreement with experimental data. The frequency-dependent viscoelastic properties show purely viscous behavior at low frequencies with increasing elasticity and hardening at higher frequencies, as expected. The model dynamics are analyzed in the framework of longitudinal hydrodynamics. The thermal process is two orders of magnitude slower than the attenuation of the density-wave propagation; hence the dynamic structure factor is dominated by a sharp Rayleigh peak and a relatively broad Brillouin peak. The model is applied to study triblock-copolymer-modified bitumen mixtures. Effects of the polymer concentration and end-block interactions with the bitumen are investigated. While the polymer concentration has an effect on the mechanical properties, the effect of increasing repulsive interactions between the bitumen and the polymer end-blocks is much more dramatic; it increases the viscosity of the mixture and shifts the onset of the elastic behavior to lower frequencies. For increased repulsion, the polymer end-blocks form small clusters that can be connected by a dynamic polymer backbone network. A simple Flory-Huggins analysis reveals the onset of segregation of the end-blocks in the bitumen mixture in agreement with the simulation data. Hence the changed mechanical properties are due to the emergence of large-scale structures as the repulsion is increased, which conforms to known mechanisms of microphase separation in polymer-modified bitumens.


Label-free peptide quantification coupled with in silico mapping of proteases for identification of potential serum biomarkers in gastric adenocarcinoma patients.
We aimed to identify serum level variations in protein-derived peptides between patients diagnosed with gastric adenocarcinoma (GAC) and non-cancer persons (control) to detect the activity changes of proteases and explore the auxiliary diagnostic value in the context of GAC physiopathology. The label-free quantitative peptidome approach was applied to identify variants in serum levels of peptides that can differentiate GAC patients from the control group. Peptide sequences were submitted against Proteasix tool predicting proteases potentially involved in their generation. The activity change of proteases was subsequently estimated based on the peptides with significantly altered relative abundance. In turn, activity change prediction of proteases was correlated with relevant protease expression data from the literature. A total of 191 peptide sequences generated by the cleavage of 36 precursor proteins were identified. Using the label-free quantification approach, 33 peptides were differentially quantified (adjusted fold change ≥ 1.5 and p-value < 0.05) in which 19 were up-regulated and 14 were down-regulated in GAC samples. Of these peptides, fibrinopeptide A was significantly decreased and its phosphorylated form ADpSGEGDFLAEGGGVR was upregulated in GAC samples. Activity change prediction yielded 10 proteases including 6 Matrix Metalloproteinases (MMPs), Thrombin, Plasmin, and kallikreins 4 and 14. Among predicted proteases in our analysis, MMP-7 was presented as a more promising biomarker associated with useful assays of clinical practice for GAC diagnosis. Our experimental results demonstrate that the serum levels of peptides were significantly differentiated in GAC physiopathology. The hypotheses built on protease regulation could be used for further investigations to measure proteases and their activity levels that have been poorly studied for GAC diagnosis.


Cervical carcinoma in the European Union: an update on disease burden, screening program state of activation, and coverage as of March 2014.
Cervical cancer (CC) is defined as a disease of disparity. This is due to marked differences in CC incidence and mortality between developed and developing countries. As a continent, Europe is no exception. This study examines the state of activation of CC screening in the European Union as of March 2014, reviews CC incidence and mortality data, and highlights the initiatives adopted to extend program coverage to nonresponders. The present study is based on the most recent data available from PubMed-indexed journals, the Web sites of the health ministries of each member state, and the Web sites of national cancer observatories; failing these sources, information was sought in scientific journals published in the local language. In 2003, the European Council recommended that priority be given to organized screening program activation. Nonetheless, a number of European Union member states still lack population-based organized screening programs, and few have implemented programs directed at disadvantaged populations. Several investigations have demonstrated that the women at higher CC risk are unscreened and underscreened ones. Since then, several member states have made significant efforts to set up effective prevention programs by adopting international quality standards and centralizing screening organization and result evaluation. Several developed countries and some new central-eastern European member states have poorly organized prevention programs that result in poor women's health. Diagnosis of CC is emotionally traumatic, but it is highly preventable. When CC is found early, it is highly treatable and associated with long survival and good quality of life.