Digital papular calcific elastosis: a histopathological, histochemical and ultrastructural study of 20 patients.
In 1960, 5 patients were reported with a condition termed "degenerative collagenous plaques of the hands". Ultraviolet light and chronic pressure seem to be the inciting factors. Clinically, it is characterized by keratotic, translucent papules, in linear array, on the radial border of the hands. Histology shows hyperkeratosis and dermal elastosis. The current study documented the histopathological, histochemical and ultrastructural features of 20 patients with this condition and considered the differential diagnoses. The findings were in accordance with those of previous studies, but peculiar, basophilic elastotic masses (BEMs), were a prominent finding. Ultrastructurally, elastic tissue appeared in the form of degenerated non-fragmented and fragmented elastic fibres, degenerated fibres showing foci of increased density, with or without a fibrillar component and as amorphous, structureless material. BEMs arose almost exclusively from degenerated elastic tissue and contained calcium. Disintegrated collagen may be incorporated in the amorphous material and, subsequently, form a minor part of BEMs. Solar elastosis, and its variants, show some similarity to degenerative collagenous plaques of the hands, but lack the constant presence of these calcified angular elastotic masses. BEMs show resemblance to elastic globes, and elastotic bodies found in elastotic nodules of the anthelix and cartilage-hair hypoplasia. In the clinical setting of "degenerative collagenous plaques of the hands", BEMs seem to be unique and due to their extensive presence serve as a non-specific marker for this condition. Digital papular calcific elastosis therefore seems to be more appropriate nomenclature.


Estimates of local biodiversity change over time stand up to scrutiny.
We present new data and analyses revealing fundamental flaws in a critique of two recent meta-analyses of local-scale temporal biodiversity change. First, the conclusion that short-term time series lead to biased estimates of long-term change was based on two errors in the simulations used to support it. Second, the conclusion of negative relationships between temporal biodiversity change and study duration was entirely dependent on unrealistic model assumptions, the use of a subset of data, and inclusion of one outlier data point in one study. Third, the finding of a decline in local biodiversity, after eliminating post-disturbance studies, is not robust to alternative analyses on the original data set, and is absent in a larger, updated data set. Finally, the undebatable point, noted in both original papers, that studies in the ecological literature are geographically biased, was used to cast doubt on the conclusion that, outside of areas converted to croplands or asphalt, the distribution of biodiversity trends is centered approximately on zero. Future studies may modify conclusions, but at present, alternative conclusions based on the geographic-bias argument rely on speculation. In sum, the critique raises points of uncertainty typical of all ecological studies, but does not provide an evidence-based alternative interpretation.


Gastrointestinal lymphoma: a spectrum of fluoroscopic and CT findings.
Gastrointestinal lymphomas can occur in nodular, polypoid, cavitary, ulcerative or diffuse infiltrating (submucosal) forms. Barium studies and computed tomography (CT) are the most popular imaging techniques used to diagnose these lymphomas. Barium studies are superior to CT in evaluating mild mucosal and submucosal changes. However, CT is the technique of choice because it provides a complete evaluation of the extent of disease dissemination, recent disease development, therapeutic response, and related complications.


A review of autopsy reports on chimpanzees in or from US laboratories.
Approximately 1000 chimpanzees are currently held in five federally owned, or supported, US laboratories. This study reviews 110 autopsy reports on chimpanzees who died from 2001-2011 in laboratories or in sanctuaries (but who were from laboratories), in order to glean information about their premorbid health and causes of death. The findings raise questions about the health status of the chimpanzees remaining in laboratories. Most of the chimpanzees currently held are not involved in active protocols. The Chimpanzee Health Improvement, Maintenance, and Protection (CHIMP) Act 2000 states that chimpanzees "not needed" for research "shall" be accepted into the federal sanctuary system, but criteria for when a chimpanzee is deemed "not needed" are not given. The assessment of "not needed" lies with the Secretary of Health and Human Services, who has left the decision to the discretion of the laboratories. This autopsy review revealed that the majority of the chimpanzees who died in laboratories had been suffering from significant chronic or incurable illnesses, and most often had multi-system diseases that should have made them ineligible for future research, on scientific, as well as ethical, grounds. The study's findings are significant in establishing the need for defined criteria for chimpanzee retirement to sanctuary.


Comparison of skin hydration in combination and single use of common moisturizers (cream, toner, and spray water).
This study aims to assess the moisturization in combination or single use (including seven general applications) of three common moisturizers: cream, toner, and spray water. Groups were set as C: cream only; T: toner only; C+T, T+C: cream or toner applied successively within a few minutes; C-T, C-S: cream applied with repeated toner or spray water every 2 h; T-T: toner applied with repeated toner every 2 h; and N: untreated group. Outcomes were the change in skin hydration from baseline at 2, 4, 6, and 8 h after applications. All treated zones displayed a significantly higher degree of hydration compared with the untreated zone ( p < 0.05). For normal skin (hydration value at baseline >35 a.u.), C-T led to greatest hydration change rate compared with others, followed by C+T, T+C, and C. Those three applications exhibited analogous hydration at each test point ( p > 0.05). The hydration rate of C-S differed slightly from T-T, followed by those four mentioned above, with T being the last. For dry skin (hydration value at baseline <35 a.u.), no statistical significance could be detected between C-T zone and C+T, T+C, and C zones ( p > 0.05), the other results were identical. When cream and toner were applied successively, the application order has little effect on skin hydration. The application of cream only was an effective and brief way to achieve favorable moisturization especially for dry skin. As a complement, repeated application of toner rather than spray water is efficacious for skin hydration.


Within-species differences in primate social structure: evolution of plasticity and phylogenetic constraints.
Primate socioecological studies have attempted to derive general frameworks using the average behavioural traits of species or genera to place them into categories. However, with the accumulation of primate studies, it is timely to place more emphasis on understanding within-species variation in social structure. In this review we have four objectives. First, we examine within-species variation in the potential determinants of social structure, including diet, demography, predation and infanticide, and document considerable variation. Second, we present case studies of within-species variation in social structure to illustrate the potential magnitude of this variation. For example, there are cases within a single interbreeding population where multi-male, uni-male, fission-fusion and monogamous groups are found. Third, by examining widespread primate lineages that occur in a variety of habitats, we note that there are differences in the magnitude of variation in social structures across different lineages and as a result we consider phylogenetic constraints on phenotypic variation in social structure. Finally, we reflect on the implications of extensive variation in social structure. We suggest that primate social structure will represent a combination of adaptation to present-day environment and phylogenetic inertia. To advance our understanding of the relative contribution of phylogeny versus ecology we propose two approaches. One approach is to compare groups in the same interbreeding population that inhabit different ecological conditions. Any differences that are found can be attributed to ecological differences, since phylogeny should not play a role within a single population. The second approach is to study distantly related species that have similar social structures to illustrate how similar ecological pressures might be operating to select for parallel social structures.


A heuristic mathematical model for the dynamics of sensory conflict and motion sickness.
The etiology of motion sickness is now usually explained in terms of a qualitatively formulated "sensory conflict" hypothesis. By consideration of the information processing task faced by the central nervous system in estimating body spatial orientation and in controlling active body movement using an "internal model" referenced control strategy, a mathematical model for sensory conflict generation is developed. The model incorporates and extends models proposed by von Holst, Held, and Reason, and is congruent with multisensory models for spatial orientation developed by Young and coworkers. The model postulates a major dynamic functional role for sensory conflict signals in movement control, as well as in sensory-motor adaptation. It accounts for the role of active movement in creating motion sickness symptoms in some experimental circumstances, and in alleviating them in others. The relationship between motion sickness produced by "sensory rearrangement" and that resulting from external motion disturbances is explicitly defined. A nonlinear conflict averaging model is proposed which describes dynamic aspects of experimentally observed subjective discomfort sensation, and suggests resulting behaviours. The model admits several possibilities for adaptive mechanisms which do not involve internal model updating. Further systematic efforts to experimentally refine and validate the model are indicated.


Solidarity and disparity: Declining labor union density and changing racial and educational mortality inequities in the United States.
Recently, United States life expectancy has stagnated or declined for the poor and working class and risen for the middle and upper classes. Declining labor-union density-the percent of workers who are unionized-has precipitated burgeoning income inequity. We examined whether it has also exacerbated racial and educational mortality inequities. From CDC, we obtained state-level all-cause and overdose/suicide mortality overall and by gender, gender-race, and gender-education from 1986-2016. State-level union density and demographic and economic confounders came from the Current Population Survey. State-level policy confounders included the minimum wage, the generosity of Aid to Families with Dependent Children or Temporary Assistance for Needy Families, and the generosity of unemployment insurance. To model the exposure-outcome relationship, we used marginal structural modeling. Using state-level inverse-probability-of-treatment-weighted Poisson models with state and year fixed effects, we estimated 3-year moving average union density's effects on the following year's mortality rates. Then, we tested for gender, gender-race, and gender-education effect-modification. Finally, we estimated how racial and educational all-cause mortality inequities would change if union density increased to 1985 or 1988 levels, respectively. Overall, a 10% increase in union density was associated with a 17% relative decrease in overdose/suicide mortality (95% confidence interval [CI]: 0.70, 0.98), or 5.7 lives saved per 100 000 person-years (95% CI: -10.7, -0.7). Union density's absolute (lives-saved) effects on overdose/suicide mortality were stronger for men than women, but its relative effects were similar across genders. Union density had little effect on all-cause mortality overall or across subgroups, and modeling suggested union-density increases would not affect mortality inequities. Declining union density (as operationalized in this study) may not explain all-cause mortality inequities, although increases in union density may reduce overdose/suicide mortality.


Anterior cervical debridement and strut-grafting for osteomyelitis of the cervical spine.
A retrospective review of the surgical experience in treating 18 patients with osteomyelitis of the cervical spine is reported. The patients ranged in age from 20 to 60 years and all complained of neck pain upon admission. Ten patients had a prior history of intravenous drug abuse, three had previously suffered penetrating injuries of the neck, and one had an extraspinal site of osteomyelitis. Bacteria were isolated in 13 cases and tuberculosis in three. Neurological abnormalities were present in over one-half of the patients, consisting of myelopathy (nine cases) or radiculopathy (four cases). Plain cervical spine films and polytomography demonstrated vertebral and end-plate destruction, spinal instability, and increased paravertebral soft-tissue shadow in all cases. Computerized tomography and, more recently, magnetic resonance imaging have proven helpful in detecting bone involvement and the presence of epidural extension associated with cervical osteomyelitis. The risk of vertebral body collapse, kyphosis, and myelopathy in the osteomyelitic cervical spine has standardized the management of this problem in this institution to consist of skeletal traction, needle aspiration or blood culture for organism identification, anterior cervical debridement, autogenous iliac graft fusion, and intravenous administration of antibiotics. Spinal stability and neurological improvement were achieved in all 18 patients.


Genetics of rheumatoid arthritis contributes to biology and drug discovery.
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.


Prediction of liver cirrhosis, using diagnostic imaging tools.
Early diagnosis of liver cirrhosis is important. Ultrasound-guided liver biopsy is the gold standard for diagnosis of liver cirrhosis. However, its invasiveness and sampling bias limit the applicability of the method. Basic imaging for the diagnosis of liver cirrhosis has developed over the last few decades, enabling early detection of morphological changes of the liver by ultrasonography (US), computed tomography, and magnetic resonance imaging (MRI). They are also accurate diagnostic methods for advanced liver cirrhosis, for which early diagnosis is difficult. There are a number of ways to compensate for this difficulty, including texture analysis to more closely identify the homogeneity of hepatic parenchyma, elastography to measure the stiffness and elasticity of the liver, and perfusion studies to determine the blood flow volume, transit time, and velocity. Amongst these methods, elastography using US and MRI was found to be slightly easier, faster, and able to provide an accurate diagnosis. Early diagnosis of liver cirrhosis using MRI or US elastography is therefore a realistic alternative, but further research is still needed.


Effect of covalent serpin-heparinoid complexes on plasma thrombin generation on fetal distal lung epithelium.
Extravascular coagulation within the lung airspace is a hallmark of respiratory distress syndrome (RDS) in premature infants. We previously showed that covalent antithrombin-heparin complex (ATH) is superior to noncovalent antithrombin (AT) + heparin (H) mixtures at inhibiting plasma thrombin generation on rat fetal distal lung epithelium (FDLE) in vitro. However, heparin cofactor II (HC) has been shown to selectively inhibit thrombin, which may be advantageous if other enzyme activities are present in the airspace. We compared the abilities of ATH, covalent HC-heparin complex (HCH), and covalent HC-dermatan sulfate (HCD) to inhibit thrombin generation on FDLE in plasmas from either adults or newborns. In the presence of ATH, peak free thrombin generation in adult plasma on the cell surface was reduced by 92% compared with controls (no anticoagulant). However, whereas HCH reduced peak free thrombin generation in adult plasma by 81%, HCD was only able to reduce activity by 33%. All covalent complexes caused a greater decrease in thrombin activity compared with that with the corresponding noncovalent serpin + heparinoid mixtures. Experiments in plasma from newborns resulted in peak free thrombin that was less than or equal to that in adult plasma when covalent conjugates were added. Relative peak free thrombin was proportional to rate of prothrombin consumption and amount of thrombin-inhibitor complexes formed. In vivo, experiments in newborn rats showed that a greater percentage of intratracheally instilled ATH and HCH could be recovered in lung lavage fluid compared withwith that for HCD. In summary, ATH, HCH, and HCD are inhibitors of thrombin generation on FDLE superior to the corresponding noncovalent mixtures, with ATH and HCH being more potent than HCD. Covalent conjugates of AT or HC with H may be preferred in treatment of extravascular coagulation.


Window anatomy for neurosurgical approaches. Laboratory investigation.
Knowledge of the cranium projections of the gyral structures is essential to reduce the surgical complications and to perform minimally invasive interventions in daily neurosurgical practice. Thus, in this study the authors aimed to provide detailed information on cranial projections of the eloquent cortical areas. Ten formalin-fixed adult human skulls were obtained. Using sutures and craniometrical points, the crania were divided into 8 windows: superior frontal, inferior frontal, superior parietal, inferior parietal, sphenoidal, temporal, superior occipital, and inferior occipital. The projections of the precentral gyrus, postcentral gyrus, inferior frontal gyrus, superior temporal gyrus, transverse temporal gyri, Heschl gyrus, genu and splenium of the corpus callosum, supramarginal gyrus, angular gyrus, calcarine sulcus, and sylvian fissure to cranial vault were evaluated. Three-fourths of the precentral gyrus and postcentral gyrus were in the superior parietal window. The inferior frontal gyrus extended to the inferior parietal window in 80%. The 3 important parts of this gyrus were located below the superior temporal line in all hemispheres. The orbital and triangular parts were in the inferior frontal window, and the opercular part was in the inferior parietal window. The superior temporal gyrus was usually located in the inferior parietal and temporal windows, whereas the supramarginal gyrus and angular gyrus were usually located in the superior and inferior parietal windows. The farthest anterior point of the Heschl gyrus was usually located in the inferior parietal window. The mean positions of arachnoid granulations were measured as 3.9 +/- 0.39 cm anterior and 7.3 +/- 0.51 cm posterior to the bregma. Given that recognition of the gyral patterns underlying the craniotomies is not always easy, awareness of the coordinates and projections of certain gyri according to the craniometric points may considerably contribute to surgical interventions.


Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells.
Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas.


FbpA, a novel multifunctional Listeria monocytogenes virulence factor.
Listeria monocytogenes is a Gram-positive intracellular bacterium responsible for severe opportunistic infections in humans and animals. Signature-tagged mutagenesis (STM) was used to identify a gene named fbpA, required for efficient liver colonization of mice inoculated intravenously. FbpA was also shown to be required for intestinal and liver colonization after oral infection of transgenic mice expressing human E-cadherin. fbpA encodes a 570-amino-acid polypeptide that has strong homologies to atypical fibronectin-binding proteins. FbpA binds to immobilized human fibronectin in a dose-dependent and saturable manner and increases adherence of wild-type L. monocytogenes to HEp-2 cells in the presence of exogenous fibronectin. Despite the lack of conventional secretion/anchoring signals, FbpA is detected using an antibody generated against the recombinant FbpA protein on the bacterial surface by immunofluorescence, and in the membrane compartment by Western blot analysis of cell extracts. Strikingly, FbpA expression affects the protein levels of two virulence factors, listeriolysin O (LLO) and InlB, but not that of InlA or ActA. FbpA co-immunoprecipitates with LLO and InlB, but not with InlA or ActA. Thus, FbpA, in addition to being a fibronectin-binding protein, behaves as a chaperone or an escort protein for two important virulence factors and appears as a novel multifunctional virulence factor of L. monocytogenes.


Increased frequency of the transferrin C2 subtype in Alzheimer's disease.
Several genetic variants of transferrin can be separated by polyacrylamide gel isoelectric focusing. Studies by other workers have revealed that the genetic type Tf C2 has an increased frequency in certain malfunctions which are associated with the formation of free radicals, suggesting that the iron binding of Tf C2 promotes the formation of hydroxyl radicals. In our study population of 20 patients with Alzheimer's disease, 13 had the C2 genetic subtype. Since the frequency of C2 in the South African population is 0.136 (14%), this represents a significant increase (p < 0.005) in the appearance of this genetic subtype.


Genomes, diversity and resistance gene analogues in Musa species.
Resistance genes (R genes) in plants are abundant and may represent more than 1% of all the genes. Their diversity is critical to the recognition and response to attack from diverse pathogens. Like many other crops, banana and plantain face attacks from potentially devastating fungal and bacterial diseases, increased by a combination of worldwide spread of pathogens, exploitation of a small number of varieties, new pathogen mutations, and the lack of effective, benign and cheap chemical control. The challenge for plant breeders is to identify and exploit genetic resistances to diseases, which is particularly difficult in banana and plantain where the valuable cultivars are sterile, parthenocarpic and mostly triploid so conventional genetic analysis and breeding is impossible. In this paper, we review the nature of R genes and the key motifs, particularly in the Nucleotide Binding Sites (NBS), Leucine Rich Repeat (LRR) gene class. We present data about identity, nature and evolutionary diversity of the NBS domains of Musa R genes in diploid wild species with the Musa acuminata (A), M. balbisiana (B), M. schizocarpa (S), M. textilis (T), M. velutina and M. ornata genomes, and from various cultivated hybrid and triploid accessions, using PCR primers to isolate the domains from genomic DNA. Of 135 new sequences, 75% of the sequenced clones had uninterrupted open reading frames (ORFs), and phylogenetic UPGMA tree construction showed four clusters, one from Musa ornata, one largely from the B and T genomes, one from A and M. velutina, and the largest with A, B, T and S genomes. Only genes of the coiled-coil (non-TIR) class were found, typical of the grasses and presumably monocotyledons. The analysis of R genes in cultivated banana and plantain, and their wild relatives, has implications for identification and selection of resistance genes within the genus which may be useful for plant selection and breeding and also for defining relationships and genome evolution patterns within the genus using the multi-copy and variable resistance genes.


Inflammation and insulin resistance.
Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.


Physiological simulation of blood flow in the aorta: comparison of hemodynamic indices as predicted by 3-D FSI, 3-D rigid wall and 1-D models.
Interest in patient-specific blood-flow circulation modeling has increased substantially in recent years. The availability of clinical data for geometric and elastic properties together with efficient numerical methods has now made model rendering feasible. This work uses 3-D fluid-structure interaction (FSI) to provide physiological simulation resulting in modeling with a high level of detail. Comparisons are made between results using FSI and rigid wall models. The relevance of wall compliance in determining parameters of clinical importance, such as wall shear stress, is discussed together with the significance of differences found in the pressure and flow waveforms when using the 1-D model. Patient-specific geometry of the aorta and its branches was based on MRI angiography data. The arterial wall was created with a variable thickness. The boundary conditions for the fluid domain were pressure waveform at the ascending aorta and flow for each outlet. The waveforms were obtained using a 1-D model validated by in vivo measurements performed on the same person. In order to mimic the mechanical effect of surrounding tissues in the simulation, a stress-displacement relation was applied to the arterial wall. The temporal variation and spatial patterns of wall shear stress are presented in the aortic arch and thoracic aorta together with differences using rigid wall and FSI models. A comparison of the 3-D simulations to the 1-D model shows good reproduction of the pressure and flow waveforms.


Systematic review of women veterans' health: update on successes and gaps.
We assessed the state of women veterans' health research by conducting a systematic review of scientific literature published from 2004 to 2008, updating a prior review spanning the history of this literature to 2004. We identified articles by searching scientific databases and contacting experts. Relevant articles were independently evaluated by two physician reviewers. We categorized 195 articles by study design, funding source, period of military service, research topic, and health condition. More research was published during this 5-year review (n = 195) than in the 25 years beforehand (n = 182). The 195 studies included five trials, but only one randomized trial, a study that examined treatment outcomes for women with posttraumatic stress disorder (PTSD). The large number of articles focused on Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) soldiers' health issues (n = 23) reflects the growing participation of women in these conflicts. High rates of positive PTSD symptoms (range, 10%-19%) and other mental health disorders were found among OEF/OIF returning military women. The recent post-deployment literature underscores the need for repeated PTSD/mental health screening in returning veterans, and points to continuity of care needs for psychiatric and gynecological problems which occur in the field. The psychiatric and access/utilization literature confirmed the positive relationship between military sexual trauma and PTSD and the associated negative health effects. Although most VA women's health research remains observational, methods are evolving toward an analytical focus. Even though successes are evident in the breadth and depth of publications, remaining gaps in the literature include post-deployment readjustment for veterans/families, and quality-of-care interventions/outcomes for physical and mental conditions.


Comprehensive evaluation of the host responses to infection with differentially virulent classical swine fever virus strains in pigs.
Classical swine fever virus (CSFV) infection causes most variable clinical syndromes from chronic or latent infection to acute death, and it is generally acknowledged that the course of disease is affected by both virus and host factors. To compare host immune responses to differentially virulent CSFV strains in pigs, fifteen 8-week-old specific-pathogen-free pigs were randomly divided into four groups and inoculated with the CSFV Shimen strain (a highly virulent strain), the HLJZZ2014 strain (a moderately virulent strains), C-strain (an avirulent strain), and DMEM (mock control), respectively. Infection with the Shimen or HLJZZ2014 strain resulted in fever, clinical signs and histopathological lesions, which were not observed in the C-strain-inoculated pigs, though low viral genome copies were detected in the peripheral blood and tissue samples. The data showed that the virulence of the strains affected the outcome of duration and intensity of the disease rather than the tissue tropism of the virus. Furthermore, leukopenia, lymphocytopenia, differentiation of T-cells, and the secretion of cytokines associated with inflammation or apoptosis such as interferon alpha (IFN-α), tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2), IL-4, IL-6, and IL-10 were induced by the virulent CSFV infection, the differences reflected in onset and extent of the regulation. Taken together, our results revealed that the major differences among the three strains resided in the kinetics of host response to the infection: severe and immediate with the highly virulent strain, while progressive and delayed with the moderately virulent one. This comparative study will help to dissect the pathogenesis of CSFV.


Localized and stationary dynamic gratings via stimulated Brillouin scattering with phase modulated pumps.
A novel technique for the localization of stimulated Brillouin scattering (SBS) interaction is proposed, analyzed and demonstrated experimentally. The method relies on the phase modulation of two counter-propagating optical waves by a common pseudo-random bit sequence (PRBS), these waves being spectrally detuned by the Brillouin frequency shift. The PRBS symbol duration is much shorter than the acoustic lifetime. The interference between the two modulated waves gives rise to an acoustic grating that is confined to narrow correlation peaks, as short as 1.7 cm. The separation between neighboring peaks, which is governed by the PRBS length, can be made arbitrarily long. The method is demonstrated in the generation and applications of dynamic gratings in polarization maintaining (PM) fibers. Localized and stationary acoustic gratings are induced by two phase modulated pumps that are polarized along one principal axis of the PM fiber, and interrogated by a third, readout wave which is polarized along the orthogonal axis. Using the proposed technique, we demonstrate the variable delay of 1 ns-long readout pulses by as much as 770 ns. Noise due to reflections from residual off-peak gratings and its implications on the potential variable delay of optical communication data are discussed. The method is equally applicable to the modulation of pump and probe waves in SBS over standard fibers.


Multicenter Study of Sexual Functioning in Spouses/Partners of Persons With Traumatic Brain Injury.
To investigate sexual functioning and its predictors in spouses/partners of persons with traumatic brain injury (TBI). Inception cohort survey. Community. Persons (N=70) with complicated mild to severe TBI admitted to 1 of 6 participating TBI Model Systems inpatient rehabilitation units and their spouses/partners who were both living in the community and assessed 1 year after injury. Not applicable. Derogatis Interview for Sexual Functioning Self-Report; Global Sexual Satisfaction Index. Twenty percent of spouses/partners of persons with TBI reported sexual dysfunction, and 44% reported dissatisfaction with sexual functioning. Sixty-two percent of spouses/partners reported a decrease in sexual activity during the year postinjury, 34% reported a decrease in sexual drive or desire, and 34% indicated that sexuality was less important in comparison to preinjury. The sexual functioning of spouses/partners of persons with TBI was highly associated with the sexual functioning of the person with TBI. Age of spouses/partners and sexual functioning in persons with the TBI were significant predictors of spouses'/partners' sexual functioning, even after controlling for sex of partners and the physical, cognitive, participation, and sexual functioning of the persons with injury. Greater sexual dysfunction in spouses/partners was associated with older age and with poorer sexual functioning in the person with injury. Rehabilitation professionals should provide education on the potential impact of TBI on sexual functioning for both persons with TBI and their spouses/partners, and integrate the assessment of sexual functioning into their clinical assessment, making appropriate referrals for therapy.


Sensitivity to punishment and reward omission: evidence from error-related ERP components.
In a recent experiment [Boksem, M.A.S., Tops, M., Wester, A.E., Meijman, T.F., Lorist, M.M., 2006. Error-related ERP components and individual differences in punishment and reward sensitivity. Brain Research 1101, 92-101], we showed that error-related ERP components were related to punishment and reward sensitivity. The present study was conducted to further evaluate the relationship between punishment/reward sensitivity and these ERP components. Therefore, we scored our subjects on the BIS/BAS measures of punishment and reward sensitivity. Then, subjects performed one of two versions of a Flanker task: in one, they were financially punished for committing errors; in the other, they were financially rewarded for correct performance. Analyses of ERN/Ne amplitudes indicated significant interactions between personality measures of punishment (BIS) and reward (BAS) and actual punishment and reward, while analyses of Pe amplitudes showed significant interactions between personality measures of reward sensitivity and actual reward. We suggest that ERN/Ne amplitude is related to concerns over mistakes and depends on the level of aversion experienced by individual subjects for making these mistakes. Subjects that are highly sensitive to punishment are strongly motivated or engaged in avoiding punishment, while subjects sensitive to rewards are motivated to obtain rewards and therefore show high task engagement when rewards may be earned. The error-related ERP components appear to track this level of engagement in task performance.


Insects on plants: explaining the paradox of low diversity within specialist herbivore guilds.
Classical niche theory explains the coexistence of species through their exploitation of different resources. Assemblages of herbivores coexisting on a particular plant species are thus expected to be dominated by species from host-specific guilds with narrow, coexistence-facilitating niches rather than by species from generalist guilds. Exactly the opposite pattern is observed for folivores feeding on trees in New Guinea. The least specialized mobile chewers were the most species rich, followed by the moderately specialized semiconcealed and exposed chewers. The highly specialized miners and mesophyll suckers were the least species-rich guilds. The Poisson distribution of herbivore species richness among plant species in specialized guilds and the absence of a negative correlation between species richness in different guilds on the same plant species suggest that these guilds are not saturated with species. We show that herbivore assemblages are enriched with generalists because these are more completely sampled from regional species pools. Herbivore diversity increases as a power function of plant diversity, and the rate of increase is inversely related to host specificity. The relative species diversity among guilds is thus scale dependent, as the importance of specialized guilds increases with plant diversity. Specialized insect guilds may therefore comprise a larger component of overall diversity in the tropics (where they are also poorly known taxonomically) than in the temperate zone, which has lower plant diversity.


Synthesis, Characterization and Crystal Structures of Cobalt(II), Zinc(II) and Cadmium(II) Complexes Derived from 2-Hydroxy-N'-(pyridin-2-ylmethylene)benzohydrazide with Antimicrobial Activity.
Three new cobalt(II), zinc(II) and cadmium(II) complexes, [CoL2]·2CH3OH·H2O (1), [ZnL2] (2) and [Cd(HL)2(NO3)]N3 (3), were prepared from 2-hydroxy-N'-(pyridin-2-ylmethylene)benzohydrazide (HL). The complexes have been characterized by IR, UV-Vis and single-crystal X-ray diffraction techniques. X-ray analysis indicates that the complexes are mononuclear species, with the metal atoms in octahedral coordination. The hydrazone compound and its complexes were evaluated for their antibacterial (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas fluorescence) and antifungal (Candida albicans and Aspergillus niger) activities. The complexes have effective activities against the bacteria.


Lower serum uric acid level predicts mortality in dialysis patients.
We evaluated the impact of serum uric acid (SUA) on mortality in patients with chronic dialysis. A total of 4132 adult patients on dialysis were enrolled prospectively between August 2008 and September 2014. Among them, we included 1738 patients who maintained dialysis for at least 3 months and had available SUA in the database. We categorized the time averaged-SUA (TA-SUA) into 5 groups: <5.5, 5.5-6.4, 6.5-7.4, 7.5-8.4, and ≥8.5 mg/dL. Cox regression analysis was used to calculate the hazard ratio (HR) of all-cause mortality according to SUA group. The mean TA-SUA level was slightly higher in men than in women. Patients with lower TA-SUA level tended to have lower body mass index (BMI), phosphorus, serum albumin level, higher proportion of diabetes mellitus (DM), and higher proportion of malnourishment on the subjective global assessment (SGA). During a median follow-up of 43.9 months, 206 patients died. Patients with the highest SUA had a similar risk to the middle 3 TA-SUA groups, but the lowest TA-SUA group had a significantly elevated HR for mortality. The lowest TA-SUA group was significantly associated with increased all-cause mortality (adjusted HR, 1.720; 95% confidence interval, 1.007-2.937; P = 0.047) even after adjusting for demographic, comorbid, nutritional covariables, and medication use that could affect SUA levels. This association was prominent in patients with well nourishment on the SGA, a preserved serum albumin level, a higher BMI, and concomitant DM although these parameters had no significant interaction in the TA-SUA-mortality relationship except DM. In conclusion, a lower TA-SUA level <5.5 mg/dL predicted all-cause mortality in patients with chronic dialysis.


Effect of intravenous glucagon on the urinary excretion of adenosine 3',5'-monophosphate in man and in rats. Evidence for activation of renal adenylate cyclase and formation of nephrogenous cAMP.
To examine the effect of glucagon in vivo on renal formation and excretion of cAMP, clearance studies were performed in patients with hypoparathyroidism and in parathyroidectomized rats. Four patients with idiopathic hypoparathyroidism and 2 patients with pseudohypoparathyroidism were studied during an intravenous glucagon infusion (20 micrograms/kg body weight). In all patients, glucagon induced a significant increase in nephrogenous cAMP and a 2- to 3-fold increase in fractional excretion of phosphate. The average increase in nephrogenous cAMP was from a baseline of 784 +/- 229 to 18,748 +/- 3,842 pmol/100 ml glomerular filtrate (GF) (p less than 0.01) and occurred 30-60 min after the beginning of the glucagon infusion. The effect of intravenous glucagon, given as a bolus, was further examined in parathyroidectomized rats. Glucagon elicited a significant increase in the urinary excretion of the nucleotide. The excreted cAMP was compared with its filtered load for each urine collection period. In the first two collections, 0-15 and 15-30 min, the filtered load of cAMP was higher than its urinary excretion. During the following periods, 30-90 min, the excreted urinary cAMP exceeded by far its filtered load, suggesting a net nephrogenous contribution to the excretion of the nucleotide. Infusion of exogenous cAMP to parathyroidectomized rats induced significant increments in the filtered load and urinary excretion of the nucleotide. Tubular secretion of extrarenal cAMP could not be detected during the cAMP infusion. These results provide evidence supporting in vivo a possible parathyroid-independent formation of nephrogenous cAMP after glucagon administration, in men and in rats. The glucagon-induced increase in nephrogenous cAMP seems to account, at least partly, for some of the renal actions of this hormone.


Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival.
Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression.


Mineralocorticoid receptor blockade prevents vascular remodelling in a rodent model of type 2 diabetes mellitus.
Mineralocorticoid receptors (MRs), which are activated by mineralocorticoids and glucocorticoids, actively participate in mechanisms that affect the structure and function of blood vessels. Although experimental and clinical evidence shows that vascular damage in diabetes is associated with structural alterations in large and small arteries, the role of MR in this process needs further studies. Thus, we tested the hypothesis that MR, through redox-sensitive mechanisms, plays a role in diabetes-associated vascular remodelling. Male, 12-14-weeks-old db/db mice, a model of type 2 diabetes and their non-diabetic counterpart controls (db/+) were treated with spironolactone (MR antagonist, 50 mg/kg/day) or vehicle for 6 weeks. Spironolactone treatment did not affect blood pressure, fasting glucose levels or weight gain, but increased serum potassium and total cholesterol in both, diabetic and control mice. In addition, spironolactone significantly reduced serum insulin levels, but not aldosterone levels in diabetic mice. Insulin sensitivity, evaluated by the HOMA (homoeostatic model assessment)-index, was improved in spironolactone-treated diabetic mice. Mesenteric resistance arteries from vehicle-treated db/db mice exhibited inward hypertrophic remodelling, increased number of smooth muscle cells and increased vascular stiffness. These structural changes, determined by morphometric analysis and with a myography for pressurized arteries, were prevented by spironolactone treatment. Arteries from vehicle-treated db/db mice also exhibited augmented collagen content, determined by Picrosirius Red staining and Western blotting, increased reactive oxygen species (ROS) generation, determined by dihydroethidium (DHE) fluorescence, as well as increased expression of NAD(P)H oxidases 1 and 4 and increased activity of mitogen-activated protein kinases (MAPKs). Spironolactone treatment prevented all these changes, indicating that MR importantly contributes to diabetes-associated vascular dysfunction by inducing oxidative stress and by increasing the activity of redox-sensitive proteins.


Systematic review of serious games for medical education and surgical skills training.
The application of digital games for training medical professionals is on the rise. So-called 'serious' games form training tools that provide a challenging simulated environment, ideal for future surgical training. Ultimately, serious games are directed at reducing medical error and subsequent healthcare costs. The aim was to review current serious games for training medical professionals and to evaluate the validity testing of such games. PubMed, Embase, the Cochrane Database of Systematic Reviews, PsychInfo and CINAHL were searched using predefined inclusion criteria for available studies up to April 2012. The primary endpoint was validation according to current criteria. A total of 25 articles were identified, describing a total of 30 serious games. The games were divided into two categories: those developed for specific educational purposes (17) and commercial games also useful for developing skills relevant to medical personnel (13). Pooling of data was not performed owing to the heterogeneity of study designs and serious games. Six serious games were identified that had a process of validation. Of these six, three games were developed for team training in critical care and triage, and three were commercially available games applied to train laparoscopic psychomotor skills. None of the serious games had completed a full validation process for the purpose of use. Blended and interactive learning by means of serious games may be applied to train both technical and non-technical skills relevant to the surgical field. Games developed or used for this purpose need validation before integration into surgical teaching curricula.


Regulation of gap junctional communication by astrocytic mitochondrial K(ATP) channels following neurotoxin administration in in vitro and in vivo models.
It is known that neuronal ATP-sensitive potassium (K(ATP)) channels and astrocytic gap junctions (GJs) are involved in the mechanism underlying neurodisorders. The K(ATP) channels exist also in glial cells, and the objective of this study was to determine whether the astrocytic K(ATP) channels exert their effect on neurotoxin-induced neurodysfunction through regulating the astrocytic GJ function. The results showed that diazoxide, a selective mitochondrial K(ATP) (mitoK(ATP)) channel opener, enhanced the GJ coupling, but 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker that significantly inhibits GJ coupling in vitro did not. Activation of astrocytic mitoK(ATP) channels alleviated kainic acid-induced dysfunction of GJ intercellular communication. Finally, activation of mitoK(ATP) channels improved the astrocytic GJ coupling in the hippocampus after seizures due to the colabeling of GJ subunit connexin 43 and connexin 45 with glial marker and was increased substantially by the administration of diazoxide. Western blot demonstrated that the mitoK(ATP) channels regulated the expression of connexin 43 (P2; active form) and connexin 45 in the epileptic hippocampus. These findings demonstrate that activation of astrocytic mitoK(ATP) channels improves the GJ function in astrocytes, indicating that the effect of the astrocytic mitoK(ATP) channels on neurotoxin-induced neurodysfunction might be, in part, through the regulation of the GJ-coupled spatial buffering in the hippocampus.


Bacterial strategies to overcome insect defences.
Recent genetic and molecular analyses have revealed how several strategies enable bacteria to persist and overcome insect immune defences. Genetic and genomic tools that can be used with Drosophila melanogaster have enabled the characterization of the pathways that are used by insects to detect bacterial invaders and combat infection. Conservation of bacterial virulence factors and insect immune repertoires indicates that there are common strategies of host invasion and pathogen eradication. Long-term interactions of bacteria with insects might ensure efficient dissemination of pathogens to other hosts, including humans.


Monitoring of Therapy for Mucopolysaccharidosis Type I Using Dysmorphometric Facial Phenotypic Signatures.
There is a pattern of progressive facial dysmorphology in mucopolysaccharidosis type I (MPS I). Advances in 3D facial imaging have facilitated the development of tools, including dysmorphometrics, to objectively and precisely detect these facial phenotypes. Therefore, we investigated the application of dysmorphometrics as a noninvasive therapy-monitoring tool, by longitudinally scoring facial dysmorphology in a child with MPS I receiving enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). Both dysmorphometric measures showed a decreasing trend, and the greatest differences were found in the severity of facial discordance (Z-RMSE), displaying scores >3 SD higher than the mean at their peak, in comparison to Z-RSD scores that mostly fell within the normative range (maximum; 1.5 SD from the mean). In addition to the general trend of reduced facial dysmorphology with treatment, initial fluctuations were also evident that may have related to transient subcutaneous facial fluctuations, in the context of conditioning for bone marrow transplant. These findings support the potential of our approach as a sensitive, noninvasive, and rapid means of assessing treatment response or failure in clinical trials, and for established therapies, and would be applicable for other inherited disorders of metabolism.


CO tolerance of Pt/FeOx catalyst in both thermal catalytic H2 oxidation and electrochemical CO oxidation: the effect of Pt deficit electron state.
CO poisoning of Pt catalysts is one of the major challenges to the commercialization of proton exchange membrane fuel cells. One promising solution is to develop CO-tolerant Pt-based catalysts. A facilely synthesized Pt/FeOx catalyst exhibited outstanding CO tolerance in the oxidation of H2 and electrochemical CO stripping. Light-off temperature of H2O formation over Pt/FeOx was achieved even below 30 °C in the presence of 3000 ppm CO at a space velocity of 18 000 mL g-1cat h-1. For the electrochemical oxidation of CO, the onset and peak potentials decreased by 0.17 V and 0.10 V, respectively, in comparison with those of commercial Pt/C. More importantly, by a combination of hard X-ray photoemission spectroscopy and in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) studies it was found that the decreased electron density of Pt in Pt/FeOx enhanced the mobility of adsorbed CO, suppressed Pt-CO bonding and significantly increased the CO tolerance of Pt/FeOx.


Clinical utility of insulin-like growth factor 1 and 2; determination by high resolution mass spectrometry.
Measurement of insulin-like growth factor-1 (IGF-I) has utility for the diagnosis and management of growth disorders, but inter-assay comparison of results has been complicated by a multitude of reference standards, antibodies, detection methods, and pre-analytical preparation strategies. We developed a quantitative LC-MS method for intact IGF-I, which has advantages in throughput and complexity when compared to mass spectrometric approaches that rely on stable isotope dilution analysis of tryptic peptides. Since the method makes use of full-scan data, the assay was easily extended to provide quantitative measurement of IGF-II using the same assay protocol. The validated LC-MS assay for IGF-I and IGF-II provides accurate results across the pediatric and adult reference range and is suitable for clinical use.


Autonomous concentration-dependent activation and repression of Krüppel by hunchback in the Drosophila embryo.
The subdivision of the anterior-posterior axis in Drosophila is achieved by a cascade of spatially regulated transcription factors which form short-range gradients at the syncytial blastoderm stage. These factors are assumed to have concentration-dependent regulatory effects on their target genes. However, there is so far little direct in vivo evidence that a single factor can autonomously activate and repress a given target gene. We have analysed here the regulatory capabilities of the gap gene hunchback by creating an artificial gradient of hunchback in the early embryo. This was achieved by providing the maternally expressed mRNA of hunchback with the anterior localization signal of the bicoid RNA. The effects of this artificial hunchback gradient were then studied in different types of mutant background. We show that under these conditions hb is autonomously capable of activating the target gene Krüppel at low concentrations and repressing it at high concentrations. In addition, we show that the artificially created hunchback gradient can organize a large part of the segment pattern, although it is expressed at a different position and in a different shape than the wild-type gradient of hunchback.


Association Between Sulfur-Metabolizing Bacterial Communities in Stool and Risk of Distal Colorectal Cancer in Men.
Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (H2S), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men. We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC. Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14-1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65-1.14; P-trend = .31). In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.


Ethanol-induced small heat shock protein genes in the differentiation of mouse embryonic neural stem cells.
Neural stem cells (NSCs) of the neuroepithelium differentiate into one of three central nervous system (CNS) cell lineages: neurons, astrocytes, or oligodendrocytes. In this study, the differentiation potential of NSCs from the forebrain of embryonic day 15 (E15) mouse embryos was analyzed using immunocytochemistry. NSCs were differentiated early in the presence or absence of ethanol (50 mM), and gene expression patterns among NSCs, differentiated cells and ethanol-treated differentiated cells were assessed by microarray and real-time PCR analysis. Genes that were up-regulated in differentiated cells both in the presence and in the absence of ethanol when compared to NSCs were related to the Wnt signaling pathway, including Ctnna1, Wnt5a, Wnt5b, Wnt7a, Fzd3, and Fzd2; genes related to cell adhesion, including Cadm1, Ncam1, and Ncam2; and genes encoding small heat shock proteins, including HspB2, HspB7, and HspB8. In particular, the expression levels of HspB2 and HspB7 were elevated in ethanol-treated differentiated cells compared to non-treated differentiated cells. The gene expression patterns of various heat shock transcription factors (HSFs), proteins that regulate the transcription of heat shock genes, were also analyzed. The expression levels of HSF2 and HSF5 increased in differentiated cells in the presence and absence of ethanol when compared to NSCs. Of these two genes, HSF5 demonstrated an enhanced up-regulation, particularly in ethanol-treated differentiated cells compared to cells that were differentiated in the absence of ethanol. These results imply that HspB2 and HspB7, which are small heat shock proteins with tissue-restricted expression profiles, might be up-regulated by ethanol during the short-term differentiation of NSCs.


Coordination of patterning and growth by the morphogen DPP.
The elegance of animal body plans derives from an intimate connection between function and form, which during organ formation is linked to patterning and growth. Yet, how patterning and growth are coordinated still remains largely a mystery. To study this question the Drosophila wing imaginal disc, an epithelial primordial organ that later forms the adult wing, has proven to be an invaluable and versatile model. Wing disc development is organized around a coordinate system provided by morphogens such as the TGF-β homolog Decapentaplegic (DPP). The function of DPP has been studied at multiple levels: ranging from the kinetics of gradient formation to the establishment and maintenance of target gene domains as well as DPP's role in growth control. Here, we focus on recent publications that both enrich our view of DPP signaling but also highlight outstanding questions of how DPP coordinates patterning and growth during development.


Proteases involved in cartilage matrix degradation in osteoarthritis.
Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.


Children's comprehension of plural predicate conjunction.
Previous developmental studies of conjunction have focused on the syntax of phrasal and sentential coordination (Lust, 1977; de Villiers, Tager-Flusberg & Hakuta, 1977; Bloom, Lahey, Hood, Lifter & Fiess, 1980, among others). The present study examined the flexibility of children's interpretation of conjunction. Specifically, when two predicates that can apply simultaneously to a single individual are conjoined in the scope of a plural definite (The bears are big and white), conjunction receives a Boolean, intersective interpretation. However, when the conjoined predicates cannot apply simultaneously to an individual (The bears are big and small), conjunction receives a weaker 'split' interpretation (Krifka, 1990; Lasersohn, 1995; Winter, 1996). Our experiments reveal that preschool-aged children are sensitive to both intersective and split interpretations, and can use their lexical and world knowledge of the relevant predicates in order to select an appropriate reading.


Acute type A aortic dissection complicated by aortic regurgitation: composite valve graft versus separate valve graft versus conservative valve repair.
To clarify the merits of various surgical approaches, we studied the outcome after composite valve graft versus separate valve and graft replacement versus conservative valve treatment with replacement of the ascending aorta in patients with acute type A aortic dissection complicated by aortic regurgitation. Between 1967 and 1999, 123 patients (mean age 56 +/- 15 years) underwent composite valve graft replacement (n = 21), separate valve and graft replacement (n = 20), or conservative valve treatment (n = 82 [commissural resuspension in 46]); follow-up averaged 6.5 years (95% complete). The 30-day, 1-year, and 6-year survival estimates of 85% +/- 4%, 79% +/- 5%, and 69% +/- 5% (+/-1 standard error of mean), respectively, after conservative valve treatment were similar to 86% +/- 8%, 81% +/- 9%, and 65% +/- 16%, respectively, with composite valve graft replacement and better (but insignificantly so) than 70% +/- 10%, 70% +/- 10%, and 45% +/- 11%, respectively, with separate valve and graft replacement. The 6-year freedom from proximal reoperation was 95% +/- 3%, 89% +/- 10%, and 100% in conservative valve graft, separate valve and graft, and composite valve graft subgroups, respectively (P = not significant). Cox regression multivariable analysis identified that previous sternotomy (hazard ratio [or e(beta)] 95% confidence interval 1.4-10.9, P =.006), hypertension (0.99-2.9, P =.05), cardiac tamponade (1.1-4.0, P =.03), and stroke (1.7-7.0, P =.001) increased the hazard of death. No factors predicting a higher likelihood of late proximal reoperation were identified. In patients with acute type A aortic dissection and aortic regurgitation, there was no significant difference in overall survival or reoperation rates among these surgical approaches. We try to save the valve whenever possible unless the aortic root is pathologically dilated (eg, Marfan syndrome or annuloaortic ectasia) or destroyed by the dissection process, when composite valve graft or valve-sparing aortic root replacement is indicated.


M13 virus-directed synthesis of nanostructured metal oxides for lithium-oxygen batteries.
Transition metal oxides are promising electrocatalysts for both water oxidations and metal-air batteries. Here, we report the virus-mediated synthesis of cobalt manganese oxide nanowires (NWs) to fabricate high capacity Li-O2 battery electrodes. Furthermore, we hybridized Ni nanoparticles (NPs) on bio Co3O4 NWs to improve the round trip efficiency as well as the cycle life of Li-O2 batteries. This biomolecular directed synthesis method is expected to provide a selection platform for future energy storage electrocatalysts.


Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.
Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 μg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.


Trends in consumption of ultra-processed foods and obesity in Sweden between 1960 and 2010.
To investigate how consumption of ultra-processed foods has changed in Sweden in relation to obesity. Nationwide ecological analysis of changes in processed foods along with corresponding changes in obesity. Trends in per capita food consumption during 1960-2010 were investigated using data from the Swedish Board of Agriculture. Food items were classified as group 1 (unprocessed/minimally processed), group 2 (processed culinary ingredients) or group 3 (3·1, processed food products; and 3·2, ultra-processed products). Obesity prevalence data were pooled from the peer-reviewed literature, Statistics Sweden and the WHO Global Health Observatory. Nationwide analysis in Sweden, 1960-2010. Swedish nationals aged 18 years and older. During the study period consumption of group 1 foods (minimal processing) decreased by 2 %, while consumption of group 2 foods (processed ingredients) decreased by 34 %. Consumption of group 3·1 foods (processed food products) increased by 116 % and group 3·2 foods (ultra-processed products) increased by 142 %. Among ultra-processed products, there were particularly large increases in soda (315 %; 22 v. 92 litres/capita per annum) and snack foods such as crisps and candies (367 %; 7 v. 34 kg/capita per annum). In parallel to these changes in ultra-processed products, rates of adult obesity increased from 5 % in 1980 to over 11 % in 2010. The consumption of ultra-processed products (i.e. foods with low nutritional value but high energy density) has increased dramatically in Sweden since 1960, which mirrors the increased prevalence of obesity. Future research should clarify the potential causal role of ultra-processed products in weight gain and obesity.


Being the next of kin of an adult person with muscular dystrophy.
A chronic disorder affects all members of the family in various ways. The aim of this study is to elucidate the next of kin's (N= 36) experiences when an adult family member has muscular dystrophy. The relationships were partner (36%, n= 14), parent (18%, n= 7), child (21%, n= 8), sibling (15%, n= 6), and other relative (3%, n= 1). Latent content analysis is employed and involves an interpretation of the interviewtext. The results showthe meaning of being close to a person with muscular dystrophy through the themes that emerged: exposure of the family; the span between obligation and love; being vigilant, protective, and supportive; and striving for an ordinary life. This study reveals a need for healthcare staff to understand the next of kin's narrated meaning of changes when a family member has a progressive disease.


n-3 polyunsaturated fatty acids prevent d-galactose-induced cognitive deficits in prediabetic rats.
Nutritional deficit of n-3 polyunsaturated fatty acids (PUFAs) is closely related to cognitive impairment and depression in later life. Cognitive impairment and depression lead to comorbidities, such as metabolic syndrome, in elderly people. The aim of this study is to evaluate the effects of dietary n-3 PUFAs on cognition and depressive-like behavior in an accelerated senescence rat model with prediabetic status. Rats were cotreated with d-gal and sucrose solution for 7 months and then fed fish-oil- or flaxseed-oil-rich diets for 3 months. Cognitive impairment analysis and depressive-like behavioral testing were conducted using the Morris water maze (MWM) test and forced swimming test (FST), respectively. The MWM test results revealed that the d-gal + sucrose + flaxseed oil (DSFS) group had a significantly shorter mean latency time in the short-term spatial memory trial on day 2 than did the d-gal + sucrose + fish oil (DSFO) group. The FST results demonstrated that the DSFO group exhibited a significantly shorter immobility time and longer climbing time than did the control group. Western blot analysis of the receptor for advanced glycation end-product (RAGE) level identified a significant difference in the DSFO group compared with the control group. Significantly lower n-6/n-3 PUFA ratios were observed in the frontal cortices of the DSFO and DSFS groups. In conclusion, fish and flaxseed oils exerted a protective effect on cognitive impairment and decreased the incidence of depressive-like behavior in d-gal- and sucrose-fed prediabetic aging rats. n-3 PUFA-rich oil diets, particularly the fish oil diet, reduced the plasma levels of nonesterified fatty acids, tumor necrosis factor-α, and brain dopamine and RAGE expression but not glycemic status, resulting in an improvement in the time of escape latency and the time spent in the target quadrant in the MWM test.


Needs of individuals recovering from a first episode of mental illness: A scoping review.
Central to the role of mental health clinicians is the assessment of needs. A number of assessment tools have been used to evaluate the needs of individuals diagnosed with a mental illness. These tools have largely been developed for people with a severe and persistent mental illness and may not be suitable for individuals who are recovering from a first episode of mental illness. The aims of this review were therefore to identify the needs experienced by individuals recovering from a first episode of mental illness; determine what tools have been used to evaluate these needs; and explore whether existing tools adequately reflect the needs described in the literature. Twenty-one articles were included, comprising articles which identified needs (n = 10), needs assessment tools (n = 1), or articles which identified both needs and a needs assessment tool (n = 10). Results indicate that individuals who have been admitted to a specialized mental health unit and are recovering from a first episode of mental illness may experience an extensive range of needs, spanning emotional, psychological, social, informational, functional, practical, and relationship needs. Four established needs assessment tools were found to have been used to evaluate these needs; however, these do not appear to represent all needs discovered in this review, were mostly developed for populations with a long-term mental illness, and may not be suitable for assessing the needs of individuals recovering from a first episode of mental illness following a presentation to a specialized mental health unit.


Dendritic cells stimulate primary human cytolytic lymphocyte responses in the absence of CD4+ helper T cells.
Cytotoxic lymphocytes are typically generated from unfractionated suspensions of human lymphocytes by stimulating with heterogeneous APCs and exogeneous growth factors. We have found that human blood dendritic cells can directly stimulate allogeneic human CD8+ T cells to proliferate and express antigen-specific cytotoxic activity. These primary responses, which are accompanied by the release of T cell growth factor(s), are induced in the absence of CD4+ helper T cells and are not inhibited by anti-CD4 mAb. Both antigen-specific CTL as well as nonspecific NK cells can be elicited by dendritic cells. The NK cell response can be depleted at the precursor level by panning with an anti-CD11b mAb, which removes a CD11b+/CD28-, CD16+ subset from the starting CD4- responders. Allogeneic blood monocytes are neither stimulatory nor inhibitory of these primary CD4- MLRs, even though monocytes present alloantigen in such a way as to be recognized as specific targets for CTL that have been sensitized by dendritic cells. The number of CD8+ cells that are blast transformed and express an activated phenotype (i.e., HLA DR/DQ+, CD25/IL-2R+, CD45R-) reaches 30-40% of the culture at day 4-5, the peak of the helper-independent response. We conclude that antigen-presentation by dendritic cells is sufficient in itself to prime cytolytic precursors. We speculate that using dendritic cell stimulators and CD4- responders in MLRs may be more efficient than standard tissue typing approaches for the detection of subtle, but important class I MHC-restricted histoincompatibilities in human transplantation.


Androgens inhibit tumor necrosis factor-α-induced cell adhesion and promote tube formation of human coronary artery endothelial cells.
Endothelial cells contribute to the function and integrity of the vascular wall, and a functional aberration may lead to atherogenesis. There is increasing evidence on the atheroprotective role of androgens. Therefore, we studied the effect of the androgens-testosterone and dihydrotestosterone-and estradiol on human coronary artery endothelial cell (HCAEC) function. We found by MTT assay that testosterone is not cytotoxic and enhances HCAEC proliferation. The effect of testosterone (10-50 nM), dihydrotestosterone (5-50 nM), and estradiol (0.1-0.4 nM) on the adhesion of tumor necrosis factor-α (TNF-α)-stimulated HCAECs was determined at different time points (12-96 h) by assessing their binding with human monocytic THP-1 cells. In addition, the expression of adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1), was determined by ELISA and Western blot analysis. Both testosterone and dihydrotestosterone attenuated cell adhesion and the expression of VCAM-1 and ICAM-1 in a dose- and time-dependent manner. Furthermore, androgen treatment for a longer duration inhibited cell migration, as demonstrated by wound-healing assay, and promoted tube formation on a Matrigel. Western blot analysis demonstrated that the expression of phosphorylated endothelial nitric oxide synthase (eNOS) increased, whereas that of inducible nitric oxide synthase (iNOS) decreased following the 96-h steroid treatment of TNF-α-stimulated HCAECs. Our findings suggest that androgens modulate endothelial cell functions by suppressing the inflammatory process and enhancing wound-healing and regenerative angiogenesis, possibly through an androgen receptor (AR)-dependent mechanism.


Linkages of nuclear architecture to biological and pathological control of gene expression.
Functional interrelationships between components of nuclear architecture and control of gene expression are becoming increasingly evident. There is growing appreciation that multiple levels of nuclear organization integrate the regulatory cues that support activation and suppression of genes as well as the processing of gene transcripts. The linear organization of genes and promoter elements provide the potential for responsiveness to physiological regulatory signals. Parameters of chromatin structure and nucleosome organization support synergism between activities at independent regulatory sequences and render promoter elements accessible or refractory to transcription factors. Association of genes, transcription factors, and the machinery for transcript processing with the nuclear matrix facilitates fidelity of gene expression within the three-dimensional context of nuclear architecture. Mechanisms must be defined that couple nuclear morphology with enzymatic parameters of gene expression. The recent characterization of factors that mediate chromatin remodeling and intranuclear targeting signals that direct transcription factors to subnuclear domains where gene expression occurs, reflect linkage of genetic and structural components of transcriptional control. Nuclear reorganization and aberrant intranuclear trafficking of transcription factors for developmental and tissue-specific control that occurs in tumor cells and in neurological disorders provides a basis for high resolution diagnostic and targeted therapy.


Autocorrelation-driven diffusion filtering.
In this paper, we present a novel scheme for anisotropic diffusion driven by the image autocorrelation function. We show the equivalence of this scheme to a special case of iterated adaptive filtering. By determining the diffusion tensor field from an autocorrelation estimate, we obtain an evolution equation that is computed from a scalar product of diffusion tensor and the image Hessian. We propose further a set of filters to approximate the Hessian on a minimized spatial support. On standard benchmarks, the resulting method performs favorable in many cases, in particular at low noise levels. In a GPU implementation, video real-time performance is easily achieved.


Evaluation and Management of Pediatric Bone Lesions.
Bone abnormalities on pediatric radiographs are not uncommon findings for both the general orthopedist as well as the specialist. Although the majority of lesions encountered are benign, the treating physician should also be aware of more concerning diagnoses. General orthopedists and pediatric orthopedists should exhibit a basic level of comfort with working up and diagnosing these benign lesions. When evaluating the pediatric patient with a bone lesion it is crucial to keep in mind important aspects of the clinical history, physical exam, and radiographic findings. Here we provide a review of important findings for the orthopedic surgeon in each of these areas. Many times diagnoses can be made with these alone. With better understanding of clinical and radiographic features of these lesions the orthopedist should be comfortable knowing which lesions he or she can reasonably treat and which should be referred to an oncologic specialist.


Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.
Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.


Inhibition of human breast carcinoma cell proliferation by ascorbate and copper.
We tested the effect of different concentrations of ascorbic acid (AA), 50, 100, 250 mg/500 mg/dL) with copper sulfate (CS), 10 mg/dL) on human breast carcinoma (MDA-MB231) cell proliferation in vitro. Cell proliferation was measured using a colori-metric assay (Cell proliferation kit II (XTT), Boehringer, NJ). The results of the mean absorbance of the tissue culture at different AA concentrations and a constant CS concentration were as follow: 0.82 +/- 0.03 (control, mean +/- SE), 0.64 +/- 0.02 (CS above); 0.48 +/- 0.03 (50 mg/dL) AA), 0.21 +/- 0.02 (100 mg/dL), 0.08 +/- 0.01 (250 mg/dL) AA, 0.60 +/- 0.05 (500 mg/dL). These results show that a combination of AA and CS inhibits human breast carcinoma cell proliferation in vitro. This cell proliferation inhibitory effect is directly proportional to the AA concentration with the exception of the 500 mg/dL AA dose. This chemotherapeutic effect was optimally enhanced when AA was added at a concentration of 250 mg/dL. The AA concentrations of 500 mg/dL had a biphasic effect on tumor cell proliferation probably due to back and forth redox reactions between AA and dehydroascorbic acid in a closed system. This study provides preliminary evidence that AA and SC can be used as biological response modifiers (BRM) for tumor growth inhibition.


A pilot, prospective evaluation of a novel alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412].
Prospective investigations of complete decongestive lymphatic physiotherapy (CDPT), including manual lymphatic drainage (MLD), have validated the efficacy of these interventions for the initial reduction of edema and long-term maintenance of limb volume in lymphedema. However, CDPT demands substantial time and effort from patients to maintain these benefits; the treatments are not always well-accepted, and patients may suffer from a deterioration in quality-of-life or a time-dependent loss of initial treatment benefits. A new device designed for home use by the patient, the Flexitouch, has been developed to mechanically simulate MLD. We have undertaken a prospective, randomized, crossover study of the efficacy of the Flexitouch, when compared to massage, in the self-administered maintenance therapy of lymphedema. A prospective, randomized, crossover study of maintenance therapy was performed in 10 patients with unilateral breast cancer-associated lymphedema of the arm. Each observation phase included self-administered treatment with the Flexitouch or massage, 1 hour daily for 14 days, respectively, followed by crossover to the alternate treatment phase. Each treatment phase was preceded by a 1 week treatment washout, with use of garment only. The sequence of treatment was randomly assigned. The potential impact of treatment modality on quality of life was assessed with serial administration of the SF-36. Statistical analysis disclosed that the order of treatment had no outcome influence, permitting 10 comparisons within each treatment group. Post-treatment arm volume reduced significantly after the Flexitouch, but not after self-administered massage. The patients' mean weight decreased significantly with Flexitouch use, but not with massage. The Flexitouch device was apparently well-tolerated and accepted by patients. Serial SF-36 administration showed no deterioration in physical or psychosocial scores compared to baseline measurements; there were no statistical differences in scores when the two treatment modalities were compared. This short-term prospective evaluation of the Flexitouch suggests that the device may provide better maintenance edema control than self-adiminstered massage in breast cancer-associated lymphedema. The apparent ease of use and reliability of response to the device suggest that further broad-scale testing is warranted.


Psychiatric diagnoses of medical service users: evidence from the Epidemiologic Catchment Area Program.
Based on data from the five sites of the National Institute of Mental Health-sponsored Epidemiologic Catchment Area (ECA) Program, this paper examines the prevalence of psychiatric disorder among recent medical service users versus nonusers, with a particular focus on affective disorders, substance abuse/dependence, and phobias. The rate of current Diagnostic Interview Schedule (DIS) disorders among medical users in all five ECA sites is 21.7 per cent (slightly higher than general population rates) versus 16.7 per cent among nonusers; there is generally no difference between users and nonusers with past DIS diagnoses. Affective disorders were among the most common mental disorders of medical service users, especially among females, with little variation between sites: females: users: 6.9 per cent to 9.3 per cent, nonusers: 3.4 per cent to 6.4 per cent, and males: users: 3.3 per cent to 6.5 per cent, nonusers: 1.2 per cent to 4.1 per cent. Rates of phobias among persons using medical services are also higher than among nonusers. Substance abuse disorders are at least as common among persons who use medical services (8 per cent to 14 per cent of male users) as among those who do not (9 per cent to 11 per cent of male nonusers). The high rates of affective disorders among women and of substance abuse among male medical service users underscore the need to increase the ability of general medical practitioners to recognize and manage or refer these conditions.


Mechanisms of spontaneous activity in the developing spinal cord and their relevance to locomotion.
The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic activity. Muscle nerve recordings show that the discharge of sartorius (flexor) and femorotibialis (extensor) motoneurons alternates even though the motoneurons are depolarized simultaneously during each cycle. The alternation occurs because sartorius motoneuron firing is shunted or voltage-clamped by its synaptic drive at the time of peak femorotibialis discharge. Ablation experiments have identified a region dorsomedial to the lateral motor column that may be required for the alternation of sartorius and femorotibialis motoneurons. This region overlaps the location of interneurons activated by ventral root stimulation. Wholecell recordings from interneurons receiving short latency ventral root input indicate that they fire at an appropriate time to contribute to the cyclical pause in firing of sartorius motoneurons. Spontaneous activity was modeled by the interaction of three variables: network activity and two activity-dependent forms of network depression. A "slow" depression which regulates the occurrence of episodes and a "fast" depression that controls cycling during an episode. The model successfully predicts several aspects of spinal network behavior including spontaneous rhythmic activity and the recovery of network activity following blockade of excitatory synaptic transmission.


'Lager, lager shouting': the role of music and DJs in nightclub disorder control.
This paper explores how music and music genre can govern the nightlife experience, specifically how a nightclub's music policy can impact on clientele, health behaviours, bar sales and levels of disorder. Participant observations were conducted in sample of eight city centre nightclubs in Glasgow, Scotland. Music policy was found to influence nightclubs' clientele and their behaviours, for example in relation to differences in levels of alcohol or illegal drug use, sexual activity and violence between venues. Further, within individual venues, music policy was also observed operating as a crowd control tool, with for example such entertainment being used in alcohol marketing, in 'soft policing' and in the temporal management of patrons' movements. This research acknowledges the centrality of the DJ in implementing these controls. It is clear that music is a central component of the Nighttime Economy. Despite this, to date music has tended to play 'second fiddle' to sex and drugs within Club Health research. From this research it is recommended that music policy be incorporated into responsible bar server training packages.


TU-E-BRB-08: Dual Gated Volumetric Modulated Arc Therapy.
Gated Volumetric Modulated Arc Therapy (VMAT) is an emerging treatment modality for Stereotactic Body Radiotherapy (SBRT). However, gating significantly prolongs treatment time. In order to enhance treatment efficiency, a novel dual gated VMAT, in which dynamic arc deliveries are executed sequentially in alternating exhale and inhale phases, is proposed and evaluated experimentally. The essence of dual gated VMAT is to take advantage of the natural pauses that occur at inspiration and exhalation by alternatively delivering the dose at the two phases, instead of the exhale window only. The arc deliveries at the two phases are realized by rotating gantry forward at the exhale window and backward at the inhale in an alternative fashion. Custom XML scripts were developed in Varian's TrueBeam STx Developer Mode to enable dual gated VMAT delivery. RapidArc plans for a lung case were generated for both inhale and exhale phases. The two plans were then combined into a dual gated arc by interleaving the arc treatment nodes of the two RapidArc plans. The dual gated plan was delivered in the development mode of TrueBeam LINAC onto a motion phantom and the delivery was measured by using pinpoint chamber/film/diode array (delta 4). The measured dose distribution was compared with that computed using Eclipse AAA algorithm. The treatment delivery time was recorded and compared with the corresponding single gated plans. Relative to the corresponding single gated delivery, it was found that treatment time efficiency was improved by 95.5% for the case studied here. Pinpoint chamber absolute dose measurement agreed the calculation to within 0.7%. Diode chamber array measurements revealed that 97.5% of measurement points of dual gated RapidArc delivery passed the 3% and 3mm gamma-test criterion. A dual gated VMAT treatment has been developed and implemented successfully with nearly doubled treatment delivery efficiency.


Acute pulmonary embolism: endovascular therapy.
Pulmonary embolism (PE) is a leading cause of morbidity and mortality worldwide. PE is a complex disease with a highly variable presentation and the available treatment options for PE are expanding rapidly. Anticoagulation (AC), systemic lysis, surgery, and catheter-directed thrombolysis (CDT) play important roles in treating patients with PE. Thus, a multidisciplinary approach to diagnosis, risk stratification, and therapy is required to determine which treatment option is best for a given patient with this complex disease.


Metal-free synthesis of isatin oximes via radical coupling reactions of oxindoles with t-BuONO in water.
A metal-free method for the synthesis of isatin oximes was developed through the radical coupling reactions of oxindoles with t-BuONO. This protocol provides a practical and environmentally benign method for the construction of C-N bonds in water at room temperature without using any other reagents. The advantages of this strategy are its mild reaction conditions and clean procedure.


Food and Beverage Marketing to Youth.
After nearly a decade of concern over the role of food and beverage marketing to youth in the childhood obesity epidemic, American children and adolescents - especially those from communities of color - are still immersed in advertising and marketing environments that primarily promote unhealthy foods and beverages. Despite some positive steps, the evidence shows that the food and beverage industry self-regulation alone is not likely to significantly reduce marketing of unhealthy foods and beverages to youth. A variety of research is needed to monitor industry marketing of unhealthy products to young people, and identify the most promising approaches to improve children's food marketing environments. The continued presence of unhealthy marketing toward children despite years of industry self-regulation suggests it is time for stronger action by policymakers to protect young people from harmful marketing practices.


Low-threshold Brillouin laser at 2 μm based on suspended-core chalcogenide fiber.
We present, to the best of our knowledge, the first demonstration of a 2 μm Brillouin laser based on a thulium-doped fiber pump and a chalcogenide fiber. A short 1.5 m piece of suspended-core chalcogenide As38Se62 fiber is employed as a gain medium, taking advantage of its small effective mode area and high Brillouin gain coefficient. A record-low lasing threshold of 52 mW is achieved, which is about 10 times lower than previously demonstrated in silica fiber cavities.


Geodesic active fields--a geometric framework for image registration.
In this paper we present a novel geometric framework called geodesic active fields for general image registration. In image registration, one looks for the underlying deformation field that best maps one image onto another. This is a classic ill-posed inverse problem, which is usually solved by adding a regularization term. Here, we propose a multiplicative coupling between the registration term and the regularization term, which turns out to be equivalent to embed the deformation field in a weighted minimal surface problem. Then, the deformation field is driven by a minimization flow toward a harmonic map corresponding to the solution of the registration problem. This proposed approach for registration shares close similarities with the well-known geodesic active contours model in image segmentation, where the segmentation term (the edge detector function) is coupled with the regularization term (the length functional) via multiplication as well. As a matter of fact, our proposed geometric model is actually the exact mathematical generalization to vector fields of the weighted length problem for curves and surfaces introduced by Caselles-Kimmel-Sapiro. The energy of the deformation field is measured with the Polyakov energy weighted by a suitable image distance, borrowed from standard registration models. We investigate three different weighting functions, the squared error and the approximated absolute error for monomodal images, and the local joint entropy for multimodal images. As compared to specialized state-of-the-art methods tailored for specific applications, our geometric framework involves important contributions. Firstly, our general formulation for registration works on any parametrizable, smooth and differentiable surface, including nonflat and multiscale images. In the latter case, multiscale images are registered at all scales simultaneously, and the relations between space and scale are intrinsically being accounted for. Second, this method is, to the best of our knowledge, the first reparametrization invariant registration method introduced in the literature. Thirdly, the multiplicative coupling between the registration term, i.e. local image discrepancy, and the regularization term naturally results in a data-dependent tuning of the regularization strength. Finally, by choosing the metric on the deformation field one can freely interpolate between classic Gaussian and more interesting anisotropic, TV-like regularization.