Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma.
Carcinogenesis is a multi-step series of somatic genetic events. The complexity of this multi-hit process makes it difficult to determine each single event and the definitive outcome of such events. To investigate the genetic alterations in cancer-related genes, sensitive and reliable detection methods are of major importance for generating relevant results. Another critical issue is the quality of starting material which largely affects the outcome of the analysis. Microdissection of cells defined under the microscope ensures a selection of representative material for subsequent genetic analysis. Skin cancer provides an advantageous model for studying the development of cancer. Detectable lesions occur early during tumor progression, facilitating molecular analysis of the cell populations from both preneoplastic and neoplastic lesions. Alterations of the p53 tumor suppressor gene are very common in non-melanoma skin cancer, and dysregulation of p53 pathways appear to be an early event in the tumor development. A high frequency of epidermal p53 clones has been detected in chronically sun-exposed skin. The abundance of clones containing p53 mutated keratinocytes adjacent to basal cell (BCC) and squamous cell carcinoma (SCC) suggests a role in human skin carcinogenesis. Studies using p53 mutations as a clonality marker have suggested a direct link between actinic keratosis, SCC in situ and invasive SCC. Microdissection-based studies have also shown that different parts of individual BCC tumors can share a common p53 mutation yet differ with respect to additional alterations within the p53 gene, consistent with subclonal development within tumors. Here, we present examples of using well-defined cell populations, including single cells, from complex tissue in combination with molecular tools to reveal features involved in skin carcinogenesis.


Insulin-resistant lipolysis in abdominally obese hypertensive individuals. Role of the renin-angiotensin system.
Resistance to the capacity of insulin to suppress lipolysis may be an important link in the association between abdominal obesity and hypertension. Furthermore, a more active renin-angiotensin system in adipose tissue may contribute to insulin-resistant lipolysis in abdominally obese hypertensive subjects. We determined nonesterified fatty acid concentrations and turnover as well as lipid oxidation under basal conditions and during steady-state euglycemia with two levels of insulinemia (72 and 287 pmol/L) in lean normotensive, abdominally obese normotensive, and abdominally obese hypertensive subjects. To assess the role of the renin-angiotensin system in determining non-esterified fatty acid turnover, we repeated studies in the abdominally obese hypertensive subjects after double-blind random assignment to placebo or enalapril for 1 month each. The main findings were the following: (1) Nonesterified fatty acid flux was significantly higher in abdominally obese hypertensive subjects at both levels of insulinemia than in either abdominally obese normotensive or lean normotensive subjects and correlated significantly with both mean blood pressure and total systemic resistance during the higher level of insulinemia. (2) Enalapril significantly improved insulin-resistant lipolysis in the abdominally obese hypertensive subjects. The improvement in insulin suppressibility of nonesterified fatty acid flux at the high hormonal concentrations correlated positively with the magnitude of reduction in blood pressure. (3) Basal lipid oxidation and suppression in response to insulin were similarly impaired in both obese groups. Resistance to the antilipolytic actions of insulin is thus a characteristic feature in abdominally obese hypertensive subjects and may be linked to the elevated blood pressure in these individuals. A more active renin-angiotensin system may partly explain the insulin-resistant lipolysis in this form of hypertension.


Sketching Designs Using the Five Design-Sheet Methodology.
Sketching designs has been shown to be a useful way of planning and considering alternative solutions. The use of lo-fidelity prototyping, especially paper-based sketching, can save time, money and converge to better solutions more quickly. However, this design process is often viewed to be too informal. Consequently users do not know how to manage their thoughts and ideas (to first think divergently, to then finally converge on a suitable solution). We present the Five Design Sheet (FdS) methodology. The methodology enables users to create information visualization interfaces through lo-fidelity methods. Users sketch and plan their ideas, helping them express different possibilities, think through these ideas to consider their potential effectiveness as solutions to the task (sheet 1); they create three principle designs (sheets 2,3 and 4); before converging on a final realization design that can then be implemented (sheet 5). In this article, we present (i) a review of the use of sketching as a planning method for visualization and the benefits of sketching, (ii) a detailed description of the Five Design Sheet (FdS) methodology, and (iii) an evaluation of the FdS using the System Usability Scale, along with a case-study of its use in industry and experience of its use in teaching.


Disciplined Improvisation: Characteristics of Inquiry in Mindfulness-Based Teaching.
Evidence for the effectiveness of mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) is rapidly growing as interest in this field expands. By contrast, there are few empirical analyses of the pedagogy of MBSR and MBCT. Development of the evidence base concerning the teaching of MBCT or MBSR would support the integrity of the approach in the context of rapid expansion. This paper describes an applied conversation analysis (CA) of the characteristics of inquiry in the MBSR and MBCT teaching process. Audio-recordings of three 8-week MBCT and MBSR classes, with 24, 12, and 6 participants, were transcribed and systematically examined. The study focused on the teacher-led interactive inquiry which takes place in each session after a guided meditation practice. The study describes and analyzes three practices within the inquiry process that can be identified in sequences of talk: turn-taking talk involving questions and reformulations; the development of participant skills in a particular way of describing experience; and talk that constructs intersubjective connection and affiliation within the group. CA enables fine-grained analysis of the interactional work of mindfulness-based inquiry. Inquiry is a process of disciplined improvisation which is both highly specific to the conditions of the moment it took place in and uses repeated and recognizable patterns of interaction.


Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study.
Shigellosis is an acute, severe bacterial colitis that, in high-income countries, is typically associated with travel to high-risk regions (Africa, Asia, and Latin America). Since the 1970s, shigellosis has also been reported as a sexually transmitted infection in men who have sex with men (MSM), in whom transmission is an important component of shigellosis epidemiology in high-income nations. We aimed to use sophisticated subtyping and international sampling to determine factors driving shigellosis emergence in MSM linked to an outbreak in the UK. We did a large-scale, cross-sectional genomic epidemiological study of shigellosis cases collected from 29 countries between December, 1995, and June 8, 2014. Focusing on an ongoing epidemic in the UK, we collected and whole-genome sequenced clinical isolates of Shigella flexneri serotype 3a from high-risk and low-risk regions, including cases associated with travel and sex between men. We examined relationships between geographical, demographic, and clinical patient data with the isolate antimicrobial susceptibility, genetic data, and inferred evolutionary relationships. We obtained 331 clinical isolates of S flexneri serotype 3a, including 275 from low-risk regions (44 from individuals who travelled to high-risk regions), 52 from high-risk regions, and four outgroup samples (ie, closely related, but genetically distinct isolates used to determine the root of the phylogenetic tree). We identified a recently emerged lineage of S flexneri 3a that has spread intercontinentally in less than 20 years throughout regions traditionally at low risk for shigellosis via sexual transmission in MSM. The lineage had acquired multiple antimicrobial resistance determinants, and prevailing sublineages were strongly associated with resistance to the macrolide azithromycin. Eight (4%) of 206 isolates from the MSM-associated lineage were obtained from patients who had previously provided an isolate; these serial isolations indicated atypical infection patterns (eg, reinfection). We identified transmission-facilitating behaviours and atypical course(s) of infection as precipitating factors in shigellosis-affected MSM. The intercontinental spread of antimicrobial-resistant shigella through established transmission routes emphasises the need for new approaches to tackle the public health challenge of sexually transmitted infections in MSM. Wellcome Trust (grant number 098051).


Phytophthora species recovered from the Connecticut River Valley in Massachusetts, USA.
Little is currently known about the assemblage of Phytophthora species in northeastern North America, representing a gap in our understanding of species incidence. Therefore, Phytophthora species were surveyed at 20 sites in Massachusetts, with 16 occurring in the Connecticut River Valley. Many of the sampled waterways were adjacent to active agricultural lands, yet were buffered by mature floodplain forests composed of Acer, Platanus, Populus and Ulmus. Isolates were recovered with three types of baits (rhododendron leaves, pear, green pepper) in 2013 and water filtration in 2014. Overall, 457 isolates of Phytophthora were recovered and based on morphological characters and rDNA internal transcribed spacer (ITS), β-tubulin (β-tub) and cytochrome oxidase c subunit I (cox1) sequences, 18 taxa were identified, including three new species: P. taxon intercalaris, P. taxon caryae and P. taxon pocumtuck. In addition, 49 isolates representing five species of Phytopythium also were identified. Water filtration captured a greater number of taxa (18) compared to leaf and fruit baits (12). Of the three bait types rhododendron leaves yielded the greatest number of isolates and taxa, followed by pear and green pepper, respectively. Despite the proximity to agricultural lands, none of the Phytophthora species baited are considered serious pathogens of vegetable crops in the region. However, many of the recovered species are known woody plant pathogens, including four species in the P. citricola s.l. complex that were identified: P. plurivora, P. citricola III, P. pini and a putative novel species, referred to here as P. taxon caryae. An additional novel species, P. taxon pocumtuck, is a close relative of P. borealis based on cox1 sequences. The results illustrate a high level of Phytophthora species richness in the Connecticut River Valley and that major rivers can serve as a source of inoculum for pathogenic Phytophthora species in the northeast.


Melanopsin Contributions to the Representation of Images in the Early Visual System.
Melanopsin photoreception enhances retinal responses to variations in ambient light (irradiance) and drives non-image-forming visual reflexes such as circadian entrainment [1-6]. Melanopsin signals also reach brain regions responsible for form vision [7-9], but melanopsin's contribution, if any, to encoding visual images remains unclear. We addressed this deficit using principles of receptor silent substitution to present images in which visibility for melanopsin versus rods+cones was independently modulated, and we recorded evoked responses in the mouse dorsal lateral geniculate nucleus (dLGN; thalamic relay for cortical vision). Approximately 20% of dLGN units responded to patterns visible only to melanopsin, revealing that melanopsin signals alone can convey spatial information. Spatial receptive fields (RFs) mapped using melanopsin-isolating stimuli had ON centers with diameters ∼13°. Melanopsin and rod+cone responses differed in the temporal domain, and responses to slow changes in radiance (<0.9 Hz) and stationary images were deficient when stimuli were rendered invisible for melanopsin. We employed these data to devise and test a mathematical model of melanopsin's involvement in form vision and applied it, along with further experimental recordings, to explore melanopsin signals under simulated active view of natural scenes. Our findings reveal that melanopsin enhances the thalamic representation of scenes containing local correlations in radiance, compensating for the high temporal frequency bias of cone vision and the negative correlation between magnitude and frequency for changes in direction of view. Together, these data reveal a distinct melanopsin contribution to encoding visual images, predicting that, under natural view, melanopsin augments the early visual system's ability to encode patterns over moderate spatial scales.


Electron microscope observations on the submicroscopic organization of the retinal rods.
The submicroscopic organization of the retinal rods of the rabbit has been studied with high resolution electron microscopy in thin longitudinal and cross-sections. The outer rod segment consists of a stack of flattened sacs or cisternae each of them limited by a thin homogeneous membrane of about 30 A. The membrane of the rod sacs is attached to the surface membrane and is also in continuity with short tubular stalks of about 100 to 150 A which apparently end in relation with the connecting cilium. The bundle of filaments that constitute the connection between the outer and the inner segments is described under the name of connecting cilium. This fibrous component has a structure that is very similar to that of the cilium. It shows 9 pairs of peripheral filaments of about 160 A in diameter, a matrix material, and a surface membrane. Very infrequently two central single filaments are observed. The connecting cilium has a typical basal body in the inner segment; its distal end penetrates the outer segment, where it establishes some structural relation to the rod sacs. The relationships and submicroscopic organization of the connecting cilium were studied in longitudinal and in cross-sections passing at different levels of the rod segments. The inner rod segment shows two distinct regions: a distal and a proximal one. The distal region, corresponding to the ellipsoid of classical histology is mainly composed of longitudinally packed mitochondria. It also contains the basal body of the cilium, vacuoles of the endoplasmic reticulum, dense particles, and intervening matrix with very fine filaments. In the proximal region of the inner segment the mitochondria are lacking and within the matrix it is possible to recognize elements of the Golgi complex, vacuoles of the endoplasmic reticulum, dense particles and numerous neuroprotofibrils of 160 to 200 A in diameter which collect and form a definite bundle at the exit of the rod fiber. The interpretation of the connecting fibers as a portion of a cilium and of the outer segment as a differentiation of the distal part of a primitive cilium are discussed. The importance of the continuity of the surface membranes of the outer segment, connecting cilium, and inner segment is emphasized and its possible physiological role is discussed.


Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial.
Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease. In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244. Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only. Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion. Patient Centered Outcomes Research Institute.


Understanding three-body contributions to coarse-grained force fields.
Coarse-graining is a systematic reduction of the number of degrees of freedom used to describe a system of interest. Coarse-graining can be thought of as a projection on the coarse-grained degrees of freedom and is therefore dependent on the number and type of basis functions used to represent the coarse-grained force field. We show that many-body extensions of the coarse-grained force field can result in substantial changes of the two-body interactions, making them much more attractive at short distances. This interplay can be alleviated by first parametrizing the two-body potential and then fitting the additional three-body contribution to the residual forces. The approach is illustrated on liquid water where three-body interactions are essential to reproduce the structural properties, and liquid methanol where two-body interactions are sufficient to reproduce the main structural features of the atomistic system. Furthermore, we demonstrate that the structural and thermodynamic accuracy of the coarse-grained models can be controlled by varying the magnitude of the three-body interactions. Our findings motivate basis set extensions which separate the many-body contributions of different order.


Subthreshold membrane depolarization as memory trace for perceptual learning.
Experience-dependent synaptic plasticity characterizes the adaptable brain and is believed to be the cellular substrate for perceptual learning. A chemical agent such as gamma-aminobutyric acid (GABA) is known to affect synaptic alteration, perhaps gating perceptual learning. We examined whether and how ambient (extrasynaptic) GABA affects experience-dependent synaptic alteration. A cortical neural network model was simulated. Transporters on GABAergic interneurons regulate ambient GABA levels around their axonal target neurons by removing GABA from (forward transport) or releasing it into (reverse transport) the extracellular space. The ambient GABA provides neurons with tonic inhibitory currents by activating extrasynaptic GABA(a) receptors. During repeated exposures to the same stimulus, we modified the synaptic connection strength between principal cells in a spike-timing-dependent manner. This modulated the activity of GABAergic interneurons, and reduced or augmented ambient GABA concentration. Reduction in ambient GABA concentration led to slight depolarization (less than several millivolts) in ongoing-spontaneous membrane potential. This was a subthreshold neuronal behavior because ongoing-spontaneous spiking activity remained almost unchanged. The ongoing-spontaneous subthreshold depolarization improved a suprathreshold neuronal response. If the stimulus was long absent for perceptual learning, augmentation of ambient GABA concentration took place and the ongoing-spontaneous subthreshold depolarization was depressed. We suggest that a perceptual memory trace could be left in neuronal circuitry as an ongoing-spontaneous subthreshold membrane depolarization, which would allow that memory to be accessed easily afterward, whereas a trace of a memory that has not recently been retrieved fades away when the ongoing-spontaneous subthreshold membrane depolarization built by previous perceptual learning is depressed. This would lead that memory to be accessed with some difficulty. In the brain, ambient GABA, whose level could be regulated by transporter may have an important role in leaving memory trace for perceptual learning.


Factors associated with open practices: results from the Canadian National Family Physician Survey.
Closed and conditionally closed practices appear to be increasing in many parts of Canada as reflected in the fact that more and more patients report difficulties finding family physicians who accept new patients. But the extent of, nature of, and factors related to open, closed, and conditionally closed practices are still largely unknown. This study used data from the 2001 National Family Physician Workforce Survey for secondary analysis. Chi-square tests and logistic regression were used to examine factors related to FPs' decisions to keep their practices open or to close them. Private offices, clinics, community health centres, and academic family medicine practice units in Canada. Of 10,325 FPs surveyed, 2360 respondents who practised in emergency departments, hospitals, nursing homes, homes for the aged, walk-in clinics, and more than one setting were excluded. Overall response rate was 51.2%. Practice status (open, conditionally closed, and closed), restrictions placed on conditionally closed practices, and factors associated with open practices. The odds of having an open practice increased if respondents were male, younger than 35, working fewer hours at the time, or working in a group practice that included other types of physicians. Family physicians in rural and remote areas were much less likely than those in urban centres to close their practices. Conversely, FPs were more likely to close their practices when they perceived their communities to have good emergency department services and when other FPs in the community also had closed their practices. Demographic and practice characteristics of physicians have an effect on whether practices are open, conditionally closed, or completely closed. But the broader practice environment, determined by such factors as geographic location and medical services available in the community, is equally important.


Spatial and temporal regulation of a foreign gene by a prestalk-specific promoter in transformed Dictyostelium discoideum.
We analyzed a developmentally regulated prestalk-specific gene from Dictyostelium discoideum encoding a cathepsin-like protease. A hybrid gene was constructed by fusing 2.5 kilobases of 5' flanking sequences and part of the coding region of the gene in-frame to the Escherichia coli beta-glucuronidase gene and was transformed into D. discoideum cells. In cells transformed with this vector, the gene fusion showed the same temporal regulation as the endogenous gene during multicellular development and, like endogenous prestalk genes, was highly inducible by cyclic AMP in in vitro cell cultures. Moreover, immunofluorescence studies showed that the fusion protein had the same spatial distribution within the migrating pseudoplasmodium as the endogenous gene. The results indicate that the regions of the D. discoideum prestalk-specific cathepsin gene contain all the necessary information for proper temporal, spatial, and cyclic AMP regulation of a prestalk cell-type gene in D. discoideum transformants and leads the way for experiments to identify the cell-type-specific regulatory elements.


Sustained incentive value of heroin-related cues in short- and long-term abstinent heroin users.
Models of addiction and addiction memory propose that drug-associated cues elicit incentive effects in drug users, which play an important role in maintenance of drug use and relapse. Incentive effects have been demonstrated for smoking and alcohol-related cues but evidence for heroin-related cues has been inconclusive. Furthermore, it is unknown whether appetitive effects of heroin-related cues persist after prolonged abstinence, although heroin addiction is known to have high relapse rates. Therefore, we investigated implicit and explicit valence of heroin-related cues in dependent users at different stages of abstinence using affective startle modulation. In Study I, 15 current heroin users were measured before and after detoxification. Correspondingly, 15 healthy control participants were tested twice at an interval of 14 days. In Study II, 14 long-term abstinent heroin users were additionally measured in a single session. Implicit processing of drug-related stimuli was assessed using affective startle modulation by pictures of heroin and smoking scenes. Explicit reactions were measured using ratings of valence and craving. In contrast to controls, heroin-dependent participants showed a clear reduction of startle response during heroin-related pictures (p<0.05). Detoxification did not significantly change their startle responses to heroin-cues. No difference between non-detoxified current and long-term abstinent heroin users was found in implicit reactions to heroin-cues, whereas explicit measures differed between both groups (all p<0.05). After detoxification and even after prolonged abstinence, heroin cues still exert implicit appetitive effects in heroin users. This implies that drug-induced adaptations of reward circuits are long-lasting, resulting in a highly stable addiction memory.


[Effects of PTHrP and Notch signaling on the proliferation of epiphysis stem cells].
To study the regulation of the proliferation of epiphysis stem cells by the PTHrP (parathyroid hormone related peptide) and Notch signaling systems. An organ culture system of femurs of SD rat in 24 h after birth was employed. PTHrP (1 - 34) was used as the activator of the PTHrP signaling pathway and PTHrP (7 - 34) as the antagonist of PTH (parathyroid hormone)-receptor. For Notch signaling system, Jagged1/Fc was used as the activator and DAPT as its inhibitor. The femurs were cultured in DMEM (Dulbecco's modified Eagle's medium)/F12 medium while phosphate buffered saline was used for the control groups. Hematoxylin and eosin staining and bromodeoxyuridine analysis were used to analyze the length of the epiphysis stem cells zone and the proliferation of epiphysis stem cells. The expression of NICD (Notch intra-cellular domain) and Jagged1 were analyzed by immunohistochemistry. The epiphysis stem cells were transfected with the lentiviral vectors with rat PTHrP gene overexpression or inhibition properties, the cells transfected with the PGC-GFP-lentivirus or NC-GFP-lentivirus were used as control. Western blot was employed to detect the expression of NICD and Jagged1 genes. PTHrP (1 - 34) and Jagged1/Fc could dramatically elevate the rate of epiphysis stem cells zone by the whole growth plate length measurement while PTHrP (7 - 34) and DAPT could decrease the rate. Brdu analysis also showed that the number of proliferative epiphysis stem cells could be up-regulated by the PTHrP (1 - 34) or Jagged1/Fc signaling. By contrast, the treatment with PTHrP (7 - 34) or DAPT reduced the number of proliferative epiphysis stem cells. Immunohistochemistry and Western blot showed a significantly elevated expression of NICD and Jagged1 when PTHrP signaling was activated while a reductive expression of NICD and Jagged1 when PTHrP signaling was inactivated. Both of PTHrP and Notch signaling system could promote the proliferation of epiphysis stem cells. And the PTHrP signaling can stimulate Notch signaling to promote the proliferation of epiphysis stem cells.


Systematic review and meta-analysis of test accuracy for the diagnosis of suspected pulmonary embolism.
Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.


Secondary Metabolites Produced by Heterorhabditis Symbionts and Their Application in Agriculture: What We Know and What to Do Next.
Gram-negative Photorhabdus bacteria have a dual lifestyle: they are mutualists of Heterorhabditis nematodes and are pathogens of insects. Together, this nematode-bacterium partnership has been used to successfully control a wide range of agricultural insect pests. Photorhabdus produce a diverse array of small molecules that play key biological roles in regulating their dual roles. In particular, several secondary metabolites (SM) produced by this bacterium are known to play a critical role in the maintenance of a monoxenic infection in the insect host and are also known to prevent contamination of the cadaver from soil microbes and/or predation by arthropods. A few of the SM this bacteria produce have been isolated and identified, and their biological activities have also been tested in laboratory assays. Over the past two decades, analyses of the genomes of several Photorhabdus spp. have revealed the presence of SM numerous gene clusters that comprise more than 6% of these bacteria genomes. Furthermore, genome mining and characterization of biosynthetic pathways, have uncovered the richness of these compounds, which are predicted to vary across different Photorhabdus spp. and strains. Although progress has been made in the identification and function of SM genes and gene clusters, the targeted testing for the bioactivity of molecules has been scarce or mostly focused on medical applications. In this review, we summarize the current knowledge of Photorhabdus SM, emphasizing on their activity against plant pathogens and parasites. We further discuss their potential in the management of agricultural pests and the steps that need to be taken for the implementation of Photorhabdus SM in pest management.


Erythrocyte membranes convert monomeric ferriprotoporphyrin IX to β-hematin in acidic environment at malarial fever temperature.
Hemozoin production makes it possible for intraerythrocytic malaria parasites to digest massive quantities of hemoglobin but still avoid potential ferriprotoporphyrin IX (FP) toxicity, which they cannot decompose further. Some antimalarial drugs, such as chloroquine, work by inhibiting this production, forcing the parasite to starve to death. As part of the efforts to identify possible biological mechanisms of FP polymerization, we have used normal human erythrocyte membranes as a model, to promote β-hematin (β-h) synthesis. Hemin in 35% aqueous dimethyl sulfoxide (DMSO) was reacted with isolated erythrocyte membranes and incubated overnight in sodium acetate buffer, pH 4.8, at 41°C. Infrared spectroscopy and electron microscopy showed that β-h was produced. Hemin in 10% was less effective as the substrate than when it was in 35% DMSO. A high malarial temperature seemed to be necessary, because FP polymerization was less at 37°C than at 41°C. Production was partially inhibited by chloroquine. These observations are of interest because other investigators have reported that membrane lipids mediated FP polymerization, but whole membranes were ineffective. On the other hand, our hypothesis is that the transport vesicles (TV) in malaria parasites could provide the receptor for FP and the lipids that promote hemozoin formation. Erythrocyte membranes may not be directly involved, but Plasmodium species transport hemoglobin in membrane-bound TV into food vacuoles, where hemoglobin catabolism is completed and hemozoin crystals are stored.


The Tamiflu fiasco and lessons learnt.
Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for seasonal flu by US Food and Drug Administration in 1999. A number of randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile. Majority of them were funded by Roche, which also first marketed and promoted this drug. In 2005 and 2009, the looming fear of pandemic flu led to recommendation by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in treatment and prophylaxis of influenza, and it's stockpiling as a measure to tide over the crisis. Serious Adverse Events, especially neuropsychiatric events associated with Tamiflu started getting reported leading to a cascade of questions on clinical utility of this drug. A recent Cochrane review and related articles have questioned the risk-benefit ratio of the drug, besides raising doubts about the regulatory decision of approving it. The recommendations for stockpiling the said drug as given by various international organizations viz WHO have also been put to scrutiny. Although many reviewers have labeled the Tamiflu saga as a "costly mistake," the episode leaves us with some important lessons. This article takes a comprehensive relook on the subject, and we proceed to suggest some ways and means to avoid a similar situation in the future.


Use of existing data for public health planning: a study of the prevalence of hepatitis B surface antigen and core antibody in Al Ain Medical District, United Arab Emirates.
Hepatitis B is of major public health importance. Accurate information on its occurrence, with particular reference to the prevalence of immunity and chronic infection (marked by the presence of hepatitis B core antibody and surface antigen, respectively, in serum), is essential for planning public health programmes for the control of the disease. The generation of marker prevalence data through serological surveys is costly and time-consuming. The present study in Al Ain Medical District, United Arab Emirates, investigated the possibility of obtaining sufficiently accurate marker prevalence estimates from existing data to plan public health programmes. Two antenatal screening databases, one student serological survey database, one immunization programme database and one pre-marriage screening database containing information on marker prevalence were identified. Epidemiological data were abstracted from these databases and analysed. The data showed that the prevalence of hepatitis B surface antigen and the prevalence of core antibody in young citizens in 1998 were approximately 2% and 14% respectively, that any immunization campaign aimed at citizens of the United Arab Emirates should target teenagers as they had the highest risk of acquiring the disease, and that pre-immunization screening of young adults would be wasteful. However, the data did not yield information on the prevalence of hepatitis B surface antigen and core antibody in other population subgroups of public health significance. While data generated by the study are sufficient to support a hepatitis B immunization programme targeted at teenaged citizens, more accurate data, generated by a well-designed serological survey, would be essential for optimal public health planning.


Anticancer activity of Amauroderma rude.
More and more medicinal mushrooms have been widely used as a miraculous herb for health promotion, especially by cancer patients. Here we report screening thirteen mushrooms for anti-cancer cell activities in eleven different cell lines. Of the herbal products tested, we found that the extract of Amauroderma rude exerted the highest activity in killing most of these cancer cell lines. Amauroderma rude is a fungus belonging to the Ganodermataceae family. The Amauroderma genus contains approximately 30 species widespread throughout the tropical areas. Since the biological function of Amauroderma rude is unknown, we examined its anti-cancer effect on breast carcinoma cell lines. We compared the anti-cancer activity of Amauroderma rude and Ganoderma lucidum, the most well-known medicinal mushrooms with anti-cancer activity and found that Amauroderma rude had significantly higher activity in killing cancer cells than Ganoderma lucidum. We then examined the effect of Amauroderma rude on breast cancer cells and found that at low concentrations, Amauroderma rude could inhibit cancer cell survival and induce apoptosis. Treated cancer cells also formed fewer and smaller colonies than the untreated cells. When nude mice bearing tumors were injected with Amauroderma rude extract, the tumors grew at a slower rate than the control. Examination of these tumors revealed extensive cell death, decreased proliferation rate as stained by Ki67, and increased apoptosis as stained by TUNEL. Suppression of c-myc expression appeared to be associated with these effects. Taken together, Amauroderma rude represented a powerful medicinal mushroom with anti-cancer activities.


PERFORMANCE GUARANTEES FOR INDIVIDUALIZED TREATMENT RULES.
Because many illnesses show heterogeneous response to treatment, there is increasing interest in individualizing treatment to patients [11]. An individualized treatment rule is a decision rule that recommends treatment according to patient characteristics. We consider the use of clinical trial data in the construction of an individualized treatment rule leading to highest mean response. This is a difficult computational problem because the objective function is the expectation of a weighted indicator function that is non-concave in the parameters. Furthermore there are frequently many pretreatment variables that may or may not be useful in constructing an optimal individualized treatment rule yet cost and interpretability considerations imply that only a few variables should be used by the individualized treatment rule. To address these challenges we consider estimation based on l(1) penalized least squares. This approach is justified via a finite sample upper bound on the difference between the mean response due to the estimated individualized treatment rule and the mean response due to the optimal individualized treatment rule.


Risk Factors of Progression to Frailty: Findings from the Singapore Longitudinal Ageing Study.
To investigate risk factors of incident physical frailty. A population-based observational longitudinal study. Community-dwelling elderly with age 55 years and above recruited from 2009 through 2011 in the second wave Singapore Longitudinal Ageing Study-2 (SLAS-2) were followed up 3-5 years later. A total of 1297 participants, mean age of 65.6 ±0.19, who were free of physical frailty. Incident frailty defined by three or more criteria of the physical phenotype used in the Cardiovascular Health Study was determined at follow-up. Potential risk factors assessed at baseline included demographic, socioeconomic, medical, psychological factors, and biochemical markers. A total of 204 (15.7%) participants, including 81 (10.87%) of the robust and 123 (22.28%) of the prefrail transited to frailty at follow-up. Age, no education, MMSE score, diabetes, prediabetes and diabetes, arthritis, ≥5 medications, fair and poor self-rated health, moderate to high nutritional risk (NSI ≥3), Hb (g/dL), CRP (mg/L), low B12, low folate, albumin (g/L), low total cholesterol, adjusted for sex, age and education, were significantly associated (p<0.05) with incident frailty. In stepwise selection models, age (year) (OR=1.07, 95%CI=1.03-1.10, p<0.001), albumin (g/L) (OR=0.85, 95%CI=0.77-0.94, p=0.002), MMSE score (OR=0.88, 95%CI=0.78-0.98, p=0.02), low folate (OR=3.72, 95%CI=1.17-11.86, p=0.03, and previous hospitalization (OR=2.26, 95%CI=1.01-5.04,p=0.05) were significantly associated with incident frailty. The study revealed multiple modifiable risk factors, especially related to poor nutrition, for which preventive measures and early management could potentially halt or delay the development of frailty.


Phylogenetic analysis of Streptomyces spp. causing potato scab based on 16S rRNA sequences.
The complete 16S rRNA sequences of 12 strains of Streptomyces spp., including potato scab pathogens, were determined. Among the strains of Streptomyces scabies that were isolated from diverse geographical areas and differed in melanoid pigment production, either no difference or one difference in sequence was observed. The sequence of S. scabies was most similar to the sequences of Streptomyces diastatochromogenes, Streptomyces bottropensis, and Streptomyces neyagawaensis, which belong to the Diastatochromogenes group. The levels of similarity of the 16S rRNA sequences of Streptomyces acidiscabies and S. scabies were almost the same as the levels of similarity between S. acidiscabies and other Streptomyces strains. Streptomyces sp. strain 91-Sy-13, which was isolated in Japan from potato scab and belongs to a distinct species on the basis of phenotypic characteristics and DNA relatedness, exhibited lower levels of 16S rRNA sequence similarity with other potato scab pathogens, as well as other Streptomyces species. The phylogenetic tree constructed on the basis of 16S rRNA sequence data showed that the Streptomyces spp. that cause potato scab composed unique branches. The results of our phylogenetic analysis based on complete 16S rRNA sequences confirmed the lack of close relationships among Streptomyces spp. that cause potato scab. Our findings suggest that potato scab is caused by phylogenetically diverse Streptomyces species and that the pathogenicities of these organisms developed independently.


Mutagenic and recombinagenic effects of diethylstilbestrol quinone.
Estrogens are believed to be major contributors to many cancers of the human female genital tract, but the mechanism of their carcinogenic action is not well-understood. While a tumor-promoting role for estrogens is well-supported, whether they also act as tumor initiators has remained controversial. Here, we have sought to examine the mutagenic potential of diethylstilbestrol, a synthetic estrogen that is a powerful carcinogen in hamsters, and is suspected to be a human carcinogen. Phage M13 single-stranded DNA was treated in vitro with diethylstilbestrol quinone (DES Q: 1.25 mM) and transfected into Escherichia coli cells. DES Q treatment resulted in an apparent enhancement of mutagenesis in the LacZ(alpha) gene segment. DNA sequence analysis of LacZ(alpha) mutants obtained by transfection of DES Q-treated DNA revealed that the major effect of DES Q treatment has been a 6-fold elevation of recombination between the phage-borne LacZ(alpha) sequence and the LacZ delta M15 sequence on the E. coli fertility plasmid F. To confirm whether DES Q treatment is recombinagenic, we used an experimental system that allows the detection of recombination between a defective E. coli chromosomal LacY gene and a normal counterpart borne on a plasmid. Transfection of DES Q (0.06-12 mM) treated plasmid DNA showed significant enhancement (2-100-fold) in recombination, but not in mutagenesis. These results raise the possibility that estrogen quinones may induce recombinagenic DNA damage.


Agency practices in assigning fieldwork experiences to occupational therapy students.
Practices by agencies in assigning Level II fieldwork experiences to occupational therapy students were examined. Time-specific logs were collected from students and from agency personnel during a 3-month period. The data generated were used to answer questions about how effectively student time was used in meeting the stated purposes of the assignment. The focus was on "average" student fieldwork activities. The study suggests that more careful and systematic development and design of Level II fieldwork programs are needed to meet the established educational goals and to maximize educational opportunities during the allotted time.


Evidence suggesting that the ARS elements associated with silencers of the yeast mating-type locus HML do not function as chromosomal DNA replication origins.
The silent mating-type loci of Saccharomyces cerevisiae, HML and HMR, are flanked by transcriptional silencers that have ARS activity (i.e., they function as replication origins when in plasmids). To test whether these ARS elements are chromosomal origins, we mapped origins near HML (close to the left telomere of chromosome III). Our results indicate that the HML-associated ARS elements either do not function as chromosomal replication origins or do so at a frequency below our detection level, suggesting that replication from a silencer-associated origin in each S phase is not essential for the maintenance of transcriptional repression at HML. Our results also imply that the ability of a DNA fragment to function as an ARS element in a plasmid does not ensure its ability to function as an efficient chromosomal replication origin. Telomere proximity is not responsible for inactivating these ARS elements, because they are not detectably functional as chromosomal origins even in genetically modified strains in which they are far from the telomere.


Axonal degeneration as substrate of fractional anisotropy abnormalities in multiple sclerosis cortex.
Cortical microstructural abnormalities are associated with clinical and cognitive deterioration in multiple sclerosis. Using diffusion tensor MRI, a higher fractional anisotropy has been found in cortical lesions versus normal-appearing cortex in multiple sclerosis. The pathological substrates of this finding have yet to be definitively elucidated. By performing a combined post-mortem diffusion tensor MRI and histopathology study, we aimed to define the histopathological substrates of diffusivity abnormalities in multiple sclerosis cortex. Sixteen subjects with multiple sclerosis and 10 age- and sex-matched non-neurological control donors underwent post-mortem in situ at 3 T MRI, followed by brain dissection. One hundred and ten paraffin-embedded tissue blocks (54 from multiple sclerosis patients, 56 from non-neurological controls) were matched to the diffusion tensor sequence to obtain regional diffusivity measures. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, astrocytes and axons, and density and volume of neurons and glial cells were evaluated. Correlates of diffusivity abnormalities with histological markers were assessed through linear mixed-effects models. Cortical lesions (77% subpial) were found in 27/54 (50%) multiple sclerosis cortical regions. Multiple sclerosis normal-appearing cortex had a significantly lower fractional anisotropy compared to cortex from non-neurological controls (P = 0.047), whereas fractional anisotropy in demyelinated cortex was significantly higher than in multiple sclerosis normal-appearing cortex (P = 0.012) but not different from non-neurological control cortex (P = 0.420). Compared to non-neurological control cortex, both multiple sclerosis normal-appearing and demyelinated cortices showed a lower density of axons perpendicular to the cortical surface (P = 0.012 for both) and of total axons (parallel and perpendicular to cortical surface) (P = 0.028 and 0.012). In multiple sclerosis, demyelinated cortex had a lower density of myelin (P = 0.004), parallel (P = 0.018) and total axons (P = 0.029) versus normal-appearing cortex. Regarding the pathological substrate, in non-neurological controls, cortical fractional anisotropy was positively associated with density of perpendicular, parallel, and total axons (P = 0.031 for all). In multiple sclerosis, normal-appearing cortex fractional anisotropy was positively associated with perpendicular and total axon density (P = 0.031 for both), while associations with myelin, glial and total cells and parallel axons did not survive multiple comparison correction. Demyelinated cortex fractional anisotropy was positively associated with density of neurons, and total cells and negatively with microglia density, without surviving multiple comparison correction. Our results suggest that a reduction of perpendicular axons in normal-appearing cortex and of both perpendicular and parallel axons in demyelinated cortex may underlie the substrate influencing cortical microstructural coherence and being responsible for the different patterns of fractional anisotropy changes occurring in multiple sclerosis cortex.


Successful delivery of RRT in Ebola virus disease.
AKI has been observed in cases of Ebola virus disease. We describe the protocol for the first known successful delivery of RRT with subsequent renal recovery in a patient with Ebola virus disease treated at Emory University Hospital, in Atlanta, Georgia. Providing RRT in Ebola virus disease is complex and requires meticulous attention to safety for the patient, healthcare workers, and the community. We specifically describe measures to decrease the risk of transmission of Ebola virus disease and report pilot data demonstrating no detectable Ebola virus genetic material in the spent RRT effluent waste. This article also proposes clinical practice guidelines for acute RRT in Ebola virus disease.


Short communication: Signs of host genetic regulation in the microbiome composition in 2 dairy breeds: Holstein and Brown Swiss.
This study aimed to evaluate whether the host genotype exerts any genetic control on the microbiome composition of the rumen in cattle. Microbial DNA was extracted from 18 samples of ruminal content from 2 breeds (Holstein and Brown Swiss). Reads were processed using mothur (https://www.mothur.org/) in 16S and 18S rRNA gene-based analyses. Then, reads were classified at the genus clade, resulting in 3,579 operational taxonomic units (OTU) aligned against the 16S database and 184 OTU aligned against the 18S database. After filtering on relative abundance (>0.1%) and penetrance (95%), 25 OTU were selected for the analyses (17 bacteria, 1 archaea, and 7 ciliates). Association with the genetic background of the host animal based on the principal components of a genomic relationship matrix based on single nucleotide polymorphism markers was analyzed using Bayesian methods. Fifty percent of the bacteria and archaea genera were associated with the host genetic background, including Butyrivibrio, Prevotella, Paraprevotella, and Methanobrevibacter as main genera. Forty-three percent of the ciliates analyzed were also associated with the genetic background of the host. In total, 48% of microbes were associated with the host genetic background. The results in this study support the hypothesis and provide some evidence that there exists a host genetic component in cattle that can partially regulate the composition of the microbiome.


Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans.
Large data sets on human genetic variation have been collected recently, but their usefulness for learning about history and natural selection has been limited by biases in the ways polymorphisms were chosen. We report large subsets of SNPs from the International HapMap Project that allow us to overcome these biases and to provide accurate measurement of a quantity of crucial importance for understanding genetic variation: the allele frequency spectrum. Our analysis shows that East Asian and northern European ancestors shared the same population bottleneck expanding out of Africa but that both also experienced more recent genetic drift, which was greater in East Asians.


The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study of patients who underwent hip or knee arthroplasty. Canadian Collaborative Group.
Despite low molecular weight heparin prophylaxis, the incidence of venographically detected, residual deep vein thrombosis after hip and knee arthroplasty remains high, at approximately 15% and 30%, respectively. Most of these thrombi are asymptomatic and of unknown clinical significance. Nevertheless, because they have the potential to grow, limiting prophylaxis to the in-hospital period may provide inadequate protection. We studied a cohort of 1984 consecutive patients who had hip or knee arthroplasty at 1 of 28 participating hospitals. Patients received enoxaparin prophylaxis, 30 mg subcutaneously every 12 hours for up to 14 days, and underwent predischarge compression ultrasonography. Study end points were symptomatic deep vein thrombosis or pulmonary embolism during and after prophylaxis, asymptomatic venous thrombosis detected by predischarge compression ultrasonography, and major hemorrhage. The duration of follow-up was 84 days. Enoxaparin treatment was started a mean (+/- SD) of 17.9 +/- 10.4 hours after the completion of surgery and was given for a mean of 18.0 +/- 6.9 doses. Eighty-two patients (4.1%; 95% confidence interval, 3.3%-5.0%) developed venous thromboembolism. The rates of thromboembolic events during and after prophylaxis were 2.1% and 2.0%, respectively. Only 3 patients (0.15%) had abnormal predischarge compression ultrasonography. Three patients (0.15%) died of pulmonary embolism. Major hemorrhage occurred in 58 patients (2.9%; 95% confidence interval, 2.2%-3.7%). Postoperative prophylaxis with enoxaparin for a mean of 9 days is associated with a clinically acceptable rate of symptomatic venous thromboembolism and major hemorrhage. Predischarge compression ultrasonography cannot be justified.


Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer.
Although interactions between estrogen and growth factor signaling pathways have been studied extensively, how growth factors and progesterone regulate each other is less clear. In this study, we found that IGF-I sharply lowers progesterone receptor (PR) mRNA and protein levels in breast cancer cells. Other growth factors, such as epidermal growth factor, also showed the same effect. The decrease of PR levels was associated with reduced PR activity. Unlike progestins, IGF-I does not utilize the proteasome for down-regulating PR. Instead, the IGF-I-mediated decrease in PR levels is via an inhibition of PR gene transcription. In addition, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was found to be specifically involved in this IGF-I effect. Our data also suggest that the IGF-I down-regulation of PR is not mediated via a reduction of estrogen receptor (ER) levels or activity. First, IGF-I induced ligand-independent ER activity while reducing ER-dependent PR levels. Second, whereas PR and cyclin D1 are both ER up-regulated, IGF-I increased cyclin D1 levels while decreasing PR levels. Third, constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity. Taken together, our data indicate that IGF-I inhibits PR expression in breast cancer cells via the PI3K/Akt/mTOR pathway. Because low or absent PR in primary breast cancer is associated with poor prognosis and response to hormone therapy, our results suggest that low PR status may serve as an indicator of activated growth factor signaling in breast tumor cells, and therefore of an aggressive tumor phenotype and resistance against hormonal therapy.


The use of non-standard motorcycle helmets in low- and middle-income countries: a multicentre study.
The use of non-standard motorcycle helmets has the potential to undermine multinational efforts aimed at reducing the burden of road traffic injuries associated with motorcycle crashes. However, little is known about the prevalence or factors associated with their use. Collaborating institutions in nine low- and middle-income countries undertook cross-sectional surveys, markets surveys, and reviewed legislation and enforcement practices around non-standard helmets. 5563 helmet-wearing motorcyclists were observed; 54% of the helmets did not appear to have a marker/sticker indicating that the helmet met required standards and interviewers judged that 49% of the helmets were likely to be non-standard helmets. 5088 (91%) of the motorcyclists agreed to be interviewed; those who had spent less than US$10 on their helmet were found to be at the greatest risk of wearing a non-standard helmet. Data were collected across 126 different retail outlets; across all countries, regardless of outlet type, standard helmets were generally 2-3 times more expensive than non-standard helmets. While seven of the nine countries had legislation prohibiting the use of non-standard helmets, only four had legislation prohibiting their manufacture or sale and only three had legislation prohibiting their import. Enforcement of any legislation appeared to be minimal. Our findings suggest that the widespread use of non-standard helmets in low- and middle-income countries may limit the potential gains of helmet use programmes. Strategies aimed at reducing the costs of standard helmets, combined with both legislation and enforcement, will be required to maximise the effects of existing campaigns.


The Bipolarity Index: a clinician-rated measure of diagnostic confidence.
The Bipolarity Index is a clinician-rated scale that rates cardinal features of the disorder across five domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. We tested the Index in routine clinical practice to identify the optimal cut-off for distinguishing bipolar from non-bipolar disorders. Sequential patients in a private practice were rated with the Bipolarity Index (n=1903) at intake. Diagnoses were made with the MINI-6.0.0 International Neuropsychiatric Interview according to DSM-IV-TR criteria, except that cases of antidepressant-induced mania and hypomania were included in the bipolar group. A subset completed the self-rated Mood Disorder Questionnaire (MDQ) (n=1620) or Bipolar Spectrum Diagnostic Scale (BSDS) (n=1179). The primary analysis compared Bipolarity Index scores for bipolar vs. non-bipolar patients using receiver operator curves (ROC) to determine the optimal cut-off score. Secondary outcomes repeated this analysis with the MDQ, MDQ-7 (using only the symptomatic items of the MDQ) and BSDS. At a cut-off of ≥50, the Bipolarity Index had a high sensitivity (0.91) and specificity (0.90). Optimal cut-offs for self-rated scales were: MDQ: ≥7 (sensitivity 0.74, specificity 0.71); MDQ-7: ≥6 (sensitivity 0.77, specificity 0.77); BSDS: ≥12 (sensitivity 0.71, specificity 0.77). The study utilized one rater at a single practice site; the rater was not blinded to the results of the MINI. The Bipolarity Index can enhance the clinical assessment of mood disorders and, at a score ≥50 has good sensitivity and specificity for identifying bipolar disorders.


Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.
Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.


Disparities in Prevalence of Cardiometablic Risk Factors in Rural, Urban-Poor, and Urban-Middle Class Women in India.
Urbanization is an important determinant of cardiovascular disease (CVD) risk. To determine location-based differences in CVD risk factors in India we performed studies among women in rural, urban-poor and urban middle-class locations. Population-based cross-sectional studies in rural, urban-poor, and urban-middle class women (35-70 y) were performed at multiple sites. We evaluated 6853 women (rural 2616, 5 sites; urban-poor 2008, 4 sites; urban middle-class 2229, 11 sites) for socioeconomic, lifestyle, anthropometric and biochemical risk factors. Descriptive statistics are reported. Mean levels of body mass index (BMI), waist circumference, waist-hip ratio (WHR), systolic BP, fasting glucose and cholesterol in rural, urban-poor and urban-middle class women showed significantly increasing trends (ANOVAtrend, p <0.001). Age-adjusted prevalence of diabetes and risk factors among rural, urban-poor and urban-middle class women, respectively was, diabetes (2.2, 9.3, 17.7%), overweight BMI ≥25 kg/m2 (22.5, 45.6, 57.4%), waist >80 cm (28.3, 63.4, 61.9%), waist >90 cm (8.4, 31.4, 38.2%), waist hip ratio (WHR) >0.8 (60.4, 90.7, 88.5), WHR>0.9 (13.0, 44.3, 56.1%), hypertension (31.6, 48.2, 59.0%) and hypercholesterolemia (13.5, 27.7, 37.4%) (Mantel Haenszel X2 ptrend <0.01). Inverse trend was observed for tobacco use (41.6, 19.6, 9.4%). There was significant association of hypertension, hypercholesterolemia and diabetes with overweight and obesity (adjusted R2 0.89-0.99). There are significant location based differences in cardiometabolic risk factors in India. The urban-middle class women have the highest risk compared to urban-poor and rural.


Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities.
Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained.


Characterization of X-ray Dose in Murine Animals Using microCT, a New Low-Dose Detector and nanoDot Dosimeters.
Dose continues to be an area of concern in preclinical imaging studies, especially for those imaging disease progression in longitudinal studies. To our knowledge, this work is the first to characterize and assess dose from the Inveon CT imaging platform using nanoDot dosimeters. This work is also the first to characterize a new low-dose configuration available for this platform. nanoDot dosimeters from Landauer, Inc. were surgically implanted into 15 wild type mice. Two nanoDots were placed in each animal: one just under the skin behind the spine and the other located centrally within the abdomen. A manufacturer-recommended CT protocol was created with 1 projection per degree of rotation acquired over 360 degrees. For best comparison of the low dose and standard configurations, noise characteristics of the reconstructed images were used to match the acquisition protocol parameters. Results for all dose measurements showed the average dose delivered to the abdomen to be 13.8 cGy±0.74 and 0.97 cGy±0.05 for standard and low dose configurations respectively. Skin measurements of dose averaged 15.99 cGy±0.72 and 1.18 cGy±0.06. For both groups, the standard deviation to mean was less than 5.6%. The maximum dose received for the abdomen was 15.12 cGy and 0.97 cGy while the maximum dose for the skin was 17.3 cGy and 1.32 cGy. Control dosimeters were used for each group to validate that no unwanted additional radiation was present to bias the results. This study shows that the Inveon CT platform is suitable for imaging mice both for single and longitudinal studies. Use of low-dose detector hardware results in significant reductions in dose to subjects with a >12x (90%) reduction in delivered dose. Installation of this hardware on another in vivo microCT platform resulted in dose reductions of over 9x (89%).


Diagnostic labels applied to model case histories of chronic airflow obstruction. Responses to a questionnaire in 11 North American and Western European countries.
In Canada, USA and 9 Western European Countries, 121 respiratory physicians responded to an English language questionnaire asking them to state how they would investigate, treat and label four model patients, chosen to represent well-recognized patterns of clinical features of chronic airflow obstruction. Selection of further investigations appeared to be determined more by the probable diagnostic label than by the need to define selected characteristics in the whole range of such patients. Differences in recommended treatment between countries were less than others have reported for the treatment of asthma. Analysis of the diagnostic labels showed: the classic terms asthma, chronic bronchitis, emphysema still predominated in clinical practice and were considered to be better defined entities than any of the many terms introduced to describe chronic airflow obstruction in the last 30 yrs; the term chronic bronchitis was a source of confusion unless qualified to indicate presence or absence of obstruction; the use of combination terms such as chronic asthmatic bronchitis and chronic obstructive bronchitis showed large differences between countries; there were few differences related to national language. The implications of these findings are discussed.


Toxoplasma gondii infection and behavioral outcomes in humans: a systematic review.
Studies suggest that the protozoan Toxoplasma gondii can disturb human behavior. This study aimed to systematically review the scientific literature on the possible associations between Toxoplasma gondii infection and neurobehavioral abnormalities in humans. We reviewed and summarized the studies published since 1990. The descriptors used were related to T. gondii infection and behavioral outcomes in humans; the main databases of the medical literature were accessed. The results of eight original articles published between 1994 and 2016 were evaluated and described. The most common serological method was the enzyme immunoassay. Most of the researchers used validated instruments for behavioral evaluation. Seven studies reported some association between the prevalence of anti-T. gondii antibodies and some altered behavioral aspects in adult humans; these studies focused on adult population in Europe and the USA. The most reported behavioral deviations are related to greater impulsivity and aggressiveness. There are very few studies on this subject, which present some limitations for inference and conclusions: most were cross-sectional studies, with a small sample size and in similar populations. Investigations with a larger sample size of different population groups should be performed to evaluate multiple factors.


Comprehension of inferential meaning in language-impaired and language normal children.
Three groups of language-normal (LN) 6, 8 and 16/17 year olds, and a group of language-impaired (LI) children were given a task answering questions about pictures that involved inferential meaning. A developmental progression in the types of responses given is seen, with the LI children performing like the youngest LN children. A similar progression is seen in the ability to justify the answers given to inferential questions with the young adult group giving the fewest justifications that were problematical in some way. Larger numbers of problematical justifications in the LI group can be related to some extent to non-pragmatic aspects of their impairment, but overall this group also gave more pragmatically irrelevant responses when asked to justify answers given. It was not possible to identify any major differences between subgroups of children within the LI group, identified as pragmatically impaired (PI) and non pragmatically impaired (NPI), in terms of either answers given to inferential questions or in terms of problematical justifications for these answers. Possible reasons for these findings are discussed.


A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.
Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.


Simultaneous and group determination methods for designated substances by HPLC with multi-channel electrochemical detection and their application to real samples.
Many psychotropic substances are illegally available on the streets and/or via the Internet. This wide distribution has become a serious social problem. To control this problem, many substances have been controlled as 'designated substances' (Shitei-Yakubutsu) in Japan since April 2007 by the Pharmaceutical Affairs Law, including tryptamines, phenethylamines and piperazines. In the present study, simultaneous determination methods using HPLC with multi-channel electrochemical detection (MECD) were developed for the designated substances. The proposed methods utilizing online electrochemical oxidation are the first report on the simultaneous determination of various designated substances. The methods involve direct determination and require no complicated pretreatments such as fluorescence labeling. The designated substances were separated by reversed-phase chromatography using a TSK-gel ODS-100V (4.6 × 250 mm, i.d., 3 µm) and gradient elution by a mixture of potassium phosphate buffer, methanol and acetonitrile. The total separation of 31 designated substances was successfully performed but required long chromatographic run times. Thus, the designated substances were divided into three groups: (1) tryptamines, (2) phenethylamines and (3) piperazines and others. They were then analyzed by HPLC-MECD as another separation method. The suitable applied voltages for each designated substance were determined based upon the hydrodynamic voltammogram. The limits of detection (signal-to-noise ratio of 3) of the designated substances for the most suitable voltages were in the range of 17.1 pg (5-MeO-MIPT) to 117 ng (indan-2-amine). The calibration curves based on the peak heights were linearly related to the amounts of the designated substances (R(2) > 0.999). Good accuracy and precision by intra-day assay and inter-day assay were also obtained using the present procedures. The proposed methods were applied to the analyses of the designated substance in several real samples.


Requisite models for strategic commissioning: the example of type 1 diabetes.
A developing emphasis of health care reforms has been creating organisations with responsibilities for strategic commissioning of services for defined populations. Such organisations must set priorities in aiming to meet their populations' needs subject to a budget constraint. This requires estimates of the health benefits and costs of different interventions for their populations. This paper outlines a framework that does this and shows how this requires modelling to produce estimates in a way that is transparent to commissioners, of requisite complexity to produce sound estimates for priority setting using routinely available data. The example illustrated in this paper is an intervention that would improve glucose control in the English population with type 1 diabetes. It takes many years for a change in glucose management to deliver maximum benefits; hence the intervention is not good value-for-money in the short run. We aim to give a more strategic view of the costs and benefits modelling costs and benefits in a steady-state model which suggests that the intervention is good value-for-money in the long run.


Whole-body cryotherapy: empirical evidence and theoretical perspectives.
Whole-body cryotherapy (WBC) involves short exposures to air temperatures below -100°C. WBC is increasingly accessible to athletes, and is purported to enhance recovery after exercise and facilitate rehabilitation postinjury. Our objective was to review the efficacy and effectiveness of WBC using empirical evidence from controlled trials. We found ten relevant reports; the majority were based on small numbers of active athletes aged less than 35 years. Although WBC produces a large temperature gradient for tissue cooling, the relatively poor thermal conductivity of air prevents significant subcutaneous and core body cooling. There is weak evidence from controlled studies that WBC enhances antioxidant capacity and parasympathetic reactivation, and alters inflammatory pathways relevant to sports recovery. A series of small randomized studies found WBC offers improvements in subjective recovery and muscle soreness following metabolic or mechanical overload, but little benefit towards functional recovery. There is evidence from one study only that WBC may assist rehabilitation for adhesive capsulitis of the shoulder. There were no adverse events associated with WBC; however, studies did not seem to undertake active surveillance of predefined adverse events. Until further research is available, athletes should remain cognizant that less expensive modes of cryotherapy, such as local ice-pack application or cold-water immersion, offer comparable physiological and clinical effects to WBC.


Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier.
Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. Mol Cancer Ther; 17(9); 1893-901. ©2018 AACR.


Short-term immobilization has a minimal effect on the strength and fatigability of a human hand muscle.
The purpose of this study was to determine the association between reduced fatigability typically observed in disused muscle and an improved resistance to the impairment of neuromuscular propagation. Endurance time of an isometric contraction sustained at 35% of maximum voluntary contraction (MVC) force and the fatigue-induced change in the evoked compound muscle action potential (M wave) were measured in the first dorsal interosseus muscle of human subjects before, during, and after 3 (n = 9) or 5 wk (n = 2) of immobilization. The immobilization procedure caused a substantial decline in the chronic electromyographic (EMG) activity (to 4% of control value) of the first dorsal interosseus muscle. Endurance time was found to be significantly correlated to the maintenance of M-wave amplitude during the fatigue task. However, neither of these variables was significantly affected by immobilization. Also, immobilization had no significant effect on the prefatigue values of MVC force and EMG or twitch contraction time or on the postfatigue changes in MVC force and EMG, M wave duration, twitch amplitude, and contraction time. In the unfatigued muscle, immobilization did cause an increase in twitch force (153%) and a decrease in M-wave amplitude (67%). It appears, therefore, that a healthy first dorsal interosseus muscle is generally resistant to adaptation when its use has been reduced for 3-5 wk by immobilization.


Magnesium and strength in elite judo athletes according to intracellular water changes.
Magnesium (Mg) deficiency strongly affects muscle performance. In judo, many athletes often undergo impressive weight changes associated with severe dehydration. Common practices used by athletes to achieve a target weight can lead to Mg deficit. This study aimed to understand the impact of Mg changes on strength from periods of weight stability to prior to competition in a sample of elite judo athletes who differentially changed their intracellular water (ICW). The sample consisted of 20 elite male judo athletes. Subjects were divided according to ICW changes: losses below 2% and losses equal to or above 2%. Mg was measured in serum, red blood cells and urine by atomic absorption spectrophotometry. ICW was calculated as the difference between total-body water and extracellular water using dilution techniques. Maximal handgrip strength was evaluated using Jamar Hydraulic Hand Dynamometer. Upper-body power was determined in a bench press. Higher ICW decreases were associated with higher strength reductions, though our results suggest that an increase in red blood cell Mg might attenuate those strength reductions in athletes who decrease the ICW compartment. As Mg losses can be considerable and intake is frequently insufficient, athletes should consider supplementation, especially during periods of weight reduction.


Conservative management of fractures of the third metatarsal bone in the racing greyhound.
To assess (2006 to 2012) conservative management for treatment of fractures of the third metatarsal bone (MT3) in racing greyhounds. All racing greyhounds with MT3 fractures seen prospectively between 2006 and 2012 were included. Fracture morphology, type of conservative management, outcome and the time to a return to racing were recorded. Outcome was assessed either by communication with the trainer or by accessing the website of the Greyhound Board of Great Britain to find the complete racing history of the dog. Eighteen cases were evaluated. Six had a support dressing and 12 had no external dressings, treatment consisting of kennel rest alone. Two dogs were retired from racing at the time of injury, two dogs sustained other injuries and the remainder (n=14) returned to successful racing with no loss of form. Conservative management for MT3 fractures consisting of a programme of exercise restriction carries an excellent prognosis for a return to previous racing form. External support dressings do not appear to be necessary either for the welfare of the dog or for fracture management.


Targets and dynamics of promoter DNA methylation during early mouse development.
DNA methylation is extensively reprogrammed during the early phases of mammalian development, yet genomic targets of this process are largely unknown. We optimized methylated DNA immunoprecipitation for low numbers of cells and profiled DNA methylation during early development of the mouse embryonic lineage in vivo. We observed a major epigenetic switch during implantation at the transition from the blastocyst to the postimplantation epiblast. During this period, DNA methylation is primarily targeted to repress the germline expression program. DNA methylation in the epiblast is also targeted to promoters of lineage-specific genes such as hematopoietic genes, which are subsequently demethylated during terminal differentiation. De novo methylation during early embryogenesis is catalyzed by Dnmt3b, and absence of DNA methylation leads to ectopic gene activation in the embryo. Finally, we identify nonimprinted genes that inherit promoter DNA methylation from parental gametes, suggesting that escape of post-fertilization DNA methylation reprogramming is prevalent in the mouse genome.


Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells.
Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 microg/mL; inhibitory concentration of 50%, 6.5 microg/mL). At normal therapeutic serum concentration (5 microg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37%; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 microg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 microg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50% and 30%, respectively (P <.05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.


Work design for airport security officers: Effects of rest break schedules and adaptable automation.
This study investigated whether there is empirical support for the current EU regulation mandating breaks of at least 10 min after each period of 20 min continuously reviewing X-ray images in airport security screening. As a second goal, it examined whether providing more autonomy to airport security officers (in the form of spontaneous rest breaks and adaptable automation) would improve their performance and subjective state. Seventy-two student participants had to indicate the presence (or absence) of a threat item (either a gun or a knife) in a series of grey-scaled X-ray images of cabin baggage. Three work-rest schedules were examined: spontaneous breaks (i.e. participants could take breaks at any time), two 5-min breaks and two 10-min breaks during a 1-h testing session. Furthermore, half of the participants were assisted in their task by an adaptable support system offering three levels of automation: (1) no support, (2) cues indicating the presence of a potential threat item, and (3) cues indicating the exact location of a potential threat item. Results showed no performance differences between break regimes, which suggests that there may be viable alternatives to the current EU regulations. It also emerged that providing participants with adaptable automation did not lead to better detection performance but resulted in a less positive response bias than participants without automatic support. Implications for current aviation security regulations are discussed.


Atopy and work.
Atopy denotes the exceptional capacity to produce immunoglobulin (Ig)E antibody when exposed to common environmental allergens. The characteristic is frequently used for preemployment screening purposes. Too little attention has, however, been paid to the rationale and the consequences of this practice. Atopy is very common, and so decisions made because of atopy probably affect about a third of the working population. Work-related hypersensitivity symptoms cannot be eradicated by the weeding out of atopics. The intensity of exposure and/or the sensitizing properties of causative agents are often extremely strong in occupational settings and trigger the production of specific IgE antibodies even in nonatopics. Atopy is probably not sufficiently discriminative for screening purposes even in environments where atopics are known to have a greater risk of developing asthma (eg, laboratories with animals). Moreover, weeding out atopics may be used instead of hygienic and technical measures to reduce exposure levels. Separate decisions on medical, as well as legal, grounds may be warranted when a person with atopic symptoms, ie, rhinitis, asthma, or dermatitis, enters a new occupational environment. There is an urgent need for prospective studies in various occupational environments.


Treatment of postoperative pain after total hip arthroplasty: comparison between metamizol and paracetamol as adjunctive to opioid analgesics-prospective, double-blind, randomised study.
Metamizole use has been limited because of its risk of agranulocytosis. However, more recent literature seems to support its safety. This prospective, randomised, double-blind study was conducted to compare the analgesic effects of intravenous metamizole or intravenous paracetamol in combination with morphine PCA during the first 24 h following total hip arthroplasty. One hundred ten consecutive patients were selected for study. The two study groups were (A) metamizole, (B) paracetamol. Postoperative pain therapy was provided by Morphine PCA pump. In the first treatment group (A group), all patients received intravenous metamizole 1.5 g every 8 h during the first 24 postoperative hours. In the second treatment group (B group), all patients received intravenous paracetamol 1 g every 8 h during the first 24 postoperative hours. Postoperative pain intensity was measured 1, 2, 3, 4, 6, 8, 10, 14, 18, 22 h after the end of surgery by a VAS. Statistically significant differences in VAS pain values favoring metamizole were reported at 6-h (p = 0.038), 8-h (p = 0.036), 14-h (p = 0.011), 18-h (p < 0.001) and 22-h (p = 0.025) post-baseline. Mean cumulative pain values were 17.9 for metamizole and 30.6 for paracetamol. In this study, we have also shown excellent efficacy of paracetamol and metamizole combined with opioids, but metamizole proved to be a better analgesic than paracetamol. It is also necessary to mention the financial aspect considering that intravenous paracetamol is about ten times more expensive than an equivalent analgesic doses of intravenous metamizole.


Combined Effects of Dust and Dietary Exposure of Occupational Workers and Local Residents to Short- and Medium-Chain Chlorinated Paraffins in a Mega E-Waste Recycling Industrial Park in South China.
Four types of dust samples and nine categories of locally produced staple foods were collected from a mega e-waste recycling industrial park and its surrounding regions, and simultaneously analyzed for short-chain and medium-chain chlorinated paraffins (CPs) to estimate dust and dietary exposure and their combined effects on occupational workers and local residents. All samples related to e-waste activities contained considerably high concentrations of CPs. The highest dust concentration was found in e-waste workshops. CPs were highly accumulated in local plant and animal origin foods, most markedly in fish, vegetables, and rice. The main contribution to CP intake under a median exposure scenario was from the diet, and vegetables, fish, and rice were the three largest dietary intake sources. Only the combined dust and food exposure from the present study has approached or even exceeded the highest tolerable daily intake (TDI) set up by the International Program on Chemical Safety (IPCS). However, due to lack of official threshold values for CP exposure on adverse human health, there are limitations on accurate risk assessment. Considering the presence of other exposure pathways, CPs' endocrine disrupter properties, as well as the multicomponent chemical "cocktails" effects, potential high risks from CP exposure may be posed to e-waste workers and local residents.


Interaction between hydrogen sulfide, nitric oxide, and carbon monoxide pathways in the bovine isolated retina.
Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are physiologically relevant gaseous neurotransmitters that are endogenously produced in mammalian tissues. In the present study, we investigated the possibility that NO and CO can regulate the endogenous levels of H2S in bovine isolated neural retina. Isolated bovine neural retina were homogenized and tissue homogenates were treated with a NO synthase inhibitor, NO donor, heme oxygenase-1 inhibitor, and/donor. H2S concentrations in bovine retinal homogenates were measured using a well-established colorimetric assay. L-NAME (300 nM-500 µM) caused a concentration-dependent decrease in basal endogenous levels of H2S by 86.2%. On the other hand, SNP (10-300 µM) elicited a concentration-related increase in H2S levels from 18.3 nM/mg of protein to 65.7 nM/mg of protein. ZnPP-IX (300 nM-10 µM) caused a concentration-dependent increase in the endogenous production of H2S whereas hemin (300 nM-20 µM) attenuated the basal levels of H2S. We conclude that changes in the biosynthesis and availability of both NO and CO can interfere with the pathway/s involved in the production of H2S in the retina. The demonstrated ability of NO, CO and H2S to interact in the mammalian retina affirms a physiological/pharmacological role for these gaseous mediators in the eye.


Overview of inactivating mutations in the protein-coding genome of the mouse reference strain C57BL/6J.
Mice are extremely important as the premier model organism in human biomedical and mammalian genetic research. The genomes of several tens of mouse inbred strains have been sequenced. They have been compared to the genome of C57BL/6J, considered by convention as the reference genome. Based on a comparison of this reference genome with 36 other sequenced mouse strains, we generated an overview of all protein-coding genes that are deviant in this reference genome, compared with consensus protein-coding mouse gene sequences. We provide PROVEAN scores, reflecting the likelihood that these C57BL/6J proteins have lost function. We thus identified numerous abnormal proteins, and biological pathways, specifically present in C57BL/6J, suggesting the important caveats of this reference mouse strain, and linking candidate genes to some of the best-known phenotypes of this strain.