Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy.
Ischemic cardiomyopathy is a global health concern with limited therapy. We recently described endogenous revascularization utilizing granulocyte-macrophage colony stimulating factor (GMCSF) to induce endothelial progenitor cell (EPC) production and intramyocardial stromal cell-derived factor-1alpha (SDF) as a specific EPC chemokine. The EPC-mediated neovascularization and enhancement of myocardial function was observed. In this study we examined the regional biologic mechanisms underlying this therapy. Lewis rats underwent left anterior descending coronary artery (LAD) ligation and developed ischemic cardiomyopathy over 6 weeks. Three weeks after ligation, the animals received either subcutaneous GMCSF and intramyocardial SDF injections or saline injections as control. Six weeks after LAD ligation circulating EPC density was studied by flow cytometry. Quadruple immunofluorescent vessel staining for mature, proliferating vasculature was performed. Confocal angiography was utilized to identify fluorescein lectin-lined vessels to assess perfusion. Ischemia reversal was studied by measuring myocardial adenosine triphosphate (ATP) levels. Myocardial viability was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detection of apoptosis and quantitation of myofilament density. The GMCSF/SDF therapy enhanced circulating leukocyte (13.1 +/- 4.5 x 10(6) vs 3.1 +/- 0.5 x 10(6)/cc, p = 0.001, n = 6) and EPC (14.2 +/- 6.6 vs 2.2 +/- 2.1/cc, p = 0.001, n = 6) concentrations. Tetraimmunofluorescent labeling demonstrated enhanced stable vasculature with this therapy (39.2 +/- 8.1 vs 25.4 +/- 5.1%, p = 0.006, n = 7). Enhanced perfusion was shown by confocal microangiography of borderzone lectin-labeled vessels (28.2 +/- 5.4 vs 11.5 +/- 3.0 vessels/high power field [hpf], p = 0.00001, n = 10). Ischemia reversal was demonstrated by enhanced cellular ATP levels in the GMCSF/SDF borderzone myocardium (102.5 +/- 31.0 vs 26.9 +/- 4.1 nmol/g, p = 0.008, n = 5). Borderzone cardiomyocyte viability was noted by decreased apoptosis (3.2 +/- 1.4% vs 5.4 +/- 1.0%, p = 0.004, n = 10) and enhanced cardiomyocyte density (40.0 +/- 5.6 vs 27.0 +/- 6 myofilaments/hpf, p = 0.01, n=10). Endogenous revascularization for ischemic cardiomyopathy utilizing GMCSF EPC upregulation and SDF EPC chemokinesis upregulates circulating EPCs, enhances vascular stability, and augments myocardial function by enhancing perfusion, reversing cellular ischemia, and increasing cardiomyocyte viability.


Transfer effects of practice for simple alternating movements.
In studies on transfer of practice effects, researchers use simple or complex movements that involve a significant cognitive element. In the present study, the authors studied intermanual and intramanual transfer of practice with a task that can be considered intermediate in difficulty. Using finger tapping as a motor task, 30 participants practiced tapping 6 days per week for 2 weeks with the left or right middle finger in a between-subject design. Compared with controls, the unpracticed middle finger of both hands showed significant improvement, along with all of the other unpracticed digits. There was no significant difference in the strength of transfer from the practiced finger to other fingers of the same (intramanual transfer) or the other (intermanual transfer) hand. The authors did not observe an asymmetry of transfer effects (the degree to which transfer depends on the particular hand trained). Last, in terms of speed and regularity of movement, the digits broke down into 2 different clusters; the thumb, index finger, and middle finger formed 1 cluster superior to that formed by the ring and small fingers.


In vivo germination of Bacillus anthracis spores during murine cutaneous infection.
Germination is a key step for successful Bacillus anthracis colonization and systemic dissemination. Few data are available on spore germination in vivo, and the necessity of spore and host cell interactions to initiate germination is unclear. To investigate the early interactions between B. anthracis spores and cutaneous tissue, spores were inoculated in an intraperitoneal cell-free device in guinea pigs or into the pinna of mice. Germination and bacterial growth were analyzed through colony-forming unit enumeration and electron microscopy. In the guinea pig model, germination occurred in vivo in the absence of cell contact. Similarly, in the mouse ear, germination started within 15 minutes after inoculation, and germinating spores were found in the absence of surrounding cells. Germination was not observed in macrophage-rich draining lymph nodes, liver, and spleen. Edema and lethal toxin production were not required for germination, as a toxin-deficient strain was as effective as a Sterne-like strain. B. anthracis growth was locally controlled for 6 hours. Spore germination involving no cell interactions can occur in vivo, suggesting that diffusible germinants or other signals appear sufficient. Different host tissues display drastic differences in germination-triggering capacity. Initial control of bacterial growth suggests a therapeutic means to exploit host innate defenses to hinder B. anthracis colonization.


Strategies to prevent injury in adolescent sport: a systematic review.
This systematic review set out to identify randomised controlled trials and controlled intervention studies that evaluated the effectiveness of preventive strategies in adolescent sport and to draw conclusions on the strength of the evidence. A literature search in seven databases (Medline, SportDiscus, EMBASE, CINAHL, PEDro, Cochrane Review and DARE) was carried out using four keywords: adolescent, sport, injury and prevention (expanded to capture any relevant literature). Assessment of 154 papers found 12 studies eligible for inclusion. It can be concluded that injury prevention strategies that focus on preseason conditioning, functional training, education, balance and sport-specific skills, which should be continued throughout the sporting season, are effective. The evidence for the effectiveness of protective equipment in injury prevention is inconclusive and requires further assessment.


Untargeted analysis of the airway proteomes of children with respiratory infections using mass spectrometry based proteomics.
The upper airway - which consists mainly of the naso- and oro-pharynx - is the first point of contact between the respiratory system and microbial organisms that are ubiquitous in the environment. It has evolved highly specialised functions to address these constant threats whilst facilitating seamless respiratory exchange with the lower respiratory tract. Dysregulation of its critical homeostatic and defence functions can lead to ingress of pathogens into the lower respiratory tract, potentially leading to serious illness. Systems-wide proteomic tools may facilitate a better understanding of mechanisms in the upper airways in health and disease. In this study, we aimed to develop a mass spectrometry based proteomics method for characterizing the upper airways proteome. Naso- and oropharyngeal swab samples used in all our experiments had been eluted in the Universal Transport Media (UTM) containing significantly high levels of bovine serum albumin. Our proteomic experiments tested the optimal approach to characterize airway proteome on swab samples eluted in UTM based on the number of proteins identified without BSA depletion (Total proteome: Protocol A) and with its depletion using a commercial kit; Allprep, Qiagen (cellular proteome: Protocol B, Ci, and Cii). Observations and lessons drawn from protocol A, fed into the design and implementation of protocol B, and from B to protocol Ci and finally Cii. Label free proteome quantification was used in Protocol A (n = 6) and B (n = 4) while commercial TMT 10plex reagents were used for protocols Ci and ii (n = 83). Protocols Ci and ii were carried out under similar conditions except for the elution gradient: 3 h and 6 h respectively. Swab samples tested in this study were from infants and children with and without upper respiratory tract infections from Kilifi County Hospital on the Kenyan Coast. Protocol A had the least number of proteins identified (215) while B produced the highest number of protein identifications (2396). When Protocol B was modified through sample multiplexing with TMT to enable higher throughput (Protocol Ci), the number of protein identified reduced to 1432. Modification of protocol Ci by increasing the peptide elution time generated Protocol Cii that substantially increased the number of proteins identified to 1875. The coefficient of variation among the TMT runs in Protocol Cii was <20%. There was substantial overlap in the identity of proteins using the four protocols. Our method was were able to identify marker proteins characteristically expressed in the upper airway. We found high expression levels of signature nasopharyngeal and oral proteins, including BPIFA1/2 and AMY1A, as well as a high abundance of proteins related to innate and adaptive immune function in the upper airway. We have developed a sensitive systems-level proteomic assay for the systematic quantification of naso-oro-pharyngeal proteins. The assay will advance mechanistic studies of respiratory pathology, by providing an untargeted and hypothesis-free approach of examining the airway proteome.


The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding.
TGF-beta ligands stimulate diverse cellular differentiation and growth responses by signaling through type I and II receptors. Ligand antagonists, such as follistatin, block signaling and are essential regulators of physiological responses. Here we report the structure of activin A, a TGF-beta ligand, bound to the high-affinity antagonist follistatin. Two follistatin molecules encircle activin, neutralizing the ligand by burying one-third of its residues and its receptor binding sites. Previous studies have suggested that type I receptor binding would not be blocked by follistatin, but the crystal structure reveals that the follistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif and occupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can be explained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The mode of ligand binding by follistatin has important implications for its ability to neutralize homo- and heterodimeric ligands of this growth factor family.


Saturation in qualitative research: exploring its conceptualization and operationalization.
Saturation has attained widespread acceptance as a methodological principle in qualitative research. It is commonly taken to indicate that, on the basis of the data that have been collected or analysed hitherto, further data collection and/or analysis are unnecessary. However, there appears to be uncertainty as to how saturation should be conceptualized, and inconsistencies in its use. In this paper, we look to clarify the nature, purposes and uses of saturation, and in doing so add to theoretical debate on the role of saturation across different methodologies. We identify four distinct approaches to saturation, which differ in terms of the extent to which an inductive or a deductive logic is adopted, and the relative emphasis on data collection, data analysis, and theorizing. We explore the purposes saturation might serve in relation to these different approaches, and the implications for how and when saturation will be sought. In examining these issues, we highlight the uncertain logic underlying saturation-as essentially a predictive statement about the unobserved based on the observed, a judgement that, we argue, results in equivocation, and may in part explain the confusion surrounding its use. We conclude that saturation should be operationalized in a way that is consistent with the research question(s), and the theoretical position and analytic framework adopted, but also that there should be some limit to its scope, so as not to risk saturation losing its coherence and potency if its conceptualization and uses are stretched too widely.


Kondo physics in antiferromagnetic Weyl semimetal Mn3+x Sn1-x films.
Topology and strong electron correlations are crucial ingredients in emerging quantum materials, yet their intersection in experimental systems has been relatively limited to date. Strongly correlated Weyl semimetals, particularly when magnetism is incorporated, offer a unique and fertile platform to explore emergent phenomena in novel topological matter and topological spintronics. The antiferromagnetic Weyl semimetal Mn3Sn exhibits many exotic physical properties such as a large spontaneous Hall effect and has recently attracted intense interest. In this work, we report synthesis of epitaxial Mn3+x Sn1-x films with greatly extended compositional range in comparison with that of bulk samples. As Sn atoms are replaced by magnetic Mn atoms, the Kondo effect, which is a celebrated example of strong correlations, emerges, develops coherence, and induces a hybridization energy gap. The magnetic doping and gap opening lead to rich extraordinary properties, as exemplified by the prominent DC Hall effects and resonance-enhanced terahertz Faraday rotation.


Molecular indicators of Nitrobacter spp. population and growth activity during an induced inhibition event in a bench scale nitrification reactor.
The Nitrobacter spp. ribosomal RNA gene (rDNA) and transcript (rRNAt) abundance were quantified in a bench scale nitrification reactor during baseline periods of high nitrification efficiency and an intervening staged inhibition event. The transcript to gene ratio (rRNAt/rDNA) was highly sensitive to changes in the reactor nitrite oxidation rate. During high nitrification efficiency, the rRNAt/rDNA metric displayed a range from 0.68 to 2.01 with one-sided (α=0.10) lower and upper prediction intervals of 0.70 and 1.78, respectively. When nitrification was inhibited by disabling the reactor pH control system, this activity metric declined an order of magnitude to ≈ 0.05, well below the lower prediction interval reflecting high nitrification efficiency. The decline was rapid (2h) and preceded a significant drop in reactor nitrification performance, which occurred as ammonia accumulated. The rRNAt/rDNA ratio remained low (≈ 0.05) for several days after the pH control system was re-enabled at a setpoint of 8.0, which otherwise induced rapid oxidation of accumulated ammonia and produced high free ammonia concentrations. The timing of a subsequent increase in the rRNAt/rDNA ratio, which transiently exceeded the upper prediction interval established during the baseline period of high nitrification efficiency, was not coincidental with resumption of pH control at 7.2 that lowered free ammonia concentrations to non-inhibitory levels. Rather, nitrite oxidation resumed and the rRNAt/rDNA ratio increased only after oxidation of accumulated ammonia was complete, which was coincidental with reduced reactor oxygen demand. In summary, the Nitrobacter rRNAt/rDNA activity metric reflected timely and easily recognizable changes in nitrite oxidation activity, illustrating that molecular data can be used to diagnose poor biological wastewater treatment performance.


Do violence dynamics matter?
Intimate partner violence is a complex, non-linear phenomenon. The purpose of this study was to determine whether violence dynamics (pattern, degree of non-linearity, optimal non-linearity) contributed to outcomes in violent relationships. The study was conducted in six primary care clinics, enrolling 200 adult women in violent relationships. In addition to baseline and end-of-study interviews, women completed daily telephone assessments of household environment and partner violence using interactive verbal response. Three non-linearity measures of violence were computed with 'optimal' non-linearity estimated using Z-transformations. Assignment of dynamic patterns (periodic, chaotic, random) was made based upon Lyapunov exponent and correlation dimension. Outcomes across dynamic patterns were analysed using analysis of variance. In addition, stepped multiple linear regression explained factor-analysed outcomes, adjusting for demographic, childhood, mental health and marital variables; attitudinal/behavioural outcomes were also adjusted for when explaining clinical outcomes. Women experiencing periodic violence recognized the importance of violence and used their active coping to seek mental health care. Those with chaotic dynamics recognized that they were not responsible, experienced fewer psychological symptoms and emotional role limitations, and did not seek help. Those experiencing random violence recognized its unpredictability and uncontrollability. Violence non-linearity predicted negative coping, positive appraisals and hope/support in regression analyses, while optimal non-linearity contributed to readiness for change and symptoms functioning. Of the nine outcomes investigated, violence non-linearity contributed to five outcomes. Dynamic pattern of violence, degree of violence non-linearity and optimal non-linearity correlated with several attitudinal/behavioural and clinical outcomes. Knowledge of violence dynamics may have applications when working with violent couples.


Transcriptome profiling of gene expression during immunisation trial against Fasciola hepatica: identification of genes and pathways involved in conferring immunoprotection in a murine model.
Fasciolosis remains a significant food-borne trematode disease causing high morbidity around the world and affecting grazing animals and humans. A deeper understanding concerning the molecular mechanisms by which Fasciola hepatica infection occurs, as well as the molecular basis involved in acquiring protection is extremely important when designing and selecting new vaccine candidates. The present study provides a first report of microarray-based technology for describing changes in the splenic gene expression profile for mice immunised with a highly effective, protection-inducing, multi-epitope, subunit-based, chemically-synthesised vaccine candidate against F. hepatica. The mice were immunised with synthetic peptides containing B- and T-cell epitopes, which are derived from F. hepatica cathepsin B and amoebapore proteins, as novel vaccine candidates against F. hepatica formulated in an adjuvant adaptation vaccination system; they were experimentally challenged with F. hepatica metacercariae. Spleen RNA from mice immunised with the highest protection-inducing synthetic peptides was isolated, amplified and labelled using Affymetrix standardised protocols. Data was then background corrected, normalised and the expression signal was calculated. The Ingenuity Pathway Analysis tool was then used for analysing differentially expressed gene identifiers for annotating bio-functions and constructing and visualising molecular interaction networks. Mice immunised with a combination of three peptides containing T-cell epitopes induced high protection against experimental challenge according to survival rates and hepatic damage scores. It also induced differential expression of 820 genes, 168 genes being up-regulated and 652 genes being down-regulated, p value <0.05, fold change ranging from -2.944 to 7.632. A functional study of these genes revealed changes in the pathways related to nitric oxide and reactive oxygen species production, Interleukin-12 signalling and production in macrophages and Interleukin-8 signalling with up-regulation of S100 calcium-binding protein A8, Matrix metallopeptidase 9 and CXC chemokine receptor 2 genes. The data obtained in the present study provided us with a more comprehensive overview concerning the possible molecular pathways implied in inducing protection against F. hepatica in a murine model, which could be useful for evaluating future vaccine candidates.


Mass Die-Off of Saiga Antelopes, Kazakhstan, 2015.
In 2015, a mass die-off of ≈200,000 saiga antelopes in central Kazakhstan was caused by hemorrhagic septicemia attributable to the bacterium Pasteurella multocida serotype B. Previous analyses have indicated that environmental triggers associated with weather conditions, specifically air moisture and temperature in the region of the saiga antelope calving during the 10-day period running up to the event, were critical to the proliferation of latent bacteria and were comparable to conditions accompanying historically similar die-offs in the same areas. We investigated whether additional viral or bacterial pathogens could be detected in samples from affected animals using 3 different high-throughput sequencing approaches. We did not identify pathogens associated with commensal bacterial opportunisms in blood, kidney, or lung samples and thus concluded that P. multocida serotype B was the primary cause of the disease.


Stopping the Train of Thought: A Pilot Study Using an Ecological Momentary Intervention with Twice-Daily Exposure to Natural versus Urban Scenes to Lower Stress and Rumination.
Stress, and specifically perseverative cognition, is considered to have considerable detrimental effects on mental and physical health. Interventions that can offer temporary stress relief could, therefore, bring considerable health benefits. Previous research has pointed to stress-reducing effects of exposure to nature after acute stressors, but has not yet investigated effects in the realm of everyday life. The present pilot study explores whether an ecological momentary intervention using exposure to natural images could be effective in lowering stress and improve mood. Fifteen participants (12 females) scoring above threshold on stress, depression, or anxiety completed two study periods of 6 days. They watched an urban (control) or natural slideshow twice daily. Using Ecological Momentary Assessment, effects on mood, and stress-related complaints were measured in everyday life. Compliance to the study protocol was high, especially in the first week, with slightly more videos watched in the morning than in the evening. We found indications of improvements in mood, self-reported worrying (but not stress levels), and heart rate. The results suggest that twice-daily exposure to restorative visual content could be a viable Ecological Momentary Intervention, with the potential to reduce self-reported worry, lower autonomic activity, and increase positive affect.


Avian use of introduced plants: ornithologist records illuminate interspecific associations and research needs.
Introduced species have the potential to impact processes central to the organization of ecological communities. Although hundreds of nonnative plant species have naturalized in the United States, only a small percentage of these have been studied in their new biotic communities. Their interactions with resident (native and introduced) bird species remain largely unexplored. As a group, citizen scientists such as ornithologists possess a wide range of experiences. They may offer insights into the prevalence and form of bird interactions with nonnative plants on a broad geographic scale. We surveyed 173 ornithologists from four U.S. states, asking them to report observations of bird interactions with nonnative plants. The primary goal of the survey was to obtain information useful in guiding future empirical research. In all, 1143 unique bird-plant interactions were reported, involving 99 plant taxa and 168 bird species. Forty-seven percent of reported interactions concerned potential dispersal (feeding on seeds or fruits). Remaining "habitat interactions" involved bird use of plants for nesting, perching, woodpecking, gleaning, and other activities. We utilized detrended correspondence analysis to ordinate birds with respect to the plants they reportedly utilize. Results illuminate the new guilds formed by these interactions. We assessed the existing level of knowledge about invasiveness of those plants reported most often in feeding interactions, identifying information gaps for biological invasions research priority. To exemplify the usefulness of citizen science data, we utilized survey results to guide field research on invasiveness in some of these plant species and observed both qualitatively and quantitatively strong agreement between survey reports and our empirical data. Questionnaire reports are therefore heuristically informative for the fields of both avian ecology and invasion biology.


A prospective study of asthma desensitization in 1182 children, 592 asthmatic children and 590 nonatopic controls.
The aim of this prospective study was to evaluate the prevalence of allergic asthma and or rhinitis (AR) in 1182 children. Systemic reactions (SRs) to asthma desensitization, previously, specific immunotherapy (SIT) in children with allergic asthma and or AR are scarcely known. Since 1999, we have consecutively enrolled all children ranging in age from 3 to 11 years attending our Division because affected with severe asthma (592). Controls were 590 nonatopic children matched for age and sex recruited from our outpatient clinic. The study children were treated with a personalized asthma desensitization, the controls were treated with all usual medications. The parents of all children gave their informed consent. Data were analyzed using the X2 method. The 592 atopic children with severe asthma, 370 males and 222 females, aged 3.5 to 10.5 years, tested positive for Der p and Der f (47.1%) or for pollen allergens (52.9%). We have demonstrated a high increase of ashma incidence, since at the start there were 135 asthmatic children and 215 during 2000, with a 62.5% increase. During 2001 there were 242 children, with a 88.8% increase compared to 1999. All of these children were subjected to asthma desensitization, previously SIT (SARM, Roma). At the third yearly control, the study children had a significantly greater reduction as regards days (p = 0.0001) and nights (p = 0.0005) without asthma and drug usage (p = 0.0003) compared with drug-treated children. The number of SPTs and/or sigE to inhalants also decreased, spirometry data were also notably improved The clinically adverse events only were mild or transient. The positive results obtained in this large study add to its safety in our opinion because the children were followed by their doctors also on the basis of "as frequently as needed". Accordingly, the early onset of childhood asthma emphasizes that an early treatment is the only means to significantly abate the march of atopic asthma. We have documented an unexpected prevalence of pediatric asthma that should by evaluated in light of the very early asthma development in children which is present even before asthma would be diagnosed based on clinical symptoms The causes of this dramatic increment (10.4%/month in the last six months) may be identified chiefly in the worldwide increase in air pollution and secondhand tobacco smoke.


Merging drops in a Teflon tube, and transferring fluid between them, illustrated by protein crystallization and drug screening.
The ability to manipulate drops with small volumes has many practical applications. Current microfluidic devices generally exploit channel geometry and/or active external equipment to control drops. Here we use a Teflon tube attached to a syringe pump and exploit the properties of interfaces between three immiscible liquids to create particular fluidic architectures. We then go on to merge any number of drops (with volumes of micro- to nano-liters) at predefined points in time and space in the tube; for example, 51 drops were merged in a defined order to yield one large drop. Using a different architecture, specified amounts of fluid were transferred between 2 nl drops at specified rates; for example, 2.5 pl aliquots were transferred (at rates of ~500 fl s(-1)) between two drops through inter-connecting nano-channels (width ~40 nm). One proof-of-principle experiment involved screening conditions required to crystallize a protein (using a concentration gradient created using such nano-channels). Another demonstrated biocompatibility; drugs were mixed with human cells grown in suspension or on surfaces, and the treated cells responded like those grown conventionally. Although most experiments were performed manually, moderate high-throughput potential was demonstrated by mixing ~1000 different pairs of 50 nl drops in ~15 min using a robot. We suggest this reusable, low-cost, and versatile methodology could facilitate the introduction of microfluidics into workflows of many experimental laboratories.


Tn2008-driven carbapenem resistance in Acinetobacter baumannii isolates from a period of increased incidence of infections in a Southwest Virginia hospital (USA).
The objectives of this study were (i) to determine the genetic basis for carbapenem resistance in multidrug-resistant (MDR) Acinetobacter baumannii strains isolated from patients affected by a sudden increase in the incidence of infections by such organisms in a tertiary care hospital in Virginia, USA, in 2009-2010 and (ii) to examine whether such strains are commonly encountered in the hospital setting. The whole genomes of one outbreak strain as well as one carbapenem-resistant and one carbapenem-sensitive strain from sporadic infections in 2010-2012 were sequenced and analysed. Then, 5 outbreak isolates and 57 sporadic isolates (of which 39 were carbapenem-resistant) were screened by PCR for relevant DNA elements identified in the genomics investigation. All three strains for which whole-genome sequences were obtained carried resistance genes linked to MDR phenotypes and a ca. 111-kbp plasmid (pCMCVTAb1) without drug resistance genes. Of these, the two carbapenem-resistant strains possessed a ca. 74-kbp plasmid (pCMCVTAb2) carrying a Tn2008 transposon that provides high-level carbapenem resistance. PCR analysis showed that all of the outbreak isolates carried both plasmids and Tn2008, and of the sporadic isolates 88% carried pCMCVTAb1, 25% contained pCMCVTAb2 and 50% of the latter group carried Tn2008. Carbapenem resistance in outbreak strains and 12% of sporadic isolates was due to the pCMCVTAb2-borne Tn2008. This is the first report of a Tn2008-driven outbreak of carbapenem-resistant A. baumannii infections in the Commonwealth of Virginia, which followed similar cases in Pennsylvania and Ohio.


Parallel wavefront measurements in ultrasound pulse guided digital phase conjugation.
Ultrasound pulse guided digital phase conjugation has emerged to realize fluorescence imaging inside random scattering media. Its major limitation is the slow imaging speed, as a new wavefront needs to be measured for each voxel. Therefore 3D or even 2D imaging can be time consuming. For practical applications on biological systems, we need to accelerate the imaging process by orders of magnitude. Here we propose and experimentally demonstrate a parallel wavefront measurement scheme towards such a goal. Multiple focused ultrasound pulses of different carrier frequencies can be simultaneously launched inside a scattering medium. Heterodyne interferometry is used to measure all of the wavefronts originating from every sound focus in parallel. We use these wavefronts in sequence to rapidly excite fluorescence at all the voxels defined by the focused ultrasound pulses. In this report, we employed a commercially available sound transducer to generate two sound foci in parallel, doubled the wavefront measurement speed, and reduced the mechanical scanning steps of the sound transducer to half.


Gut symbiotic bacteria of the genus Burkholderia in the broad-headed bugs Riptortus clavatus and Leptocorisa chinensis (Heteroptera: Alydidae).
The Japanese common broad-headed bugs Riptortus clavatus and Leptocorisa chinensis possess a number of crypts in the posterior region of the midgut, whose lumen contains a copious amount of bacterial cells. We characterized the gut symbiotic bacteria by using molecular phylogenetic analysis, light and electron microscopy, in situ hybridization, and PCR-based detection techniques. Restriction fragment length polymorphism analysis of 16S rRNA gene clones suggested that a single bacterium dominated the microbiota in the crypts of the both bug species. The predominant 16S rRNA gene sequences obtained from different individuals and species of the bugs were not identical but were very similar to each other. Homology searches in the DNA databases revealed that the sequences showed the highest levels of similarity (96% to 99%) to the sequences of Burkholderia spp. belonging to the beta subdivision of the class Proteobacteria. In situ hybridization with specific oligonucleotide probes confirmed the localization of the Burkholderia symbiont in the lumen of the midgut crypts. Electron microscopy showed that the lumen of the crypts was filled with rod-shaped bacteria of a single morphotype. Molecular phylogenetic analysis demonstrated that the Burkholderia symbionts of the bugs formed a well-defined monophyletic group, although the group also contained several environmental Burkholderia strains. The phylogenetic relationship of the Burkholderia symbionts did not reflect the relationship of the host bug species at all. The sequences from R. clavatus and the sequences from L. chinensis did not form clades but were intermingled in the phylogeny, suggesting that horizontal transmission of the symbiont might have occasionally occurred between populations and species of the bugs.


A Comparison of Exogenous Labels for the Histological Identification of Transplanted Neural Stem Cells.
The interpretation of cell transplantation experiments is often dependent on the presence of an exogenous label for the identification of implanted cells. The exogenous labels Hoechst 33342, 5-bromo-2'-deoxyuridine (BrdU), PKH26, and Qtracker were compared for their labeling efficiency, cellular effects, and reliability to identify a human neural stem cell (hNSC) line implanted intracerebrally into the rat brain. Hoechst 33342 (2 mg/ml) exhibited a delayed cytotoxicity that killed all cells within 7 days. This label was hence not progressed to in vivo studies. PKH26 (5 μM), Qtracker (15 nM), and BrdU (0.2 μM) labeled 100% of the cell population at day 1, although BrdU labeling declined by day 7. BrdU and Qtracker exerted effects on proliferation and differentiation. PKH26 reduced viability and proliferation at day 1, but this normalized by day 7. In an in vitro coculture assay, all labels transferred to unlabeled cells. After transplantation, the reliability of exogenous labels was assessed against the gold standard of a human-specific nuclear antigen (HNA) antibody. BrdU, PKH26, and Qtracker resulted in a very small proportion (<2%) of false positives, but a significant amount of false negatives (∼30%), with little change between 1 and 7 days. Exogenous labels can therefore be reliable to identify transplanted cells without exerting major cellular effects, but validation is required. The interpretation of cell transplantation experiments should be presented in the context of the label's limitations.


Immunoresponses to Neisseria meningitidis epitopes: suppression of secondary response to phosphorylcholine is carrier specific.
Results of our previous work have shown that Neisseria meningitidis serogroup B M986 can induce a phosphorylcholine (PC)-specific plaque-forming cell immunoresponse in mice. Also, a single injection of a relatively low dose of meningococci in NBF1 female mice induced a priming time-dependent suppression on subsequent meningococcus challenge. This suppression was not due to switching to another class of immunoglobulin nor to the presence of a capsule on N. meningitidis. In this study we show that suppression induced by meningococcus is carrier specific. Furthermore, we offer evidence suggesting that the structure(s) on meningococcus that trigger this suppression is heat labile and different from the antigenic structure(s) recognized by the suppressed B cells. In addition, we found that there is a gradual increase in antibody secretion rates of N. meningitidis-induced anti-PC plaque-forming cells that correlates with N. meningitidis priming time. Rather unexpected was the fact that pretreatment of mice with PC-keyhole limpet hemocyanin (thymus-dependent antigen) had a great influence on the subsequent PC-specific immunoresponses induced by N. meningitidis and PC-coupled heat-inactivated meningococcus [PC-(NMB)HI], as shown by (i) a striking decrease in T15 idiotype expression, (ii) concomitant direct anti-PC plaque-forming cells reduction, (iii) switching to immunoglobulin G (N. meningitidis-induced immunoresponse) or immunoglobulin G plus immunoglobulin A [PC-(NMB)HI-induced immunoresponse], and (iv) a significant increase in heterogeneity of plaque-forming cell secretion rates. The possibility that N. meningitidis, PC-(NMB)HI, and PC-KLH stimulate B lymphocytes pertaining to three different subpopulations embedded in distinct regulatory circuits is discussed, with emphasis on the interrelationships between T-dependent and T-independent lymphocyte compartments. We focus on the possibility of the existence of high-level regulatory circuits in which lymphocyte subpopulations or sets of lymphocyte subpopulations with different requirements of activation are connected.


Prevalence of perceived experiences of emotional, physical, sexual, and health care abuse in a Swedish male patient sample.
The aim of the present study was to estimate the prevalence of and current suffering from emotional abuse (EA), physical abuse (PA), and sexual abuse (SA) and abuse in health care (AHC) among male Swedish patients and compare prevalences of abuse between female and male patients at a Swedish university hospital. For data collection we used the NorVold Abuse Questionnaire, which has been validated in a female sample and in the present study. The lifetime prevalences were EA = 12.8%, PA = 45.7%, SA = 3.8%, and AHC = 8.1%. Current suffering from abuse among participants was 1% to 9%. The women reported higher rates than men of current suffering from all kinds of abuse and more severe forms of abuse, such as life-threatening PA. Health care staff should be aware of the documented high prevalences of abuse and learn to make good judgments as to when to ask male as well as female patients about experiences of abuse.


Endoscopy during laparoscopy. Reduced postprocedural bowel distention with intraluminal CO2 insufflation.
Intraluminal endoscopy during laparoscopy can substitute for manual palpation in defining anatomy and pathology, but a potential problem is the persistent bowel distention associated with intraluminal air insufflation. To compare the rates of intraluminal absorption, a 30-cm segment of small bowel with an intact vascular supply was insufflated with either air or CO2 during CO2 pneumoperitoneum. Intraluminal pressures and bowel circumferences were monitored after the insufflation was stopped. To study the metabolic and hemodynamic effects of CO2 endoscopy during laparoscopy, the small bowel was insufflated to an intraluminal pressure of 15 mmHg during CO2 pneumoperitoneum. Nitrogen pneumoperitoneum was used to differentiate the effects from intraluminal and peritoneal CO2 insufflation. The intraluminal pressures remained elevated and the bowel distended for the entire 3 h following bowel insufflation with air. Following intraluminal CO2 insufflation, both the intraluminal pressures and the bowel circumferences returned to preinsufflation values within 15 min. Intraluminal CO2 insufflation also led to systemic absorption of CO2 with significant metabolic and hemodynamic changes. These changes were effectively corrected by doubling minute ventilation. Intraluminal CO2 was absorbed faster than intraluminal air. Although decreased bowel distention is certainly of practical value, endotracheal intubation needs to be done to effectively ventilate the absorbed CO2.


The gas bubble sign-a reliable indicator of laryngeal fractures in hanging on post-mortem CT.
The purpose was to evaluate the presence of gas in the tissue adjacent to the laryngeal structures, "the gas bubble sign", in cases of hanging as a diagnostic indicator of neck trauma. In this study, post-mortem CT (PMCT) scans and autopsies of 35 victims of hanging were examined to reveal age-dependent changes, laryngeal fracture, fracture location and the presence of gas. A matched group with cardiac arrest or intoxication was used as controls (n = 35). An autopsy was performed in each case. Incomplete suspension was the most common method in hanging. The thyroid horns (90.5%) were identified as the most vulnerable location for fractures. Laryngeal deformity and dislocation, which was only detected on PMCT, was observed in 57.1% and was concomitant with fractures in 83.3%. Laryngeal fractures are more common with advanced age (>40 years, 88.9%) and less common in younger subjects (<40 years, 29.4%). The gas bubble sign with regard to laryngeal fractures yielded a sensitivity of 79.2%, a positive predictive value of 95%, a specificity of 90.9%, a negative predictive value of 34.5% and an accuracy of 83%. The complex evaluation of the larynx is profoundly supported by PMCT and the detection of the gas bubble sign as a diagnostic indicator of neck trauma. This relevant diagnostic finding might aid in not only post-mortem cases but also clinical cases, for patients who survive an assault to the neck. Advances in knowledge: (1) The gas bubble sign is a diagnostic indicator of neck trauma in not putrefied bodies. (2) PMCT supports evaluation of trauma to the neck in hanging tremendously. (3) The diagnostic finding of gas located at the laryngeal structures may not only aid in post-mortem cases but also clinical cases of people who survive an assault to the neck.


Managing intensive care admissions when there are not enough beds during the COVID-19 pandemic: a systematic review.
The surge in cases of severe COVID-19 has resulted in clinicians triaging intensive care unit (ICU) admissions in places where demand has exceeded capacity. In order to assist difficult triage decisions, clinicians require clear guidelines on how to prioritise patients. Existing guidelines show significant variability in their development, interpretation, implementation and an urgent need for a robust synthesis of published guidance. To understand how to manage which patients are admitted to ICU, and receive mechanical ventilatory support, during periods of high demand during the COVID-19 pandemic, a systematic review was performed. Databases of indexed literature (Medline, Embase, Web of Science, and Global Health) and grey literature (Google.com and MedRxiv), published from 1 January until 2 April 2020, were searched. Search terms included synonyms of COVID-19, ICU, ventilation, and triage. Only formal written guidelines were included. There were no exclusion criteria based on geographical location or publication language. Quality appraisal of the guidelines was performed using the Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Appraisal of Guidelines for Research and Evaluation Instrument Recommendation EXcellence (AGREE REX) appraisal tools, and key themes related to triage were extracted using narrative synthesis. Of 1902 unique records identified, nine relevant guidelines were included. Six guidelines were national or transnational level guidance (UK, Switzerland, Belgium, Australia and New Zealand, Italy, and Sri Lanka), with one state level (Kansas, USA), one international (Extracorporeal Life Support Organization) and one specific to military hospitals (Department of Defense, USA). The guidelines covered several broad themes: use of ethical frameworks, criteria for ICU admission and discharge, adaptation of criteria as demand changes, equality across health conditions and healthcare systems, decision-making processes, communication of decisions, and guideline development processes. We have synthesised the current guidelines and identified the different approaches taken globally to manage the triage of intensive care resources during the COVID-19 pandemic. There is limited consensus on how to allocate the finite resource of ICU beds and ventilators, and a lack of high-quality evidence and guidelines on resource allocation during the pandemic. We have developed a set of factors to consider when developing guidelines for managing intensive care admissions, and outlined implications for clinical leads and local implementation.


Postnatal growth of the human temporal bone. Implications for cochlear implants in children.
Recent interest in cochlear implantation for children has made it important to understand how postnatal growth of the ear will affect such devices. In this study, the postnatal growth of the labyrinth, middle ear, and mastoid was measured in three dimensions using radiographic and temporal bone data. Measurements were made from histologic sections of 48 temporal bones from children and compared to adult temporal bones. Radiographic measurements were made from 253 sets of skull radiographs of children and compared to adult skull series. In the three dimensions measured, there was no postnatal growth of the labyrinth and little variation in size between individuals. Measurements of the middle ear showed greater variation between individuals than measurements of the inner ear, but growth only in the distance from stapes footplate to the tympanic membrane. The mastoid showed growth in all three dimensions: length, width, and depth. The pattern of growth for mastoid length and width appears to follow a double logistic model, with differences between males and females. The growth in mastoid depth is smaller and appears to follow a single exponential curve. The implications for cochlear implantation in children are discussed.


In silico design of low molecular weight protein-protein interaction inhibitors: Overall concept and recent advances.
Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are playing a major role in the health and disease states. Low molecular weight (LMW) "drug-like" inhibitors of PPIs would be very valuable not only to enhance our understanding over physiological processes but also for drug discovery endeavors. However, PPIs were deemed intractable by LMW chemicals during many years. But today, with the new experimental and in silico technologies that have been developed, about 50 PPIs have already been inhibited by LMW molecules. Here, we first focus on general concepts about protein-protein interactions, present a consensual view about ligandable pockets at the protein interfaces and the possibilities of using fast and cost effective structure-based virtual screening methods to identify PPI hits. We then discuss the design of compound collections dedicated to PPIs. Recent financial analyses of the field suggest that LMW PPI modulators could be gaining momentum over biologics in the coming years supporting further research in this area.


Breathe easy at home: a web-based referral system linking clinical sites with housing code enforcement for patients with asthma.
Asthma, the most significant cause of pediatric morbidity and mortality, is exacerbated by adverse environmental conditions, especially substandard housing. The clinical care provider is often unable to address housing and environmental trigger issues. In Boston, Massachusetts, a web-based referral system called Breathe Easy At Home has been put in place, through which clinicians can refer patients to have their homes inspected for housing code violations that may be contributing to their asthma. Violations will then be brought to the attention of the landlord, who then has the option of redressing the issue or be taken to housing court. By bringing the local public health department, the city's inspectional services department, and the clinical care provider together with the help of a program coordinator, Breathe Easy At Home is able to provide comprehensive care to asthma patients. This program also serves as a replicable model for other cities and jurisdictions to follow.


Development of a Smartphone-based reading system for lateral flow immunoassay.
This study was conducted to develop and evaluate the performance of the Smartphone-based reading system for the lateral flow immunoassay (LFIA). Smartphone-based reading system consists of a Samsung Galaxy S2 Smartphone, Smartphone application, and a LFIA reader. LFIA reader is composed of the close-up lens with a focal length up to 30 mm, white LED light, lithium polymer battery, and main body. The Smartphone application for image acquisition and data analysis was developed on the Android platform. The standard curve was obtained by plotting the measured P(T)/P(c) or A(T)/A(c) ratio versus Salmonella standard concentration. The mean, standard deviation (SD), recovery, and relative standard deviation (RSD) were also calculated using additional experimental results. These data were compared with that obtained from the benchtop LFIA reader. The LOD in both systems was observed with 10(6) CFU/mL. The results show high accuracy and good reproducibility with a RSD less than 10% in the range of 10(6) to 10(9) CFU/mL. Due to the simple structure, good sensitivity, and high accuracy of the Smartphone-based reading system, this system can be substituted for the benchtop LFIA reader for point-of-care medical diagnostics.


Multicentre randomized clinical trial of inspiratory muscle training versus usual care before surgery for oesophageal cancer.
Up to 40 per cent of patients undergoing oesophagectomy develop pneumonia. The aim of this study was to assess whether preoperative inspiratory muscle training (IMT) reduces the rate of pneumonia after oesophagectomy. Patients with oesophageal cancer were randomized to a home-based IMT programme before surgery or usual care. IMT included the use of a flow-resistive inspiratory loading device, and patients were instructed to train twice a day at high intensity (more than 60 per cent of maximum inspiratory muscle strength) for 2 weeks or longer until surgery. The primary outcome was postoperative pneumonia; secondary outcomes were inspiratory muscle function, lung function, postoperative complications, duration of mechanical ventilation, length of hospital stay and physical functioning. Postoperative pneumonia was diagnosed in 47 (39·2 per cent) of 120 patients in the IMT group and in 43 (35·5 per cent) of 121 patients in the control group (relative risk 1·10, 95 per cent c.i. 0·79 to 1·53; P = 0·561). There was no statistically significant difference in postoperative outcomes between the groups. Mean(s.d.) maximal inspiratory muscle strength increased from 76·2(26·4) to 89·0(29·4) cmH2 O (P < 0·001) in the intervention group and from 74·0(30·2) to 80·0(30·1) cmH2 O in the control group (P < 0·001). Preoperative inspiratory muscle endurance increased from 4 min 14 s to 7 min 17 s in the intervention group (P < 0·001) and from 4 min 20 s to 5 min 5 s in the control group (P = 0·007). The increases were highest in the intervention group (P < 0·050). Despite an increase in preoperative inspiratory muscle function, home-based preoperative IMT did not lead to a decreased rate of pneumonia after oesophagectomy. Registration number: NCT01893008 (https://www.clinicaltrials.gov).


Atezolizumab: A Review in Extensive-Stage SCLC.
Atezolizumab (Tecentriq®), a fully humanized, monoclonal anti-programmed cell death ligand-1 (PD-L1) antibody, is the first immune checkpoint inhibitor to be approved, in combination with carboplatin and etoposide, for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Approval was based on primary data from the multinational phase I/III IMpower133 trial in PD-L1-unselected patients with previously untreated ES-SCLC. In this trial, induction therapy with atezolizumab plus carboplatin and etoposide followed by maintenance therapy with atezolizumab alone significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with carboplatin and etoposide alone. The addition of atezolizumab to chemotherapy was generally well tolerated, with no new safety signals being identified beyond those previously reported for the individual agents. The most common grade 3-4 treatment-related adverse events with this regimen were haematological; the most common immune-related adverse events included rash and hypothyroidism. Importantly, the addition of atezolizumab to chemotherapy improved survival outcomes without adversely impacting patient-reported health-related quality of life (HRQOL). Thus, atezolizumab in combination with carboplatin plus etoposide has emerged as a valuable option for the first-line treatment of ES-SCLC and is being accepted as a standard of care in this setting.


Rouxiella badensis sp. nov. and Rouxiella silvae sp. nov. isolated from peat bog soil and emendation description of the genus Rouxiella.
Four bacterial strains isolated from peat bog soil or swampy meadow in Baden-Württemberg (Germany) and found to have rrs sequences close to that of Rouxiella chamberiensis were compared to this species by using multi-locus sequence analysis and phenotypic tests. The four strains constituted two discrete groups (referred to as the Baden and the Silva groups) belonging to the genus Rouxiella. These groups differed in their ability to grow at 37 °C, reduce nitrate into nitrite, and to produce acid from several carbohydrates. Two novel species are, therefore, proposed: Rouxiella badensis sp. nov. for the Baden group (type strain, 323T=CIP 111153T=DSM 100043T) and Rouxiella silvae for the Silva group (type strain, 213T=CIP 111154T=DSM 103735T). The definition of the genus Rouxiellahas also been emended in order to take these two novel species into account.


Aspartame Intake Relates to Coronary Plaque Burden and Inflammatory Indices in Human Immunodeficiency Virus.
Dietary sweeteners may contribute to metabolic dysregulation and cardiovascular disease (CVD), but this has not been assessed in human immunodeficiency virus (HIV). One hundred twenty-four HIV-infected and 56 non-HIV-infected participants, without history of known coronary artery disease were included. Dietary intake was assessed using a 4-day food record. Coronary plaque was determined using cardiac computed tomography angiography. Human immunodeficiency virus-infected participants had significantly greater intake of dietary sweeteners, including total sugar (P = .03) and added sugar (P = .009); intake of aspartame (artificial sweetener) was greater among aspartame consumers with HIV versus non-HIV consumers (P = .03). Among HIV-infected participants, aspartame intake was significantly associated with coronary plaque (P = .002) and noncalcified plaque (P = .007) segments, as well as markers of inflammation/immune activation (monocyte chemoattractant protein 1 and lipoprotein-associated phospholipase A2), which may contribute to increased atherogenesis. In multivariable regression modeling, aspartame remained an independent predictor of plaque in HIV. In contrast, among non-HIV-infected participants, no sweetener type was shown to relate to plaque characteristics. We demonstrate increased intake of dietary sweeteners and a potential novel association between aspartame intake, plaque burden, and inflammation in HIV. Our data suggest that aspartame may contribute to CVD risk in HIV. Further studies should address potential mechanisms by which aspartame may contribute to increased plaque burden and cardiovascular benefits of dietary strategies targeting aspartame intake in HIV.


Primary amine recognition in water by a calix[6]aza-cryptand incorporated in dodecylphosphocholine micelles.
Water is a unique solvent and the design of selective artificial hosts that can efficiently work in an aqueous medium is a challenging task. It is known that the calix[6]tren zinc complex can recognize neutral guests in organic solvents. This complex was incorporated into dodecylphosphocholine micelles (DPC) and studied by NMR. The incorporated complex is able to extract selectively primary amines from the aqueous environment driven by an important hydrophobic effect which also affects the selectivity of the complex for these amines. This work shows how the incorporation of organo-soluble receptors in micelles can be an elegant and very efficient strategy to obtain water compatible nanosized supramolecular recognition devices which can be prepared via a straightforward self-assembly process.


Using Contemporary Behavior Change Science to Design and Implement an Effective Nutritional Intervention Within Professional Rugby League.
Designing and implementing successful dietary intervention is integral to the role of sport nutrition professionals as they attempt to positively change the dietary behavior of athletes. High-performance sport is a time-pressured environment where immediate results can often supersede pursuit of the most effective evidence-based practice. However, efficacious dietary intervention necessitates comprehensive, systematic, and theoretical behavioral design and implementation, if the habitual dietary behaviors of athletes are to be positively changed. Therefore, this case study demonstrates how the Behaviour Change Wheel was used to design and implement an effective nutritional intervention within a professional rugby league. The eight-step intervention targeted athlete consumption of a high-quality dietary intake of 25.1 MJ each day to achieve an overall body mass increase of 5 kg across a 12-week intervention period. The capability, opportunity, motivation, and behavior model and affordability, practicability, effectiveness/cost-effectiveness, acceptability, safety, and equity criteria were used to identify population-specific intervention functions, policy categories, behavior change techniques, and modes of intervention delivery. The resulting intervention was successful, increasing the average daily energy intake of the athlete to 24.5 MJ, which corresponded in a 6.2 kg body mass gain. Despite consuming 0.6 MJ less per day than targeted, secondary outcome measures of diet quality, strength, body composition, and immune function all substantially improved, supporting sufficient energy intake and the overall efficacy of a behavioral approach. Ultimately, the Behaviour Change Wheel provides sport nutrition professionals with an effective and practical stepwise method to design and implement effective nutritional interventions for use within high-performance sport.


Prevalence of use and acute toxicity associated with the use of NBOMe drugs.
The 25X-NBOMe series are N-2-methoxybenzyl analogues of the respective 2C-X substituted phenethylamine and include 25B-N(BOMe)2, 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25E-NBOMe, 25G-NBOMe, 25H-NBOMe, 25I-NBOMe, 25N-NBOMe and 25iP-NBOMe. There are reports of their use as novel psychoactive substances and associated acute toxicity from Europe, the United States and elsewhere over the last five years. This review will discuss the epidemiology of use and pattern of acute toxicity associated with use of these compounds. A PubMed search was performed using the search terms 'NBOMe', '25B-N(BOMe)2', '25B-NBOMe', '25C-NBOMe', '25D-NBOMe', '25E-NBOMe', '25G-NBOMe', '25H-NBOMe', '25I-NBOMe', '25N-NBOMe' and '25iP-NBOMe' covering the years 1966-2014. In addition, abstracts from the 2010-2014 congresses of the European Association of Poisons Centres and Clinical Toxicologists and the 2010-2013 North American Congress of Clinical Toxicology were reviewed using these search terms. Further information was obtained from the European Information System and Database on New Drugs co-ordinated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). PREVALENCE OF USE: There are no national or international surveys collecting data on the prevalence of use of NBOMe drugs. The only information on prevalence of use is from two sub-population surveys of individuals who frequent nightclubs. Of 22,289 respondents of the 2013 Global Drugs Survey, 582 (2.6%) had previously used an NBOMe; the most commonly used NBOMe was 25I-NBOMe (442 respondents, 2.0% of whole cohort and 75.9% of those who had used an NBOMe). In a survey of 397 clubbers in London nightclubs in 2013, 11.8% had heard of the NBOMe drugs (compared with 96.0% for mephedrone), and 4.8% had ever used an NBOMe (compared with 76.6% for mephedrone). ACUTE TOXICITY: There were 29 published cases in the literature of acute toxicity associated with the use of an NBOMe: 25I-NBOMe - 23 cases; 25B-NBOMe - 3 cases; 25C-NBOMe - 3 cases. Commonly reported features include tachycardia (96.6%), hypertension (62.0%), agitation/aggression (48.2%), seizures (37.9%) and hyperthermia (27.6%). Five patients were reported to have developed acute kidney injury. There were an additional 25 reports of acute toxicity related to the use of 25I-NBOMe reported to the EMCDDA. The pattern of toxicity in these cases is similar to that seen in the published cases. NBOMe-related deaths. 25I-NBOMe has been detected in eight fatalities; in one of these, 25C-NBOMe was also detected. The role of the NBOMe drugs in these deaths has not been determined in all cases. Currently, there is evidence suggesting limited use of the NBOMe class of drugs as novel psychoactive substances compared with that of classical recreational drugs and other novel psychoactive substances such as mephedrone.


Does heart failure etiology, New York Heart Association class, or ejection fraction affect the ability of clopidogrel to inhibit heightened platelet activity?
The ability of clopidogrel to inhibit platelet function in patients with congestive heart failure (CHF) was proved by the PLUTO-CHF trial. We retrospectively analyzed platelet characteristics with respect to CHF etiology, class, and ejection fraction in patients enrolled in the PLUTO-CHF study. Twenty-five patients were divided by CHF etiology, severity, and ejection fraction. All patients received aspirin 325 mg for at least 1 month prior to screening. Platelet function studies were performed at baseline and after 30 days of therapy. There were no differences in platelet parameters dependent on clinical characteristics of CHF, except for a significant (P = 0.023) decrease in platelet/endothelial cell adhesion molecule 1 (PECAM-1) expression in the New York Heart Association class III-IV due to the higher baseline values. Therapy with clopidogrel resulted in a significant inhibition of platelet activity assessed by ADP-induced and epinephrine-induced aggregation, closure time, expression of PECAM-1, glycoprotein Ib, glycoprotein IIb/IIIa antigen, glycoprotein IIb/IIIa activity with PAC-1, CD151, and reduced formation of platelet-leukocyte conjugates when compared with baseline. Clopidogrel provides antiplatelet protection in the broad spectrum of patients with CHF independently of its etiology, severity, or myocardial contractility. This uniform platelet inhibition with clopidogrel may be an important consideration in designing future large-scale clinical trials.


Cigarette smoking and large cell carcinoma of the lung.
Large cell carcinoma is the fourth most common histological type of lung cancer in the United States. Cigarette smoking causes large cell lung cancer, but it is uncertain whether the effect varies with the amount and duration of smoking. This uncertainty stems from ambiguity in the histopathological classification of large cell cancer, especially before 1971, and the relatively infrequent occurrence of large cell cancer in epidemiological studies. The present case-control investigation demonstrates that the risk of large cell cancer increases with both the frequency and number of years of cigarette smoking. The odds ratio associated with smoking two or more packs/day was 37.0 (95% confidence interval, 16.4-83.2) in men and 72.9 (35.4-150.2) in women. It is concluded that cigarette smoking is the predominant cause of large cell lung cancer.


Evaluation of the OptiMAL test for rapid diagnosis of Plasmodium vivax and Plasmodium falciparum malaria.
The development of rapid and specific diagnostic tests to identify individuals infected with malaria is of paramount importance in efforts to control the severe public health impact of this disease. This study evaluated the ability of a newly developed rapid malaria diagnostic test, OptiMAL (Flow Inc., Portland, Oreg.), to detect Plasmodium vivax and Plasmodium falciparum malaria during an outbreak in Honduras. OptiMAL is a rapid (10-min) malaria detection test which utilizes a dipstick coated with monoclonal antibodies against the intracellular metabolic enzyme parasite lactate dehydrogenase (pLDH). Differentiation of malaria parasites is based on antigenic differences between the pLDH isoforms. Since pLDH is produced only by live Plasmodium parasites, this test has the ability to differentiate live from dead organisms. Results from the OptiMAL test were compared to those obtained by reading 100 fields of traditional Giemsa-stained thick-smear blood films. Whole-blood samples were obtained from 202 patients suspected of having malaria. A total of 96 samples (48%) were positive by blood films, while 91 (45%) were positive by the OptiMAL test. The blood films indicated that 82% (79 of 96) of the patients were positive for P. vivax and 18% (17 of 96) were infected with P. falciparum. The OptiMAL test showed that 81% (74 of 91) were positive for P. vivax and 19% (17 of 91) were positive for P. falciparum. These results demonstrated that the OptiMAL test had sensitivities of 94 and 88% and specificities of 100 and 99%, respectively, when compared to traditional blood films for the detection of P. vivax and P. falciparum malaria. Blood samples not identified by OptiMAL as malaria positive normally contained parasites at concentrations of less than 100/microl of blood. Samples found to contain P. falciparum were further tested by two other commercially available rapid malaria diagnostic tests, ParaSight-F (Becton Dickinson, Cockeysville, Md.) and ICT Malaria P.f. (ICT Diagnostics, Sydney, Australia), both of which detect only P. falciparum. Only 11 of the 17 (65%) P. falciparum-positive blood samples were identified by the ICT and ParaSight-F tests. Thus, OptiMAL correctly identified P. falciparum malaria parasites in patient blood samples more often than did the other two commercially available diagnostic tests and showed an excellent correlation with traditional blood films in the identification of both P. vivax malaria and P. falciparum malaria. We conclude that the OptiMAL test is an effective tool for the rapid diagnosis of malaria.


A New Machine Learning Framework for Understanding the Link Between Cannabis Use and First-Episode Psychosis.
Lately, several studies started to investigate the existence of links between cannabis use and psychotic disorders. This work proposes a refined Machine Learning framework for understanding the links between cannabis use and 1st episode psychosis. The novel framework concerns extracting predictive patterns from clinical data using optimised and post-processed models based on Gaussian Processes, Support Vector Machines, and Neural Networks algorithms. The cannabis use attributes' predictive power is investigated, and we demonstrate statistically and with ROC analysis that their presence in the dataset enhances the prediction performance of the models with respect to models built on data without these specific attributes.


[Search of natural occurrence of xiphidiocercariae (trematoda) in fresh water snails of nine countries from São Paulo State, Brazil].
Xiphidiocercariae, aquatic larval stages of some trematodes are considered a potential instrument for biological control of mosquitoes. In this study we evaluated its natural occurrence in Campinas region and two places in Vale do Ribeira (Registro and Miracatu), São Paulo State. Snails were obtained from fresh water collections from September 1996 to February 1999. The species collected were Lymnaea columella, Physa marmorata, Biomphalaria tenagophila, Biomphalaria sp., Drepanotrema cimex, D. lucidum and Drepanotrema sp. Fasciola hepatica, xiphidiocercariae (Haematoloechidae) and echinostomatid cercariae were detected in the lymnaeids snails from Miracatu, SP. In the same locality were found planorbids snails parasitized by furcocercariae, echinostomatid cercariae and xiphidiocercariae. The xiphidiocercariae found in the planorbids were different from those obtained from lymnaeids. One Biomphalaria sp. infected with furcocercariae was found in Louveira, SP. In the ROSA place (Campinas, SP) an individual of Biomphalaria sp. and one of L. columella were found infected by the furcocercariae and echinostomatid cercariae, respectively. In the place UNI-I, in Campinas, one L. columella was infected by furcocercariae. Double infection in snails from Miracatu was also observed.


A MAP kinase encoded by the ubc3 gene of Ustilago maydis is required for filamentous growth and full virulence.
Ustilago maydis, the causal agent of corn smut disease, displays dimorphic growth in which it alternates between a budding haploid saprophyte and a filamentous dikaryotic pathogen. We are interested in identifying the genetic determinants of filamentous growth and pathogenicity in U. maydis. To do this, we have taken a forward genetic approach. Previously, we showed that haploid adenylate cyclase (uac1) mutants display a constitutively filamentous phenotype. Mutagenesis of a uac1 disruption strain allowed the isolation of a large number of budding suppressor mutants. These mutants are named ubc, for Ustilago bypass of cyclase, as they no longer require the production of cAMP to grow in the budding morphology. Complementation of one of these suppressor mutants led to the identification of ubc3, which is required for filamentous growth and encodes a MAP kinase most similar to those of the yeast pheromone response pathway. In addition to filamentous growth, the ubc3 gene is required for pheromone response and for full virulence. Mutations in the earlier identified fuz7 MAP kinase kinase also suppress the filamentous phenotype of the uac1 disruption mutant, adding evidence that both ubc3 and fuz7 are members of this same MAP kinase cascade. These results support an important interplay of the cAMP and MAP kinase signal transduction pathways in the control of morphogenesis and pathogenicity in U. maydis.


European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.
This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.


Assessing the ecological impacts of transportation infrastructure development: A reconnaissance study of the Standard Gauge Railway in Kenya.
Transportation infrastructure, such as railways, roads and power lines, contribute to national and regional economic, social and cultural growth and integration. Kenya, with support from the Chinese government, is currently constructing a standard gauge railway (SGR) to support the country's Vision 2030 development agenda. Although the actual land area affected by the SGR covers only a small proportion along the SGR corridor, a significant proportion of the area supports a wide range of ecologically fragile and important ecosystems in the country, with potential wider impacts. This study used a qualitative content analysis approach to gain an understanding and perceptions of stakeholders on the potential ecological impacts of the interactions between the SGR and the traversed ecological systems in Kenya. Three dominant themes emerged: 1) ecosystem degradation; 2) ecosystem fragmentation; and 3) ecosystem destruction. Ecosystem degradation was the most commonly cited impact at while ecosystem destruction was of the least concern and largely restricted to the physical SGR construction whereas the degradation and fragmentation have a much wider footprint. The construction and operation of the SGR degraded, fragmented and destroyed key ecosystems in the country including water towers, protected areas, community conservancies and wildlife dispersal areas. Therefore, we recommend that project proponents develop sustainable and ecologically sensitive measures to mitigate the key ecosystem impacts.


Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.
Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.


The Microbe Directory: An annotated, searchable inventory of microbes' characteristics.
The Microbe Directory is a collective research effort to profile and annotate more than 7,500 unique microbial species from the MetaPhlAn2 database that includes bacteria, archaea, viruses, fungi, and protozoa. By collecting and summarizing data on various microbes' characteristics, the project comprises a database that can be used downstream of large-scale metagenomic taxonomic analyses, allowing one to interpret and explore their taxonomic classifications to have a deeper understanding of the microbial ecosystem they are studying. Such characteristics include, but are not limited to: optimal pH, optimal temperature, Gram stain, biofilm-formation, spore-formation, antimicrobial resistance, and COGEM class risk rating. The database has been manually curated by trained student-researchers from Weill Cornell Medicine and CUNY-Hunter College, and its analysis remains an ongoing effort with open-source capabilities so others can contribute. Available in SQL, JSON, and CSV (i.e. Excel) formats, the Microbe Directory can be queried for the aforementioned parameters by a microorganism's taxonomy. In addition to the raw database, The Microbe Directory has an online counterpart ( https://microbe.directory/) that provides a user-friendly interface for storage, retrieval, and analysis into which other microbial database projects could be incorporated. The Microbe Directory was primarily designed to serve as a resource for researchers conducting metagenomic analyses, but its online web interface should also prove useful to any individual who wishes to learn more about any particular microbe.


Imaging findings in musculoskeletal complications of AIDS.
Patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are susceptible to a variety of complications that can affect the musculoskeletal system. These complications can be infectious, inflammatory, or neoplastic or can take some other form. Infection (cellulitis, necrotizing fasciitis, soft-tissue abscess, pyomyositis, osteomyelitis, septic arthritis) is the most common complication. Inflammatory processes include various arthritides as well as polymyositis. Non-Hodgkin lymphoma and Kaposi sarcoma are the two most common neoplasms in this patient population. Miscellaneous disorders include osteonecrosis, osteoporosis, rhabdomyolysis, anemia-related abnormal bone marrow, and hypertrophic osteoarthropathy. The underlying mechanisms leading to these diseases are complex and not fully understood but are thought to be multifactorial. Radiology may play an important role in early diagnosis and treatment planning in this population, in whom clinical and laboratory findings are commonly equivocal and nonspecific. Although biopsy is often necessary for the final diagnosis, it is important for the radiologist to be familiar with the different types of musculoskeletal disease in HIV-positive and AIDS patients so that an appropriate differential diagnosis can be established.


Glucocorticoids for bronchiolitis-should they be used?: …reducing waste in child health one intervention at a time.
Eco-paediatrics is an occasional feature in Evidence-Based Child Health: A Cochrane Review Journal. Our goal is to contribute to the worldwide discussion on reducing waste in health care. In each instalment, we will select a recent Cochrane review highlighting a practice, still in use, which the available evidence tells us should be discontinued.


1,25-Dihydroxyvitamin D(3) and extracellular inorganic phosphate activate mitogen-activated protein kinase pathway through fibroblast growth factor 23 contributing to hypertrophy and mineralization in osteoarthritic chondrocytes.
Hypertrophy and impaired mineralization are two processes closely associated with osteoarthritis (OA). 1,25-dihydroxyvitamin D(3) (1a,25(OH)(2)D(3)) and inorganic phosphate (Pi) are two important factors that are implicated in calcium and phosphate homeostasis of bone metabolism and both can be regulated by the circulating phosphaturic factor fibroblast growth factor 23 (FGF23). The objective of this study was to investigate the role of 1a,25(OH)(2)D(3) and Pi and the molecular mechanism through which they contribute to hypertrophy and mineralization in human osteoarthritic chondrocytes. For this purpose, primary human chondrocytes were obtained from articular cartilage which was collected after total knee replacement surgery in OA patients. FGF23, fibroblast growth factor receptor 1c (FGFR1c), vitamin D(3) receptor (VDR), and phosphate inorganic transporter-1 and -2 (PiT-1 and PiT-2) expression levels were evaluated and found to be significantly higher in OA chondrocytes compared with normal. In addition, we observed that the binding of FGF23 to FGFR1c was stronger in OA chondrocytes compared with normal. Chromatin immunoprecipitation (ChIP) assay revealed, for the first time, the presence of two vitamin D response elements (VDREs) in the FGF23 promoter. Treatment of normal chondrocytes with 1a,25(OH)(2)D(3) or Pi resulted in significant up-regulation of VDR, FGF23, PiT-1, PiT-2 mRNA and protein levels, extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation and induction of hypertrophy markers collagen type X (COL10A1), osteopontin (OPN), osteocalcin (OC), catabolic markers metalloproteinase-13 (MMP-13) and the apoptotic marker caspase-9. Furthermore, VDR silencing in OA chondrocytes negatively regulated FGF23, COL10A1, OPN, OC, MMP-13 and caspase-9 expressions and ERK1/2 phosphorylation. Finally, combined VDR silencing and PiT-1, PiT-2 inhibition in OA chondrocytes resulted in additive down-regulation of FGF23 expression, ERK1/2 activation and COL10A1, OPN, OC, MMP-13 and caspase-9 expression levels. We propose that 1a,25(OH)(2)D(3) and Pi act synergistically through FGF23 signaling and ERK1/2 phosphorylation contributing to late hypertrophic events and impaired mineralization in osteoarthritic chondrocytes.


Tamoxifen in men: a review of adverse events.
Tamoxifen is an off-label option to treat men for breast cancer, infertility, and idiopathic gynecomastia. Lately, tamoxifen has been proposed as a treatment to prevent gynecomastia in prostate cancer patients receiving antiandrogen therapy. We reviewed the adverse events (AEs) reported in studies of men prescribed tamoxifen for these conditions to better understand its side-effect profile. We searched PubMed for randomized controlled trials (RCTs) that included safety data of tamoxifen treatment in men with prostate cancer, breast cancer, infertility, and idiopathic gynecomastia. Non-RCTs were also reviewed. The results demonstrate that the AE profile in tamoxifen-treated male populations varied. Excluding breast events, gastrointestinal, and cardiovascular problems were the most commonly reported AEs in prostate cancer patients, whereas more psychiatric disorders were reported in male breast cancer patients. Few AEs have been documented in men receiving tamoxifen for infertility and idiopathic gynecomastia. Less than 5% of men withdrew from tamoxifen therapy because of toxicity. This suggests that for most men, tamoxifen is well-tolerated. Of those who discontinued tamoxifen, the majority were male breast cancer patients, and cardiovascular events were the most common reason for stopping tamoxifen treatment. Unfortunately, in many cases, the reasons for withdrawing tamoxifen were unspecified. Based on the available evidence, tamoxifen's AE profile appears to vary depending upon which male population is treated. Also, the frequency at which AEs occur varies - less AEs in men with infertility and idiopathic gynecomastia compared to men with prostate cancer or breast cancer. Long-term studies that rigorously document the side-effect profile of tamoxifen in men are lacking.


Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study.
To assess the safety and efficacy of memantine, an uncompetitive antagonist of the N-methyl-D-aspartate receptor as treatment of HIV-associated cognitive impairment. This was a Phase II randomized, double-blind, placebo-controlled, multicenter trial within the Adult AIDS Clinical Trials Group. One-hundred and forty HIV-infected adults with mild to severe AIDS dementia complex receiving stable antiretroviral therapy were enrolled. Memantine was initiated at 10 mg daily escalated to 40 mg daily, or up to the maximum tolerated dose and continued for 16 weeks (primary evaluation visit) followed by a 4-week washout period and re-evaluation at week 20. Changes in cognitive performance were measured as percent change from baseline to week 16 in the average of eight neuropsychological test scores (NPZ-8). Brain metabolism was measured by magnetic resonance spectroscopy in a subgroup of subjects. Sixty-one percent of subjects in the memantine group and 85% in the placebo group reached the 40 mg dose while the reported adverse experiences between the two groups were similar. There were no significant improvements in neuropsychological performance over 16 weeks; however, memantine was associated with a significant increase at week 16 in the N-acetyl aspartate to creatine ratio, in the frontal white matter (P = 0.040) and parietal cortex (P = 0.023). Memantine was safe and tolerated by HIV-infected subjects with cognitive impairment. Although we observed no significant differences in cognitive performance, the magnetic resonance spectroscopy data suggest that memantine may ameliorate neuronal metabolism, an important step to stabilizing or preventing neuronal injury. These results underscore the need for longer studies to assess the full potential of neuroprotective agents.


Frontal mucocele presenting with forehead subcutaneous mass: an unusual presentation.
Frontal mucocele usually presents with visual complaints like diplopia, diminution of vision, visual field defect, ptosis, orbital swelling, retro-orbital pain, displacement of eye-globe and proptosis. Very rarely it can present as a subcutaneous swelling. To the best of the authors' knowledge, only two cases of frontal mucocele presenting with a forehead mass have been reported in the western literature. Authors report an unusual case of frontal mucocele in a 53-year- old female who presented with painless slowly progressive subcutaneous swelling of five-year duration on the forehead. The case is discussed and the pertinent literature is reviewed.


Percutaneous Coronary Interventions for the Treatment of Stenoses in Small Coronary Arteries: A Network Meta-Analysis.
This study evaluated the most appropriate percutaneous coronary intervention (PCI) for the treatment of stenoses in small coronary arteries. PCI in small coronary arteries is associated with an increased risk of lesion failure and restenosis. Randomized trials comparing different PCI strategies were identified through a broad search of published reports. Primary angiographic outcome was %DS (%DS). A pairwise meta-analysis was performed by using random effects model, followed by a network meta-analysis synthesizing direct and indirect evidence. Overall, 19 trials were eligible, which included 5,072 patients comprising a network without closed loops among 5 identified interventions (early generation sirolimus-eluting stents [SES], paclitaxel-eluting stents [PES], drug-coated balloons [DCB], bare-metal stents [BMS], and balloon angioplasty [BA]). No dedicated trial was identified evaluating new generation drug-eluting stents. Early generation SES yielded the best angiographic results according to %DS. For %DS, SES was ranked as the most effective treatment, followed by PES (standardized mean differences [SMD]: -0.44; 95% confidence interval [CI]: -0.92 to 0.05 vs. SES) and DCB (SMD: -0.89; 95% CI: -1.53 to -0.25 vs. SES). In terms of absolute differences, SES yielded a reduction of 18% in diameter stenosis compared to DCB. SES significantly reduced the risk of target-lesion revascularization compared to PES (odds ratio [OR]: 0.39; 95% CI: 0.16 to 0.93), DCB (OR: 0.34; 95% CI: 0.10 to 0.97), BMS (OR: 0.21; 95% CI: 0.13 to 0.36), and BA (OR: 0.16; 95% CI: 0.09 to 0.29). Early generation SES yielded the most favorable angiographic and clinical outcomes for the treatment of stenoses in small coronary arteries. New generation DES need to be evaluated against this standard in future randomized trials.


Downregulation of protein tyrosine phosphatase PTP-BL represses adipogenesis.
The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is a major regulator of adipose tissue growth and differentiation. We recently demonstrated that human protein tyrosine phosphatase (PTP) L1, a large cytoplasmic phosphatase also known as PTP-BAS/PTPN13/PTP-1E, is a negative regulator of IGF-1R/IRS-1/Akt pathway in breast cancer cells. This triggered us to investigate the potential role of PTPL1 in adipogenesis. To evaluate the implication of PTP-BL, the mouse orthologue of PTPL1, in adipose tissue biology, we analyzed PTP-BL mRNA expression in adipose tissue in vivo and during proliferation and differentiation of 3T3-L1 pre-adipocytes. To elucidate the role of PTP-BL and of its catalytic activity during adipogenesis we use siRNA techniques in 3T3-L1 pre-adipocytes, and mouse embryonic fibroblasts that lack wildtype PTP-BL and instead express a variant without the PTP domain (Delta P/Delta P MEFs). Here we show that PTP-BL is strongly expressed in white adipose tissue and that PTP-BL transcript and protein levels increase during proliferation and differentiation of 3T3-L1 pre-adipocytes. Strikingly, knockdown of PTP-BL expression in 3T3-L1 adipocytes caused a dramatic decrease in adipogenic gene expression levels (PPAR gamma, aP2) and lipid accumulation but did not interfere with the insulin/Akt pathway. Delta P/Delta P MEFs differentiate into the adipogenic lineage as efficiently as wildtype MEFs. However, when expression of either PTP-BL or PTP-BL Delta P was inhibited a dramatic reduction in the number of MEF-derived adipocytes was observed. These findings demonstrate a key role for PTP-BL in 3T3-L1 and MEF-derived adipocyte differentiation that is independent of its enzymatic activity.


The body schema and the multisensory representation(s) of peripersonal space.
In order to guide the movement of the body through space, the brain must constantly monitor the position and movement of the body in relation to nearby objects. The effective 'piloting' of the body to avoid or manipulate objects in pursuit of behavioural goals (Popper & Eccles, 1977, p. 129), requires an integrated neural representation of the body (the 'body schema') and of the space around the body ('peripersonal space'). In the review that follows, we describe and evaluate recent results from neurophysiology, neuropsychology, and psychophysics in both human and non-human primates that support the existence of an integrated representation of visual, somatosensory, and auditory peripersonal space. Such a representation involves primarily visual, somatosensory, and proprioceptive modalities, operates in body part-centred reference frames, and demonstrates significant plasticity. Recent research shows that the use of tools, the viewing of one's body or body parts in mirrors, and in video-monitors, may also modulate the visuotactile representation of peripersonal space.


Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.
Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years. A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. The interventions were active monitoring, radical prostatectomy and radical radiotherapy. Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. Current Controlled Trials ISRCTN20141297. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.


Assessing the benefits and risks of translocations in changing environments: a genetic perspective.
Translocations are being increasingly proposed as a way of conserving biodiversity, particularly in the management of threatened and keystone species, with the aims of maintaining biodiversity and ecosystem function under the combined pressures of habitat fragmentation and climate change. Evolutionary genetic considerations should be an important part of translocation strategies, but there is often confusion about concepts and goals. Here, we provide a classification of translocations based on specific genetic goals for both threatened species and ecological restoration, separating targets based on 'genetic rescue' of current population fitness from those focused on maintaining adaptive potential. We then provide a framework for assessing the genetic benefits and risks associated with translocations and provide guidelines for managers focused on conserving biodiversity and evolutionary processes. Case studies are developed to illustrate the framework.


Epidemiological features of irritable bowel syndrome and its subtypes among Iranian adults.
The epidemiological features of irritable bowel syndrome (IBS) have not been properly investigated in Iran. Also, worldwide there is limited knowledge about the characteristics of IBS subtypes. The aim of the study was to explore the epidemiological features of IBS and its subtypes among Iranian adults. This is a cross-sectional study in Iranian adults living in Isfahan province. Demographic characteristics and common gastrointestinal symptoms were assessed using a self-administered modified Persian version of the Rome III questionnaire. In 4763 subjects aged 19-70 years the overall prevalence of IBS was 21.5%. IBS was more prevalent in women than men (24.0 vs. 18.3%, P<0.001). In multivariate analysis, being married was associated with 27% increased odds of IBS (95% confidence interval: 1.03-1.57, P<0.05). However, IBS was not associated with age (P=0.71) or educational attainment (P=0.61). Constipation-predominant IBS (IBS-C) was the most prevalent subtype of IBS followed by mixed IBS (IBS-M), diarrhea-predominant IBS (IBS-D), and unsubtyped IBS. Female gender was associated with IBS-C while male gender was associated with IBS-D and IBS-M. IBS is highly prevalent among Iranian adults, affecting particularly women in whom IBS-C is the most prevalent subtype.