Nephrolithiasis and pyelonephritis in two West Indian manatees (Trichechus manatus spp.).
Two West Indian manatees (Trichechus manatus spp.) were reported with severe emaciation. One animal was a Florida manatee from the Everglades; the other was an Antillean manatee from Cuba. On necropsy, both animals had nephrolithiasis, pyelonephritis, and moderate to severe renomegaly. Histopathology revealed multifocal to diffuse pyelonephritis, interstitial nephritis, and nephrocalcinosis. The stones were analyzed and consisted primarily of calcium carbonate. Serum chemistry values for the Florida animal revealed no renal abnormalities. The mechanism of calculus formation remains unclear in manatees. In horses, another hindgut fermenter, the most common urolith is also calcium carbonate. Urinalyses performed on manatees are very similar to those of horses (i.e., alkaline urine, low specific gravity, and calcium carbonate crystals). Formation of uroliths in manatees may have a pathogenesis similar to equine urolithiasis.


Evaluation of the Abbott LCx Mycobacterium tuberculosis assay in comparison with culture methods in selected Italian patients.
A ligase chain reaction (LCR) DNA amplification method for the molecular diagnosis of Mycobacterium tuberculosis (Abbott LCx MTB) was evaluated in comparison with solid and liquid phase culture on 622 selected samples collected in two large Italian hospitals, of which 310 obtained from HIV-1 positive patients and 312 from HIV-negative individuals. The overall prevalence of mycobacteria by culture was 22% (137/622), and the apparent sensitivity and specificity of LCx vs. culture were 87.6% and 98.2%. Of the 26 culture positive/LCx negative samples, 22 were positive for MOTT and 4 for M. tuberculosis. All 9 samples positive by LCx and negative by culture were classified as true positive by clinical criteria. The final values of sensitivity, specificity, positive predictive value and negative predictive value for LCx rose to 96.8%, 100%, 100% and 99.2%, respectively. The adjusted sensitivity of culture methods was 89.5% for solid phase and 92.7% for Bactec. In view of the high sensitivity on both smear-positive (100%) and smear-negative (92.4%) samples and of the high negative predictive value, the LCR-based amplification method appears suitable as a routine screening method for the rapid diagnosis of M. tuberculosis in high-risk patients.


[Chemistry and toxicology of cigarette smoke in the lungs].
Cigarettes appearance in the middle of 19th century turns tobacco into a general consumption product with ill-fated consequences. Technological process and the means by which tobacco dependence appears were hidden from medical world for a long time by the tobacco companies. Cigarette smoke represents a mixture of 4000 toxic substances including carcinogens, organic compounds, solvents, gas substances (CO). We can add another 600 additives which are used in the technological process. Tobacco dependence is defined by the daily cigarette consumption, difficult quitting and probability for withdraw symptoms. Among the smoke effects on respiratory system, we can identify two main mechanisms: inducing inflammation and mutagen if - carcinogenic effect. Inflammation consists of ciliary toxicity, increased mucus secretion and accumulation of activated inflammatory cells in the respiratory tract. The risk for lung cancer is directly related to the presence of CYPlA1 alleles and reduced glutathione S-reductase activity.


U.S. state policy contexts and mortality of working-age adults.
The rise in working-age mortality rates in the United States in recent decades largely reflects stalled declines in cardiovascular disease (CVD) mortality alongside rising mortality from alcohol-induced causes, suicide, and drug poisoning; and it has been especially severe in some U.S. states. Building on recent work, this study examined whether U.S. state policy contexts may be a central explanation. We modeled the associations between working-age mortality rates and state policies during 1999 to 2019. We used annual data from the 1999-2019 National Vital Statistics System to calculate state-level age-adjusted mortality rates for deaths from all causes and from CVD, alcohol-induced causes, suicide, and drug poisoning among adults ages 25-64 years. We merged that data with annual state-level data on eight policy domains, such as labor and taxes, where each domain was scored on a 0-1 conservative-to-liberal continuum. Results show that the policy domains were associated with working-age mortality. More conservative marijuana policies and more liberal policies on the environment, gun safety, labor, economic taxes, and tobacco taxes in a state were associated with lower mortality in that state. Especially strong associations were observed between certain domains and specific causes of death: between the gun safety domain and suicide mortality among men, between the labor domain and alcohol-induced mortality, and between both the economic tax and tobacco tax domains and CVD mortality. Simulations indicate that changing all policy domains in all states to a fully liberal orientation might have saved 171,030 lives in 2019, while changing them to a fully conservative orientation might have cost 217,635 lives.


Multidimensional Analysis on the Effect of Vocal Function Exercises on Aged Vocal Fold Atrophy.
Age-related voice change is characterized as weak, harsh, and breathy. These changes are caused by histologic alteration of the lamina propria of the vocal fold mucosa as well as atrophy of the thyroarytenoid muscle. Several therapeutic strategies involving laryngeal framework surgery and injection laryngoplasty have been tried, but effects have been limited. Vocal function exercises (VFE) have been used to treat age-related vocal fold atrophy although the effectiveness has been shown with limited analysis. The present study aims to determine the effectiveness of VFE for the treatment of aged atrophy using multidimensional analysis. This is a retrospective study. Sixteen patients with vocal fold atrophy aged 65-81 years underwent voice therapy using VFE. Six patients with vocal fold atrophy aged 65-85 years were involved as a historical control group. The grade, roughness, breathiness, asthenia, strain (GRBAS) scale, stroboscopic examinations, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 (VHI-10) were performed before and after VFE. Normalized mucosal wave amplitude (NMWA), normalized glottal gap (NGG), and bowing index (BI) were measured by image analysis during stroboscopic examinations. After VFE, significant improvements were shown in GRBAS, maximum phonation time, jitter, NMWA, NGG, and VHI-10 although BI has not changed significantly. There were no significant improvements in the historical control. The data suggest that VFE produces significant improvement in subjective, objective, and patient self-evaluation and deserves further attention as a treatment for aged atrophy of the vocal fold. It was also suggested that VFE does not improve the vocal fold bowing but may improve muscular function during voicing.


A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.
PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib. The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.


Multistatic-multiview resolution from Born fields for strips in Fresnel zone.
We address the inverse scattering problem of estimating the resolution limits achievable in the reconstruction of a dielectric strip object within a two-dimensional and scalar geometry. The scattered field is observed over a bounded rectilinear domain located in the Fresnel zone, and a single-frequency multistatic-multiview configuration is considered. The analysis is performed by casting the problem as the inversion of the linearized scattering operator arising from the Born approximation and by means of its singular-value decomposition. Finally, the role of the geometrical parameters of the measurement configuration is highlighted.


Subproteomics analysis of phosphorylated proteins: application to the study of B-lymphoblasts from a patient with Scott syndrome.
Proteomics based approaches, which examine the expressed proteins of a tissue or cell type, complement the genome initiatives and are increasingly used to address biomedical questions. Proteins are the main functional output, and post-translational modifications such as phosphorylation are very important in determining protein function. To address this question, we developed a method for specific immunoprecipitation using anti-phosphotyrosine antibodies. This method is directly compatible with two-dimensional gel electrophoresis (2-DE). In this report data are presented on B-lymphoblasts from a patient suffering of Scott syndrome. Scott syndrome is an orphan inherited hemorrhagic disorder due to a lack of exposure of procoagulant phosphatidylserine at the exoplasmic leaflet of plasma membrane of blood cells. We hypothesized that a consequence of the mutation is to alter phosphorylation of proteins involved in signal transduction leading to breakdown in cellular signaling pathways mediating phosphatidylserine exposure. An immunoprecipitation method combined with 2-DE was applied to search for modifications in the expression of phosphorylated polypeptides related to Scott syndrome phenotype. We report here the construction of a B-lymphoblast subproteomic map comprising of polypeptides observed after immunoprecipitation using antibodies to phosphotyrosine. The polypeptides were identified either by mass fingerprinting, by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and/or by matching with various lymphoid cell 2-DE maps included in the Laboratoire de Biochimie des Protéines et Protéomique 2-DE database. A differential analysis was further performed to explore several hundred proteins in Scott B-lymphoblasts in comparison with control B-lymphoblasts. Then, image analysis allowed detection of variations between control and Scott syndrome phenotype lymphoblasts. Five spots were specifically found on 2-DE from Scott syndrome phenotype lymphoblasts, and four only appeared on 2-DE from control cells. Protein identification was achieved using a combination of mass fingerprinting and peptide identification using LC-MS/MS.


Associations of alcohol use disorder, alcohol use, housing, and service use in a homeless sample of 255 individuals followed over 2 years.
Homeless individuals with alcohol use disorders have multiple comorbidities and therefore various service needs. Despite need for services, homeless individuals face numerous barriers to treatment. Little is known about the associations of specific services in relation to homelessness in the context of alcohol problems. The current study analyzed 2-year prospective longitudinal data on a homeless sample, examining relationships between alcohol use disorder, alcohol use, housing status, and service use over time. Two hundred fifty-five of 400 individuals recruited systematically from shelters and street locations completed 3 annual assessments (69% completion). Data on lifetime and current psychiatric disorders, housing status, and past-year service use were obtained and merged with service use data gathered from local agencies. Generalized estimating equation (GEE) models were created to predict dependent outcome variables of stable housing, alcohol use, and service use in both follow-up years. Lifetime alcohol use disorder was positively associated with substance and medical service use. Alcohol problems did not hinder attainment of stable housing, and placement in housing did not necessarily increase risk for alcohol use. Stable housing was negatively associated with psychiatric and substance service use. In the second year, when alcohol use was finally associated with receiving substance services, it appears that these services provided a gateway to psychiatric services. The psychiatric services in turn appeared to provide a gateway to medical services. Alcohol use behaved differently compared with lifetime alcohol use disorder in relation to service use. Lack of association between alcohol use and housing supports Housing First policy. Obtaining housing may have ameliorative effects on mental health, diminishing perceived need for psychiatric services. Services may also be more accessible during homelessness. Obtaining substance treatment may provide a gateway for those who use alcohol after becoming homeless to connect with psychiatric and medical services, informing policy and practice.


The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases.
Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.


Time-resolved fluorescence spectroscopy and ultrasound backscatter microscopy for nondestructive evaluation of vascular grafts.
Quantitative and qualitative evaluations of structure and composition are important in monitoring development of engineered vascular tissue both in vitro and in vivo. Destructive techniques are an obstacle for performing time-lapse analyses from a single sample or animal. This study demonstrates the ability of time-resolved fluorescence spectroscopy (TRFS) and ultrasound backscatter microscopy (UBM), as nondestructive and synergistic techniques, for compositional and morphological analyses of tissue grafts, respectively. UBM images and integrated backscatter coefficients demonstrate the ability to visualize and quantify postimplantation changes in vascular graft biomaterials such as loss of the external elastic lamina and intimal/medial thickening over the grafted region as well as graft integration with the surrounding tissue. TRFS results show significant changes in spectra, average lifetime, and fluorescence decay parameters owing to changes in collagen, elastin, and cellular content between normal and grafted tissue regions. These results lay the foundation for the application of a catheter-based technique for in vivo evaluation of vascular grafts using TRFS and UBM.


Noise annoyance during COVID-19 lockdown: A research of public opinion before and during the pandemic.
Strict lockdown strategies to stop the spread of COVID-19 have caused a decrease in environmental noise levels and introduced new noise conditions in dwellings. The present study has investigated the impact of the forced lockdown in Turkey on noise annoyances due to traffic, neighbors, and personal dwellings, as well as the concern of being heard by neighbors, and overall dwelling satisfaction in an online questionnaire. The stress and anxiety levels of respondents were also investigated. The survey obtained 1053 respondents. Additionally, environmental noise levels were measured over 24-h at two locations and compared with results before the pandemic. The results clearly exhibit that environmental noise levels and annoyance due to the noise levels dropped significantly. The annoyance drop was larger in previously noisier environments than previously tranquil locations. Noise annoyance due to neighbor noise did not change significantly; however, noise annoyance due to one's own dwelling increased. The results also confirmed an overall increase in dwelling satisfactions indicating a correlation between dwelling satisfaction and lower environmental noise levels. Although the results confirmed that noise annoyance was positively correlated with stress and anxiety levels, the change of annoyance between before and during lockdown was shown to be independent from the stress and anxiety level.


Electrohydrodynamic preparation of polymeric drug-carrier particles: mapping of the process.
Submicrometre size spheres prepared from biocompatible polymers are becoming increasingly popular in drug and gene delivery. This paper describes the preparation of polymeric spheres with a mean diameter of 0.4 μm with a polydispersivity index of 8%, using coaxial electrohydrodynamic atomization (CEHDA) microbubbling. An 18 wt.% solution of polymethylsilsesquioxane, a hydrophobic biocompatible polymer, was subjected to CEHDA microbubbling by passing air through the inner needle and polymer solution through the outer needle of a twin needle co-axial device, under the influence of an electric field. A parametric plot of the flow rate of air and the flow rate of polymer solution was constructed and used for systematic process control to reduce the diameter of the microspheres from micrometre size to submicrometre size. CEHDA is an excellent method for obtaining polymer microspheres. By studying the process in detail and mapping it, we can now demonstrate it can also be used to prepare submicrometre sized particles with the ability to control size and polydispersivity.


Temporal and Spatial Comparisons of Underwater Sound Signatures of Different Reef Habitats in Moorea Island, French Polynesia.
As environmental sounds are used by larval fish and crustaceans to locate and orientate towards habitat during settlement, variations in the acoustic signature produced by habitats could provide valuable information about habitat quality, helping larvae to differentiate between potential settlement sites. However, very little is known about how acoustic signatures differ between proximate habitats. This study described within- and between-site differences in the sound spectra of five contiguous habitats at Moorea Island, French Polynesia: the inner reef crest, the barrier reef, the fringing reef, a pass and a coastal mangrove forest. Habitats with coral (inner, barrier and fringing reefs) were characterized by a similar sound spectrum with average intensities ranging from 70 to 78 dB re 1 μPa.Hz(-1). The mangrove forest had a lower sound intensity of 70 dB re 1 μPa.Hz(-1) while the pass was characterized by a higher sound level with an average intensity of 91 dB re 1 μPa.Hz(-1). Habitats showed significantly different intensities for most frequencies, and a decreasing intensity gradient was observed from the reef to the shore. While habitats close to the shore showed no significant diel variation in sound intensities, sound levels increased at the pass during the night and barrier reef during the day. These two habitats also appeared to be louder in the North than in the West. These findings suggest that daily variations in sound intensity and across-reef sound gradients could be a valuable source of information for settling larvae. They also provide further evidence that closely related habitats, separated by less than 1 km, can differ significantly in their spectral composition and that these signatures might be typical and conserved along the coast of Moorea.


Variation in umami perception and in candidate genes for the umami receptor in mice and humans.
The unique taste induced by monosodium glutamate is referred to as umami taste. The umami taste is also elicited by the purine nucleotides inosine 5'-monophosphate and guanosine 5'-monophosphate. There is evidence that a heterodimeric G protein-coupled receptor, which consists of the T1R1 (taste receptor type 1, member 1, Tas1r1) and the T1R3 (taste receptor type 1, member 3, Tas1r3) proteins, functions as an umami taste receptor for rodents and humans. Splice variants of metabotropic glutamate receptors, mGluR(1) (glutamate receptor, metabotropic 1, Grm1) and mGluR(4) (glutamate receptor, metabotropic 4, Grm4), also have been proposed as taste receptors for glutamate. The taste sensitivity to umami substances varies in inbred mouse strains and in individual humans. However, little is known about the relation of umami taste sensitivity to variations in candidate umami receptor genes in rodents or in humans. In this article, we summarize current knowledge of the diversity of umami perception in mice and humans. Furthermore, we combine previously published data and new information from the single nucleotide polymorphism databases regarding variation in the mouse and human candidate umami receptor genes: mouse Tas1r1 (TAS1R1 for human), mouse Tas1r3 (TAS1R3 for human), mouse Grm1 (GRM1 for human), and mouse Grm4 (GRM4 for human). Finally, we discuss prospective associations between variation of these genes and umami taste perception in both species.


Guided self-help for depression in autistic adults: the ADEPT feasibility RCT.
Co-occurring depression frequently occurs in autism. Evidence-based psychological interventions have been successfully adapted to treat co-occurring anxiety, but there is little evidence about the usefulness of adapted cognitive-behavioural therapy for depression. To the authors' knowledge, to date there have been no randomised trials investigating the usefulness of low-intensity cognitive-behavioural therapy for depression in autism. The objectives of the study were to (1) develop a low-intensity psychological intervention for depression adapted for autism, (2) assess the feasibility and patient and therapist acceptability of the intervention, (3) estimate the rates of recruitment and retention for a full-scale randomised controlled trial and (4) identify an appropriate measure of depression to be used in a full-scale randomised controlled trial. The study comprised a randomised controlled trial (n = 70) with a nested qualitative evaluation (n = 21). Seventy eligible and consenting participants were randomly allocated to guided self-help or to treatment as usual. Adult autism services in two NHS regions. Adults with a diagnosis of autism spectrum disorder with depression, that is, a Patient Health Questionnaire-9 items score of ≥ 10. People who had attended more than six sessions of cognitive-behavioural therapy in the previous 6 months were excluded. The low-intensity intervention (guided self-help) comprised materials for nine individual sessions, based on behavioural activation adapted for autism, facilitated by therapist guides (coaches) who were graduate-level psychologists who attended training and regular supervision. Treatment as usual was standard NHS care for depression. Outcomes were measured 10, 16 and 24 weeks post randomisation using self-report and interview measures of depression, anxiety, obsessive-compulsive symptoms, social function and quality of life, and a health-care and service use questionnaire. As this was a feasibility study also designed to identify the most appropriate measure of depression, it was not possible to specify the primary outcome measure or outcome point a priori. The aims of the study were met in full. The guided self-help intervention was feasible and well received by participants and coaches. The majority of allocated participants attended the intervention in full. The most practical outcome point was determined to be 16 weeks. There were differential rates of attrition across the treatment groups: 86% of the guided self-help group remained in the study at 24 weeks, compared with 54% of treatment as usual group. The qualitative study suggested that guided self-help had enhanced credibility with participants at the point of randomisation. Inter-rater reliability of the interview measure of depression was less than adequate, limiting the conclusions that can be drawn from the prespecified sensitivity to change analyses. The intervention was feasible and well received. Although this feasibility study was not a fully powered trial, it provided some evidence that the guided self-help intervention was effective in reducing depressive symptoms. A full-scale clinical effectiveness and cost-effectiveness trial of the intervention is warranted. Improvements to the intervention materials as a result of qualitative interviews. Stakeholder consultation to consider future trial design, consider strategies to improve retention in a treatment as usual arm and select a self-report measure of depression to serve as the primary outcome measure. Current Controlled Trials ISRCTN54650760. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 68. See the NIHR Journals Library website for further project information. This study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.


Ultrasound modulates ion channel currents.
Transcranial focused ultrasound (US) has been demonstrated to stimulate neurons in animals and humans, but the mechanism of this effect is unknown. It has been hypothesized that US, a mechanical stimulus, may mediate cellular discharge by activating mechanosensitive ion channels embedded within cellular membranes. To test this hypothesis, we expressed potassium and sodium mechanosensitive ion channels (channels of the two-pore-domain potassium family (K2P) including TREK-1, TREK-2, TRAAK; NaV1.5) in the Xenopus oocyte system. Focused US (10 MHz, 0.3-4.9 W/cm(2)) modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. The effects were reversible upon repeated stimulation and were abolished when a channel blocker (ranolazine to block NaV1.5, BaCl2 to block K2P channels) was applied to the solution. These data reveal at the single cell level that focused US modulates the activity of specific ion channels to mediate transmembrane currents. These findings open doors to investigations of the effects of US on ion channels expressed in neurons, retinal cells, or cardiac cells, which may lead to important medical applications. The findings may also pave the way to the development of sonogenetics: a non-invasive, US-based analogue of optogenetics.


Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer.
Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.


Robust gene expression signature from formalin-fixed paraffin-embedded samples predicts prognosis of non-small-cell lung cancer patients.
The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes. We randomly selected 100 Non-Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model. This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature. We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings.


Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders.
Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4-6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.


Imaging live humans through smoke and flames using far-infrared digital holography.
The ability to see behind flames is a key challenge for the industrial field and particularly for the safety field. Development of new technologies to detect live people through smoke and flames in fire scenes is an extremely desirable goal since it can save human lives. The latest technologies, including equipment adopted by fire departments, use infrared bolometers for infrared digital cameras that allow users to see through smoke. However, such detectors are blinded by flame-emitted radiation. Here we show a completely different approach that makes use of lensless digital holography technology in the infrared range for successful imaging through smoke and flames. Notably, we demonstrate that digital holography with a cw laser allows the recording of dynamic human-size targets. In this work, easy detection of live, moving people is achieved through both smoke and flames, thus demonstrating the capability of digital holography at 10.6 μm.


Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction. The TIMI-II pilot and randomized clinical trial combined experience.
Ischemic cerebral infarction (CI) is a serious complication of acute myocardial infarction (MI). Little information exists on CI after thrombolytic therapy for MI. Of 3924 MI patients treated with recombinant tissue plasminogen activator (rt-PA) and heparin, 29 (0.7%) developed CI after treatment. All CI patients had detailed neurological evaluations, and 27 (93%) had CT scans centrally reviewed. Age range was 40 to 74 years (mean, 60 years); 25 patients (86%) were men, and 22 (76%) were white. The electrocardiographic location of MI was anterior in 22 (76%) and nonanterior in 7 (24%). Five CIs occurred within 6 hours, 4 between 6 to 24 hours, 8 during the remainder of the first week, 10 during the second week, and 2 others distributed over the 4 weeks after study entry. Six of 29 CIs did not involve the cerebral cortex; 9 patients (31%) had multiple CIs. Of 28 CIs thought to be embolic in origin, 17 showed strong evidence for at least one cardiac abnormality (mural clot, wall-motion abnormality, aneurysm, or atrial fibrillation) known to be associated more specifically with embolism than MI. Eight of 27 CIs (30%) with CT scans had hemorrhagic transformation of varying degrees; 5 were symptomatic. The time of occurrence and sites of CI after rt-PA and heparin therapy for acute MI are similar to those reported during the prethrombolytic era.


Cardiometabolic health, prescribed antipsychotics and health-related quality of life in people with schizophrenia-spectrum disorders: a cross-sectional study.
People with schizophrenia-spectrum disorders (SSD) often have high levels of obesity and poor cardiometabolic health. Certain types of antipsychotics have been shown to contribute towards weight gain and there is some equivocal evidence that obesity is related to poor health-related quality of life (HRQoL) in people with SSD. It is also still uncertain if antipsychotic polypharmacy/higher doses of antipsychotics are linked with HRQoL and/or increased risk of obesity/Cardiovascular Disease (CVD). Therefore, this study aimed to examine potential relationships between prescribed antipsychotic medication regimens, cardiometabolic health risks and HRQoL in community-based Chinese people with SSD. This cross-sectional study reports the results of baseline measurements of a random sample of patients in an ongoing controlled trial of physical health intervention for people with severe mental illness. Data from these randomly-selected participants (n = 82) were analysed to calculate 10-year CVD relative-risk (using QRISK®2 score), estimate the prevalence of metabolic syndrome and contextualize patients' prescribed antipsychotics (types, combinations and Daily Defined Dose equivalent). Patients self-reported their HRQoL (SF12v2) and their obesity condition was assessed by waist-circumference and Body Mass Index (BMI). Two-thirds of patients had a BMI ≥23 kg/m2, almost half were centrally obese and 29% met the criteria for metabolic syndrome. The individual relative-risk of CVD ranged from 0.62 to 15, and 13% had a moderate-to-high 10-year CVD risk score. Regression models showed that lower physical HRQoL was predicted by higher BMI and lower mental HRQoL. Higher Defined Daily Dose, clozapine, younger age and male gender were found to explain 40% of the variance in CVD relative risk. The findings indicate that cardiometabolic health risks in people with SSD may be more common than those reported in the general Hong Kong population. The results also provide further support for the need to consider antipsychotic polypharmacy and higher doses of antipsychotics as factors that may contribute towards cardiometabolic risk in Chinese patients with SSD. Clinicians in Hong Kong should consider using routine CVD risk screening, and be aware that younger male patients who are taking clozapine and prescribed higher Defined Daily Dose seem to have the highest relative-risk of CVD. Clinicaltrials.gov NCT02453217 . Prospectively registered on 19th May 2015.


Interplay between Developmental Flexibility and Determinism in the Evolution of Mimetic Heliconius Wing Patterns.
To what extent can we predict how evolution occurs? Do genetic architectures and developmental processes canalize the evolution of similar outcomes in a predictable manner? Or do historical contingencies impose alternative pathways to answer the same challenge? Examples of Müllerian mimicry between distantly related butterfly species provide natural replicates of evolution, allowing us to test whether identical wing patterns followed parallel or novel trajectories. Here, we explore the role that the signaling ligand WntA plays in generating mimetic wing patterns in Heliconius butterflies, a group with extraordinary mimicry-related wing pattern diversity. The radiation is relatively young, and numerous cases of wing pattern mimicry have evolved within the last 2.5-4.5 Ma. WntA is an important target of natural selection and is one of four major effect loci that underlie much of the pattern variation in the group. We used CRISPR/Cas9 targeted mutagenesis to generate WntA-deficient wings in 12 species and a further 10 intraspecific variants, including three co-mimetic pairs. In all tested butterflies, WntA knockouts affect pattern broadly and cause a shift among every possible scale cell type. Interestingly, the co-mimics lacking WntA were very different, suggesting that the gene networks that pattern a wing have diverged considerably among different lineages. Thus, although natural selection channeled phenotypic convergence, divergent developmental contexts between the two major Heliconius lineages opened different developmental routes to evolve resemblance. Consequently, even under very deterministic evolutionary scenarios, our results underscore a surprising unpredictability in the developmental paths underlying convergence in a recent radiation.


Microbial degradation of halogenated compounds.
The mode of degradation of various halogenated compounds in isolated pure cultures and the disposition of the degradative genes have been studied. In many cases the degradative genes are found to be clustered on plasmids and appear to be under positive control. Genetic selection in vivo and genetic manipulations in vitro have allowed construction of strains having wider biodegradative potentials than their natural counterparts. Molecular cloning of the degradative gene clusters for halogenated compounds in vectors with a broad host range also allows the transfer of such genes to a large number of Gram-negative bacteria. The application of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)-degrading microorganisms has demonstrated the effectiveness of this strain in removing large amounts of 2,4,5-T from contaminated soil within a short period, and such soil has been shown to support the growth of plants normally sensitive to low concentrations of 2,4,5-T. The two major challenges that must be addressed in the near future are the development of appropriate microbial technology for the decontamination of soil containing hazardous halogenated compounds, and the promulgation of appropriate regulations to ensure the safety and well-being of the public during the application of genetically improved strains in an open environment.


Chemical fossils: the geological fate of steroids.
Steroids are used to illustrate some of the significant advances that have been made in recent years in understanding the biological origin and geological fate of the organic compounds in sediments. The precursor sterols are transformed, initially by microbial activity and later by physicochemical constraints, into thermodynamically more stable saturated and aromatic hydrocarbons in mature sediments and petroleums. The steps in this transformation result in a complex web linking biogenesis, diagenesis, and catagenesis. Indeed, the complexity and variety of biological lipids such as the steroids are evidently matched in the corresponding geolipids. The extent of preservation of the biochemical imprint in the structures and stereochemistry of these geolipids, even over hundreds of millions of years, is startling, as is the systematic and sequential nature of the geochemical changes they evidently undergo. This new understanding of molecular organic geochemistry has applications in petroleum geochemistry, where biological marker compounds are valuable in the assessment of sediment maturity and in correlation work.


Dielectric barrier discharge induced degradation of diclofenac in aqueous solution.
A dielectric barrier discharge (DBD) reactor as one of the advanced oxidation processes was applied to the degradation of diclofenac in aqueous solution. The various parameters that affect the degradation of diclofenac and the proposed evolutionary process were investigated. The results indicated that the inner concentrations of 10 mg/L diclofenac can be all removed within 10 min under conditions of 50 W and pH value of 6.15. The existence of Fe(2+) in the liquid phase can promote the degradation of diclofenac. But it was rather ineffective in mineralization, because the intermediates containing the aromatic rings were recalcitrant to be degraded. Five intermediates were identified by liquid chromatography-mass spectrometry (LC-MS), the OH · radical and O(3) were the major reactive species, and played an important role in the degradation of diclofenac. The toxicity of diclofenac degraded by DBD was assessed and the results indicated the efficiency of the DBD in the detoxification of the diclofenac solution.


Interaction between systolic and diastolic time intervals in atrial fibrillation.
To assess determinants of left ventricular filling time at rest simultaneous phonocardiograms, M mode echocardiograms, and indirect carotid pulse traces were performed on 50 patients with atrial fibrillation. Thus the effect of random variation in RR interval in the absence of atrial contraction on the inter-relation between systolic and diastolic events could be seen. Left ventricular filling time was closely related to RR interval and affected by it to a much greater extent than ejection time, so that filling time became very short when heart rate was fast. Two mechanisms were, however, identified whereby filling time was preserved: (a) prolongation of filling during the pre-ejection period of the following cycle, so that when the RR interval was less than 400 ms all of ventricular filling frequently occurred at this time; and (b) abbreviation of the QA2 interval of the succeeding beat with reduced filling, so that mitral valve opening occurred early. Changes in the duration of isovolumic contraction or relaxation time were not involved, neither could alteration in left ventricular contractile state resulting from variation in the interval between beats be shown to affect time at rest. The striking sensitivity of left ventricular filling time to rapid heart rate in atrial fibrillation suggests that it may be a major factor limiting cardiac performance. Diastolic as well as systolic events should, therefore, be taken into account when the effects of drugs or other physiological manoeuvres are studied in these patients.


Scattering Signatures of Normal versus Abnormal Livers with Support Vector Machine Classification.
Fifty years of research on the nature of backscatter from tissues has resulted in a number of promising diagnostic parameters. We recently introduced two analyses tied directly to the biophysics of ultrasound scattering: the H-scan, based on a matched filter approach to distinguishing scattering transfer functions, and the Burr distribution for quantification of speckle patterns. Together, these analyses can produce at least five parameters that are directly linked to the mathematics of ultrasound in tissue. These have been measured in vivo in 35 rat livers under normal conditions and after exposure to compounds that induce inflammation, fibrosis, and steatosis in varying combinations. A classification technique, the support vector machine, is employed to determine clusters of the five parameters that are signatures of the different liver conditions. With the multiparametric measurement approach and determination of clusters, the different types of liver pathology can be discriminated with 94.6% accuracy.


P190-B Rho GTPase-activating protein overexpression disrupts ductal morphogenesis and induces hyperplastic lesions in the developing mammary gland.
p190-B Rho GTPase activating protein is essential for mammary gland development because p190-B deficiency prevents ductal morphogenesis. To investigate the role of p190-B during distinct stages of mammary gland development, tetracycline-regulatable p190-B-overexpressing mice were generated. Short-term induction of p190-B in the developing mammary gland results in abnormal terminal end buds (TEBs) that exhibit aberrant budding off the neck, histological anomalies, and a markedly thickened stroma. Overexpression of p190-B throughout postnatal development results in increased branching, delayed ductal elongation, and disorganization of the ductal tree. Interestingly, overexpression of p190-B during pregnancy results in hyperplastic lesions. Several cellular and molecular alterations detected within the aberrant TEBs may contribute to these phenotypes. Signaling through the IGF pathway is altered, and the myoepithelial cell layer is discontinuous at sites of aberrant budding. An increase in collagen and extensive infiltration of macrophages, which have recently been implicated in branching morphogenesis, is observed in the stroma surrounding the p190-B-overexpressing TEBs. We propose that the stromal response, disruption of the myoepithelial layer, and alterations in IGF signaling in the p190-B-overexpressing mice impact the TEB architecture, leading to disorganization and increased branching of the ductal tree. Moreover, we suggest that alterations in tissue architecture and the adjacent stroma as a consequence of p190-B overexpression during pregnancy leads to loss of growth control and the formation of hyperplasia. These data demonstrate that precise control of p190-B Rho GTPase-activating protein activity is critical for normal branching morphogenesis during mammary gland development.


Synthesis of PbS/PbI2 nanocomposites in mixed solvent and their composition-dependent electrogenerated chemiluminescence performance.
PbS/PbI2 nanocomposites were prepared by choosing K[PbI3] as both a lead salt and an iodide precursor and acetone/water as a reaction medium. It was found that the amount of the PbI2 component could be controlled, to some extent, by varying the amount of water used. Further, this simple bicomponent precursor-based synthetic route can be extended to prepare other lead-containing nanocomposites such as Pb3O4/PbI2 and PbSe/PbI2. Because of the heavy-atom effect, PbS/PbI2 nanocomposites exhibited good and composition-dependent electrogenerated chemiluminescence (ECL) performance, demonstrating their potential in the development of novel ECL sensors for analytical and clinical applications. These interesting findings would encourage us to gain deep insight on these phenomena, which could lead to the further development of these new inorganic materials and their applications.


Is manipulative therapy more effective than sham manipulation in adults : a systematic review and meta-analysis.
Manipulative therapy is widely used in the treatment of spinal disorders. Manipulative techniques are under debate because of the possibility of adverse events. To date, the efficacy of manipulations compared to sham manipulations is unclear. The purpose of the study is: to assess the efficacy of manipulative therapy compared to sham in adults with a variety of complaints. Systematic review and meta-analysis. Bibliographic databases (PubMed, EMBASE, CINAHL, PEDro, Central) along with a hand search of selected bibliographies were searched from inception up to April 2012. In total 965 references were screened for eligibility and 19 RCTs (n = 1080) met the selection criteria. Eight studies were considered of low risk of bias. There is moderate level of evidence that manipulative therapy has a significant effect in adults on pain relief immediately after treatment (standardized mean difference [SMD] - 0.68, 95% confidence interval (-1.06 to -0.31). There is low level of evidence that manipulative therapy has a significant effect in adults on pain relief (SMD - 0.37, -0.69 to -0.04) at short- term follow-up. In patients with musculoskeletal disorders, we found moderate level of evidence for pain relief (SMD - 0.73, -1.21 to -0.25) immediate after treatment and low level of evidence for pain relief (SMD - 0.52, -0.87 to -0.17) at short term-follow-up. We found very low level of evidence that manipulative therapy has no statistically significant effect on disability and perceived (asthma) recovery. Sensitivity analyses did not change the main findings. No serious adverse events were reported in the manipulative therapy or sham group. Manipulative therapy has a clinical relevant effect on pain, but not on disability or perceived (asthma) recovery. Clinicians can refer patients for manipulative therapy to reduce pain.


Spatiotemporal human facial expression recognition using fisher independent component analysis and Hidden Markov Model.
Facial expression recognition is an essential research area in the field of Human Computer Interface. In this work, we present a spatiotemporal approach of facial expression recognition using image sequences. The system proposed in this paper describes fisher independent component analysis as a feature extractor where the higher order moment classification method (i.e., independent component analysis) is augmented with fisher linear discriminant. This procedure is simply abbreviated as FICA and produces the shape based spatial facial expression features. For recognition, we have utilized Hidden Markov Model (HMM) to learn the obtained spatial features with the temporal dynamics in six different expressions. Our proposed approach for the first time deals with sequential images of emotion-specific facial expression data analyzed with FICA and recognized with HMM. Performance of our proposed system has been compared with four conventional approaches where principal component analysis, generic independent component analysis, enhanced independent component analysis, and augmented principal component analysis with linear discriminant analysis are utilized for feature extraction. Our preliminary results show that our proposed system yields much improved recognition rates reaching the mean recognition rate of 92.85%.


The importance of weak physical performance in older adults for the development of musculoskeletal pain that interferes with normal life. A prospective cohort study.
There are associations between pain, comorbidity and risk of falling, and falling increases the risk of mortality in older persons, but few studies have investigated the development of pain as a result of impaired physical function. The aim of this study was to examine possible associations between weak physical performance and the development of musculoskeletal pain that interferes with normal life in a sample of older adults. The sample derived from a national, longitudinal multicenter study; the Swedish National Study on Ageing and Care; SNAC-B. The participants (n = 490) were between 60 and 78 years at the baseline examinations. Three variables were chosen for the exposure physical function, from the baseline examinations; One Leg Stand, Grip strength and Sit-to-Stand. The outcome musculoskeletal pain that interferes with normal life was measured using EQ5D and SF-12 6 years later, and logistic regression was used to investigate possible associations between the exposures and the outcome. Maximum grip strength (Grippit) was inversely associated with musculoskeletal pain that interferes with normal life (OR 2.31; 95% CI 1.15-4.61), and One-Leg Stand and Sit-to-Stand were not associated with the development of pain (OR 1.30; 95% CI 0.64-2.64) and (OR 0.91; 95% CI 0.45-1.86), respectively. Weak grip strength was inversely associated with the development of musculoskeletal pain that interferes with normal life in older adults. Impaired proprioceptive function, strength and mobility in elderly with pain have been found in earlier research. Since pain increases the risk of falling, it is important to investigate if it may develop as a function of an impaired physical function. The results of the present study could be of importance for future prevention programs aiming to protect elderly from falling.


Reliability of the TekScan MatScan® system for the measurement of postural stability in older people with rheumatoid arthritis.
Postural stability can be measured in clinical and research settings using portable plantar pressure systems. People with rheumatoid arthritis (RA) have decreased postural stability compared to non-RA populations and impaired postural stability is associated with falls in people with RA. The purpose of this study was therefore to investigate the reliability of the TekScan MatScan® system in assessing postural stability in people with RA. Twenty three participants with RA, mean (SD) age 69.74 (10.1) years, were assessed in barefoot double-limb quiet standing, with eyes open and eyes closed, for antero-posterior and medio-lateral postural sway values. Three repetitions, at a sampling frequency of 40 Hz, were recorded for each test condition to obtain a mean value. Measurements were repeated one hour later. Intraclass correlation coefficients (ICC) with 95% confidence intervals (CI) were calculated to determine between-session reliability. Measurement error was assessed through the calculation of the standard error of the measurement (SEM) and the smallest real difference (SRD). The system displayed good to excellent reliability for antero-posterior and medio-lateral sway, with eyes open and closed, as indicated by ICC values ranging from 0.84 to 0.92. Measurement error, as evidenced by the SEM, ranged from 1.27 to 2.35 mm. The degree of change required to exceed the expected trial to trial variability was relatively high, compared to mean values, with SRD ranging from 3.08 to 5.71 mm. The portability and ease of use of the TekScan MatScan® makes it a useful tool for the measurement of postural stability in clinical and research settings. The TekScan MatScan® system can reliably measure double-limb quiet standing in older people, aged 60 to 80 years, with RA.


Neurogenic activity--angiotensin II interaction during the development and maintenance of renal hypertension in the rat.
1. Pentolinium tartrate (a ganglionic blocker) was injected in conscious rats during the early and late phases of two-kidney renal hypertension produced by aortic ligation. 2. In the early phase ( 5 days after aortic ligation), ganglionic blockade resulted in a decrease in blood pressure equal to that obtained in normotensive rats. Later, at days 12 and 40, for equally severe hypertension, ganglion blockade resulted in a greater decrease in blood pressure. 3. A 30 min infusion of [Sar1, Ala8]angiotensin II during the pentolinium-induced nadir in blood pressure resulted in a further decrease in blood pressure at day 5. Later, at days 12 and 40, this effect was smaller. 4. A 300 min infusion of [Sar1, Ala8]angiotensin II normalized the blood pressure in hypertensive rats at day 40. This delay response may be secondary to a central effect of the antagonist, reducing neurogenic tone or peripheral antagonism of locally generated angiotensin II in the blood vessel walls. 5. At day 40, removal of the small left kidney resulted in a greater decrease in blood pressure. This suggests the presence of a renal factor other than renin in the chronic phase of this hypertension.


Evaluation of the two-needle strategy for reducing reactions to DPT vaccination.
Using a blinded crossover design, we tested the hypothesis that changing the needle on the syringe after drawing up diphtheria-pertussis-tetanus vaccine and before injecting it reduces local complications by eliminating deposition of aluminum phosphate adjuvant in the subcutaneous track of the needle. Two hundred twenty-three children (52.7%) received a two-needle vaccination while 200 (47.3%) received a one-needle vaccination. Three hundred forty-six parents (81.8%) returned a questionnaire reporting their child's reaction within 48 hours of injection. There was no significant difference in the occurrence of redness, swelling, tenderness, or limp or in parental measurements of redness and swelling between the one- and two-needle groups. Moreover, we found no differences in the frequency of systemic side effects, including fever, vomiting, anorexia, and crying. These results do not support the practice of changing needles to reduce diphtheria-pertussis-tetanus vaccine reactions.


A novel role for ezrin in breast cancer angio/lymphangiogenesis.
Recent evidence suggests that tumour lymphangiogenesis promotes lymph node metastasis, a major prognostic factor for survival of breast cancer patients. However, signaling mechanisms involved in tumour-induced lymphangiogenesis remain poorly understood. The expression of ezrin, a membrane cytoskeletal crosslinker and Src substrate, correlates with poor outcome in a diversity of cancers including breast. Furthermore, ezrin is essential in experimental invasion and metastasis models of breast cancer. Ezrin acts cooperatively with Src in the regulation of the Src-induced malignant phenotype and metastasis. However, it remains unclear if ezrin plays a role in Src-induced tumour angio/lymphangiogenesis. The effects of ezrin knockdown and mutation on angio/lymphangiogenic potential of human MDA-MB-231 and mouse AC2M2 mammary carcinoma cell lines were examined in the presence of constitutively active or wild-type (WT) Src. In vitro assays using primary human lymphatic endothelial cells (hLEC), an ex vivo aortic ring assay, and in vivo tumour engraftment were utilized to assess angio/lymphangiogenic activity of cancer cells. Ezrin-deficient cells expressing activated Src displayed significant reduction in endothelial cell branching in the aortic ring assay in addition to reduced hLEC migration, tube formation, and permeability compared to the controls. Intravital imaging and microvessel density (MVD) analysis of tumour xenografts revealed significant reductions in tumour-induced angio/lymphangiogenesis in ezrin-deficient cells when compared to the WT or activated Src-expressing cells. Moreover, syngeneic tumours derived from ezrin-deficient or Y477F ezrin-expressing (non-phosphorylatable by Src) AC2M2 cells further confirmed the xenograft results. Immunoblotting analysis provided a link between ezrin expression and a key angio/lymphangiogenesis signaling pathway by revealing that ezrin regulates Stat3 activation, VEGF-A/-C and IL-6 expression in breast cancer cell lines. Furthermore, high expression of ezrin in human breast tumours significantly correlated with elevated Src expression and the presence of lymphovascular invasion. The results describe a novel function for ezrin in the regulation of tumour-induced angio/lymphangiogenesis promoted by Src in breast cancer. The combination of Src/ezrin might prove to be a beneficial prognostic/predictive biomarker for early-stage metastatic breast cancer.


Prophylactic Onlay Mesh Implantation During Definitive Fascial Closure After Open Abdomen Therapy (PROMOAT): Absorbable or Non-absorbable? Methodical Description and Results of a Feasibility Study.
Introduction: Incisional hernia development after open abdomen therapy (OAT) remains a common complication in the long run. To demonstrate the feasibility, we describe our method of prophylactic onlay mesh implantation with definitive fascial closure after open abdomen therapy (PROMOAT). To display the feasibility of this concept, we evaluated the short-term outcome after absorbable and non-absorbable synthetic mesh implantation as prophylactic onlay. Material and Methods: Ten patients were prospectively enrolled, and prophylactic onlay mesh (long-term absorbable or non-absorbable) was implanted at the definitive fascial closure operation. The cohort was followed up with a special focus on incisional hernia development and complications. Results: OAT duration was 21.0 ± 12.6 days (95% CI: 16.9-25.1). Definitive fascial closure was achieved in all cases. No incisional hernias were present during a follow-up interval of 12.4 ± 10.8 months (range 1-30 months). Two seromas and one infected hematoma occurred. The outcome did not differ between mesh types. Conclusion: The prophylactic onlay mesh implantation of alloplastic, long-term absorbable, or non-absorbable meshes in OAT showed promising results and only a few complications that were of minor concern. Incisional hernias did not occur during follow-up. To validate the feasibility and safety of prophylactic onlay mesh implantation long-term data and large-scaled prospective trials are needed to give recommendations on prophylactic onlay mesh implantation after OAT.


Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.
Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTENConclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639-47. ©2017 AACR.


Animal reactions to oncoming vehicles: a conceptual review.
Animal-vehicle collisions (AVCs) are a substantial problem in a human-dominated world, but little is known about what goes wrong, from the animal's perspective, when a collision occurs with an automobile, boat, or aircraft. Our goal is to provide insight into reactions of animals to oncoming vehicles when collisions might be imminent. Avoiding a collision requires successful vehicle detection, threat assessment, and evasive behaviour; failures can occur at any of these stages. Vehicle detection seems fairly straightforward in many cases, but depends critically on the sensory capabilities of a given species. Sensory mechanisms for detection of collisions (looming detectors) may be overwhelmed by vehicle speed. Distractions are a likely problem in vehicle detection, but have not been clearly demonstrated in any system beyond human pedestrians. Many animals likely perceive moving vehicles as non-threatening, and may generally be habituated to their presence. Slow or minimal threat assessment is thus a likely failure point in many AVCs, but this is not uniformly evident. Animals generally initiate evasive behaviour when a collision appears imminent, usually employing some aspect of native antipredator behaviour. Across taxa, animals exhibit a variety of behaviours when confronted with oncoming vehicles. Among marine mammals, right whales Eubalaena spp., manatees Trichechus spp., and dugongs Dugong dugon are fairly unresponsive to approaching vehicles, suggesting a problem in threat assessment. Others, such as dolphins Delphinidae, assess vehicle approach at distance. Little work has been conducted on the behavioural aspects of AVCs involving large mammals and automobiles, despite their prevalence. Available observations suggest that birds do not usually treat flying aircraft as a major threat, often allowing close approach before taking evasive action, as they might in response to natural predators. Inappropriate antipredator behaviour (often involving immobility) is a major source of AVCs in amphibians and terrestrial reptiles. Much behavioural work on AVCs remains to be done across a wide variety of taxa. Such work should provide broad phylogenetic generalizations regarding AVCs and insights into managing AVCs.


The role of urbanization in soil and groundwater contamination by heavy metals and pathogenic bacteria: A case study from Oman.
This study assessed the perception of urban residents of A'Seeb city, Oman, about the impact of their activities on environment. A sociological survey using questionnaire was used to know the residents' perceptions about urban gardening, municipal-waste disposal, and soil and water contamination. Viable pathogenic bacteria, water soluble metals, basic cations, salinity, and texture were quantified and identified in soil and groundwater in proximity of urban gardens and municipal-waste disposal sites. The majority of surveyed residents are not paying attention to the negative consequences of their activities on soil and environment. Although the measured heavy metals concentrations in some of the contaminated sites were significant but still below the international standards. Fecal contaminants reported in in some samples from gardens, garbage-disposal sites and groundwater. Human pathogens belonging to risk group-2 including Klebsiella pneumonia, Shigella spp and E. Coil were identified. More socio-environmental studies required to correlate the behavior of urban residents and pollution and to delineate the sources of the detected pathogenic bacteria. Our results set a foundation for future studies on urban soils and associated residence behaviors and practices in Oman and the neighboring Gulf countries.


Children's Rough-and-Tumble Play in a Supportive Early Childhood Education and Care Environment.
While a growing body of evidence highlights the benefits of rough-and-tumble play (R&T) in young children, it remains one of the most challenging kinds of play to support in early childhood education and care environment (ECEC) institutions. The present study explores the occurrence and characteristics of R&T in indoor and outdoor environments in a Norwegian sociocultural context where children can freely choose what, where, and with whom to play. The data consist of 100 randomly recorded two-minute videos, which were coded second by second for R&T. Qualitative analysis reveals that in a physically and culturally supportive environment for R&T, children aged 3-5 years perceive indoor spaces that afford physically active play to be more attractive for R&T than outdoor environments. The findings indicate gender differences related to R&T and how girls and boys use the physical environment in different ways. The quantitative findings are discussed within interactional affordances theory and show that children practise perceptual, motor, and social skills to successfully engage in R&T. Enhanced knowledge of children's skill acquisition in R&T can support practitioners in developing pedagogical skills to facilitate challenging and safe environments for appropriate indoor R&T for both girls and boys.


[Opinion of medical and nursing students on the autonomy of adolescents in health care services].
In an effort to better understand some of the ethical and legal dilemmas that health professionals face in their daily activities, this study identified and analyzed the opinions and expectations of medical and nursing students at the University of São Paulo, Brazil, regarding the autonomy of adolescents in receiving health care services. Over the 1995-1996 period, interviews were done with students in the first and last years of their programs in the School of Medicine and the School of Nursing of the University of São Paulo. The results from the first-year students were compared with those of the final-year students. The interview questions dealt with such issues as providing medical care to adolescents when a parent or guardian was not present, adolescents making their own decisions on health care services, the confidentiality of information that adolescents provide, the circumstances in which that information could be given to parents or guardians, and situations where there were conflicts between the decisions of parents and adolescents. Despite variations among the opinions and expectations of the students, the overall results suggest that most of the medical and nursing students do not accept the concept of "health adulthood" or autonomy for adolescents and that the students instead choose to rely on current legal definitions of adulthood.


Integrating the ecological approach in health promotion for older adults: a survey of programs aimed at elder abuse prevention, falls prevention, and appropriate medication use.
This study assesses the extent of integration of the ecological approach in disease prevention and health promotion (DPHP) programs for older adults in a sample of organisations offering such programming in Québec, Canada. Following from our previous work, the study used a model identifying intervention settings, targets, and strategies as independent dimensions of ecological programming. As a first step, public health units, local community health centres and seniors' day centres were surveyed to identify DPHP programs for older adults. In a second phase, detailed data were obtained about programs in the theme areas of elder abuse prevention, falls prevention, and appropriate medication use. Overall, 132 programs were investigated including 17 public health unit programs, 72 local community health centre programs, and 43 day centre programs. All data were obtained through telephone interviews. The DPHP programs for these organisations tended to be situated in organisational (especially health organisation) and community settings, with individual clients and organisations as main intervention targets. Assessment of the level of integration of the ecological approach showed it to be relatively low, especially in the local community health centres and seniors' day centres.


Asymmetric synthesis of substituted NH-piperidines from chiral amines.
Previously, we reported an efficient asymmetric synthesis of substituted piperidines through an exocyclic chirality induced nitroalkene/amine/enone (NAE) condensation reaction. An effective protecting group strategy was developed herein to achieve enantiopure piperidines (yields up to 92%) with complete chirality retention (ee > 95%). A simple derivatization of the obtained piperidines gave thiourea catalysts, indicating the strong potential of this method for producing new amine-based dual functional organocatalysts for future development.


Onset of adolescent eating disorders: population based cohort study over 3 years.
To study the predictors of new eating disorders in an adolescent cohort. Cohort study over 3 years with six waves. Students, initially aged 14-15 years, from 44 secondary schools in the state of Victoria, Australia. Weight (kg), height (cm), dieting (adolescent dieting scale), psychiatric morbidity (revised clinical interview schedule), and eating disorder (branched eating disorders test). Eating disorder (partial syndrome) was defined when a subject met two criteria for either anorexia nervosa or bulimia nervosa according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). At the start of the study, 3.3% (29/888) of female subjects and 0.3% (2/811) of male subjects had partial syndromes of eating disorders. The rate of development of new eating disorder per 1000 person years of observation was 21.8 in female subjects and 6.0 in male subjects. Female subjects who dieted at a severe level were 18 times more likely to develop an eating disorder than those who did not diet, and female subjects who dieted at a moderate level were five times more likely to develop an eating disorder than those who did not diet. Psychiatric morbidity predicted the onset of eating disorder independently of dieting status so that those subjects in the highest morbidity category had an almost sevenfold increased risk of developing an eating disorder. After adjustment for earlier dieting and psychiatric morbidity, body mass index, extent of exercise, and sex were not predictive of new eating disorders. Dieting is the most important predictor of new eating disorders. Differences in the incidence of eating disorders between sexes were largely accounted for by the high rates of earlier dieting and psychiatric morbidity in the female subjects. In adolescents, controlling weight by exercise rather than diet restriction seems to carry less risk of development of eating disorders.


Management and outcomes of major bleeding during treatment with dabigatran or warfarin.
The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46-1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44-1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259.


Clinicopathological features and outcome for dogs with mast cell tumors and bone marrow involvement.
Mast cell tumors (MCTs) with bone marrow (BM) involvement are poorly documented in dogs and are associated with a poor prognosis. Successful treatment strategies have not been described. Clinicopathologic findings of affected dogs are not specific. Administration of lomustine or imatinib is beneficial. Fourteen dogs with MCT and BM involvement. Clinical and laboratory evaluations were performed in each dog on admission and during follow-up. All dogs received prednisone. Additionally, 8 dogs received lomustine and 3 dogs received imatinib. Imatinib was administered if tumor-associated tyrosine kinase KIT was aberrant. On admission, 11 dogs had a single cutaneous nodule and 3 dogs had multiple nodules. Involvement of regional lymph nodes, liver, or spleen was observed in each dog. BM infiltration with mast cells (MCs) was observed in all dogs. On CBC, nonregenerative anemia, leukopenia, or thrombocytopenia was common. Four dogs had circulating MCs. Increased alkaline phosphatase or alanine transferase activity was observed in 12 and 10 dogs, respectively. Treatment with lomustine induced partial remission in 1 of 8 dogs. Median survival time was 43 days (range, 14-57). Dogs on imatinib experienced complete remission. Two dogs survived for 117 and 159 days, and the third was alive after 75 days. Dogs treated symptomatically did not improve and were euthanized after 1, 14, and 32 days. A combination of clinical and laboratory evaluation helps in identifying dogs with MCT and BM infiltration. Administration of lomustine is not helpful in affected dogs. The beneficial effect of imatinib warrants further investigation.


Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy.
Triple-negative breast cancer (TNBC) lacks effective treatment options due to the absence of traditional therapeutic targets. The epidermal growth factor receptor (EGFR) has emerged as a promising target for TNBC therapy because it is overexpressed in about 50% of TNBC patients. Here we describe a PEG engager that simultaneously binds polyethylene glycol and EGFR to deliver PEGylated nanomedicines to EGFR+ TNBC. The PEG engager displays conditional internalization by remaining on the surface of TNBC cells until contact with PEGylated nanocarriers triggers rapid engulfment of nanocargos. PEG engager enhances the anti-proliferative activity of PEG-liposomal doxorubicin to EGFR+ TNBC cells by up to 100-fold with potency dependent on EGFR expression levels. The PEG engager significantly increases retention of fluorescent PEG probes and enhances the antitumour activity of PEGylated liposomal doxorubicin in human TNBC xenografts. PEG engagers with specificity for EGFR are promising for improved treatment of EGFR+ TNBC patients.


Spontaneous resolution of diffuse alveolar septal amyloidosis.
Amyloidosis is a generic term for a heterogeneous group of disorders associated with deposition of protein in an abnormal fibrillar form. Amyloidosis can be hereditary or acquired, localised or systemic and potentially lethal or merely an incidental finding. We report a case of a male who was totally asymptomatic and was incidentally detected to have lung amyloidosis. He was not given any treatment but kept under observation., His chest radiograph (CXR) and high resolution computed tomograph (HRCT) of the chest cleared spontaneously after one year and the patient continues to remain asymptomatic even after two years.


Quantitative assessment of tumour extraction from dermoscopy images and evaluation of computer-based extraction methods for an automatic melanoma diagnostic system.
The aims of this study were to provide a quantitative assessment of the tumour area extracted by dermatologists and to evaluate computer-based methods from dermoscopy images for refining a computer-based melanoma diagnostic system. Dermoscopic images of 188 Clark naevi, 56 Reed naevi and 75 melanomas were examined. Five dermatologists manually drew the border of each lesion with a tablet computer. The inter-observer variability was evaluated and the standard tumour area (STA) for each dermoscopy image was defined. Manual extractions by 10 non-medical individuals and by two computer-based methods were evaluated with STA-based assessment criteria: precision and recall. Our new computer-based method introduced the region-growing approach in order to yield results close to those obtained by dermatologists. The effectiveness of our extraction method with regard to diagnostic accuracy was evaluated. Two linear classifiers were built using the results of conventional and new computer-based tumour area extraction methods. The final diagnostic accuracy was evaluated by drawing the receiver operating curve (ROC) of each classifier, and the area under each ROC was evaluated. The standard deviations of the tumour area extracted by five dermatologists and 10 non-medical individuals were 8.9% and 10.7%, respectively. After assessment of the extraction results by dermatologists, the STA was defined as the area that was selected by more than two dermatologists. Dermatologists selected the melanoma area with statistically smaller divergence than that of Clark naevus or Reed naevus (P = 0.05). By contrast, non-medical individuals did not show this difference. Our new computer-based extraction algorithm showed superior performance (precision, 94.1%; recall, 95.3%) to the conventional thresholding method (precision, 99.5%; recall, 87.6%). These results indicate that our new algorithm extracted a tumour area close to that obtained by dermatologists and, in particular, the border part of the tumour was adequately extracted. With this refinement, the area under the ROC increased from 0.795 to 0.875 and the diagnostic accuracy showed an increase of approximately 20% in specificity when the sensitivity was 80%. It can be concluded that our computer-based tumour extraction algorithm extracted almost the same area as that obtained by dermatologists and provided improved computer-based diagnostic accuracy.


Efficacy of clorsulon for the treatment of experimentally induced infections of Fasciola hepatica in goats.
A dose titration study was undertaken to determine the efficacy of clorsulon against the adult stage of Fasciola hepatica in goats. Thirty-nine goats were experimentally infected with metacercariae of F hepatica. At 14 weeks after infection, each goat was assigned randomly to 1 of 5 groups. Goats in groups 1 to 4 received a single oral administration of clorsulon at dosages of 3.5, 7, 11, and 15 mg/kg of body weight, respectively. The fifth group of goats (control group) was infected with F hepatica, but were not treated with clorsulon. Postmortem examination of goats at 3 weeks after treatment revealed mean reductions in numbers of flukes of 83, 98, 99, and 100% for groups 1 to 4, respectively. Mean percentage of reduction in eggs following treatment of groups was 82, 98, 100, and 100%, respectively. The clinical effects of clorsulon in 24 goats that were not infected with F hepatica were studied. Goats in groups 1 to 3 received a single oral administration of clorsulon at dosages of 7, 21, and 35 mg/kg, respectively, every other day for a total of 3 doses/goat. Group-4 goats (control group) received a vehicle placebo. Goats in group 3 were subject to postmortem examination at 14 days after dosing. Abnormal signs or lesions that could be attributed to clorsulon were not found in any goat.


Two-dimensional sum-frequency generation (2D SFG) spectroscopy: summary of principles and its application to amyloid fiber monolayers.
By adding a mid-infrared pulse shaper to a sum-frequency generation (SFG) spectrometer, we have built a 2D SFG spectrometer capable of measuring spectra analogous to 2D IR spectra but with monolayer sensitivity and SFG selection rules. In this paper, we describe the experimental apparatus and provide an introduction to 2D SFG spectroscopy to help the reader interpret 2D SFG spectra. The main aim of this manuscript is to report 2D SFG spectra of the amyloid forming peptide FGAIL. FGAIL is a critical segment of the human islet amyloid polypeptide (hIAPP or amylin) that aggregates in people with type 2 diabetes. FGAIL is catalyzed into amyloid fibers by many types of surfaces. Here, we study the structure of FGAIL upon deposition onto a gold surface covered with a self-assembled monolayer of methyl-4-mercaptobenzoate (MMB) that produces an ester coating. FGAIL deposited on bare gold does not form ordered layers. The measured 2D SFG spectrum is consistent with amyloid fiber formation, exhibiting both the parallel (a+) and perpendicular (a-) symmetry modes associated with amyloid β-sheets. Cross peaks are observed between the ester stretches of the coating and the FGAIL peptides. Simulations are presented for two possible structures of FGAIL amyloid β-sheets that illustrate the sensitivity of the 2D SFG spectra to structure and orientation. These results provide some of the first molecular insights into surface catalyzed amyloid fiber structure.


Food and plant bioactives for reducing cardiometabolic disease risk: an evidence based approach.
Cardiovascular diseases (CVDs) are one of the major causes of mortality and disability in Western countries. Prevention is known to be the cornerstone to lessen the incidence of CVDs and also to reduce the economic burden of both the citizen and the healthcare system. "Interventional medicine" certainly puts lifestyle modification as the first therapeutic step, including a healthy diet and physical activity. Secondly, a large body of research individuated a number of food and plant bioactives, which are potentially efficacious in preventing and reducing some highly prevalent CV risk factors, such as hypercholesterolemia, hypertension, vascular inflammation and vascular compliance. Some lipid- and blood pressure-lowering bioactives were studied for their impact on human vascular health, particularly as regards endothelial function and arterial stiffness. Several nutraceuticals showed additive or synergistic properties in combination, sometimes (but not always) allowing a reduction of the administered dose of extracts and determining a "multi-factorial" final effect on many cardiovascular risk factors. Thus, this review focuses on available evidence regarding the effects of berberine, plant sterols, green tea extract, soy, curcumin, cocoa, pycnogenol, lycopene, olive oil, soluble fibers, garlic, resveratrol, beetroot, mineral salts and vitamins on the lipid profile, blood pressure, inflammatory and endothelial markers, and vascular compliance. Future clinical research studies will have to focus more on middle term modification of the instrumental markers of vascular aging than on short-term effects on indirect laboratory risk markers.


Blindsight relies on a functional connection between hMT+ and the lateral geniculate nucleus, not the pulvinar.
When the primary visual cortex (V1) is damaged, the principal visual pathway is lost, causing a loss of vision in the opposite visual field. While conscious vision is impaired, patients can still respond to certain images; this is known as 'blindsight'. Recently, a direct anatomical connection between the lateral geniculate nucleus (LGN) and human motion area hMT+ has been implicated in blindsight. However, a functional connection between these structures has not been demonstrated. We quantified functional MRI responses to motion in 14 patients with unilateral V1 damage (with and without blindsight). Patients with blindsight showed significant activity and a preserved sensitivity to speed in motion area hMT+, which was absent in patients without blindsight. We then compared functional connectivity between motion area hMT+ and a number of structures implicated in blindsight, including the ventral pulvinar. Only patients with blindsight showed an intact functional connection with the LGN but not the other structures, supporting a specific functional role for the LGN in blindsight.


Dissolved organic matter composition drives the marine production of brominated very short-lived substances.
Brominated very short-lived substances (BrVSLS), such as bromoform, are important trace gases for stratospheric ozone chemistry. These naturally derived trace gases are formed via bromoperoxidase-mediated halogenation of dissolved organic matter (DOM) in seawater. Information on DOM type in relation to the observed BrVSLS concentrations in seawater, however, is scarce. We examined the sensitivity of BrVSLS production in relation to the presence of specific DOM moieties. A total of 28 model DOM compounds in artificial seawater were treated with vanadium bromoperoxidase (V-BrPO). Our results show a clear dependence of BrVSLS production on DOM type. In general, molecules that comprise a large fraction of the bulk DOM pool did not noticeably affect BrVSLS production. Only specific cell metabolites and humic acid appeared to significantly enhance BrVSLS production. Amino acids and lignin phenols suppressed enzyme-mediated BrVSLS production and may instead have formed halogenated nonvolatile molecules. Dibromomethane production was not observed in any experiments, suggesting it is not produced by the same pathway as the other BrVSLS. Our results suggest that regional differences in DOM composition may explain the observed BrVSLS concentration variability in the global ocean. Ultimately, BrVSLS production and concentrations are likely affected by DOM composition, reactivity, and cycling in the ocean.


Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials.
Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high-expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed.


Cervical screening result communication: a focus-group investigation of English women's experiences and needs.
To explore English women's experiences of cervical screening result communication. Qualitative study consisting of seven focus groups conducted between May 2005 and April 2006. 33 women with a range of screening results (normal, inadequate, borderline and abnormal) who had recently been for cervical screening, and five women who had attended a colposcopy appointment for the first time following screening. Three screening centres (Hampshire, Reading and Sheffield) and one colposcopy clinic (Oxford) in England. Unsatisfactory result communication (eg, delivery of out-of-date and conflicting information) on the part of both screening centres and primary care teams was highlighted. Variable levels of general practitioner involvement in screening result provision were experienced; result-giving strategies included personal as well as generic letters and telephone calls. Means for improving women's understanding of abnormal results were described including the use of diagrams to explain the progression of cell changes, the provision of updates regarding any changes in cell abnormalities between screening tests (ie, lesion progression or regression) and contact with a knowledgeable "intermediary" outside primary care. The timely provision of appropriate information is an important aspect of any screening programme. Our findings suggest that there is scope for improvement in both the delivery and content of cervical screening result notifications. Regular review of patient result-giving strategies on the part of screening centres and general practices could help ensure that screening programme standards for written information are met. Enhanced communication between primary care teams and screening centres could facilitate the provision of consistent and clear result messages thereby improving women's cervical screening experiences.


Effect of mineralocorticoid antagonists on blood pressure lowering: overview and meta-analysis of randomized controlled trials in hypertension.
Although mineralocorticoid antagonists (MRAs) have been proposed as effective fourth-line blood pressure (BP)-lowering agents in resistant hypertension, this effect in hypertension at-large is unclear. We evaluated whether MRAs-mediated BP lowering is both effective and safe against controls and whether the extent of BP lowering differs between resistant hypertension and nonresistant hypertension . We searched Medline and the Cochrane Collaboration Library databases from 1991 to mid-September 2017 for randomized controlled trials (RCTs), in which MRAs were compared with placebo or other active drugs. Main outcomes were SBP and DBP lowering and treatment-related discontinuations. Continuous outcome variables were pooled as mean difference and the categorical variables as risk ratios, both with 95% confidence interval (CI). The risk of bias was assessed by using the Cochrane collaboration tool. We included 21 RCTs (2736 patients) of MRAs compared either with placebo or with active agents. Whenever all selected trials were analyzed together (MRAs versus controls), the resulting BP reduction was -7.6 (95% CI -10 to -5.3) mmHg for SBP and -2.5 (95% CI -4.2 to -0.8) mmHg for DBP, while limiting our analysis to MRAs versus placebo mean difference was increased by -2.1/-1.3 mmHg. We find no differential BP lowering between resistant hypertension and non-resistant hypertension. Treatment-related discontinuations were not different compared with either placebo or active comparators. As the extent of BP lowering following treatment with MRAs in patients with and without resistant hypertension was similar and not accompanied by increased rate of treatment-related discontinuations compared with other active comparators, these agents may have a role in BP lowering in already treated hypertensive patients who did not reach target BP values.