c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF-beta induced epithelial-mesenchymal transition and invasion in prostate cancer.
Understanding the initial mechanisms by which epithelial cells transform to an invasive phenotype is critical to the development of diagnostics that can identify the metastatic potential of cancers as well as therapeutic agents that can prevent metastases. Changes in cellular response to the transforming growth factor-beta (TGF-β) cytokine are known to promote epithelial cell invasion and metastasis in part through induction of epithelial-mesenchymal transitions (EMTs). In this report, we demonstrate that non-metastatic human prostate cancer cell lines of increasing Gleason score can be induced to undergo EMT when treated with TGF-β in combination with epidermal growth factor. Mechanistic studies revealed that in cells stably transfected with activated Ras, TGF-β alone induced EMT and that a Ras-Raf-MEK1, but not MEK2, signaling cascade is necessary and sufficient for Erk2 nuclear localization that works in concert with TGF-β to promote EMT. Furthermore, we show for the first time that expression of the transcription factor c-myc, which is phosphorlyated by Erk2, is required for EMT. Characteristically, EMT involved adoption of a spindle-shaped morphology, loss of E-cadherin and increased expression of Vimentin, Fibronectin and Fibroblast Specific Protein-1 (S100A4). Prostate cells undergoing EMT became invasive and expressed several genes associated with metastasis, including MT-MMP1, MMP-2/9, the MMP-9 homodimer, Slug and Twist2. In sum, we demonstrate a novel mechanism by which non-invasive primary prostate tumor cells transition to an invasive phenotype characteristic of malignant tumor cells in response to TGF-β signaling.


Usefulness of high-resolution magnetic resonance cisternography in patients with hemifacial spasm.
To analyse the usefulness of preoperative magnetic resonance (MR) cisternography in patients with hemifacial spasm (HFS), MR observations were compared with surgical findings. High-definition images were obtained using MR cisternography which employed a long echo train length, fast spin-echo sequence, which revealed both nerves and blood vessels without any contrast media. In 35 HFS patients, certified radiologists examined the presence of vascular compression of the facial nerve and identified the offending vessels. MR cisternography depicted neurovascular compression in 31 patients (sensitivity 88.6%) and correctly determined the offending vessels in 28 patients. In 4 patients, MR cisternography revealed the presence of the vessel near the facial nerve, but the radiologist evaluated the compression as questionable (false-negative rate 11.4%). Even in these patients, MR cisternography revealed the precise anatomy of cerebellopontine (CP) cistern. High-resolution MR cisternography is useful in identifying the vessels and nerve bundles in the CP cistern, and in so doing can provide surgeons with valuable information regarding neurovascular decompression for HFS.


Drug-Loaded IRONSperm clusters: modeling, wireless actuation, and ultrasound imaging.
Individual biohybrid microrobots have the potential to perform biomedicalin vivotasks such as remote-controlled drug and cell delivery and minimally invasive surgery. This work demonstrates the formation of biohybrid sperm-templated clusters under the influence of an external magnetic field and essential functionalities for wireless actuation and drug delivery. Ferromagnetic nanoparticles are electrostatically assembled around dead sperm cells, and the resulting nanoparticle-coated cells are magnetically assembled into three-dimensional biohybrid clusters. The aim of this clustering is threefold: First, to enable rolling locomotion on a nearby solid boundary using a rotating magnetic field; second, to allow for noninvasive localization; third, to load the cells inside the cluster with drugs for targeted therapy. A magneto-hydrodynamic model captures the rotational response of the clusters in a viscous fluid, and predicts an upper bound for their step-out frequency, which is independent of their volume or aspect ratio. Below the step-out frequency, the rolling velocity of the clusters increases nonlinearly with their perimeter and actuation frequency. During rolling locomotion, the clusters are localized using ultrasound images at a relatively large distance, which makes these biohybrid clusters promising for deep-tissue applications. Finally, we show that the estimated drug load scales with the number of cells in the cluster and can be retained for more than 10 h. The aggregation of microrobots enables them to collectively roll in a predictable way in response to an external rotating magnetic field, and enhances ultrasound detectability and drug loading capacity compared to the individual microrobots. The favorable features of biohybrid microrobot clusters place emphasis on the importance of the investigation and development of collective microrobots and their potential forin vivoapplications.


Hydrogen sulphide: a novel endogenous gasotransmitter facilitates erectile function.
In a pilot study, we found that the novel gasotransmitter, hydrogen sulfide (H2S), had a vasodilatory and proerectile action on the cavernosum. In the present work, we explored the ability of the cavernosum to synthesize H2S and its mechanism on the cavernosal pathways. To evaluate the physiopharmacological responses and mechanism in the erectile function of H2S in rabbit cavernosum. Rabbit corpus cavernosum (CC) smooth muscle tissue (N = 5) was homogenized and incubated with L-cysteine (10 mM) and pyridoxal 5'-phosphate (2 mM) to detect H2S formation. In isometric tension studies on rabbits (N = 12), the effect of sodium hydrogen sulfide (NaHS; stable H2S donor, 100 microM-3.2 mM) was evaluated on the relaxant and contractile pathways in the cavernous smooth muscle using standard pharmacological tools. In vitro evidences for cavernosal H2S formation and proerectile pharmacological effects. H2S was readily synthesized in the rabbit CC (2.1 +/- 0.4 nmol/mg protein). In organ bath studies, NaHS consistently relaxed the rabbit CC in a concentration-dependent manner. MDL 12,330A and 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one inhibited the NaHS relaxation by 22.5% and 14.7%, respectively. All three enzyme inhibitors (aminooxyacetic acid [AOAA], beta-cyanoalanine [beta-CA], and DL-propargylglycine [PAG][1 mM]) markedly increased the noradrenergic contractile neurotransmission of CC strips to field stimulation with minimal reversal by cysteine (1 mM) indicating the possible inherent inhibition of the relaxant H2S formation. AOAA, beta-CA, or PAG had no significant effect on nitrergic relaxation of noradrenaline-precontracted CC strips. These pioneering studies provide evidence for the endogenous formation of H2S and its proerectile relaxant effect on the cavernosum, with the possibility of involvement of the cyclic adenosine monophosphate pathway.


In situ morphology of nitrifying-like bacteria in aquaculture systems.
The in situ microbiota from several aquaculture facilities with active nitrification was examined by transmission electron microscopy of thin sections for the presence of bacteria that contained intracytoplasmic membranes characteristic of the nitrifying bacteria. Colonies of bacteria with the cellular morphology of a species of Nitrosomonas were found to be present in both the culture water and in the biological filter slime of a freshwater chinook salmon (Oncorhynchus tshawytscha) culture system. bacteria in the water possessed the normal nitrosomonas type of ultrastructure, whereas similar bacteria in the slime had an aberrant morphology due to multiple invaginations of the cell wall and cyto-membranes and a significantly greater number of ribosomes. These nitrosomonas-like bacteria lysed during enrichment in commonly used media. Bacteria with the morphology of species of Nitrosomonas and Nitrosococcus were also observed in colonies in the surface slimes of marine culture systems for striped bass (Morone saxatilis) and quahaug (Mercenaria mercenaria).


The synthetic flavagline FL3 spares normal human skin cells from its cytotoxic effect via an activation of Bad.
The molecular pathways by which flavagline derivatives exert their cytotoxicity against various cancer cell types are well documented, while the mechanisms that prevent their cytotoxic effects on normal cells still have to be clarified. Here we provide the underlying molecular events by which normal skin cells remain unaffected after exposure to the synthetic flavagline FL3. Indeed, the anticancer agent fails to trigger apoptosis of healthy cells and is unable to induce the depolarization of their mitochondrial membrane and the cytosolic release of cytochrome C, in contrast to what is observed for cancer cells. Most importantly, FL3 specifically induces in normal cells, but not in malignant cells, an activation of Bad, without significant mitochondrial and cytosolic redistribution of Bax or Bcl-2. Moreover, gene knockdown of Bad sensitizes the normal fibroblastic cells to FL3 and induces a caspase-3 dependent apoptosis. Bad activation, known to promote survival and block apoptosis, explains therefore the lack of cytotoxicity of FL3 on normal skin cells. Finally, these findings provide new insights into the molecular mechanisms of resistance of healthy cells against FL3 cytotoxicity and identify it as a promising anticancer drug.


Cecal vanishing tumor associated with cytomegalovirus infection in an immunocompetent elderly adult.
Gastrointestinal involvement in cytomegalovirus (CMV) infection is well documented among immunocompromised patients and is also observed in immunocompetent individuals. The presentation of this infection can sometimes mimic those of other diseases, thus making accurate diagnosis difficult. We herein report a rare case of an immunocompetent elderly adult with gastrointestinal CMV infection that presented as a vanishing tumor at the cecum. A 76-year old man initially presented with lower abdominal pain. Colonoscopy revealed a tumorous lesion with irregular ulceration observed at the ileocecal valve. Histological findings of a biopsy specimen revealed intranuclear inclusions which were positive for CMV on immunohistochemical staining. However, this tumorous lesion disappeared within 7 wk from the initial hospital visit without any further treatment. Inflammatory pseudotumors associated with CMV infection should be considered as a differential diagnosis of tumorous lesions in the colon, even in immunocompetent adults.


A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair.
Recombinant human bone morphogenetic protein-2 (rhBMP-2), surgically implanted with a matrix material, has been shown to induce bone formation and enhance fracture repair. The purpose of this investigation was to test the hypothesis that a single, local, percutaneous injection of rhBMP-2 would accelerate fracture-healing in a standard rat femoral fracture model. Fractures were created, following intramedullary pinning, in the femora of 144 male Sprague-Dawley rats. The animals were divided into three groups of forty-eight each. Six hours after the fracture, one group received an injection of 80 micro g of rhBMP-2 in 25 micro L of buffer vehicle, one received an injection of 25 micro L of buffer vehicle alone, and one did not receive an injection. Twelve animals from each of these three groups were killed at one, two, three, and four weeks after treatment, and the femora were harvested for torsional biomechanical testing. An additional cohort of seventy-two animals, in which a fracture was also created, was divided into the same three treatment groups; six animals from each of these groups was killed at one, two, three, and four weeks; and the femora were processed for qualitative histological analysis. Torsional biomechanical testing indicated that the stiffness of the rhBMP-2-treated fractures was twice that of both control groups at the two, three, and four-week time-points. The strength of the rhBMP-2-treated fractures was 34% greater than that of the buffer-treated controls (p = 0.03) at three weeks and, at four weeks, was 60% and 77% greater than that of the buffer-treated controls and that of the untreated controls, respectively (p < 0.005). At four weeks, the stiffness and strength of the rhBMP-2-treated fractures were equal to those of the intact contralateral femora, whereas the buffer-treated and untreated fractures were significantly weaker than the intact femora. At two and three weeks, large areas of bone formation, typically spanning the fracture, were observed histologically in the rhBMP-2-treated sites. In contrast, the control fractures exhibited primarily soft cartilaginous callus at these time-points. By four weeks, remodeling of the hard callus and recorticalization were observed in the rhBMP-2-treated fracture sites, whereas cartilage and/or soft tissue was still present in the control fracture sites. These data demonstrate that a single, local, percutaneous injection of rhBMP-2 accelerates fracture repair in this rat femoral fracture model. This effect appears to result from a combination of the induction of bone formation at the fracture site and acceleration of the rate at which the fracture callus matures.


A search for decays of the Higgs boson to invisible particles in events with a top-antitop quark pair or a vector boson in proton-proton collisions at s=13TeV.
A search for decays to invisible particles of Higgs bosons produced in association with a top-antitop quark pair or a vector boson, which both decay to a fully hadronic final state, has been performed using proton-proton collision data collected at s=13TeV by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138fb-1. The 95% confidence level upper limit set on the branching fraction of the 125GeV Higgs boson to invisible particles, B(H→inv), is 0.54 (0.39 expected), assuming standard model production cross sections. The results of this analysis are combined with previous B(H→inv) searches carried out at s=7, 8, and 13TeV in complementary production modes. The combined upper limit at 95% confidence level on B(H→inv) is 0.15 (0.08 expected).


Extensive post-traumatic ossification of the patellar tendon. A report of two cases.
Two men, aged 21 and 50 years, were seen with ossification of the patellar tendon after injury to the knee in adolescence. They complained of pain and had patella alta. Large bony masses were excised from below the affected patellae. The patellar tendon was then reconstructed using a Leeds-Keio ligament. The results at six and ten years, respectively, were good, with neither patient having pain or an extension lag.


Validation of Serum Biomarkers That Complement CA19-9 in Detecting Early Pancreatic Cancer Using Electrochemiluminescent-Based Multiplex Immunoassays.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy; its early detection is critical for improving prognosis. Electrochemiluminescent-based multiplex immunoassays were developed with high analytical performance. All proteins were analyzed in sera of patients diagnosed with PDAC (n = 138), benign pancreatic conditions (111), and healthy controls (70). The clinical performance of these markers was evaluated individually or in combination for their complementarity to CA19-9 in detecting early PDAC. Logistic regression modeling including sex and age as cofactors identified a two-marker panel of CA19-9 and CA-125 that significantly improved the performance of CA19-9 alone in discriminating PDAC (AUC: 0.857 vs. 0.766), as well as early stage PDAC (0.805 vs. 0.702) from intraductal papillary mucinous neoplasm (IPMN). At a fixed specificity of 80%, the panel significantly improved sensitivities (78% vs. 41% or 72% vs. 59%). A two-marker panel of HE4 and CEA significantly outperformed CA19-9 in separating IPMN from chronic pancreatitis (0.841 vs. 0.501). The biomarker panels evaluated by assays demonstrated potential complementarity to CA19-9 in detecting early PDAC, warranting additional clinical validation to determine their role in the early detection of pancreatic cancer.


Direct evidence for increased hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type 1a receptor.
Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin II-induced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild-type and angiotensin II type-1a receptor knockout mice for 2 weeks. The angiotensin II treatment increased blood pressure and heart weight/body weight ratio in wild-type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alpha-phenyl-N-tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2-fold (p < 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type-1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.


Real-time bioluminescence imaging of mixed mycobacterial infections.
Molecular analysis of infectious processes in bacteria normally involves construction of isogenic mutants that can then be compared to wild type in an animal model. Pathogenesis and antimicrobial studies are complicated by variability between animals and the need to sacrifice individual animals at specific time points. Live animal imaging allows real-time analysis of infections without the need to sacrifice animals, allowing quantitative data to be collected at multiple time points in all organs simultaneously. However, imaging has not previously allowed simultaneous imaging of both mutant and wild type strains of mycobacteria in the same animal. We address this problem by using both firefly (Photinus pyralis) and click beetle (Pyrophorus plagiophthalamus) red luciferases, which emit distinct bioluminescent spectra, allowing simultaneous imaging of two different mycobacterial strains during infection. We also demonstrate that these same bioluminescence reporters can be used to evaluate therapeutic efficacy in real-time, greatly facilitating our ability to screen novel antibiotics as they are developed. Due to the slow growth rate of mycobacteria, novel imaging technologies are a pressing need, since they can they can impact the rate of development of new therapeutics as well as improving our understanding of virulence mechanisms and the evaluation of novel vaccine candidates.


[Study on fluorescence characteristics of pefloxacin-La(III) complex and its application].
The complex of pefloxacin-La3+ was formed in the pH 5.6 HAc-NaAc buffer. Its fluorimetric intensity was 1.5 times that of the pefloxacin, and the excitation and emission peaks of the complex were at 276 and 440 nm, respectively. The new fluorescence method was developed for determining pefloxacin in serum based on the characteristics. The content of pefloxacin in serum was 4.79 mg x L(-1), the RSD and recovery were 6.3% and 95% respectively. The determination range was 0.04-2.0 mg x L(-1) with the detection limit of 2.8 microg x L(-1). The proposed method and UV-Vis photometric method were both applied to determining the pefloxacin in the same capsules with satisfactory results.


Systemic Inflammatory Response Syndrome Is Associated With Increased Mortality Across the Spectrum of Shock Severity in Cardiac Intensive Care Patients.
The systemic inflammatory response syndrome (SIRS) frequently occurs in patients with cardiogenic shock and may aggravate shock severity and organ failure. We sought to determine the association of SIRS with illness severity and survival across the spectrum of shock severity in cardiac intensive care unit (CICU) patients. We retrospectively analyzed 8995 unique patients admitted to the Mayo Clinic CICU between 2007 and 2015. Patients with ≥2/4 SIRS criteria based on admission laboratory and vital sign data were considered to have SIRS. Patients were stratified by the 2019 Society for Cardiovascular Angiography and Interventions (SCAI) shock stages using admission data. The association between SIRS and mortality was evaluated across SCAI shock stage using logistic regression and Cox proportional-hazards models for hospital and 1-year mortality, respectively. The study population had a mean age of 67.5±15.2 years, including 37.2% women. SIRS was present in 33.9% of patients upon CICU admission and was more prevalent in advanced SCAI shock stages. Patients with SIRS had higher illness severity, worse shock, and more organ failure, with an increased risk of mortality during hospitalization (16.8% versus 3.8%; adjusted odds ratio, 2.1 [95% CI, 1.7-2.5]; P<0.001) and at 1 year (adjusted hazard ratio, 1.4 [95% CI, 1.3-1.6]; P<0.001). After multivariable adjustment, SIRS was associated with higher hospital and 1-year mortality among patients in SCAI shock stages A through D (all P<0.01) but not SCAI shock stage E. One-third of CICU patients meet clinical criteria for SIRS at the time of admission, and these patients have higher illness severity and worse outcomes across the spectrum of SCAI shock stages. The presence of SIRS identified CICU patients at increased risk of short-term and long-term mortality. Further study is needed to determine whether systemic inflammation truly drives SIRS in this population and whether patients with SIRS respond differently to supportive therapies for shock.


Mycobacterium tuberculosis in central Ethiopia: drug sensitivity patterns and association with genotype.
Drug resistance tuberculosis (TB) and the emergence of multidrug resistant (MDR) isolates are significant concerns regarding TB control programs in several countries. This study was undertaken to evaluate the drug sensitivity of Mycobacterium tuberculosis and to assess its association with strains and lineages of M. tuberculosis. A total of 279 M. tuberculosis strains isolated from Central Ethiopia were tested for their drug sensitivity patterns to first line TB drugs using the conventional proportion method on Löwenstein Jensen media. The association between drug sensitivity and strain type was assessed on 263 isolates of the 279 isolates. Of the 268 M. tuberculosis isolates obtained from new cases, 209 (78%) were susceptible to first line TB drugs, and 59 (22.2%) bacterial isolates were resistant to at least one of the first line drugs. The highest mono-resistance (7.5%) pertained to streptomycin (STM). Remarkably, seven of eleven isolates (63.6%) previous treatment for TB were resistant to at least one of the first line drugs. The prevalence of MDR-TB was 1.5% (4/268) for newly identified TB cases, all of which were members of the Euro-American Lineage. There was no statistically significant association (P > 0.05) between drug sensitivity, and either strains, sub-lineages or main lineages of M. tuberculosis. A significant proportion of M. tuberculosis was resistant to at least one first line anti-TB drug. Moreover, the frequencies of resistance to either isoniazid or rifampicin were high compared to data that were previously reported in some part of the country.


Low-Level Laser Therapy Promoted Aggressive Proliferation and Angiogenesis Through Decreasing of Transforming Growth Factor-β1 and Increasing of Akt/Hypoxia Inducible Factor-1α in Anaplastic Thyroid Cancer.
We assessed the cause of increased tumor after low-level laser therapy (LLLT) by histological analysis. LLLT is a nonthermal phototherapy used in several medical applications, including wound healing, reduction of pain, and amelioration of oral mucositis. We discovered by accident that LLLT increased tumor size while testing a photodynamic therapy (PDT) model for the treatment of thyroid cancer. Although therapeutic effects of LLLT on cancer or dysplastic cells have been studied, LLLT has been recently reported to stimulate the aggressiveness of the tumor. The anaplastic thyroid cancer cell line FRO was injected into thyroid glands of nude mice orthotopically and then laser irradiation was performed with 0, 15, and 30 J/cm(2) (100 mW/cm(2)) on the thyroid after 10 days. The tumor volume was measured for 4 weeks and the thyroid tissues underwent histological analysis. We observed that proliferation of FRO cells and macrophage infiltration was increased with energy delivery to the thyroid glands. We also assessed overproliferated FRO cells using an immunohistochemical staining with hypoxia inducible factor 1α (HIF-1α), p-Akt, vascular endothelial growth factor (VEGF), and transforming growth factor β1 (TGF-β1). HIF-1α and p-Akt were elevated after LLLT, which suggested that the phosphorylation of Akt by LLLT led to the activation of HIF-1α. Moreover, TGF-β1 expression was decreased after LLLT, which led to loss of cell cycle regulation. In conclusion, LLLT led to a decrease in TGF-β1 and increase of p-Akt/HIF-1α which resulted to overproliferation and angiogenesis of anaplastic thyroid carcinoma (ATC). Therefore, we suggest that LLLT can influence cancer aggressiveness associated with TGF-β1 and Akt/HIF-1α cascades in some poorly differentiated head and neck cancers.


The Cognitive-Evolutionary Model of Surprise: A Review of the Evidence.
Research on surprise relevant to the cognitive-evolutionary model of surprise proposed by Meyer, Reisenzein, and Schützwohl (1997) is reviewed. The majority of the assumptions of the model are found empirically supported. Surprise is evoked by unexpected (schema-discrepant) events and its intensity is determined by the degree if schema-discrepancy, whereas the novelty and the valence of the eliciting events probably do not have an independent effect. Unexpected events cause an automatic interruption of ongoing mental processes that is followed by an attentional shift and attentional binding to the events, which is often followed by causal and other event analysis processes and by schema revision. The facial expression of surprise postulated by evolutionary emotion psychologists has been found to occur rarely in surprise, for as yet unknown reasons. A physiological orienting response marked by skin conductance increase, heart rate deceleration, and pupil dilation has been observed to occur regularly in the standard version of the repetition-change paradigm of surprise induction, but the specificity of these reactions as indicators of surprise is controversial. There is indirect evidence for the assumption that the feeling of surprise consists of the direct awareness of the schema-discrepancy signal, but this feeling, or at least the self-report of surprise, is also influenced by experienced interference. In contrast, facial feedback probably does contribute substantially to the feeling of surprise and the evidence for the hypothesis that surprise is affected by the difficulty of explaining an unexpected event is, in our view, inconclusive. Regardless of how the surprise feeling is constituted, there is evidence that it has both motivational and informational effects. Finally, the prediction failure implied by unexpected events sometimes causes a negative feeling, but there is no convincing evidence that this is always the case, and we argue that even if it were so, this would not be a sufficient reason for regarding this feeling as a component, rather than as an effect of surprise.


Molecularly imprinted polymers and their application in solid phase extraction.
Solid phase extraction is routinely used in many different areas of analytical chemistry. Some of the main fields are environmental, biological, and food chemistry, where cleaning and pre-concentration of the sample are important steps in the analytical protocol. Molecularly imprinted polymers (MIPs) have attracted attention because they show promise as compound-selective or group-selective media. The application of these synthetic polymers as sorbents allows not only pre-concentration and cleaning of the sample but also selective extraction of the target analyte, which is important, particularly when the sample is complex and impurities can interfere with quantification. This review surveys the selectivity of MIPs in solid phase extraction of various kinds of analytes.


Role of colonoscopy in gallstone ileus:--a case report.
This paper reviews the role of colonoscopy in large-bowel obstruction by a gallstone. We report the case of an elderly female with a cholecystocolonic fistula who had a large-bowel obstruction caused by a gallstone that migrated to the level of narrowing in the large bowel. After multiple attempts at removal of the stone with a snare and basket retriever, the patient was taken to the operating room and the stone was removed. Colonscopy in these circumstances can be diagnostic and possibly therapeutic.


Assessment of an artificial intelligence aid for the detection of appendicular skeletal fractures in children and young adults by senior and junior radiologists.
As the number of conventional radiographic examinations in pediatric emergency departments increases, so, too, does the number of reading errors by radiologists. The aim of this study is to investigate the ability of artificial intelligence (AI) to improve the detection of fractures by radiologists in children and young adults. A cohort of 300 anonymized radiographs performed for the detection of appendicular fractures in patients ages 2 to 21 years was collected retrospectively. The ground truth for each examination was established after an independent review by two radiologists with expertise in musculoskeletal imaging. Discrepancies were resolved by consensus with a third radiologist. Half of the 300 examinations showed at least 1 fracture. Radiographs were read by three senior pediatric radiologists and five radiology residents in the usual manner and then read again immediately after with the help of AI. The mean sensitivity for all groups was 73.3% (110/150) without AI; it increased significantly by almost 10% (P<0.001) to 82.8% (125/150) with AI. For junior radiologists, it increased by 10.3% (P<0.001) and for senior radiologists by 8.2% (P=0.08). On average, there was no significant change in specificity (from 89.6% to 90.3% [+0.7%, P=0.28]); for junior radiologists, specificity increased from 86.2% to 87.6% (+1.4%, P=0.42) and for senior radiologists, it decreased from 95.1% to 94.9% (-0.2%, P=0.23). The stand-alone sensitivity and specificity of the AI were, respectively, 91% and 90%. With the help of AI, sensitivity increased by an average of 10% without significantly decreasing specificity in fracture detection in a predominantly pediatric population.


Aging influences cellular and molecular responses of apoptosis to skeletal muscle unloading.
The influence of aging on skeletal myocyte apoptosis is not well understood. In this study we examined apoptosis and apoptotic regulatory factor responses to muscle atrophy induced via limb unloading following loading-induced hypertrophy. Muscle hypertrophy was induced by attaching a weight to one wing of young and aged Japanese quails for 14 days. Removing the weight for 7 or 14 days after the initial 14 days of loading induced muscle atrophy. The contralateral wing served as the intra-animal control. A time-released bromodeoxyuridine (BrdU) pellet was implanted subcutaneously with wing weighting to identify activated satellite cells/muscle precursor cells throughout the experimental period. Bcl-2 mRNA and protein levels decreased after 7 days of unloading, but they were unchanged after 14 days of unloading in young muscles. Bcl-2 protein level but not mRNA level decreased after 7 days of unloading in muscles of aged birds. Seven days of unloading increased the mRNA level of Bax in muscles from both young and aged birds. Fourteen days of unloading increased mRNA and protein levels of Bcl-2, decreased protein levels of Bax, and decreased nuclear apoptosis-inducing factor (AIF) protein level in muscles of aged birds. BrdU-positive nuclei were found in all unloaded muscles from both age groups, but the number of BrdU-positive nuclei relative to the total nuclei decreased after 14 days of unloading compared with 7 days of unloading. The TdT-mediated dUTP nick end labeling (TUNEL) index was higher after 7 days of unloading in both young and aged muscles and after 14 days of unloading in aged muscles. Immunofluorescent staining revealed that almost all of the TUNEL-positive nuclei were also BrdU immunopositive, suggesting that activated satellite cell nuclei (both fused and nonfused) underwent nuclear apoptosis during unloading. There were significant correlations among levels of Bcl-2, Bax, and AIF and TUNEL index. Our data are consistent with the hypothesis that apoptosis regulates, at least in part, unloading-induced muscle atrophy and loss of activated satellite cell nuclei in previously loaded muscles. Moreover, these data suggest that aging influences the apoptotic responses to prolonged unloading following hypertrophy in skeletal myocytes.


Early Prediction of Neonatal Sepsis From Synthetic Clinical Data Using Machine Learning.
Neonatal sepsis is one of the most serious complications in neonatal intensive care units. Due to the often immature immune system, sepsis-related comorbidities are the major contributors to increased neonatal mortality. The rapid progression of the disease makes early treatment critical for patient survival. However, early diagnosis of sepsis remains difficult due to its non-specific symptoms. In recent years, Machine Learning-based techniques have been used in various medical applications to predict diseases using clinical data. In this work, we optimized and evaluated four prediction models with different architectural concepts. Two public datasets containing clinical data from adults and neonates were used for training. The adult data were collected to pre-train the models. Since neonatal data with sepsis diagnosis are very limited, we propose an augmentation method to generate synthetic clinical data. For the final evaluation, the real data of neonatal patients were defined as a test set. An AUROC of 0.91 and an AUPRC of 0.38 were obtained. These results are promising for early prediction of neonatal sepsis using artificial data for augmentation.Clinical relevance- This work demonstrates the potential of Machine Learning-based prediction models for the detection of sepsis to improve the early diagnosis of life-threatening conditions in neonatal intensive care units.


Boron Nitride Nanoporous Membranes with High Surface Charge by Atomic Layer Deposition.
In this work, we report the design and the fine-tuning of boron nitride single nanopore and nanoporous membranes by atomic layer deposition (ALD). First, we developed an ALD process based on the use of BBr3 and NH3 as precursors in order to synthesize BN thin films. The deposited films were characterized in terms of thickness, composition, and microstructure. Next, we used the newly developed process to grow BN films on anodic aluminum oxide nanoporous templates, demonstrating the conformality benefit of BN prepared by ALD, and its scalability for the manufacturing of membranes. For the first time, the ALD process was then used to tune the diameter of fabricated single transmembrane nanopores by adjusting the BN thickness and to enable studies of the fundamental aspects of ionic transport on a single nanopore. At pH = 7, we estimated a surface charge density of 0.16 C·m-2 without slip and 0.07 C·m-2 considering a reasonable slip length of 3 nm. Molecular dynamics simulations performed with experimental conditions confirmed the conductivities and the sign of surface charges measured. The high ion transport results obtained and the ability to fine-tune nanoporous membranes by such a scalable method pave the way toward applications such as ionic separation, energy harvesting, and ultrafiltration devices.


Cavity theory applied to the dosimetry of systemic radiotherapy of bone metastases.
A two-component model of an osteoblastic metastatic lesion has been developed to determine the absorbed dose delivered to soft tissue during systemic radiotherapy of osseous metastases. Doses to soft tissue from radioisotopes distributed in bone were calculated using Burlin's general cavity theory. A correction term was used to account for the absence of charged particle equilibrium within the metastatic lesion. Radiation doses for 153Sm, 186Re, 89Sr and 32P were calculated for several physiologically realistic lesion structures. Burlin's cavity weighting factor was greatest for higher energy isotopes and it decreased as the soft tissue cavity size increased. The correction for the absence of charged particle equilibrium also decreased with soft tissue pathlength, but increased with average bone pathlengths. Doses to soft tissue cavities ranged from 0.1 to 0.2 Gy MBq(-1) d(-1) for 153Sm to 0.5 to 0.6 Gy MBq(-1) d(-1) for 32P. Using the factors calculated in this work, the dose to soft tissue cavities within bone metastases can be calculated when the dose to adjacent bone has been determined, perhaps by autoradiography or electron paramagnetic resonance dosimetry. The doses calculated with this more accurate model of bone metastases demonstrate errors of 20% to 50% in previous calculations of the average dose to homogeneous metastatic lesions.


Radiomic Analysis of Multi-parametric MR Images (MRI) for Classification of Parotid Tumors.
Characterization of parotid tumors before surgery using multi-parametric magnetic resonance imaging (MRI) scans can support clinical decision making about the best-suited therapeutic strategy for each patient. This study aims to differentiate benign from malignant parotid tumors through radiomics analysis of multi-parametric MR images, incorporating T2-w images with ADC-map and parametric maps generated from Dynamic Contrast Enhanced MRI (DCE-MRI). MRI scans of 31 patients with histopathologically-confirmed parotid gland tumors (23 benign, 8 malignant) were included in this retrospective study. For DCE-MRI, semi-quantitative analysis, Tofts pharmacokinetic (PK) modeling, and five-parameter sigmoid modeling were performed and parametric maps were generated. For each patient, borders of the tumors were delineated on whole tumor slices of T2-w image, ADC-map, and the late-enhancement dynamic series of DCE-MRI, creating regions-of-interest (ROIs). Radiomic analysis was performed for the specified ROIs. Among the DCE-MRI-derived parametric maps, wash-in rate (WIR) and PK-derived Ktrans parameters surpassed the accuracy of other parameters based on support vector machine (SVM) classifier. Radiomics analysis of ADC-map outperformed the T2-w and DCE-MRI techniques using the simpler classifier, suggestive of its inherently high sensitivity and specificity. Radiomics analysis of the combination of T2-w image, ADC-map, and DCE-MRI parametric maps resulted in accuracy of 100% with both classifiers with fewer numbers of selected texture features than individual images. In conclusion, radiomics analysis is a reliable quantitative approach for discrimination of parotid tumors and can be employed as a computer-aided approach for pre-operative diagnosis and treatment planning of the patients.


Adsorption-induced co-assembly of hairy and isotropic particles.
We use coarse-grained molecular dynamics simulations to study the behavior of polymer-tethered particles immersed in fluids of isotropic particles. Particles modified with weakly anchored, mobile ligands are considered. We discuss how the concentration of fluid particles affects the morphology of an isolated hairy particle. It is shown that hairy particles present different morphologies including typical core-shell, octopus-like and corn-like, depending on fluid-segment interactions and the fluid density. The mechanism of changes in the shape of hairy particles is explained. The reconfiguration of the polymer corona arises from adsorption of fluid particles "on chains". The adsorbed fluid particles form bridges between the chains. This causes the mobile ligands to merge into clusters on the core surface. A part of the core remains empty so the hairy particle becomes a Janus-like object. We also study co-assembly in mixtures of hairy and isotropic particles. Depending on the strength of fluid-segment interactions, hairy particles with fluid particles trapped inside their coronas remain isolated or form mixed clusters of different structures. The aggregation of hairy particles results from the formation of bridges between chains belonging to different cores by fluid particles.


Modulation of the "blood-tumor" barrier improves immunotherapy.
Blood vessels inside tumors are crucial for cancer survival and progression but equally contribute to the tumor's intrinsic resistance to therapy. Abnormal blood flow in the local tumor environment acts as a physiological barrier to the delivery of chemotherapeutic agents. Furthermore, tumor vasculature can also act as a barrier for immune cell migration into the tumor parenchyma. Much has been made of anti-angiogenic therapies that specifically inhibit vessel growth. However, recent findings demonstrate that the chaotic architecture of tumor blood vessels can be reversed which in turn normalizes blood flow and physical parameters in the tumor environment. Importantly, vessel normalization also improves lymphocyte migration into tumor tissue and immune destruction. Identification of regulator of G protein signaling 5 (RGS5) as a key modulator of the vascular barrier in tumor progression and regression has brought new insights into the molecular basis of vessel normalization and opens new therapeutic opportunities.


NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells.
The development of cerebellar Purkinje cells is subject to regulation by multiple epigenetic signals. To define mechanisms by which trophic and presynaptic stimulation may potentially regulate Purkinje cell ontogeny, we studied the effects of NGF and excitatory transmitters on Purkinje cell survival and morphological maturation in dissociated cell culture. Purkinje cells were identified by expression of vitamin D-dependent calcium-binding protein and by their characteristic morphology. NGF receptors were selectively localized to Purkinje cells by both ligand and monoclonal antibody binding, suggesting responsivity to the trophic agent. Simultaneous exposure to depolarizing agents and NGF specifically enhanced Purkinje cell survival in culture. NGF, in combination with either high potassium or veratridine markedly increased survival of Purkinje cells. Furthermore, NGF together with the excitatory neurotransmitters aspartate or glutamate promoted a 2-fold increase in survival. In addition, NGF increased Purkinje cell size and promoted neurite elaboration. These effects required simultaneous exposure to NGF and either aspartate, glutamate, or pharmacologic depolarizing agents. Effects on survival or neurite elaboration were not evoked by exposure to trophic factors or transmitters alone. Our results suggest a novel mechanism for regulation of development, in which trophic factor and afferent stimulation interact to promote survival and morphogenesis of developing Purkinje cells.


Anti-Inflammatory Properties, Bioaccessibility and Intestinal Absorption of Sea Fennel (Crithmum maritimum) Extract Encapsulated in Soy Phosphatidylcholine Liposomes.
A sea fennel (Crithmum maritimum) aqueous extract was prepared and loaded into soybean phosphatidylcholine liposomes. Both the free extract (FE), and the empty (L) and loaded (L-FE) liposomes were shown to be non-cytotoxic to THP-1 and Caco-2 cells. The anti-inflammatory effect was tested on THP-1 cells differentiated into macrophages. FE showed anti-inflammatory activity, revealed by the induced secretion of IL-10 cytokines in macrophages that were subsequently stimulated with LPS. Also, a decrease in TNF-α production by L was observed, evidencing that liposomes reduced the pro-inflammatory mediators' secretion. The liposomes (L) showed protective anti-inflammatory activity and also were able to downregulate the inflammation. Furthermore, L-FE were also found to downregulate the inflammation response, as they were able to decrease TNF-α secretion in macrophages previously exposed to LPS. The simulated in vitro gastrointestinal digestion (GID) of FE diminished the chlorogenic acid content (the main polyphenolic compound of the extract) by 40%, while in L-FE, the amount of this phenolic compound increased with respect to the undigested liposomes. The amount of bioaccessible chlorogenic, however, was similar for FE and L-FE. The percentage of chlorogenic acid absorbed through a Caco-2 cell monolayer after 3 h of incubation, was significantly similar for the extract and the liposomes (~1.5%), without finding significant differences once the extract and liposomes were digested.


Effects of sympathetic tone on vagally induced phasic changes in heart rate and atrioventricular node conduction in the anesthetized dog.
We examined the effects of stellate ganglia stimulation on the phase-dependent chronotropic and dromotropic responses to brief vagal bursts in open-chest anesthetized dogs. Stellate stimulation affected the phasic vagal effects on heart rate by shortening the latent period, shifting the phase at which maximum decrease in heart rate occurred to earlier phases, and reducing the maximum decrease in heart rate. These effects were due primarily to an increase in the basic heart rate. No significant sympathetic-parasympathetic interaction occurred for heart rate, indicating that accentuated antagonism did not occur with brief vagal bursts. Stellate stimulation primarily decreased the amplitude of the phasic vagal effects on atrioventricular nodal conduction, regardless of the underlying heart rate, and a significant sympathetic-parasympathetic interaction was associated with this effect. The peak of the phase-dependent vagal effects on heart rate and atrioventricular nodal conduction were phase-shifted with one another. From these findings, we postulate the small changes in sympathetic tone might shift the predominant phase-dependent vagal effect from one on heart rate to one on atrioventricular nodal conduction. Furthermore, our results suggest that dynamic vagal control of heart rate and atrioventricular node conduction involves both phase-dependent and phase-independent factors. Sympathetic activity appears to affect only the phase-independent factor(s) in the control of heart rate, whereas it affects both phase-dependent and phase-independent factors in the control of atrioventricular node conduction.


Syntrophomonas palmitatica sp. nov., an anaerobic, syntrophic, long-chain fatty-acid-oxidizing bacterium isolated from methanogenic sludge.
A mesophilic, syntrophic, fatty-acid-oxidizing anaerobic strain, designated MPA(T), was isolated from granular sludge in a mesophilic upflow anaerobic sludge blanket reactor used to treat palm oil mill effluent. Cells were slightly curved, non-motile rods. Spore formation was not observed. The optimal temperature for growth was around 37 degrees C and optimal pH for growth was 7.0. Strain MPA(T) was able to grow on crotonate or pentenoate plus butyrate in pure culture. In co-culture with the hydrogenotrophic methanogen Methanospirillum hungatei, strain MPA(T) was able to oxidize straight-chain saturated fatty acids with carbon chain lengths of C4-C18. The strain was unable to utilize sulfate, sulfite, thiosulfate, nitrate, fumarate, iron(III) or DMSO as an electron acceptor. The G+C content of the DNA was 45.0 mol%. Based on comparative 16S rRNA gene sequence analysis, strain MPA(T) was found to be a member of the genus Syntrophomonas and was most closely related to the type strains of Syntrophomonas curvata and Syntrophomonas sapovorans (sequence similarities of 94 %). Genetic and phenotypic characteristics demonstrated that strain MPA(T) represents a novel species, for which the name Syntrophomonas palmitatica sp. nov. is proposed. The type strain is MPA(T) (=JCM 14374(T)=NBRC 102128(T)=DSM 18709(T)).


[Comparative follow-up of schizophrenic patients hospitalized for the first time].
A total of 798 patients who were first hospitalized 6 years before were subjected to a follow-up study. The patients were distributed in 3 groups screened depending on the initial prognosis. In the course of the follow-up studies that corresponded with the realization of the rehabilitation programs, there was a change in the ratio of the number of patients in the first screened groups at the expense of a greater number of patients with a favourable disease progress (remissions A and B), as well as of patients whose condition and disease progress proved more favourable as compared with the expected ones. It was ascertained that labour therapy exercised under individually selected conditions plays an important role for this group of patients. The least changes in the patients' status were recorded in the group of patients suffering from nuclear schizophrenia, despite the fact that the level of these patients' social adaptation also increased.


EPSDT- one quarter million screenings in Michigan.
Since the spring of 1973, Michigan's EPSDT program has screened more than 300,000 children. The Department of Social Services contracted with the Department of Public Health to design the screening and referral parts of the program; in turn the Department of Public Health contracts with local health departments to do screening with one or more teams composed of a nurse, two technicians, and a clerk. The 72 teams screen 10,000 clients each month. More than one-half of these clients are referred for diagnosis and treatment. The highest percentage (27 per cent) of referral is for dental care; the second highest (26 per cent) is for immunization. Participation in the program of state and local social services departments, local health departments, and all groups of health providers has been excellent. There continues to be a high no-show for screening and a moderate no-show rate to providers for diagnosis and treatment. Evaluation of the program elements is needed.


Optimal coding through divisive normalization models of V1 neurons.
Current models of the primary visual cortex (V1) include a linear filtering stage followed by a gain control mechanism that explains some of the nonlinear behaviour of neurons. This nonlinear stage consists of a divisive normalization in which each linear response is squared and then divided by a weighted sum of squared linear responses in a certain neighbourhood plus a constant. Simoncelli and Schwartz (1999 Adv. Neural Inform. Process. Syst. 11 153-9) have suggested that divisive normalization reduces the statistical dependence between neuron responses when the weights are adapted to the statistics of natural images, which is consistent with the efficient coding hypothesis. Nevertheless, there are still important open issues, such as, for example, how to obtain the values for the parameters that minimize statistical dependence? Does divisive normalization give a total independence between responses? In this paper, we present the general mathematical formulation of the first of these two questions. We arrive at an expression which permits us to compute, numerically, the parameters of a quasi-optimal solution adapted to an input set of natural images. This quasi-optimal solution is based on a Gaussian model of the conditional statistics of the coefficients resulting from projecting natural images onto an orthogonal linear basis. Our results show, in general, lower values of mutual information, that is, responses are more independent than those provided by previous approximations.


Loss of efficacy and safety of the switch from infliximab original to infliximab biosimilar (CT-P13) in patients with inflammatory bowel disease.
Infliximab original has changed the natural history of inflammatory bowel diseases (IBD) over the past two decades. However, the recent expiration of its patent has allowed the entry of the first Infliximab biosimilar into the European and Spanish markets. Currently switching drugs data in IBD are limited. To compare the efficacy of infliximab biosimilar, CT-P13, against infliximab original, analyzing the loss of response of both at the 12 mo follow-up in patients with IBD. An observational study of two cohorts has been conducted. One retrospective cohort that included patients with IBD treated with Infliximab original, and a prospective cohort of patients who were switching from infliximab original to infliximab biosimilar (CT-P13). We had analyzed the overall efficacy and loss of efficacy in patients in remission at the end of one year after treatment with the original drug compared to the results of the year of treatment with the biosimilar. 98 patients (CD 67, CU 31) were included in both cohorts. The overall efficacy for infliximab original per year of treatment was 71% vs 68.2% for infliximab biosimilar (P = 0.80). The loss of overall efficacy at 12 mo for infliximab original was 6.6% vs 14.5% for infliximab biosimilar (P = 0.806). The loss of efficacy in patients who were in basal remission was 16.3% for infliximab original vs 27.1% for infliximab biosimilar. Adverse events were 9.2% for infliximab original vs 11.2% for infliximab biosimilar. The overall efficacy and loss of treatment response with infliximab biosimilar (CT-P13) is similar to that observed with infliximab original in patients who were switching at the 12 mo follow-up. There is no difference in the rate of adverse events.


Atopic dermatitis: new therapeutic considerations.
Atopic dermatitis is a genetically determined inflammatory condition in which the primary defect is expressed in one or more hematopoietic cells that infiltrate the skin. It is a multifactorial disease with inflammation triggered by a variety of factors. Among these, atopic dermatitis has been experimentally induced and reproduced by emotional-stress interviews and food challenges only. The inflammatory events of atopic dermatitis appear to initiated by mast cells, but eosinophils, monocytes, and T lymphocytes (predominantly CD4) also are present in lesions. The secondary effects of inflammation are a dry, brittle stratum corneum and pruritus, causing excoriation and a lichenified epidermal layer resulting from chronic rubbing. Therapeutic approaches to atopic dermatitis may be directed at several points in the evolution of the disease. Agents including emollients are needed to preserve and restore the stratum corneum barrier, and effective antipruritics are required to reduce the self-inflicted damage to the involved skin. Various other agents may be needed to antagonize mediators or cytokines and to inhibit cytokine expression and release from lesional, immune-effector cells. Likewise, new phosphodiesterase inhibitors, calcium-active agents, and antiallergic drugs may be used to reduce the quantity and pathologic functioning of inflammatory infiltrating cells in the skin.


Structural insights into Arabidopsis ethylene response factor 96 with an extended N-terminal binding to GCC box.
The phytohormone ethylene is widely involved in many developmental processes and is a crucial regulator of defense responses against biotic and abiotic stresses in plants. Ethylene-responsive element binding protein, a member of the APETALA2/ethylene response factor (AP2/ERF) superfamily, is a transcription factor that regulates stress-responsive genes by recognizing a specific cis-acting element of target DNA. A previous study showed only the NMR structure of the AP2/ERF domain of AtERF100 in complex with a GCC box DNA motif. In this report, we determined the crystal structure of AtERF96 in complex with a GCC box at atomic resolution. We analyzed the binding residues of the conserved AP2/ERF domain in the DNA recognition sequence. In addition to the AP2/ERF domain, an N-terminal α-helix of AtERF96 participates in DNA interaction in the flanking region. We also demonstrated the structure of AtERF96 EDLL motif, a unique conserved motif in the group IX of AP2/ERF family, might involve in the transactivation of defense-related genes. Our study establishes the structural basis of the AtERF96 transcription factor in complex with the GCC box, as well as the DNA binding mechanisms of the N-terminal α-helix and AP2/ERF domain.


Role of actin in anchoring postsynaptic receptors in cultured hippocampal neurons: differential attachment of NMDA versus AMPA receptors.
We used actin-perturbing agents and detergent extraction of primary hippocampal cultures to test directly the role of the actin cytoskeleton in localizing GABAA receptors, AMPA- and NMDA-type glutamate receptors, and potential anchoring proteins at postsynaptic sites. Excitatory postsynaptic sites on dendritic spines contained a high concentration of F-actin that was resistant to cytochalasin D but could be depolymerized using the novel compound latrunculin A. Depolymerization of F-actin led to a 40% decrease in both the number of synaptic NMDA receptor (NMDAR1) clusters and the number of AMPA receptor (GluR1)-labeled spines. The nonsynaptic NMDA receptors appeared to remain clustered and to coalesce in cell bodies. alpha-Actinin-2, which binds both actin and NMDA receptors, dissociated from the receptor clusters, but PSD-95 remained associated with both the synaptic and nonsynaptic receptor clusters, consistent with a proposed cross-linking function. AMPA receptors behaved differently; on GABAergic neurons, the clusters redistributed to nonsynaptic sites, whereas on pyramidal neurons, many of the clusters appeared to disperse. Furthermore, in control neurons, AMPA receptors were detergent extractable from pyramidal cell spines, whereas AMPA receptors on GABAergic neurons and NMDA receptors were unextractable. GABAA receptors were not dependent on F-actin for the maintenance or synaptic localization of clusters. These results indicate fundamental differences in the mechanisms of receptor anchoring at postsynaptic sites, both regarding the anchoring of a single receptor (the AMPA receptor) in pyramidal cells versus GABAergic interneurons and regarding the anchoring of different receptors (AMPA vs NMDA receptors) at a single class of postsynaptic sites on pyramidal cell dendritic spines.


Antibody-coated microstructures for selective isolation of immune cells in blood.
Cell isolation from blood is an important process for diagnosing immune diseases. There are still demands for a user-friendly approach to achieve high cell extraction efficiency and purity of a target immune cell subtype for more promising diagnosis and monitoring. For selective immune cell isolation, we developed a microstructured device, which consists of antibody-coated micropillars and micro-sieve arrays, for isolating a target immune cell subtype from bovine blood samples. The focusing micropillars can guide immune cells flowing to the subsequent micro-sieves based on deterministic lateral shifts of the cells. The arrangement of these microstructures is characterized and configured for the maximal cell capture rate. Surface modification with a selected antibody offers selective cell capture in the micro-sieves based on the antigen-antibody reaction. We prepare a cell mixture of human CD14-expressing leukemia cells (THP-1) and epithelial cells (MDA-MB-231) in diluted blood to characterize the cell isolation operation, with a selective cell isolation yield of >80%, cell purity of ∼100% and cell viability of >93%. Together, this microstructured device strategy can achieve high-yield selective isolation of immune cells from blood samples and support downstream genetic and biochemical cell analyses, contributing to the medical diagnosis of a broad range of immune diseases.


Bistatic lidar measurements of clouds in the Nordic Arctic region.
Cloud studies were carried out with a polarimetric bistatic lidar setup at the Arctic Lidar Observatory for Middle Atmosphere Research in Andenes (69 degrees N, 16 degrees E), Norway. Measurements were performed at altitudes between 1.5 and 10.5 km, corresponding to scattering angles between 130 degrees and 170 degrees. The geometry, not restricted to the parallel or perpendicular laser polarization directions, gave a well-defined scattering angle, which together with polarization characterization, was used to investigate the scattering particles. The principles of the technique and the first results are presented together with an evaluation of the capabilities.


Gynecologic oncology group strategies to improve timeliness of publication.
The Gynecologic Oncology Group (GOG) is a multi-institution cooperative group funded by the National Cancer Institute to conduct clinical trials encompassing clinical and basic scientific research in gynecologic malignancies. These results are disseminated via publication in peer-reviewed journals. This process requires collaboration of numerous investigators located in diverse cancer research centers. Coordination of manuscript development is positioned within the Statistical and Data Center (SDC), thus allowing the SDC personnel to manage the process and refine strategies to promote earlier dissemination of results. A major initiative to improve timeliness utilizing the assignment, monitoring, and enforcement of deadlines for each phase of manuscript development is the focus of this investigation. Document improvement in timeliness via comparison of deadline compliance and time to journal submission due to expanded administrative and technologic initiatives implemented in 2006. Major steps in the publication process include generation of first draft by the First Author and submission to SDC, Co-author review, editorial review by Publications Subcommittee, response to journal critique, and revision. Associated with each step are responsibilities of First Author to write or revise, collaborating Biostatistician to perform analysis and interpretation, and assigned SDC Clinical Trials Editorial Associate to format/revise according to journal requirements. Upon the initiation of each step, a deadline for completion is assigned. In order to improve efficiency, a publications database was developed to track potential steps in manuscript development that enables the SDC Director of Administration and the Publications Subcommittee Chair to assign, monitor, and enforce deadlines. They, in turn, report progress to Group Leadership through the Operations Committee. The success of the strategies utilized to improve the GOG publication process was assessed by comparing the timeliness of each potential step in the development of primary Phase II manuscripts during 2003-2006 versus 2007-2010. Improvement was noted in 10 of 11 identified steps resulting in a cumulative average improvement of 240 days from notification of data maturity to First Author through first submission to a journal. Moreover, the average time to journal acceptance has improved by an average of 346 days. The investigation is based on only Phase II trials to ensure comparability of manuscript complexity. Nonetheless, the procedures employed are applicable to the development of any clinical trials manuscript. The assignment, monitoring, and enforcement of deadlines for all stages of manuscript development have resulted in increased efficiency and timeliness. The positioning and support of manuscript development within the SDC provide a valuable resource to authors in meeting assigned deadlines, accomplishing peer review, and complying with journal requirements.


GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer.
The transcription factor, Grainyhead-like 2 (GRHL2), is involved in wound healing, epidermal integrity, and epithelial-to-mesenchymal transition (EMT) in various biological processes; however, the biological function of GRHL2 in non-small cell lung cancer (NSCLC) is unknown. In the current study, we investigated the effect of GRHL2 on cell growth and migration in NSCLC cell lines and clinical tissues. Immunohistochemical analysis of clinical NSCLC specimens revealed that patients with high GRHL2 expression were associated with poor prognosis compared to patients with low GRHL2 expression. GRHL2 overexpression promoted cell growth and colony formation, and simultaneously suppressed cell migration in NSCLC cells. Furthermore, GRHL2 decreased the transcriptional activity of RhoG by directly binding to the RhoG promoter region. These findings confirm that GRHL2 plays an important role in regulating cell proliferation and migration in NSCLC.


A comparative study of the inhibitory effects of interleukin-1 receptor antagonist following administration as a recombinant protein or by gene transfer.
Anakinra, the recombinant form of IL-1 receptor antagonist (IL-1Ra), has been approved for clinical use in the treatment of rheumatoid arthritis as the drug Kineret trade mark, but it must be administered daily by subcutaneous injection. Gene transfer may offer a more effective means of delivery. In this study, using prostaglandin E2 production as a measure of stimulation, we quantitatively compared the ability of anakinra, as well as that of IL-1Ra delivered by gene transfer, to inhibit the biologic actions of IL-1beta. Human synovial fibroblast cultures were incubated with a range of doses of anakinra or HIG-82 cells genetically modified to constitutively express IL-1Ra. The cultures were then challenged with recombinant human IL-1beta either simultaneously with addition of the source of IL-1Ra or 24 hours later. In a similar manner, the potencies of the two sources of IL-1Ra were compared when human synovial fibroblasts were challenged with IL-1beta produced constitutively by genetically modified cells. No significant difference in inhibitory activity was observed between recombinant protein and IL-1Ra provided by the genetically modified cells, under static culture conditions, even following incubation for 4 days. However, under culture conditions that provided progressive dilution of the culture media, striking differences between these methods of protein delivery became readily apparent. Constitutive synthesis of IL-1Ra by the genetically modified cells provided sustained or increased protection from IL-1 stimulation over time, whereas the recombinant protein became progressively less effective. This was particularly evident under conditions of continuous IL-1beta synthesis.


Magnetic reconnection in toroidal eta(i) mode turbulence
Based on three-dimensional simulations of the Braginskii equations we show that for typical plasma-edge parameters the saturation of electromagnetic toroidal eta(i) mode turbulence is controlled by the self-generation and subsequent annihilation of radial magnetic field perturbations. This should be contrasted with the electrostatic limit, where the growth of the linear eta(i) mode is terminated by the onset of sheared flow modes driven by the radial plasma streams. The impact of the saturation amplitude on the transport level is substantial and is not in accord with simple mixing length arguments, suggesting that electromagnetic effects should generally be included in simulations of eta(i) mode turbulence.


Effect of dental implant diameter on fatigue performance. Part II: failure analysis.
The purpose of this study was to perform fracture mode analysis for in vitro failed implants in order to evaluate the relation between the fracture mode obtained and the implants' fatigue behavior. Eighty fractured dental implants were analyzed after being tested for fatigue performance. A macroscopic failure analysis was performed, which evaluated and located the fracture modes obtained, followed by a microscopic failure analysis comprising a detailed scanning electron microscopy (SEM) fractographic analysis. Four distinctive fracture loci were identified and macrofracture mode analysis was performed, showing that all 5-mm implants that fractured were fractured at the abutment neck and screw. In the 3.75-mm group, 44.4% were fractured at the implant neck and 55.5% at the implants second thread. Fifty-two percent of the 3.3-mm fractured implants had it at the implants second tread and 48% at the implants third thread. The implant's metallographic sections revealed that the different fracture loci were located where thin metal cross sections and sharp notches coexist. Using SEM, we were able to characterize the failure micromechanisms and fatigue characterization as transgranular fracture and arrays of secondary parallel microcracks at relatively low magnifications and classic fatigue striations at much higher magnifications. The results of this study indicate that proper implant design is crucial to ensure long-term fatigue performance for dental implants. The combination of sharp notches (thread) and narrow metal cross section is quite deleterious for fatigue resistance.


Mitochondrial pyruvate transport: a historical perspective and future research directions.
Pyruvate is the end-product of glycolysis, a major substrate for oxidative metabolism, and a branching point for glucose, lactate, fatty acid and amino acid synthesis. The mitochondrial enzymes that metabolize pyruvate are physically separated from cytosolic pyruvate pools and rely on a membrane transport system to shuttle pyruvate across the impermeable inner mitochondrial membrane (IMM). Despite long-standing acceptance that transport of pyruvate into the mitochondrial matrix by a carrier-mediated process is required for the bulk of its metabolism, it has taken almost 40 years to determine the molecular identity of an IMM pyruvate carrier. Our current understanding is that two proteins, mitochondrial pyruvate carriers MPC1 and MPC2, form a hetero-oligomeric complex in the IMM to facilitate pyruvate transport. This step is required for mitochondrial pyruvate oxidation and carboxylation-critical reactions in intermediary metabolism that are dysregulated in several common diseases. The identification of these transporter constituents opens the door to the identification of novel compounds that modulate MPC activity, with potential utility for treating diabetes, cardiovascular disease, cancer, neurodegenerative diseases, and other common causes of morbidity and mortality. The purpose of the present review is to detail the historical, current and future research investigations concerning mitochondrial pyruvate transport, and discuss the possible consequences of altered pyruvate transport in various metabolic tissues.


The bioinorganic chemistry and associated immunology of chronic beryllium disease.
Chronic beryllium disease (CBD) is a debilitating, incurable, and often fatal disease that is caused by the inhalation of beryllium particulates. The growing use of beryllium in the modern world, in products ranging from computers to dental prosthetics (390 tons of beryllium in the US in the year 2000) necessitates a molecular based understanding of the disease in order to prevent and cure CBD. We have investigated the molecular basis of CBD at Los Alamos National Laboratory during the past six years, employing a multidisciplinary approach of bioinorganic chemistry and immunology. The results of this work, including speciation, inhalation and dissolution, and immunology will be discussed.


InSituNet: Deep Image Synthesis for Parameter Space Exploration of Ensemble Simulations.
We propose InSituNet, a deep learning based surrogate model to support parameter space exploration for ensemble simulations that are visualized in situ. In situ visualization, generating visualizations at simulation time, is becoming prevalent in handling large-scale simulations because of the I/O and storage constraints. However, in situ visualization approaches limit the flexibility of post-hoc exploration because the raw simulation data are no longer available. Although multiple image-based approaches have been proposed to mitigate this limitation, those approaches lack the ability to explore the simulation parameters. Our approach allows flexible exploration of parameter space for large-scale ensemble simulations by taking advantage of the recent advances in deep learning. Specifically, we design InSituNet as a convolutional regression model to learn the mapping from the simulation and visualization parameters to the visualization results. With the trained model, users can generate new images for different simulation parameters under various visualization settings, which enables in-depth analysis of the underlying ensemble simulations. We demonstrate the effectiveness of InSituNet in combustion, cosmology, and ocean simulations through quantitative and qualitative evaluations.


α-Amylase sensor based on the degradation of oligosaccharide hydrogel films monitored with a quartz crystal sensor.
α-Amylase hydrolyses starch molecules to produce smaller oligosaccharides and sugars. Amylases are of great importance in biotechnology and find application in fermentation, detergents, food and the paper industry. The measurement of α-amylase activity in serum and urine has been used in the diagnosis of acute pancreatitis. Salivary amylase has also been shown to be a stress indicator. Sensor coatings suitable for the detection of α-amylase activity have been developed. Oligosaccharides such as glycogen and amylopectin were spin-coated onto gold coated quartz crystals with a base frequency of 10 MHz. The films were subsequently cross-linked with hexamethylene diisocyanate. Film degradation was monitored with a quartz crystal microbalance (QCM) and electrochemical impedance measurements. The films were shown to be stable in phosphate buffered saline (PBS). Addition of α-amylase to the solution resulted in the rapid degradation of the films. The maximum rate of degradation was found to be strongly dependent on the amylase activity in the range typically found in serum when diagnosing pancreatitis (0.08-8 U/ml). Sensor responses in serum were found to be very similar to those obtained in buffer indicating the absence of non-specific binding.


High-priority carcinogenic occupational agents and activities for health surveillance in Brazil.
The aims of the present study were to assemble a list of carcinogens considered as having high priority for occupational health actions in Brazil and to describe the process followed to validate it. Through a literature review we retrieved the main carcinogens used in production activities in Brazil, the carcinogenicity classification developed by the International Agency for Research on Cancer (IARC) and corresponding types of cancer relevant within the Brazilian context. The list thus assembled was reviewed and validated by an expert panel. It includes known and suspected carcinogens found in the production process of some industries in Brazil, and might serve as orientation for future studies on the burden of occupational cancer.


Assessing staff attitudes towards information security in a European healthcare establishment.
Information security is now recognized as an important consideration in modern healthcare establishments (HCEs), with a variety of guidelines and standards currently available to enable the environments to be properly protected. However, financial and operational constraints often exist which influence the practicality of these recommendations. This paper establishes that the staff culture of the organization is of particular importance in determining the level and types of security that will be accepted. This culture will be based upon staff awareness of and attitudes towards security and it is, therefore, important to have a clear idea of what these attitudes are. To this end, two surveys have been conducted within a reference environment to establish the attitudes of general users and technical staff, allowing the results to be fed back to HCE management to enable security policy to be appropriately defined. These results indicated that, although the establishment had participated in a European healthcare security initiative, staff attitudes and awareness were still weak in some areas.


Acceptance of an assistive robot in older adults: a mixed-method study of human-robot interaction over a 1-month period in the Living Lab setting.
There is growing interest in investigating acceptance of robots, which are increasingly being proposed as one form of assistive technology to support older adults, maintain their independence, and enhance their well-being. In the present study, we aimed to observe robot-acceptance in older adults, particularly subsequent to a 1-month direct experience with a robot. Six older adults with mild cognitive impairment (MCI) and five cognitively intact healthy (CIH) older adults were recruited. Participants interacted with an assistive robot in the Living Lab once a week for 4 weeks. After being shown how to use the robot, participants performed tasks to simulate robot use in everyday life. Mixed methods, comprising a robot-acceptance questionnaire, semistructured interviews, usability-performance measures, and a focus group, were used. Both CIH and MCI subjects were able to learn how to use the robot. However, MCI subjects needed more time to perform tasks after a 1-week period of not using the robot. Both groups rated similarly on the robot-acceptance questionnaire. They showed low intention to use the robot, as well as negative attitudes toward and negative images of this device. They did not perceive it as useful in their daily life. However, they found it easy to use, amusing, and not threatening. In addition, social influence was perceived as powerful on robot adoption. Direct experience with the robot did not change the way the participants rated robots in their acceptance questionnaire. We identified several barriers to robot-acceptance, including older adults' uneasiness with technology, feeling of stigmatization, and ethical/societal issues associated with robot use. It is important to destigmatize images of assistive robots to facilitate their acceptance. Universal design aiming to increase the market for and production of products that are usable by everyone (to the greatest extent possible) might help to destigmatize assistive devices.


The alcohol warning and adolescents: 5-year effects.
This study, a follow-up to the authors earlier report, examined the effects of the alcohol warning label on adolescents during the first 5 years that the warning was required. Surveys were administered to 10th-grade (n = 16,661) and 12th-grade (n = 15,856) students from the 1989-1990 school year through the 1994-1995 school year. The measures were awareness of, exposure to, and recognition memory of the alcohol warning label; beliefs about the risks listed on the warning; and open-ended statements about consequences of alcohol use, alcohol consumption, and self-reported driving after drinking. There were increases in warning awareness, exposure, and recognition memory. These effects leveled off approximately 3.5 years after the inclusion of the warning on alcohol beverage containers. There was no beneficial change attributable to the warning in beliefs, alcohol consumption, or driving after drinking. The initial positive effects of the alcohol warning label on adolescents have leveled off, consistent with theories of repeated exposure to persuasive information. The alcohol warning has not affected adolescents' beliefs about alcohol or alcohol-related behaviors.


1,4-Diazacubane crystal structure rectified as piperazinium.
All 21 [n]-azacubanes are proposed by theoreticians to be stable, however, to-date only the synthesis of 1,4-diazacubane has been reported - as a Ni2+ templated Kagome metal organic framework (MOF). Described herein is the structural reassignment of this Kagome MOF on the basis of deducing the precise experimental procedure, and demonstrating that rather than the formation of 1,4-diazacubane, charge is balanced by disordered piperazinium cations across a twelve-fold symmetry site. Furthermore, quantum chemical calculations reveal that 1,4-diazacubane is unlikely to form under the reported conditions due to unfavorable enthalpies for select hypothetical reactions leading to such a product. This significant structure correction upholds the unconquered synthesis status quo of azacubane.


Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection.
The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4+ T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist.


Risk factors for proteinuria in a large, multiracial, southeast Asian population.
The factors associated with proteinuria were examined in a large multiracial Asian population participating in a screening program aimed at the early detection of renal disease. Of 213,873 adults who participated, 189,117 with complete data were included. Malay race, increasing age, both extremes of body mass index (BMI), self-reported family history of kidney disease (FKD), and higher systolic and diastolic BP measurements (even at levels classified as being within the normal range) were independently associated with dipstick-positive proteinuria. The odds ratios (OR) for proteinuria increased progressively with age. There was a J-shaped relationship between BMI and proteinuria (OR of 1.3, 1.00, 1.3, 1.6, and 2.5 for BMI of < or =18.00, 23.00 to 24.99, 25.00 to 27.49, 27.50 to 29.99, and > or =30.00 kg/m(2), respectively, compared with BMI of 18.01 to 22.99 kg/m(2)). OR for proteinuria according to systolic and diastolic BP were significantly increased beginning at levels of 110 and 90 mmHg, respectively. In addition, the Malay race was associated with a significantly higher OR for proteinuria, compared with the Chinese race (OR of 1.3). Finally, FKD was significantly associated with proteinuria (OR of 1.7), whereas a family history of diabetes mellitus and a family history of hypertension were not. When family histories were analyzed by clustering, isolated FKD remained a significant determinant of proteinuria and the magnitude of the effect was not significantly different from that observed in the presence of a coexisting family history of diabetes mellitus or hypertension. This is the first study to evaluate factors associated with proteinuria in an Asian population. The epidemiologic study of renal disease in this population suggests that risk factors for renal disease might differ significantly among racial groups.


High-resolution tomographic diffractive microscopy in reflection configuration.
Tomographic diffractive microscopy (TDM) is a label-free imaging technique that reconstructs the 3D refractive index map of the probed object with an improved resolution compared to confocal microscopy. In this work, we consider a TDM implementation in which the sample is deposited on a reflective substrate. We show that this configuration requires calibration and inversion procedures that account for the presence of the substrate for getting highly resolved quantitative reconstructions.


Association of Anesthesia Duration With Complications After Microvascular Reconstruction of the Head and Neck.
Prolonged anesthesia and operative times have deleterious effects on surgical outcomes in a variety of procedures. However, data regarding the influence of anesthesia duration on microvascular reconstruction of the head and neck are lacking. To examine the association of anesthesia duration with complications after microvascular reconstruction of the head and neck. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to collect data. In total, 630 patients who underwent head and neck microvascular reconstruction were recorded in the NSQIP registry from January 1, 2005, through December 31, 2013. Patients who underwent microvascular reconstructive surgery performed by otolaryngologists or plastic surgeons were included in this study. Data analysis was performed from October 15, 2015, to January 15, 2016. Microvascular reconstructive surgery of the head and neck. Patients were stratified into 5 quintiles based on mean anesthesia duration and analyzed for patient characteristics and operative variables (mean [SD] anesthesia time: group 1, 358.1 [175.6] minutes; group 2, 563.2 [27.3] minutes; group 3, 648.9 [24.0] minutes; group 4, 736.5 [26.3] minutes; and group 5, 922.1 [128.1] minutes). Main outcomes include rates of postoperative medical and surgical complications and mortality. A total of 630 patients undergoing head and neck free flap surgery had available data on anesthesia duration and were included (mean [SD] age, 61.6 [13.8] years; 436 [69.3%] male). Bivariate analysis revealed that increasing anesthesia duration was associated with increased 30-day complications overall (55 [43.7%] in group 1 vs 80 [63.5%] in group 5, P = .006), increased 30-day postoperative surgical complications overall (45 [35.7%] in group 1 vs 78 [61.9%] in group 5, P < .001), increased rates of postoperative transfusion (32 [25.4%] in group 1 vs 70 [55.6%] in group 5, P < .001), and increased rates of wound disruption (0 in group 1 vs 10 [7.9%] in group 5, P = .02). No specific medical complications and no overall medical complication rate (24 [19.0%] in group 1 vs 22 [17.5%] in group 5, P = .80) or mortality (1 [0.8%] in group 1 vs 1 [0.8%] in group 5, P = .75) were associated with increased anesthesia duration. On multivariate analysis accounting for demographics and significant preoperative factors including free flap type, overall complications (group 5: odds ratio [OR], 1.98; 95% CI, 1.10-3.58; P = .02), surgical complications (group 5: OR, 2.46; 95% CI, 1.35-4.46; P = .003), and postoperative transfusion (group 5: OR, 2.31; 95% CI, 1.27-4.20; P = .006) remained significantly associated with increased anesthesia duration; the association of wound disruption and increased anasthesia duration was nonsignificant (group 5: OR, 2.0; 95% CI, 0.75-5.31; P = .16). Increasing anesthesia duration was associated with significantly increased rates of surgical complications, especially the requirement for postoperative transfusion. Rates of medical complications were not significantly altered, and overall mortality remained unaffected. Avoidance of excessive blood loss and prolonged anesthesia time should be the goal when performing head and neck free flap surgery. 3.


Developments in urologic oncology «OncoForum»: The best of 2016.
To put forth new findings of urologic oncology with impact on clinical practice presented during 2016 in the main annual meetings. This document reviews abstracts on prostate, kidney and bladder cancer presented at the congresses of 2016 (EAU, AUA, ASCO, ESMO and ASTRO) and publications with the highest impact in this period valued with the highest scores by the OncoForum committee. In High-Risk Renal-Cell carcinoma after nephrectomy, disease-free survival was significantly greater for sunitinib than placebo group, with adverse events more frequents. In locally advanced and metastatic urotherial carcinoma patients, aletozumab achieved overall response rate in all subgroups of patients, included poor prognostic. In localized prostate cancer, the difference of prostate-cancer-specific mortality among active monitoring, radical prostatectomy and external-beam radiotherapy was not significant (P=0,48). In TERRAIN study, with castration-resistant prostate cancer patients, adverse events was reported in 31% and 23% of patients treated with enzalutamide and bicalutamide, respectively. Moreover, enzalutamide significantly improved median progression-free survival (15.7 months) compared bicalutamide (5.8 months) (P<.0001). In SRTIVE study, Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (P<.001). In high-risk renal-cell carcinoma after nephrectomy, sunitinb has been considered as treatment choice. In localized prostate cancer, prostate-cancer-specific mortality was low irrespective of the treatment assigned (active monitoring, radical prostatectomy and external-beam radiotherapy). In metastatic castration-resistant prostate cancer new results of treatment with enzalutamide and abiraterone has been published, wich have been shown beneficial effects in metastatic and no metastatic patients.


Effects of agri-environmental schemes on farmland birds: do food availability measurements improve patterns obtained from simple habitat models?
Studies evaluating agri-environmental schemes (AES) usually focus on responses of single species or functional groups. Analyses are generally based on simple habitat measurements but ignore food availability and other important factors. This can limit our understanding of the ultimate causes determining the reactions of birds to AES. We investigated these issues in detail and throughout the main seasons of a bird's annual cycle (mating, postfledging and wintering) in a dry cereal farmland in a Special Protection Area for farmland birds in central Spain. First, we modeled four bird response parameters (abundance, species richness, diversity and "Species of European Conservation Concern" [SPEC]-score), using detailed food availability and vegetation structure measurements (food models). Second, we fitted new models, built using only substrate composition variables (habitat models). Whereas habitat models revealed that both, fields included and not included in the AES benefited birds, food models went a step further and included seed and arthropod biomass as important predictors, respectively, in winter and during the postfledging season. The validation process showed that food models were on average 13% better (up to 20% in some variables) in predicting bird responses. However, the cost of obtaining data for food models was five times higher than for habitat models. This novel approach highlighted the importance of food availability-related causal processes involved in bird responses to AES, which remained undetected when using conventional substrate composition assessment models. Despite their higher costs, measurements of food availability add important details to interpret the reactions of the bird community to AES interventions and thus facilitate evaluating the real efficiency of AES programs.


Use of health systems evidence by policymakers in eastern Mediterranean countries: views, practices, and contextual influences.
Health systems evidence can enhance policymaking and strengthen national health systems. In the Middle East, limited research exists on the use of evidence in the policymaking process. This multi-country study explored policymakers' views and practices regarding the use of health systems evidence in health policymaking in 10 eastern Mediterranean countries, including factors that influence health policymaking and barriers and facilitators to the use of evidence. This study utilized a survey adapted and customized from a similar tool developed in Canada. Health policymakers from 10 countries (Algeria, Bahrain, Jordan, Lebanon Oman, Pakistan, Palestine, Sudan, Tunisia, and Yemen) were surveyed. Descriptive and bi-variate analyses were performed for quantitative questions and thematic analysis was done for qualitative questions. A total of 237 policymakers completed the survey (56.3% response rate). Governing parties, limited funding for the health sector and donor organizations exerted a strong influence on policymaking processes. Most (88.5%) policymakers reported requesting evidence and 43.1% reported collaborating with researchers. Overall, 40.1% reported that research evidence is not delivered at the right time. Lack of an explicit budget for evidence-informed health policymaking (55.3%), lack of an administrative structure for supporting evidence-informed health policymaking processes (52.6%), and limited value given to research (35.9%) all limited the use of research evidence. Barriers to the use of evidence included lack of research targeting health policy, lack of funding and investments, and political forces. Facilitators included availability of health research and research institutions, qualified researchers, research funding, and easy access to information. Health policymakers in several countries recognize the importance of using health systems evidence. Study findings are important in light of changes unfolding in some Arab countries and can help undertake an analysis of underlying transformations and their respective health policy implications including the way evidence will be used in policy decisions.


Chum salmon Oncorhynchus keta respond to moonlight during homeward migrations.
The swimming depth of chum salmon Oncorhynchus keta equipped with archival tags was investigated off the Pacific Ocean coast of Hokkaido and North Honshu, Japan. As shown from movements of the fish with disc tags, O. keta swam at shallower depths during the full-moon phase than in the other phases and their swimming speed during this phase was faster compared to other phases. In addition, the circadian rhythm suggests a biological clock. These observations are all consistent with the view that O. keta make use of moonlight in order to navigate at night-time during homeward migration.


Hybrid DynaCT scan-guided localization single-port lobectomy. [corrected].
Small pulmonary lesions can be difficult to locate intraoperatively. Preoperative CT scan-guided localization, for example with hookwire, is a popular method to help localize such lesions. However, the delay between CT scan localization with hookwire and surgery can lead to risks of pneumothorax and wire dislodgement. We describe a 56-year-old woman who underwent DynaCT-guided hookwire localization of a ground-glass opacity in the hybrid operating room followed immediately by single-port video-assisted thoracic surgery lobectomy. The advantages, disadvantages, and special considerations in adopting this approach are discussed.


Chitosan-Based Conduits with Different Inner Diameters at both Ends Combined with Modified Formula Radix Hedysari Promote Nerve Transposition Repair.
Severe peripheral nerve injuries, such as deficits over long distances or proximal nerve trunk injuries, pose complex reconstruction challenges that often result in unfavorable outcomes. An innovative approach to repairing severe peripheral nerve damage involves using conduit suturing for nerve transposition repair. Cylindrical nerve guides are typically unsuitable for nerve transposition repair. Moreover, postsurgical adjuvant treatment is essential to promote the development of axonal lateral sprouts, proximal growth, and the restoration of neurostructure and function. The purpose of this research is to assess the impact of chitosan-based conduits with varying inner diameters on nerve transposition repair when combined with modified formula Radix Hedysari (MFRH). Using chitosan, we created conduits with varying inner diameters on both ends. These conduits were then utilized to repair the distal common peroneal and tibial nerves in SD rats using the proximal common peroneal nerve. Subsequently, MFRH was employed as a supplementary treatment. The assessment of the repair's effectiveness took place 16 weeks postsurgery, utilizing a range of techniques, including the neurological nerve function index, neuroelectrophysiological measurements, muscle wet weight, and examination of nerve and muscle histology. The outcomes of our study showed that following 16 weeks of postoperative treatment, MFRH had a significant positive impact on the recovery of neuromotor and nerve conduction abilities. Moreover, there was a significant increase in the ratio of wet weight of muscles, cross-sectional area of muscle fibers, quantity and structure of regenerated myelinated nerve fibers, and the count of neurons. A combination of chitosan-based chitin conduits possessing different inner diameters and MFRH can considerably promote the regeneration and functional recovery of damaged nerves, which in turn enhances nerve transposition repair efficacy.


Synthesis of furonaphth[1,3]oxazine and furo[1,3]oxazinoquinoline derivatives as precursors for an o-quinonemethide structure and potential antitumor agents.
The synthesis of dihydro furonaphth[1,3]oxazine derivatives 3 was performed through a Mannich-type condensation between 2-cyano-5-hydroxy-3-methylnaphtho[1,2]furan 2a, 1.5 eq of a primary amine and 3 eq of formaldehyde. Similarly, 2-cyano-5-hydroxy-3-methylfuro[2,3-f]quinoline 2b gave the dihydro furo[1,3]oxazino-quinoline compounds 4. Heating a mixture of the naphthofuran 2a, tert-butylamine and formaldehyde at toluene reflux led to the furonaphthoxazine 3e, which decomposes to afford an o-quinonemethide intermediate 5. The latter was trapped with 1-morpholinopropene to give a dihydro furonaphthopyran derivative 6. All compounds 2, 3, 4 and 6 were assayed for in vitro cytotoxic activity toward L 1210, MDA-MB 231 and PC tumor cells. Among them, furonaphth[1,3]oxazines 3b, 3c, and furo[1,3]oxazinoquinolines 4c, 4d showed significant activity against L 1210 cells, while furoquinoline 2b was the most cytotoxic compound towards all three cell lines.