Adaptive near-field beamforming techniques for sound source imaging.
Phased array signal processing techniques such as beamforming have a long history in applications such as sonar for detection and localization of far-field sound sources. Two sometimes competing challenges arise in any type of spatial processing; these are to minimize contributions from directions other than the look direction and minimize the width of the main lobe. To tackle this problem a large body of work has been devoted to the development of adaptive procedures that attempt to minimize side lobe contributions to the spatial processor output. In this paper, two adaptive beamforming procedures-minimum variance distorsionless response and weight optimization to minimize maximum side lobes--are modified for use in source visualization applications to estimate beamforming pressure and intensity using near-field pressure measurements. These adaptive techniques are compared to a fixed near-field focusing technique (both techniques use near-field beamforming weightings focusing at source locations estimated based on spherical wave array manifold vectors with spatial windows). Sound source resolution accuracies of near-field imaging procedures with different weighting strategies are compared using numerical simulations both in anechoic and reverberant environments with random measurement noise. Also, experimental results are given for near-field sound pressure measurements of an enclosed loudspeaker.


Superior survival of females among 10,538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site.
Worldwide, female melanoma patients have superior survival compared with males, which is usually ascribed to earlier detection among women and/or a more favorable site distribution. We studied gender difference in melanoma survival in a large population-based setting after adjusting for tumor-related variables and offer clues for further research. A total of 10,538 patients diagnosed with melanoma from 1993 to 2004 in The Netherlands were included. Multivariate analyses were carried out to estimate adjusted relative excess risk (RER) of dying for men compared with women, adjusted for the patient and tumor characteristics. Univariate relative survival analyses showed a RER of dying of 2.70 [95% confidence interval (CI) 2.38-3.06] for men compared with women. After adjusting for time period of diagnosis, region, age, Breslow thickness, histologic subtype, body site, nodal and metastatic status, a significant excess mortality risk was still present for males (RER 1.87, 95% CI 1.65-2.10). Among patients with advanced disease and in those < 45 or > or = 60, the adjusted risk estimates were similar. The superior survival of women compared with men persisted after adjusting for multiple confounding variables indicating that factors other than stage at diagnosis and body site reduce mortality risk in female melanoma patients.


Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive genetic disorder characterised by dysfunction of motile cilia. Ciliary dysmotility causes poor mucociliary clearance and leads to impairment of pulmonary function and severe respiratory infections. PCD has no specific therapy. With the aim to permanently restore gene function and normalise ciliary motility, we used gene editing to replace mutated with wild-type sequence in defective cells. The target gene was dynein heavy chain 11 (DNAH11), an essential component of ciliary structure. Airway ciliated cells were collected from two patients with PCD with DNAH11 nonsense mutations and altered ciliary beating and pattern. Repair of the genetic defect was performed ex vivo by site-specific recombination using transcription activator-like effector nucleases (TALENs). In an epithelial cell line engineered to contain the DNAH11 target site, TALENs cleaved over 80% of the mutated DNAH11 sequence and replaced the mutated sequence with wild-type sequence in about 50% of cells. In airway ciliated cells of patients with PCD, site-specific recombination and normalisation of ciliary beating and pattern occurred in 33% and 29% of cells, respectively. This study demonstrates that gene editing can rescue ciliary beating ex vivo, opening up new avenues for treating PCD.


Structural and Dynamic "Portraits" of Recombinant and Native Cytotoxin I from Naja oxiana: How Close Are They?
Today, recombinant proteins are quite widely used in biomedical and biotechnological applications. At the same time, the question about their full equivalence to the native analogues remains unanswered. To gain additional insight into this problem, intimate atomistic details of a relatively simple protein, small and structurally rigid recombinant cardiotoxin I (CTI) from cobra Naja oxiana venom, were characterized using nuclear magnetic resonance (NMR) spectroscopy and atomistic molecular dynamics (MD) simulations in water. Compared to the natural protein, it contains an additional Met residue at the N-terminus. In this work, the NMR-derived spatial structure of uniformly 13C- and 15N-labeled CTI and its dynamic behavior were investigated and subjected to comparative analysis with the corresponding data for the native toxin. The differences were found in dihedral angles of only a single residue, adjacent to the N-terminal methionine. Microsecond-long MD traces of the toxins reveal an increased flexibility in the residues spatially close to the N-Met. As the detected structural and dynamic changes of the two CTI models do not result in substantial differences in their cytotoxicities, we assume that the recombinant protein can be used for many purposes as a reasonable surrogate of the native one. In addition, we discuss general features of the spatial organization of cytotoxins, implied by the results of the current combined NMR and MD study.


Community acquisition of β-lactamase producing Enterobacteriaceae in neonatal gut.
Commensal flora constitutes a reservoir of antibiotic resistance. The increasing variety of β-lactamases and the emergence of Carbapenem resistant Enterobacteriaceae (CRE) in community, raise concerns regarding efficacy of β-lactams. It is important to know the exact load of antibiotic resistance in the absence of any antibiotic selection pressure including via food and water.In the present study gut colonization in neonates with no direct antibiotic pressure was used as a model to evaluate β-lactam resistance in the community. In this prospective study, 75 healthy, vaginally delivered, antibiotic naive, breast fed neonates were studied for gut colonization by Extended spectrum β-lactamases (ESBL), AmpC β-lactamases hyperproducing Enterobacteriaceae and CRE on day 0, 21 and 60. Total 267 Enterobacteriaceae were isolated and E.coli was the predominant flora. ESBL, AmpC and coproduction was seen in 20.6%, 19.9% and 11.2% isolates respectively. ESBL carriage increased threefold from day 1 to 60 showing predominance of CTX-M group 15 (82.5%), ampC genes were heterogeneous. Colonization with CRE was rare, only one baby harboured Enterobacter sp positive for kpc-2. The reservoirs for these genes are likely to be mother and the environment. Data strongly suggests that in absence of any antibiotic pressure there is tremendous load of antibiotic resistance to β-lactam drugs. Wide spread presence of ESBL and AmpC can drive rapid emergence and dissemination of CRE. This is the first report from India which depicts the smaller picture of true antibiotic pressure present in the Indian community.


Heart Rate Variability from Wearables: A Comparative Analysis Among Standard ECG, a Smart Shirt and a Wristband.
Heart Rate Variability (HRV) derived from standard one-lead electrocardiography (ECG) was compared with HRV computed by a commercial ECG shirt and with the inter-beat-intervals (IBI) measured by a research-grade photoplethysmographic (PPG) wristband. Signals from 8 subjects were recorded in three experimental phases: during sit; in upright position ("stand"); during controlled respiration. HRV and IBI from both the wearables were computed online (i.e. during the experiment) and stored for subsequent analyses, while the standard ECG was processed offline with state-of-the-art methods to obtain a clean reference HRV. Shirt and wristband signals accuracies were assessed, with respect to the reference HRV, through a between-phase and a beat-to-beat analyses. The former considered several time and frequency domain parameters; the latter was carried out through the Bland-Altman method. Time and frequency domain parameters computed from shirt HRV resulted very similar to the ones extracted from the reference HRV and generally more accurate than the parameters computed from wristband IBI. The Bland-Altman analysis showed that wristband IBI is significantly different from ECG-derived HRV, especially during "stand". Therefore, our results support the idea that some care should be paid in the interpretation of online PPG-derived IBI, while HRV measures online-derived from ECG-shirts seem to be more reliable in the analyzed conditions. The high number of missing beats also suggest that the design of wristband devices should be taken into account to reduce the rate of incorrect measurements, by maximizing sensor adhesion to the skin.


Altered gene expression in an embolic stroke model after thrombolysis with tissue plasminogen activator and Stachybotrys microspora triprenyl phenol-7.
The present study compares gene expression and infarct area in a mouse model of embolic stroke after thrombolysis with t-PA and SMTP-7. Embolic occlusion was induced by transfer of acetic acid-induced embolus into the brain. t-PA or SMTP-7 was administered 3 h after embolization. Changes in gene expression were evaluated using microarray and RT-PCR analysis. To determine the involvement of reactive oxygen species in the response to t-PA, the free radical scavenger edaravone was infused immediately before t-PA administration. The expressions of 459 genes involved in the inflammatory response, cell-to-cell signaling, cell movement, and inflammatory disease were altered by embolic occlusion. Twenty-two of those genes were upregulated after t-PA but not SMTP-7 administration. Differences between the t-PA- and SMTP-7-treated groups in the expression of genes including the proinflammatory genes Il6, Stat3, S100a8, and Mmp9 were confirmed with RT-PCR. Edaravone ameliorated the overexpression of these genes. Our data demonstrate differences in gene expression following treatment with SMTP-7 or t-PA that likely explain the difference in therapeutic time windows of the two drugs. ROS are involved in the overexpression of proinflammatory genes. The wide therapeutic time window may be achieved through an anti-oxidative effect and inhibition of proinflammatory gene overexpression.


[Content of essential amino acids in prematurely weaned piglets after a qualitatively and quantitatively variable protein diet].
A total of 60 piglets of German Landrace weaned at the age of 2 weeks were fed ad libitum with isoenergetic diets of different proteins (casein + dried skim milk, soybean protein + dried skim milk, only soybean protein) and different protein levels in the diet (20, 27, 34, 40% in D.M.). After 4 weeks the piglets were homogenized and examined for their content of essential amino acids in the whole body mass by ion exchange chromatography. On the fresh and dried material the contents of Thr, Val, Ile, Leu, Lys and Ser increased both with higher supply of protein and milk instead of soybean protein in the diet. The contents of Phe and Arg were only insignificantly changed by protein quality. Referred to the concentration of Met and Cys there were found higher standard deviations and interactions between protein supply and quality. The content of essential amino acids also was influenced by the protein quality of the diet, when related to the whole body protein. On the other hand a significant effect of increasing protein supply only took place if soybean protein was the single protein ingredient of the diet. Related to Lys the contents of Thr and Cys nearly were constant, whereas the amino acid/lysine proportion in the case of Met, Ile and Arg changed considerably.


Vertically Aligned CdO-Decked α-Fe2O3 Nanorod Arrays by a Radio Frequency Sputtering Method for Enhanced Photocatalytic Applications.
Green hydrogen production is one of the most desirable sustainable goals of the United Nations. Thus, for that purpose, we developed hematite (α-Fe2O3), an n-type semiconductor, a desirable candidate for photoelectrochemical (PEC) water splitting, enabling hydrogen evolution. High recombination losses, low efficiency, and large-scale production hinder its potential. To address these issues, we have fabricated optimized bare and cadmium oxide (CdO)-decorated hematite thin film nanorod arrays using a throughput radio frequency (RF) sputtering with efficient water splitting behavior. To the best of our knowledge, no work has been done so far on the synthesis of CdO/α-Fe2O3 via RF sputtering for PEC application. Bare α-Fe2O3 samples, with a morphology of vertically aligned nanorods, were fabricated with optimized parameters such as as-deposited 70 nm of Fe, an angle of deposition of 70°, and an annealing temperature of 600 °C, which showed a photocurrent density of 0.38 mA/cm2 at 1.65 V vs reversible hydrogen electrode (RHE). Characterizations depicted that this unique morphology with high crystallinity directly enhanced the performance of hematite photoanodes. Further, deposition of 30 nm of cadmium (CdO) on the α-Fe2O3 nanorods produced a corn-like morphology with CdO nanoparticles (∼2 nm), resulting in 4-times enhancement of the PEC performance (1.2 mA/cm2 at 1.65 V vs RHE). CdO acted as a co-catalyst, responsible for satisfactory suppression of recombination and facilitating the hole transfer, directly enhancing the overall photocurrent density. This photoanode showed an extremely stable behavior over a period of 26 h when kept under constant illumination. Furthermore, the CdO-modified photoanode showed a better dye degradation (98% in 40 min) than the bare hematite (60% in 40 min), proving to be an efficient photoanode.


Haemophilus influenzae type e meningitis and bacteremia in a healthy adult.
Haemophilus influenzae type b causes more than 95% of serious H. influenzae meningitis. H. influenzae type e (Hie) has been implicated in a few cases of meningitis. Here, we present an adult Saudi patient with Hie meningitis and review the literature. The patient, a 19-year-old Saudi male with no significant past medical history, was noted by his family to have some changes in his mentation, confusion and refusal to eat; subsequently, he became unresponsive. Cerebrospinal fluid and blood culture grew Hie. The patient was treated with intravenous ceftriaxone with full recovery.


Dynamic structure elucidation of chemical reactivity by laser pulses and X-ray probes.
Visualising chemical reactions by X-ray methods is a tantalising prospect. New light sources provide the prospect for studying atomic, electronic and energy transfers accompanying chemical change by X-ray spectroscopy and inelastic scattering. Here we assess how this adventure can illuminate inorganic and catalytic chemistry. In particular X-ray inelastic scattering provides a means of exploiting X-ray free electron lasers, as a parallel to laser Raman spectroscopy.


Nonlinear dynamic behavior of the human knee joint--Part I: Postmortem frequency domain analyses.
Characteristics results of postmortem experiments on five knee-joint specimens are reported. The experiments were performed to investigate the applicability of a local linearization technique that would make it possible to describe the dynamic behavior of the joint in terms of transfer functions. The results indicate that the stiffness of the bracing wires, attached to muscle tendons to create a static equilibrium position, can be accounted for when determining the stiffness of the joint. Besides the static equilibrium configuration, the magnitude of the dynamic load and the type of dynamic load applied to the joint can be shown to have their influence. As the influence of the dynamic load is significant, it has to be concluded that in essence the knee joint has to be regarded as a nonlinear system, making application of a Local Linearization Technique questionable. However, when the magnitude of the dynamic load is included as an additional measurement parameter, an indication can be obtained about the behavior of the joint and the degree of nonlinearity.


[The late results of inlay prosthesis].
A 1- to 7-year follow-up of 52 patients supplied with inserts has demonstrated that cast metal inserts provide effective prevention of caries recurrences, complications, and denture deformations. The best results are achieved after thorough mastering of the operation and strict adherence to indications to such prosthesis, with the methods for clinical and paraclinical examinations of patients before the treatment constantly improved.


Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver.
Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals. Baseline expression of activating and inhibitory receptors was assessed, as well as functional responses following stimulation through classic NK cell pathways. Independent of HCV infection, the liver was enriched for the immunoregulatory CD56(bright) NK cell population, which produced less IFNγ and CD107a but comparable levels of MIP1β, and was immunophenotypically distinct from their blood counterparts. This profile was mostly unaltered in chronic HCV infection, though different expression levels of NKp46 and NKG2D were associated with different grades of fibrosis. In contrast to the liver, chronic HCV infection associated with an enrichment of CD161(low)perforin(high) NK cells in the blood correlated with increased AST and 2B4 expression. However, the association of relatively discrete changes in the NK cell phenotype in the liver with the fibrosis stage nevertheless suggests an important role for the NK response. Overall these data suggest that tissue localization has a more pervasive effect on NK cells than the presence of chronic viral infection, during which these cells might be mostly attuned to limiting immunopathology. It will be important to characterize NK cells during early HCV infection, when they should have a critical role in limiting infection.


Bacteraemia in the elderly.
The aims of the study were to describe community-acquired and nosocomial bacteraemia in elderly patients and to determine the factors associated with increased mortality in these patients attending a tertiary hospital in Singapore. A consecutive series of 191 patients aged more than 60 years of age admitted in 1995 was studied retrospectively. All of them had positive blood culture results obtained from the Department of Pathology and the case notes were reviewed and entered into a standard clinical protocol. They were analysed for age, sex, place of origin, race, sites of infection, clinical parameters and bacteriology. The mean age of the study population was 75 years (SD = 8.9 years). Bacteraemia was acquired from the community in 57.5% of patients, 33% was nosocomial in origin and 9.5% acquired it in chronic long term care facilities. The common organisms cultured in community-acquired infections were Escherichia coli (26.1%), Klebsiella species (25.4%), Streptococcus species (11.1%), methicillin sensitive Staphylococcus aureus (7.6%) and Proteus mirabilis (4.8%). The common organisms cultured in nosocomial infections were Klebsiella species (19.8%), Enterobacter species (14.6%), E. coli (11.8%), Acinetobacter baumanii (9.2%), methicillin sensitive Staphylococcus aureus (7.9%) and methicillin-resistant Staphylococcus aureus (7.9%). Whilst most cases of bacteraemia were single organism cultures, 13.5% were polymicrobial. The common sources of bacteraemia were chest (27.5%), urinary tract (24.5%), skin (12.5), hepatic (8.8%), gut (4.3%), cardiovascular system (1%) and others (3.6%). In 12.5% of cases, the sources were multiple and in 5.3% of cases, the source could not be identified. Twenty-one per cent of patients with bacteraemia died. The following factors were associated with increased mortality rate: older age (median age of those that died was 78.5 years compared to survivors with a median age of 73 years, P = 0.011), patient's place of origin (patients in nursing home at higher risk of death, P = 0.04), patient's mobility status (immobile patients at higher risk, P = 0.00297), source of bacteraemia--respiratory infection at increased risk of death (P = 0.00009) but urinary tract infection had a better survival rate (P = 0.03935) and multiple sites of infection (patients with multiple sites of infection had higher risk, P = 0.00897). Methicillin-sensitive Staphylococcus aureus bacteraemia was associated with a mortality rate of 35.3%, followed by Klebsiella species 28.6%, Pseudomonas aeruginosa 28.6%, methicillin-resistant Staphylococcus aureus 25%, Proteus mirabilis 25% and E. coli 19.1%. Important clinical parameters which indicated a poor clinical outcome were: high pulse rate, hypotension, increased respiratory rate, low total white cell count, coagulopathy, hypoalbuminaemia and increased creatinine level.


A line-source method for aligning on-board and other pinhole SPECT systems.
In order to achieve functional and molecular imaging as patients are in position for radiation therapy, a robotic multipinhole SPECT system is being developed. Alignment of the SPECT system-to the linear accelerator (LINAC) coordinate frame and to the coordinate frames of other on-board imaging systems such as cone-beam CT (CBCT)-is essential for target localization and image reconstruction. An alignment method that utilizes line sources and one pinhole projection is proposed and investigated to achieve this goal. Potentially, this method could also be applied to the calibration of the other pinhole SPECT systems. An alignment model consisting of multiple alignment parameters was developed which maps line sources in three-dimensional (3D) space to their two-dimensional (2D) projections on the SPECT detector. In a computer-simulation study, 3D coordinates of line-sources were defined in a reference room coordinate frame, such as the LINAC coordinate frame. Corresponding 2D line-source projections were generated by computer simulation that included SPECT blurring and noise effects. The Radon transform was utilized to detect angles (α) and offsets (ρ) of the line-source projections. Alignment parameters were then estimated by a nonlinear least squares method, based on the α and ρ values and the alignment model. Alignment performance was evaluated as a function of number of line sources, Radon transform accuracy, finite line-source width, intrinsic camera resolution, Poisson noise, and acquisition geometry. Experimental evaluations were performed using a physical line-source phantom and a pinhole-collimated gamma camera attached to a robot. In computer-simulation studies, when there was no error in determining angles (α) and offsets (ρ) of the measured projections, six alignment parameters (three translational and three rotational) were estimated perfectly using three line sources. When angles (α) and offsets (ρ) were provided by the Radon transform, estimation accuracy was reduced. The estimation error was associated with rounding errors of Radon transform, finite line-source width, Poisson noise, number of line sources, intrinsic camera resolution, and detector acquisition geometry. Statistically, the estimation accuracy was significantly improved by using four line sources rather than three and by thinner line-source projections (obtained by better intrinsic detector resolution). With five line sources, median errors were 0.2 mm for the detector translations, 0.7 mm for the detector radius of rotation, and less than 0.5° for detector rotation, tilt, and twist. In experimental evaluations, average errors relative to a different, independent registration technique were about 1.8 mm for detector translations, 1.1 mm for the detector radius of rotation (ROR), 0.5° and 0.4° for detector rotation and tilt, respectively, and 1.2° for detector twist. Alignment parameters can be estimated using one pinhole projection of line sources. Alignment errors are largely associated with limited accuracy of the Radon transform in determining angles (α) and offsets (ρ) of the line-source projections. This alignment method may be important for multipinhole SPECT, where relative pinhole alignment may vary during rotation. For pinhole and multipinhole SPECT imaging on-board radiation therapy machines, the method could provide alignment of SPECT coordinates with those of CBCT and the LINAC.


The Relationship Between Yoga and Spirituality: A Systematic Review of Empirical Research.
Both yoga practice and spirituality are associated with beneficial mental health outcomes. Within yoga research, however, spirituality is still a widely neglected area. The present systematic review aims to explore empirical studies, which do, in fact, investigate the relationship between yoga and spirituality in order to provide an overview and future directions for research on this topic. The review examines whether available empirical research supports an association between yoga practice and spirituality and, if so, which specific aspects of spirituality are associated with yoga practice. The systematic review followed the PRISMA guideline (Prospero registration number: CRD42020155043). Empirical studies written in English, German, or Hungarian language were selected from a database search in Google Scholar, PsycINFO, and Science Direct. A total of 30 studies met the final inclusion criteria. According to the quantitative and qualitative studies reviewed, yoga practice seems to be positively associated with spirituality. This association concerns various aspects of spirituality, such as spiritual aspirations, a search for insight/wisdom, an integrative worldview, a sense of meaning and peace, faith, hope, compassion, and happiness within. To harness the potential spiritual benefits of yoga, regular practice appears to be essential. Yoga practitioners seem to have both physical and spiritual motives for practicing. At least in Western societies, however, physical intentions are more prevalent than spiritual ones. The meaning of spirituality for yoga practitioners is also discussed. Due to risk of bias of the majority of the reviewed studies, however, outcomes must be taken with caution. Yoga practice may be positively associated with several aspects of spirituality. For more evidence, further investigation of the topic is suggested. Particularly, we propose the inclusion of holistic forms of yoga practice and a comparison of Eastern and Western approaches to yoga.


Does cancer reduce labor market entry? Evidence for prime-age females.
Existing studies of the labor market status of cancer survivors have focused on the extent to which cancer disrupts the employment of individuals who were working when diagnosed with cancer. We examine how surviving cancer affects labor market entry and usual hours of work among females aged 28 to 54 years who were not working when first diagnosed. We find that prime-age females have employment rates 2 to 6 years after diagnosis that are 12 percentage points lower than otherwise similar women who were initially out of the labor force, full-time employment rates that are 10 percentage points lower, and usual hours of work that are 5 hours per week lower. These estimates are somewhat larger than estimates for prime-age women employed at the time of diagnosis and highlight the importance of considering nonworking females when assessing the economic and psychosocial burden of cancer.


Racial and Ethnic Differences in Mortality Associated with Serum Potassium in Incident Peritoneal Dialysis Patients.
Abnormalities in serum potassium are risk factors for sudden cardiac death and arrhythmias among dialysis patients. Although a previous study in hemodialysis patients has shown that race/ethnicity may impact the relationship between serum potassium and mortality, the relationship remains unclear among peritoneal dialysis (PD) patients where the dynamics of serum potassium is more stable. Among 17,664 patients who started PD between January 1, 2007 and December 31, 2011 in a large US dialysis organization, we evaluated the association of serum potassium levels with all-cause and arrhythmia-related deaths across race/ethnicity using time-dependent Cox models with adjustments for demographics. We also used restricted cubic spline functions for serum potassium levels to explore non-linear associations. Baseline serum potassium levels were the highest among Hispanics (4.2 ± 0.7 mEq/L) and lowest among non-Hispanic blacks (4.0 ± 0.7 mEq/L). Among 2,949 deaths during the follow-up of median 2.2 (interquartile ranges 1.3-3.2) years, 683 (23%) were arrhythmia-related deaths. Overall, both hyperkalemia and hypokalemia (i.e., serum potassium levels >5.0 and <3.5 mEq/L, respectively) were associated with higher all-cause and arrhythmia-related mortality. In a stratified analysis according to race/ethnicity, the association of hypokalemia with all-cause and arrhythmia-related mortality was consistent with an attenuation for arrhythmia-related mortality in non-Hispanic blacks. Hyperkalemia was associated with all-cause and arrhythmia-related mortality in non-Hispanic whites and non-Hispanic blacks, but no association was observed in Hispanics. Among incident PD patients, hypokalemia was consistently associated with all-cause and arrhythmia-related deaths irrespective of race/ethnicity. However, while hyperkalemia was associated with both death outcomes in non-Hispanic blacks and whites, it was not associated with either death outcome in Hispanic patients. Further studies are needed to demonstrate whether different strategies should be followed for the management of serum potassium levels according to race/ethnicity.


Treatment and survival of Asian women diagnosed with breast cancer in New Zealand.
This study aims to examine the differences in characteristics, treatment and survival between Asian and European women diagnosed with stage I-III breast cancer in New Zealand. The studied population included European women and Asian women diagnosed with stage I-III breast cancer between June 2000 and May 2013 identified from the combined Waikato and Auckland Breast Cancer Registers. Characteristics and treatment were compared between Asian and European women. Kaplan-Meier method was used to examine the survival difference. Cox proportional hazards model was used to estimate the hazard ratio (HR) of mortality. The studied cohort included 8608 European and 949 Asian women. Asian women were younger, had less comorbidities and were less likely to be obese than European women. Asian women were more likely to have grade 3, larger and HER2+ breast cancers. Asian women were more likely to receive mastectomy, less likely to have reconstruction after mastectomy, less likely to have chemotherapy, less likely to be treated with trastuzumab if HER2+, and had better adherence to endocrine therapy (adjusted odds ratio: 1.54; 95% CI 1.22-1.93). Asian women had better cancer-specific survival and all-cause survival than European women. The adjusted HR of cancer-specific mortality and all-cause mortality were 0.64 (95% CI 0.49-0.82) and 0.68 (95% CI 0.55-0.84), respectively. Asian women are more likely to have high grade, larger and HER2+ breast cancers than European women. In spite of this, they had better breast cancer outcomes. Possible explanations include the differences in adherence to endocrine therapy, age, BMI and comorbidities.


Inspiratory Muscle Training in the Intensive Care Unit: A New Perspective.
Prolonged use of mechanical ventilation (MV) leads to weakening of the respiratory muscles, especially in patients subjected to sedation, but this effect seems to be preventable or more quickly reversible using respiratory muscle training. The aims of the study were to assess variations in respiratory and hemodinamic parameters with electronic inspiratory muscle training (EIMT) in tracheostomized patients requiring MV and to compare these variations with those in a group of patients subjected to an intermittent nebulization program (INP). This was a pilot, prospective, randomized study of tracheostomized patients requiring MV in one intensive care unit (ICU). Twenty-one patients were randomized: 11 into the INP group and 10 into the EIMT group. Two patients were excluded in experimental group because of hemodynamic instability. In the EIMT group, maximal inspiratory pressure (MIP) after training was significantly higher than that before (P = 0.017), there were no hemodynamic changes, and the total weaning time was shorter than in the INP group (P = 0.0192). The EIMT device is safe, promotes an increase in MIP, and leads to a shorter ventilator weaning time than that seen in patients treated using INP.


PA-Fuse: deep supervised approach for the fusion of photoacoustic images with distinct reconstruction characteristics.
The methods available for solving the inverse problem of photoacoustic tomography promote only one feature-either being smooth or sharp-in the resultant image. The fusion of photoacoustic images reconstructed from distinct methods improves the individually reconstructed images, with the guided filter based approach being state-of-the-art, which requires that implicit regularization parameters are chosen. In this work, a deep fusion method based on convolutional neural networks has been proposed as an alternative to the guided filter based approach. It has the combined benefit of using less data for training without the need for the careful choice of any parameters and is a fully data-driven approach. The proposed deep fusion approach outperformed the contemporary fusion method, which was proved using experimental, numerical phantoms and in-vivo studies. The improvement obtained in the reconstructed images was as high as 95.49% in root mean square error and 7.77 dB in signal to noise ratio (SNR) in comparison to the guided filter approach. Also, it was demonstrated that the proposed deep fuse approach, trained on only blood vessel type images at measurement data SNR being 40 dB, was able to provide a generalization that can work across various noise levels in the measurement data, experimental set-ups as well as imaging objects.


3dSS: 3D structural superposition.
3dSS is a web-based interactive computing server, primarily designed to aid researchers, to superpose two or several 3D protein structures. In addition, the server can be effectively used to find the invariant and common water molecules present in the superposed homologous protein structures. The molecular visualization tool RASMOL is interfaced with the server to visualize the superposed 3D structures with the water molecules (invariant or common) in the client machine. Furthermore, an option is provided to save the superposed 3D atomic coordinates in the client machine. To perform the above, users need to enter Protein Data Bank (PDB)-id(s) or upload the atomic coordinates in PDB format. This server uses a locally maintained PDB anonymous FTP server that is being updated weekly. This program can be accessed through our Bioinformatics web server at the URL http://cluster.physics.iisc.ernet.in/3dss/ or http://10.188.1.15/3dss/.


Perinatal exposure to foodborne inorganic nanoparticles: A role in the susceptibility to food allergy?
Food allergy (FA) is an inappropriate immune response against dietary antigens. Various environmental factors during perinatal life may alter the establishment of intestinal homeostasis, thereby predisposing individuals to the development of such immune-related diseases. Among these factors, recent studies have emphasized the chronic dietary exposure of the mother to foodborne inorganic nanoparticles (NP) such as nano-sized silicon dioxide (SiO2), titanium dioxide (TiO2) or silver (Ag). Indeed, there is growing evidence that these inorganic agents, used as food additives in various products, as processing aids during food manufacturing or in food contact materials, can cross the placental barrier and reach the developing fetus. Excretion in milk is also suggested, hence continuing to expose the neonate during a critical window of susceptibility. Due to their immunotoxical and biocidal properties, such exposure may disrupt the host-intestinal microbiota's beneficial exchanges and may interfere with intestinal barrier and gut-associated immune system development in fetuses then the neonates. The resulting dysregulated intestinal homeostasis in the infant may significantly impede the induction of oral tolerance, a crucial process of immune unresponsiveness to food antigens. The current review focuses on the possible impacts of perinatal exposure to foodborne NP during pregnancy and early life on the susceptibility to developing FA.


Relation of 99mTc-sestamibi washout with myocardial properties in patients with hypertrophic cardiomyopathy.
We sought to determine the relationship between (99m)Tc-sestamibi washout and myocardial properties in hypertrophic cardiomyopathy (HCM) patients. Twenty-four HCM patients underwent biventricular cardiac catheterization, with a micromanometer-tipped catheter, both at rest and during atrial pacing, echocardiography and myocardial (99m)Tc-sestamibi scintigraphy at rest. The (99m)Tc-sestamibi washout rate (WR) was calculated using initial and delayed planar images. The HCM patients were divided into two groups as follows: Group A consisted of 13 patients showing (99m)Tc-sestamibi WR < 22.5%; group B of 11 patients showing (99m)Tc-sestamibi WR ≥ 22.5%. Significant correlations were observed between (99m)Tc-sestamibi WR and percentage changes in pressure half-time (T (1/2)), as well as those in the maximum first derivative LV pressure (LV dP/dt (max)) (r = .43, P = .033; r = -.63, P = .001). The percentage changes in LV dP/dt (max) and those in T (1/2) were significantly more reduced in group B than in group A (P < .05). The biphasic force-frequency relation was more frequently observed in group B than in group A (82% vs. 18%). Increased (99m)Tc-sestamibi washout is associated with an impaired contractile reserve and prolonged relaxation, suggesting that myocardial (99m)Tc-sestamibi scintigraphy may be useful in noninvasively detecting the early impairment of myocardial function in HCM patients.


SPTBN1 Mediates the Cytoplasmic Constraint of PTTG1, Impairing Its Oncogenic Activity in Human Seminoma.
Seminoma is the most common testicular cancer. Pituitary tumor-transforming gene 1 (PTTG1) is a securin showing oncogenic activity in several tumors. We previously demonstrated that nuclear PTTG1 promotes seminoma tumor invasion through its transcriptional activity on matrix metalloproteinase 2 (MMP-2) and E-cadherin (CDH1). We wondered if specific interactors could affect its subcellular distribution. To this aim, we investigated the PTTG1 interactome in seminoma cell lines showing different PTTG1 nuclear levels correlated with invasive properties. A proteomic approach upon PTTG1 immunoprecipitation uncovered new specific securin interactors. Western blot, confocal microscopy, cytoplasmic/nuclear fractionation, sphere-forming assay, and Atlas database interrogation were performed to validate the proteomic results and to investigate the interplay between PTTG1 and newly uncovered partners. We observed that spectrin beta-chain (SPTBN1) and PTTG1 were cofactors, with SPTBN1 anchoring the securin in the cytoplasm. SPTBN1 downregulation determined PTTG1 nuclear translocation, promoting its invasive capability. Moreover, a PTTG1 deletion mutant lacking SPTBN1 binding was strongly localized in the nucleus. The Atlas database revealed that seminomas that contained higher nuclear PTTG1 levels showed significantly lower SPTBN1 levels in comparison to non-seminomas. In human seminoma specimens, we found a strong PTTG1/SPTBN1 colocalization that decreases in areas with nuclear PTTG1 distribution. Overall, these results suggest that SPTBN1, along with PTTG1, is a potential prognostic factor useful in the clinical management of seminoma.


International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management.
The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.


Predictors of lower-than-expected posttraumatic symptom severity in war veterans: The influence of personality, self-reported trait resilience, and psychological flexibility.
Resilience following traumatic events has been studied using numerous methodologies. One approach involves quantifying lower-than-expected levels of a negative outcome following trauma exposure. Resilience research has examined personality and coping-related factors. One malleable factor is psychological flexibility, or the context-dependent ability/willingness to contact the present moment, including emotional distress, in order to engage in valued actions. Among 254 war Veterans who participated in a longitudinal study, we operationalized resilience as lower-than-expected PTSD symptoms and PTSD-related functional impairment one-year following an initial post-deployment assessment based on lifetime exposure to childhood trauma, combat trauma, and sexual trauma during military service. We evaluated the contribution of personality factors, self-reported trait resilience, and psychological flexibility, measured using the Acceptance and Action Questionnaire-II, to PTSD-related resilience after accounting for lifetime and current PTSD symptom severity and depression symptom severity. In hierarchical regression analyses, neither specific personality factors nor self-reported resilience predicted PTSD-related resilience at follow-up after accounting for PTSD and depression symptoms. In the final step, psychological flexibility predicted unique variance and was the only significant predictor of PTSD-related resilience aside from baseline PTSD symptom severity. Findings indicate that psychological flexibility is a predictor of resilience that is distinct from psychiatric symptoms, personality, and self-reported resilience. Trauma survivors may benefit from interventions that bolster psychological flexibility.


A study of the genetic variability of human respiratory syncytial virus (HRSV) in Cambodia reveals the existence of a new HRSV group B genotype.
Human respiratory syncytial virus (HRSV) is the leading cause of hospitalization of children aged <5 years due to respiratory illness in industrialized countries, and pneumonia is the leading cause of mortality among children aged <5 years worldwide. Although HRSV was first identified in 1956, a preventative vaccine has yet to be developed. Here we report the results of the first study to investigate the circulation and genetic diversity of HRSV in Cambodia among an all-ages population over 5 consecutive years. The incidences of HRSV infection among all-ages outpatient and hospitalized populations were equivalent, at 9.5% and 8.2%, respectively. Infection was most prevalent among children aged <5 years, with bronchiolitis being the most frequently observed clinical syndrome in the same age group. Circulation of HRSV was seasonal, typically coinciding with the rainy season between July and November annually. Strains belonging to HRSV groups A and B were detected with equivalent frequencies; however, we observed a potentially biennial shift in the predominant circulating HRSV genotype. The majority of HRSV group B strains belonged to the recently described BA genotype, with the exception of 10 strains classified as belonging to a novel HRSV group B genotype, SAB4, first reported here.


Effects of Fe3+ and Zn2+ on the structural and thermodynamic properties of a soybean ASR protein.
Abscisic acid-, stress-, and ripening-induced (ASR) protein play important roles in protecting plants from abiotic stress. The functions of some ASR proteins are known to be modulated by binding to metal ions. In this study, we demonstrated that the non-tagged full-length soybean (Glycine max) ASR protein (GmASR) can bind Fe(3+), Ni(2+), Cu(2+), and Zn(2+). The direct binding properties of GmASR to Fe(3+) and Zn(2+) were further confirmed by intrinsic fluorescence assays. The GmASR protein was found to have three Fe(3+) binding sites but only two Zn(2+) binding sites. Natively disordered in aqueous solution, GmASR remained disordered in the presence of Fe(3+), but was found to aggregate in the presence of Zn(2+). The aggregated GmASR protein was partially resolubilized after Zn(2+) was chelated by EDTA. GmASR exhibited Fe(3+)-binding-dependent antioxidant activity in vitro. We speculate that GmASR thus protects against oxidation damage by buffering metal ions, thus alleviating metal toxicity in plant cells under stressed conditions.


Inflammasomes in the lung.
Innate immune responses act as first line defences upon exposure to potentially noxious stimuli. The innate immune system has evolved numerous intracellular and extracellular receptors that undertake surveillance for potentially damaging particulates. Inflammasomes are intracellular innate immune multiprotein complexes that form and are activated following interaction with these stimuli. Inflammasome activation leads to the cleavage of pro-IL-1β and release of the pro-inflammatory cytokine, IL-1β, which initiates acute phase pro-inflammatory responses, and other responses are also involved (IL-18, pyroptosis). However, excessive activation of inflammasomes can result in chronic inflammation, which has been implicated in a range of chronic inflammatory diseases. The airways are constantly exposed to a wide variety of stimuli. Inflammasome activation and downstream responses clears these stimuli. However, excessive activation may drive the pathogenesis of chronic respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. Thus, there is currently intense interest in the role of inflammasomes in chronic inflammatory lung diseases and in their potential for therapeutic targeting. Here we review the known associations between inflammasome-mediated responses and the development and exacerbation of chronic lung diseases.


VEGF gene polymorphisms and susceptibility to colorectal cancer.
Colorectal cancer (CRC) is the third most common cancer in the world and its etiology involves the interaction of genetic and environmental factors. New blood vessels form through a process called angiogenesis and have an essential role in tumor growth, progression, and metastasis of malignant tumors. The vascular endothelial growth factor (VEGF), one of the most important angiogenic factors, is a specific mitogen for vascular endothelial cells. In the present case-control study, we carried out the study to evaluate whether the VEGF single-nucleotide polymorphisms play a role in modulating susceptibility to CRC. We evaluated the VEGF -2578A>C, +936C>T, and -460C>T genotypes obtained from 103 patients with CRC and 129 healthy controls by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Also, haplotype analysis was determined. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated. -2578A>C was significantly associated with CRC risk (OR 1.81; 95% CI 0.94-3.47; p=0.0495), while distribution of +936C>T and -460C>T genotypes in cases and controls did not significantly differ. The VEGF A2578-T936-T460 haplotype might be associated with the development of CRC (OR 8.77; 95% CI 1.05-73.36; p=0.0434). There was significant haplotype effect for all eight haplotypes (p=0.02). These results suggest that the VEGF polymorphisms might play a role in the development of CRC. Therefore, the VEGF polymorphisms might be further investigated to use in the determination of risk factors for CRC and to have a predictive value for anti-VEGF-targeted cancer therapies.


Accelerated anaerobic hydrolysis rates under a combination of intermittent aeration and anaerobic conditions.
Anaerobic hydrolysis in activated return sludge was investigated in laboratory scale experiments to find if intermittent aeration would accelerate anaerobic hydrolysis rates compared to anaerobic hydrolysis rates under strict anaerobic conditions. The intermittent reactors were set up in a 240 h experiment with intermittent aeration (3 h:3 h) in a period of 24 h followed by a subsequent anaerobic period of 24 h in a cycle of 48 h which was repeated five times during the experiment. The anaerobic reactors were kept under strict anaerobic conditions in the same period (240 h). Two methods for calculating hydrolysis rates based on soluble chemical oxygen demand were compared. Two-way analysis of variance with the Bonferroni post-test was performed in order to register any significant difference between reactors with intermittent aeration and strictly anaerobic conditions respectively. The experiment demonstrated a statistically significant difference in favor of the reactors with intermittent aeration showing a tendency towards accelerated anaerobic hydrolysis rates due to application of intermittent aeration. The conclusion of the work is thus that intermittent aeration applied in the activated return sludge process can improve the treatment capacity further in full scale applications.


A Review of Nonfatal Drowning in the Pediatric-Age Group: A 10-Year Experience at a University Hospital in Saudi Arabia.
The aim of this study was to evaluate the nonfatal drowning experience, risk factors, intrahospital assessment and postincidental outcomes for children admitted to King Fahd Hospital of the University, AlKhobar, Saudi Arabia, over a 10-year period. Children up to the age of 14 years who were admitted with the diagnosis of nonfatal drowning from July 2005 to June 2015 were included. Data regarding demographics, timing, season and location of drowning, presence of an assigned lifeguard, duration of submersion and transport to hospital, cardiopulmonary resuscitation, initial Glasgow Coma Scale, temperature, pH, blood sugar level, total hospital stay, and discharge status were extrapolated, and their effects on the patient's outcome analyzed. Patients' outcomes were classified into either full recovery, moderate to severe neurological damage, or brain death. Fifty-one subjects were included in the study; 66.7% were males, 57% were younger than 6 years, and 80% were Saudi citizens. Of the total cases, 94% recovered fully, and 6% were diagnosed as having brain death or discharged from the intensive care unit with severe neurological injury. Submersion time of more than 5 minutes, Glasgow Coma Scale of 4 or less, pH of less than 7.1, temperature of 35°C or less, and blood sugar of 180 mg/dL or greater were found to correlate with bad outcomes with great statistical significance. The findings of this study were in line with results of most of the international and local studies on the subject. Significant defects have been concluded in prehospital medical care and cardiopulmonary resuscitation. Adequate swimming safety regulations, assignments of lifeguards, and parental education should be taken into consideration by media and involved authorities.


Fast 2-photon stimulation using holographic patterns.
Two decades after its introduction, optogenetics - a biological technique to control the activity of neurons or other cell types with light - remains a cutting edge and promising tool to study biological processes. Its increasing usage in research varies widely from causally exploring biological mechanisms and neural computations, to neurostimulation and sensory restauration. To stimulate neurons in the brain, a variety of approaches have been developed to generate precise spatiotemporal light patterns. Yet certain constrains still exists in the current optical techniques to activate a neuronal population with both cellular resolution and millisecond precision. Here, we describe an experimental setup allowing to stimulate a few tens of neurons in a plane at sub-millisecond rates using 2-photon activation. A liquid crystal on silicon spatial light modulator (LCoS-SLM) was used to generate spatial patterns in 2 dimensions. The image of the patterns was formed on the plane of a digital micromirror device (DMD) that was used as a fast temporal modulator of each region of interest. Using fluorescent microscopy and patch-clamp recording of neurons in culture expressing the light-gated ion channels, we characterized the temporal and spatial resolution of the microscope. We described the advantages of combining the LCoS-SLM with the DMD to maximize the temporal precision, modulate the illumination amplitude, and reduce background activation. Finally, we showed that this approach can be extended to patterns in 3 dimensions. We concluded that the methodology is well suited to address important questions about the role of temporal information in neuronal coding.


Outcomes after first-time lower extremity revascularization for chronic limb-threatening ischemia between patients with and without diabetes.
The effect of diabetes type and insulin dependence on short- and long-term outcomes after lower extremity revascularization for chronic limb-threatening ischemia (CLTI) warrants additional study and more targeted focus. We sought to address this paucity of information by evaluating outcomes in insulin-dependent and noninsulin-dependent patients after any first-time revascularization. We reviewed all limbs undergoing first-time infrainguinal bypass grafting (BPG) or percutaneous transluminal angioplasty with or without stenting (PTA/S) for CLTI at our institution from 2005 to 2014. Based on preoperative medication regimen, patients were categorized as having insulin-dependent diabetes (IDDM), noninsulin-dependent diabetes (NIDDM), or no diabetes (NDM). Outcomes included wound healing; major amputation; RAS events (reintervention, major amputation, or stenosis); major adverse limb events; and mortality. Outcomes were evaluated using χ2, Kaplan-Meier, and Cox regression analyses. Of 2869 infrainguinal revascularizations from 2005 to 2014, 1294 limbs (646 BPG, 648 PTA/S) fit our criteria. Overall, our analysis included 703 IDDM, 262 NIDDM, and 329 NDM limbs. IDDM patients, compared with NIDDM and NDM patients, were younger (69 vs 73 vs 77 years; P < .001) and more often presented with tissue loss (89% vs 77% vs 67%; P < .001), coronary artery disease (57% vs 48% vs 43%; P < .001), and end-stage renal disease (26% vs 13% vs 12%; P < .001). Perioperative complications, including mortality (3% vs 2% vs 5%; P = .07), did not differ between groups; however, complete wound healing at 6-month follow-up was significantly worse among IDDM patients (41% vs 49% vs 61%; P < .001). IDDM patients had significantly higher 3-year major amputation rates (23% vs 11% vs 8%; P < .001). Multivariable analyses illustrated that compared with NDM, IDDM was associated with significantly higher risk of both major amputation and RAS events after any first-time intervention (hazard ratio, 2.0 [95% confidence interval, 1.1-4.1] and 1.4 [1.1-1.8], respectively). Similar associations between IDDM and both major amputation and RAS events were found in patients undergoing a PTA/S-first intervention (4.1 [1.3-12.6] and 1.5 [1.1-2.2], respectively), whereas IDDM in BPG-first patients was associated with only incomplete wound healing (2.0 [1.4-4.5]). Last, compared with NDM, NIDDM was associated with lower late mortality (0.7 [0.5-0.9]). Compared with NDM, IDDM is associated with similar perioperative and long-term mortality but a higher risk of incomplete wound healing, major amputation, and future RAS events, especially after a PTA/S-first approach. NIDDM, on the other hand, is associated with lower long-term mortality and few adverse limb events. Overall, these data demonstrate both the importance of distinguishing between diabetes types and the potential long-term benefit of a BPG-first strategy in appropriately selected IDDM patients with CLTI.


[Primary choriocarcinoma of the stomach. Immunohistochemistry study of a case and review of the literature].
A rare tumor, primary choriocarcinoma of the stomach occurred in a 68 year-old man. Histologic examination of the tumor revealed two components, choriocarcinoma and adenocarcinoma. The liver metastasis displayed only choriocarcinoma, the lymph nodes metastasis only adenocarcinoma. The diagnosis was confirmed by demonstration of beta HcG in serum and urines by radioimmunoassay and within syncytiotrophoblast cells by immunoperoxidase staining. A review of the literature is done. The pathogenesis is discussed with hypothesis that this tumor represents a form of retro-differentiation of a preexisting carcinoma. However, this diagnosis will only be certain when a metastasis of a non gestational, non gonadal choriocarcinoma will be eliminated.


[Knowledge and life experiences of mothers facing certain addictive behaviours in youths in the region of Tunis].
We surveyed 415 mothers who regularly consult primary healthcare centres about their knowledge of addictive behavior in teenagers in relation to tobacco, alcohol and drugs. Most mothers considered the teenage period difficult. Apprehension of this period increased with the educational level of the mothers. Mothers did not often discuss the issue of addiction with their children, especially related to alcohol and drugs. Nevertheless, the mothers were aware of the risks of addiction. They considered information campaigns about this topic an efficient means of prevention. About half of the mothers had experience of addictive conduct involving a family member. They resolved the problems through family help or consultation with a specialist.


Modulation by pterins of the phosphorylation and phenylalanine activation of phenylalanine 4-mono-oxygenase.
The interaction between phenylalanine 4-mono-oxygenase and analogues of the natural cofactor (6R)-tetrahydrobiopterin [(6R)-BH4] was studied. The rate of cyclic AMP-dependent phosphorylation of phenylalanine 4-mono-oxygenase was inhibited only by those pterins [(6R)-BH4, (6S)-BH4 and 7,8-dihydrobiopterin (BH2)] that were able to decrease the potency and efficiency of phenylalanine as an allosteric activator of the hydroxylase. Since BH2 lacks cofactor activity, this was not required to modulate either the phosphorylation or the phenylalanine-activation of the hydroxylase. Half-maximal inhibition of the phosphorylation was observed at 1.9 microM-(6R)-BH4, 9 microM-(6S)-BH4 and 17 microM-BH2. Competition experiments indicated that all three pterins acted through binding to the cofactor site of the hydroxylase. Since the phosphorylation site and the cofactor binding site are known to reside, respectively, in the N- and C-terminal domains of the hydroxylase, the pterins were able to induce an interdomain conformational change. BH2, whose dihydroxypropyl group is not subject to epimerization, and (6S)-BH4 both inhibited the phosphorylation less efficiently than did the (6R)-epimer of BH4. Pterins with different spatial arrangements of the dihydroxypropyl side chain thus appeared to elicit different conformations of the phosphorylation site. The hydroxylase reaction showed a higher apparent Km for (6S)-BH4 than for (6R)-BH4 both when the native and the phenylalanine-activated enzyme were tested. For the activated enzyme Vmax was 40% lower with the (6S)-epimer than the (6R)-epimer, also when the more rapid enzyme inactivation occurring with the former cofactor was taken into account.


Direct measurement of neuronal ensemble activity using photoacoustic imaging in the stimulated Fos-LacZ transgenic rat brain: A proof-of-principle study.
Measuring neuroactivity underlying complex behaviors facilitates understanding the microcircuitry that supports these behaviors. We have developed a functional and molecular photoacoustic tomography (F/M-PAT) system which allows direct imaging of Fos-expressing neuronal ensembles in Fos-LacZ transgenic rats with a large field-of-view and high spatial resolution. F/M-PAT measures the beta-galactosidase catalyzed enzymatic product of exogenous chromophore X-gal within ensemble neurons. We used an ex vivo imaging method in the Wistar Fos-LacZ transgenic rat, to detect neuronal ensembles in medial prefrontal cortex (mPFC) following cocaine administration or a shock-tone paired stimulus. Robust and selective F/M-PAT signal was detected in mPFC neurons after both conditions (compare to naive controls) demonstrating successful and direct detection of Fos-expressing neuronal ensembles using this approach. The results of this study indicate that F/M-PAT can be used in conjunction with Fos-LacZ rats to monitor neuronal ensembles that underlie a range of behavioral processes, such as fear learning or addiction.


Patient factors used by pediatricians to assign asthma treatment.
Although asthma is often inappropriately treated in children, little is known about what information pediatricians use to adjust asthma therapy. The purpose of this work was to assess the importance of various dimensions of patient asthma status as the basis of pediatrician treatment decisions. We conducted a cross-sectional, random-sample survey, between November 2005 and May 2006, of 500 members of the American Academy of Pediatrics using standardized case vignettes. Vignettes varied in regard to (1) acute health care use (hospitalized 6 months ago), (2) bother (parent bothered by the child's asthma status), (3) control (frequency of symptoms and albuterol use), (4) direction (qualitative change in symptoms), and (5) wheezing during physical examination. Our primary outcome was the proportion of pediatricians who would adjust treatment in the presence or absence of these 5 factors. Physicians used multiple dimensions of asthma status other than symptoms to determine treatment. Pediatricians were significantly more likely to increase treatment for a recently hospitalized patient (45% vs 18%), a bothered parent (67% vs 18%), poorly controlled symptoms (4-5 times per week; 100% vs 18%), or if there was wheezing on examination (45% vs 18%) compared with patients who only had well-controlled symptoms. Pediatricians were significantly less likely to decrease treatment for a child with well-controlled symptoms and recent hospitalization (28%), parents who reported being bothered (43%), or a child whose symptoms had worsened since the last doctor visit (10%) compared with children with well-controlled symptoms alone. Pediatricians treat asthma on the basis of multiple dimensions of asthma status, including hospitalization, bother, symptom frequency, direction, and wheezing but use these factors differently to increase and decrease treatment. Tools that systematically assess multiple dimensions of asthma may be useful to help further improve pediatric asthma care.


Exclusion bias and the false relationship of reserpine and breast cancer.
Although reserpine has an important role in treating patients with hypertension, its appeal was sharply reduced a decade ago when an alleged relationship to breast cancer was reported in case-control studies. Since the relationship was not confirmed in subsequent research and analyses, the original association is now regarded as erroneous. Since patients with cardiovascular disease were rejected as possible controls in the original reserpine-breast cancer case-control study, we suspected that the false association may have been produced by a phenomenon called exclusion bias. This bias can arise in case-control studies if patients with a particularly high (or low) rate of prior exposure to the alleged etiologic agent are excluded from the selection of either cases or controls, but not from both. To test that suspicion, we recapitulated the original study, in another medical setting. The cases were 257 women with breast cancer; and the controls were 257 hospitalized women matched according to date of admission, age, and race. The overall data showed no association between reserpine and breast cancer (odds ratio [OR] = 1.1), but when we excluded 101 women with cardiovascular disease from the control group, the OR rose to 2.5. The results suggest that exclusion bias played an important role in creating the false association between reserpine and breast cancer.


Post-cardiac arrest serum levels of glial fibrillary acidic protein for predicting neurological outcome.
To investigate serum levels of glial fibrillary acidic protein (GFAP) for evaluation of neurological outcome in cardiac arrest (CA) patients and compare GFAP sensitivity and specificity to that of more studied biomarkers neuron-specific enolas (NSE) and S100B. A prospective observational study was performed in three hospitals in Sweden during 2008-2012. The participants were 125 CA patients treated with therapeutic hypothermia (TH) to 32-34 °C for 24 hours. Samples were collected from peripheral blood (n=125) and the jugular bulb (n=47) up to 108 hours post-CA. GFAP serum levels were quantified using a novel, fully automated immunochemical method. Other biomarkers investigated were NSE and S100B. Neurological outcome was assessed using the Cerebral Performance Categories scale (CPC) and dichotomized into good and poor outcome. GFAP predicted poor neurological outcome with 100% specificity and 14-23% sensitivity at 24, 48 and 72 hours post-CA. The corresponding values for NSE were 27-50% sensitivity and for S100B 21-30% sensitivity when specificity was set to 100%. A logistic regression with stepwise combination of the investigated biomarkers, GFAP, did not increase the ability to predict neurological outcome. No differences were found in GFAP, NSE and S100B levels when peripheral and jugular bulb blood samples were compared. Serum GFAP increase in patients with poor outcome but did not show sufficient sensitivity to predict neurological outcome after CA. Both NSE and S100B were shown to be better predictors. The ability to predict neurological outcome did not increased when combining the three biomarkers.


Simultaneous reconstruction of acoustic and optical properties of heterogeneous media by quantitative photoacoustic tomography.
We report on experimental demonstration of photoacoustic tomography for simultaneous recovery of the optical and acoustic properties of heterogeneous media. Photoacoustic images are reconstructed from a series of tissue-like phantom experiments using a finite element-based reconstruction algorithm coupled with a scanning photoacoustic imaging system. The results show that the images obtained are quantitative in terms of the shape, size, location and optical and acoustic properties of the heterogeneities examined.


Prevalence of atretic corpora lutea in ovaries of bovine fetuses.
Both ovaries from 88 bovine fetuses in the fifth month or later of gestation were studied histologically to determine the prevalence, origin, and time of appearance of atretic corpora lutea (ACL). Ovaries from 36 (41%) fetuses had ACL; fetuses < 6 months of gestation did not have ACL. Six fetuses had more than 25 ACL, but there was no apparent relationship between fetal age and number of ACL. Formation of ACL involved disintegration of the stratum granulosum of secondary follicles, concomitant with proliferation and invasion by vascularized elements of the theca. Fully developed ACL consisted of a large primary oocyte surrounded by a prominent zona pellucida and encased in a well-vascularized, largely thecal, fibrocellular wall. They measured approximately 0.5 to 1.0 mm in diameter. Empty, collapsed zona pellucidas were seen in many of the degenerating ACL.


Protein deacetylation by sirtuins: delineating a post-translational regulatory program responsive to nutrient and redox stressors.
Lysine acetylation/deacetylation is increasingly being recognized as common post-translational modification that appears to be broadly operational throughout the cell. The functional roles of these modifications, outside of the nucleus, have not been extensively studied. Moreover, as acetyl-CoA donates the acetyl group for acetylation, nutrient availability and energetic status may be pivotal in this modification. Similarly, nutrient limitation is associated with the deacetylation reaction. This modification is orchestrated by a novel family of sirtuin deacetylases that function in a nutrient and redox dependent manner and targets non-histone protein deacetylation. In compartment-specific locations, candidate target proteins undergoing lysine-residue deacetylation are being identified. Through these investigations, the functional role of this post-translational modification is being delineated. We review the sirtuin family proteins, discuss their functional effects on target proteins, and postulate on potential biological programs and disease processes that may be modified by sirtuin-mediated deacetylation of target proteins.


The role of long non-coding RNAs in rheumatic diseases.
Long non-coding RNAs (lncRNAs) have emerged as key epigenetic regulators that govern gene expression and influence multiple biological processes. Accumulating evidence demonstrates that lncRNAs have critical roles in immune cell development and function. In this Review, the molecular mechanisms of gene expression regulation by lncRNAs are described and current knowledge of the role of lncRNAs in immune regulation and inflammation are presented, highlighting strategies for defining the roles of lncRNAs in the pathogenesis of multiple rheumatic diseases. Finally, research progress in understanding the role of lncRNAs in rheumatic diseases is discussed.


Clinicopathological relevance of antithyroglobulin antibodies in low-risk papillary thyroid cancer.
The extent of initial surgical management in papillary thyroid cancer (PTC) is controversial. We examined whether the presence of perioperative antithyroglobulin antibodies (TGA) could predict long-term recurrence and occurrence of adverse features among a homogenous group of patients with PTC. The clinical features of patients with PTC treated at a single institution (Jewish General Hospital, McGill University, Montreal, Canada) were obtained from the medical records, and all clinicopathologic information was reviewed. Only low-risk PTC without clinical evidence of nodal disease before surgery and treated with 30 mCi of radioactive iodine was included in the study. The chart review retrieved 361 patients with a median follow-up of 85.0 months (Q25-Q75 73-98). Forty-two (11.6%) patients had presence of perioperative TGA. Perioperative TGAs were associated with present extrathyroidal extension (P=.005), unsuspected nodal disease (P=.001) and autoimmune thyroiditis (P<.0001). Overall, 17 (4.7%) patients experienced locoregional recurrence. Perioperative TGAs were a significant predictor of recurrence in univariable (P=.021) but not in multivariable analysis (P=.13). Presence of perioperative TGAs is associated with aggressive histological features and the presence of thyroiditis. Detection of TGA perioperatively may encourage surgeons to consider more extensive initial surgery.


P-hydroxylation of phenobarbital: relationship to (S)-mephenytoin hydroxylation (CYP2C19) polymorphism.
The aim of the current study was to compare the pharmacokinetics of phenobarbital (PB) in extensive metabolizers (EMs) and poor metabolizers (PMs) of S-mephenytoin. Ten healthy volunteers (5 EMs and 5 PMs) were given 30 mg PB daily for 14 days. PB and p-hydroxyphenobarbital (p-OHPB) in serum and urine were measured by high-performance liquid chromatography (HPLC). Urinary excretion (12.5% versus 7.7%) and formation clearance (29.8 versus 21.1 mL/h) of p-OHPB, one of the main metabolites of PB, were significantly lower (p < .05) in PMs than in EMs. However, area under the serum concentration-time curve (153.3 in the EMs versus 122.9 microg x h/mL in the PMs), total (210.8 versus 254.9 mL/h) and renal clearance (53.1 versus 66.1 mL/h) of PB were identical between the two groups. To compare the inducibility of CYP2C19, mephenytoin was also given prior to and on the last day of PB treatment. The urinary level of 4'-hydroxymephenytoin was analyzed by a validated gas chromatograpy/mass spectrometry (GC/MS) method. The mephenytoin hydroxylation index did not change in either EMs (1.42 versus 1.42) or PMs (341.4 versus 403.5), showing that CYP2C19 was not induced by treatment with PB. These results indicated that the p-hydroxylation pathway of PB co-segregates with the CYP2C19 metabolic polymorphism. However, the overall disposition kinetics of PB were not different between EMs and PMs, and therefore polymorphic CYP2C19 seems have no major clinical implications.


Microfluidics-Based Fabrication of Cell-Laden Hydrogel Microfibers for Potential Applications in Tissue Engineering.
Fibrous hydrogel scaffolds have recently attracted increasing attention for tissue engineering applications. While a number of approaches have been proposed for fabricating microfibers, it remains difficult for current methods to produce materials that meet the essential requirements of being simple, flexible and bio-friendly. It is especially challenging to prepare cell-laden microfibers which have different structures to meet the needs of various applications using a simple device. In this study, we developed a facile two-flow microfluidic system, through which cell-laden hydrogel microfibers with various structures could be easily prepared in one step. Aiming to meet different tissue engineering needs, several types of microfibers with different structures, including single-layer, double-layer and hollow microfibers, have been prepared using an alginate-methacrylated gelatin composite hydrogel by merely changing the inner and outer fluids. Cell-laden single-layer microfibers were obtained by subsequently seeding mouse embryonic osteoblast precursor cells (MC3T3-E1) cells on the surface of the as-prepared microfibers. Cell-laden double-layer and hollow microfibers were prepared by directly encapsulating MC3T3-E1 cells or human umbilical vein endothelial cells (HUVECs) in the cores of microfibers upon their fabrication. Prominent proliferation of cells happened in all cell-laden single-layer, double-layer and hollow microfibers, implying potential applications for them in tissue engineering.


Release of endogenous glutamate and gamma-aminobutyric acid from rat striatal tissue slices measured by an improved method of high performance liquid chromatography with electrochemical detection.
The release of endogenous glutamate and gamma-aminobutyric acid (GABA) from rat brain tissue slices was studied using a tissue slice assay in which detectable amounts of the amino acids were released from 1-2 mg of tissue. An improved method of high performance liquid chromatography (HPLC) with electrochemical detection was employed to measure both glutamate and GABA after derivatization with o-phthalaldehyde and sulfide in a single isocratic HPLC analysis. The non-endogenous amino acid, homoglutamine, was used as an internal standard in verifying the consistent derivatization of amino acids and in quantifying amounts of glutamate and GABA released from the caudate-putamen tissue. The derivatized amino acids (1-30 pmol) were detected as chromatographic peaks eluting at baseline level and free of significant interfering co-eluates in a 25-30 min analysis time.


Proximal radiolucent lines around fully hydroxyapatite-coated tapered femoral stems: should we be concerned?
Radiolucent lines occasionally develop around the proximal aspect of fully hydroxyapatite (HA)-coated tapered femoral stems after total hip arthroplasty (THA). It was hypothesised that distal wedging of stems may predispose to proximal radiolucent line formation, which may negatively impact clinical outcome. All primary THA performed with a collarless fully HA-coated stem that had a minimum of 1 year of radiographic follow-up were identified in a surgical database (n = 244). Radiographic measures of proximal femoral morphology and femoral canal fill at the middle and distal thirds of the stem were analysed for association with the presence of proximal radiolucent lines. Linear regression was used to explore any association between radiolucent lines and patient reported outcome measures (PROMs), available in 61% of patients. Proximal radiolucent lines developed in 31 cases (12.7%) at final follow-up. Dorr A femoral morphology and increased canal-fill at the distal ⅓ of the stem correlated with the development of radiolucent lines (p < 0.001). No correlation was observed between pain or PROMs and the presence of proximal radiolucent lines. We observed an unexpectedly high incidence of proximal femoral radiolucent lines about collarless fully HA coated stems. Distal-only implant wedging in Dorr A bone may compromise proximal fixation. Although this finding did not correlate with short-term outcomes, the long-term clinical impact requires further study.


Hip fracture rates and time trends in use of anti-osteoporosis medications in Denmark for the period 2005 to 2015: Missed opportunities in fracture prevention.
Declining use of bisphosphonates (BP) in the United States and Europe may lead to a widening of the treatment gap for osteoporosis and an increase in fracture rates. However, a shift to non-bisphosphonates and to hospital administered i.v. BPs could lead to overestimation of the treatment gap if analyses are based exclusively on BP prescriptions. When a healthcare system successfully narrows the treatment gap by making appropriate use of anti-osteoporosis drugs, we would expect to see declining rates of osteoporotic fractures with much of the decrease being statistically attributable to medication uptake. We analysed a best-case scenario where all use of BPs, denosumab, raloxifene and PTH analogues - including the oncology area - was contrasted with the trend in hip fracture rates. This scenario also considered users of raloxifene and teriparatide as covered by osteoporosis drugs though the primary RCT for raloxifene showed no risk reduction in nonvertebral fractures and the RCT for teriparatide risk reductions for non-vertebral fractures but not hip fracture specifically. Sensitivity analyses were also done. We used aggregate statistics on hip fracture events and total use of the above medications estimating the number of persons potentially covered. The reduction in hip fracture rates attributable to treatment was estimated using the absolute risk reduction (ARR) found in real-world users of oral alendronate in Denmark with the ARR in the FIT primary prevention arm as an alternative scenario. A plateau in use of osteoporosis medications occurred in 2014. Between 2005 and 2015, hip fracture rates declined by 30%. However, only up to 20% of the observed reduction in hip fracture rates was statistically attributable to treatment even in a best-case scenario. Sensitivity analyses where raloxifene and teriparatide were excluded did not impact on this finding. Anti-osteoporosis treatment in Denmark reached a plateau in 2014 even in a best-case scenario where all dispensations were assumed to be for osteoporosis. Future studies may be able to distinguish between the oncology area and the osteoporosis indication as well as provide a delineation of age and gender demographics among users of hospital administered osteoporosis medications. About 80% of the decline in hip fracture rates appears to be due to factors other than osteoporosis medication. The plateau in use of osteoporosis treatment at a level that is too low to make a meaningful impact on societal fracture burden is problematic given the predicted increased age-specific hip fracture rates.


A putative protein-sequestration site involving intermediate filaments for protein degradation by autophagy. Studies with transplanted Sendai-viral envelope proteins in HTC cells.
Reconstituted Sendai-viral envelopes (RSVE) were fused with hepatoma tissue-culture (HTC) cells, thereby introducing viral membrane glycoproteins into the plasma membrane [Earl, Billett, Hunneyball & Mayer (1987) Biochem. J. 241, 801-807]. Fractionation of homogenized cells on Nycodenz gradients shows that much of the viral 125I-labelled HN and F proteins were rapidly sequestered into a dense fraction distinct from fractions containing plasma membrane, lysosomes and mitochondria. Electron microscopy (results not shown) indicates that the dense fraction contains nuclear residues, multivesicular structures, dense bodies and fibrous structures. Both the dense fraction and a hexosaminidase-enriched fraction contain trichloroacetic acid-insoluble radioactivity, including intact 125I-labelled viral proteins. The viral proteins are progressively transferred from the dense fraction to the hexosaminidase-enriched fraction; the transfer is retarded by 50 micrograms of leupeptin/ml. Trichloroacetic acid-soluble radiolabel is progressively released into the culture medium as the proteins are degraded. Within 5 h after transplantation of viral HN and F proteins into recipient cells, a proportion (approx. 45%) of the 125I-labelled glycoproteins cannot be extracted by sequentially treating cells with digitonin (1 mg/ml), Triton X-100 (1%, w/v) and 0.3 M-KI. HN and F proteins in the non-extractable residue are tightly associated with nuclear-intermediate-filament (vimentin) material, as shown by Western blots and electron microscopy. The viral proteins are progressively transferred out of the nuclear-intermediate-filament residue; the transfer is slowed when cells are cultured with leupeptin. The data are consistent with the notion that transplanted viral HN and F proteins are sequestered to a perinuclear site in tight association with intermediate filaments before transfer into the autophagolysosomal system for degradation.


Copy number variations are a rare cause of non-CMT1A Charcot-Marie-Tooth disease.
Hereditary peripheral neuropathies present a group of clinically and genetically heterogeneous entities. All known forms, including the various forms of Charcot-Marie-Tooth disease (CMT) are characterized as Mendelian traits and over 35 genes have been identified thus far. The mutational mechanism of the most common CMT type, CMT1A, is a 1.5 Mb chromosomal duplication at 17p12 that contains the gene PMP22. Only recently it has been realized that such copy number variants (CNV) are a widespread phenomenon and important for disease. However, it is not known whether CNVs play a wider role in hereditary peripheral neuropathies outside of CMT1A. In a phenotypically heterogeneous sample of 97 patients, we performed the first high-density CNV study of 34 genomic regions harboring known genes for hereditary peripheral neuropathies including the 17p12 duplication region, with comparative genomic hybridization (CGH) microarrays. We identified three CNVs that affected coding exons. A novel shorter form of a PMP22 duplication was detected in a CMT1A family previously tested negative in a commercial test. Two other CNVs in MTMR2 and ARHGEF10 are likely not disease associated. Our results indicate that CNVs are a rare cause for non-CMT1A CMT. Their potential relevance as disease modifiers remains to be evaluated. The present study design cannot rule out that specific CMT forms exist where CNVs play a larger role.


A headset-mounted mini sampler for measuring exposure to welding aerosol in the breathing zone.
There is a need for a small personal aerosol sampler for measuring occupational exposure to airborne particles in the breathing zone. Existing aerosol samplers are too large to be mounted inside modern welder's protective equipment without disturbing the worker. A headset-mounted mini sampler has been developed to fill this gap with focus on manganese exposure. This mini sampler is easy to use and can be mounted inside modern, slimline welder's face shield. The mini sampler is based on a commercially available 13-mm filter holder that has been modified to incorporate an inlet nozzle made of aluminium. The nominal flow rate of the mini sampler is 0.75 l min(-1). The mini sampler is to be worn mounted on a headset, modified from professional microphone headsets. Several aspects related to using the mini sampler have been tested by personal and static sampling at five workplaces and in the laboratory. Four headset models were tested for their suitability as a sampler holder, of which three models were accepted by the welders. The sampling bias of the mini sampler versus the IOM sampler and the open-face 25-mm filter holder, respectively, depends on the size distribution of the sampled aerosol. At the lowest encountered mass concentration ratio of the open-face 25-mm filter holder to the IOM sampler (0.65), the sampling bias of the mini sampler versus the IOM sampler is approximately -26% and versus the open-face 25-mm filter holder is approximately +12%. For manganese, the negative root mean square (RMS) sampling bias of the mini sampler versus the IOM sampler is -0.046 and versus the open-face 25-mm filter holder is non-significant. Both these biases are statistically non-significant. The mini sampler can therefore be employed for determining welders' occupational exposure to manganese. The pressure drop across the filter can become excessive due to the small filtration area. Compared to the Casella Apex pump, the SKC AirChek2000 pump was generally found to be able to keep its flow rate constant within +/-5% at higher concentrations and for longer sampling times. Our results indicate that the inhalable fraction of the welding aerosol mass at the visited plants only consisted of 25-55% welding fume particles (agglomerates of coagulated particles generated by nucleation/condensation). The rest of the mass is made up of particles from spattering and grinding. More than 65% of manganese is generally found in the fume particles. The weighing precision of 13-mm filters is 2.2 microg. The RMS sample loss due to transport when loaded samples are shipped by mail in padded envelopes is 6 microg. Both figures are very low in comparison to the mass expected to be collected by personal sampling, generally exceeding 200 microg. The headset-mounted mini sampler is user-friendly, easy to adjust individually, does not disturb the welder during sampling and allows sampling inside personal protective equipment. The headset mounting arrangement improves personal sampling as it maintains the sampler close to the nose/mouth during the whole sampling period. This study shows that the developed headset-mounted mini sampler is suitable for assessing exposure to manganese in welding aerosol.


Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas.
Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.


Emulating Quantum Entangled Biphoton Spectroscopy Using Classical Light Pulses.
We show that for a class of quantum light spectroscopy (QLS) experiments using n = 0, 1, 2, ··· classical light pulses and an entangled photon pair (a biphoton state) where one photon acts as a reference without interacting with the matter sample, identical signals can be obtained by replacing the biphotons with classical-like coherent states of light, where these are defined explicitly in terms of the parameters of the biphoton states. An input-output formulation of quantum nonlinear spectroscopy is used to prove this equivalence. We demonstrate the equivalence numerically by comparing a classical pump-quantum probe experiment with the corresponding classical pump-classical probe experiment. This analysis shows that understanding the equivalence between entangled biphoton probes and carefully designed classical-like coherent state probes leads to quantum-inspired classical experiments that yield equivalent signals and provides insights for the future design of QLS experiments that could provide a true quantum advantage.


Lactate transport in L6 skeletal muscle cells and vesicles: allosteric or multisite mechanism and functional membrane marker of differentiation.
Membrane lactate transport was studied in skeletal muscle cells and membrane vesicles from the L6 line in relation to in vitro myogenesis. In myoblasts, lactate was transported by simple diffusion and insensitive to classical inhibitors: a positive correlation between onset of creatine kinase activity and lactate transport in differentiated myotubes was observed and could be considered to be a functional marker of cell differentiation. In myotubes, complete analysis of the velocity curves (direct coordinates, Eadie-Scatchard plots, Hill plots) gave parameters showing that lactate was carried by an allosteric or multisite system. This was confirmed by using sarcolemmal vesicles and specific inhibitors. In whole cells, alpha-cyano-4-hydroxycinnamic acid (CIN) and parachloromercuribenzylsulphonic acid (pCMBS) inhibited the maximal velocity without modifying the global cooperativity of the system. The weak effect of 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), which has a low affinity constant (Ki = 22.5 microM), implicated the monocarboxylate system rather than the anionic exchanger as a carrier system in muscle cells. CIN and DIDS exhibited one type of interaction with lactate carriers, and the curvilinear shape of the lactate Hill plot with or without inhibitors suggested that inhibitors were active at the same family of interaction sites and had a common range of affinities. The apparent competitive inhibition of pyruvate (Ki = 3.2 mM) did not modify the transport pathway of lactate in L6 myotubes. In conclusion, kinetic analysis of lactate transport in the presence or absence of inhibitors gave evidence for a multisite lactate carrier activity in myotubes composed of two systems at least, related to two or three isoforms of lactate carriers.


[Hemorrhagic infarction complicated by obliteration of the superior sagittal sinus by depressed skull fracture after a hammer injury: a case report].
The authors have encountered a case of compound depressed skull fracture in a 59 year-old-man complicated by occlusion of the anterior 1/3 part of the superior sagittal sinus (SSS). He was hit by a hammer at the midline of the frontal region, and transferred to our emergency care unit. On admission, there was laceration of skin at the midline of the forehead, but the patient had no neurological deficit. Skull radiograph showed a depressed skull fracture over the SSS. Computed tomography (CT) scan showed a small brain contusion adjacent to the depressed fracture. Digital subtraction angiography (DSA) showed occlusion of the anterior 1/3 part of SSS, and extravasations of contrast medium from cortical arterioles and capillaries. CT taken at 4 hours after injury showed enlargement of the lesion with extravasations of contrast medium and the patient manifested consciousness disturbance at this point. Distribution of extravasations suggested the occurrence of hemorrhagic infarction. Elevation of the depressed skull was thus performed under general anesthesia. There was laceration of the dura 5 mm away from the SSS and lacerations of cortical vessels, but there was no apparent damage to SSS itself. The depressed bone was replaced with artificial bone. The patient was discharged without any neurological deficit. Preoperative angiography was helpful to understand the hemodynamics and risk of massive bleeding during the operation.


Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer.
We sought to develop a clinical algorithm combining serum PSA with detection of TMPRSS2:ERG fusion and PCA3 in urine collected after digital rectal exam (post-DRE urine) to predict prostate cancer on subsequent biopsy. Post-DRE urine was collected in 48 consecutive patients before prostate biopsy at 2 centers; quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect PCA3 and TMPRSS2:ERG fusion transcript expression. Serum PSA was measured by clinical assay. The performance of TMPRSS2:ERG fusion, PCA3, and serum PSA as biomarkers predicting prostate cancer at biopsy was measured; a clinically practical algorithm combining serum PSA with TMPRSS2:ERG and PCA3 in post-DRE urine to predict prostate cancer was developed. Post-DRE urine sediment provided informative RNA in 45 patients; prostate cancer was present on subsequent biopsy in 15. TMPRSS2:ERG in post-DRE urine was associated with prostate cancer (OR = 12.02; P < 0.001). PCA3 had the highest sensitivity in predicting prostate cancer diagnosis (93%), whereas TMPRSS2:ERG had the highest specificity (87%). TMPRSS2:ERG had the greatest discriminatory value in predicting prostate cancer (AUC = 0.77 compared with 0.65 for PCA3 and 0.72 for serum PSA alone). Combining serum PSA, PCA3, and TMPRSS2:ERG in a multivariable algorithm optimized for clinical utility improved cancer prediction (AUC = 0.88; specificity = 90% at 80% sensitivity). A clinical algorithm specifying biopsy for all patients with PSA ≥ 10 ng/ml, while restricting biopsy among those with PSA <10 ng/ml to only those with detectable PCA3 or TMPRSS2:ERG in post-DRE urine, performed better than the individual biomarkers alone in predicting prostate cancer.


Affective rating of audio and video clips using the EmojiGrid.
Background: In this study we measured the affective appraisal of sounds and video clips using a newly developed graphical self-report tool: the EmojiGrid. The EmojiGrid is a square grid, labeled with emoji that express different degrees of valence and arousal. Users rate the valence and arousal of a given stimulus by simply clicking on the grid. Methods: In Experiment I, observers (N=150, 74 males, mean age=25.2±3.5) used the EmojiGrid to rate their affective appraisal of 77 validated sound clips from nine different semantic categories, covering a large area of the affective space. In Experiment II, observers (N=60, 32 males, mean age=24.5±3.3) used the EmojiGrid to rate their affective appraisal of 50 validated film fragments varying in positive and negative affect (20 positive, 20 negative, 10 neutral). Results: The results of this study show that for both sound and video, the agreement between the mean ratings obtained with the EmojiGrid and those obtained with an alternative and validated affective rating tool in previous studies in the literature, is excellent for valence and good for arousal. Our results also show the typical universal U-shaped relation between mean valence and arousal that is commonly observed for affective sensory stimuli, both for sound and video. Conclusions: We conclude that the EmojiGrid can be used as an affective self-report tool for the assessment of sound and video-evoked emotions.


Patient vs provider reports of aberrant medication-taking behavior among opioid-treated patients with chronic pain who report misusing opioid medication.
During long-term opioid therapy for chronic noncancer pain, monitoring medication adherence of patients with a history of aberrant opioid medication-taking behaviors (AMTB) is an essential practice. There is limited research, however, into the concordance among existing monitoring tools of self-report, physician report, and biofluid screening. This study examined associations among patient and provider assessments of AMTB and urine drug screening using data from a randomized trial of a cognitive-behavioral intervention designed to improve medication adherence and pain-related outcomes among 110 opioid-treated patients with chronic pain who screened positive for AMTB and were enrolled in a pain program. Providers completed the Aberrant Behavior Checklist (ABC) and patients completed the Current Opioid Misuse Measure (COMM) and the Chemical Coping Inventory (CCI). In multivariate analyses, ABC scores were compared with COMM and CCI scores, while controlling for demographics and established risk factors for AMTB, such as pain severity. Based on clinical cutoffs, 84% of patients reported clinically significant levels of AMTB and providers rated 36% of patients at elevated levels. Provider reports of AMTB were not correlated with COMM or CCI scores. However, the ABC ratings of experienced providers (nurse practitioners/attending physicians) were higher than those of less experienced providers (fellows) and were correlated with CCI scores and risk factors for AMTB. Associations between patient- and provider-reported AMTB and urine drug screening results were low and largely nonsignificant. In conclusion, concordance between patient and provider reports of AMTB among patients with chronic pain prescribed opioid medication varied by provider level of training.