Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.
Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.


Dissecting hematopoietic differentiation using the embryonic stem cell differentiation model.
Embryonic stem cells (ESCs) have been successfully used to study the generation of the hematopoietic lineage. The ESC differentiation model provides access to distinct developmental stages during hematopoietic differentiation enabling us to study developmental transitions in a manner that is difficult to do with embryos. The identification of the bipotential hemangioblast/blast-colony forming cell (BL-CFC) which represents the earliest stage of hematopoietic commitment in ESC cultures has enabled the study of signalling pathways, transcription factors and enzymes at the level of this developmental stage. Reporter ESC lines, flow cytometry and serum-free culture reagents are helping the field to transition from serum-containing protocols to step-wise serum-free differentiation strategies that attempt to mimic the developmental processes in the embryo. This serves as a framework with which to approach directed differentiation of human ESCs for the purposes of regenerative medicine. This review is focused on the contributions that the ESC differentiation system has made to understanding hematopoiesis and will highlight the strengths of this model of development and the challenges it still faces.


Increased Frontal Response May Underlie Decreased Tinnitus Severity.
The overall goal of the study was to identify functional and behavioral differences between individuals with higher tinnitus distress and individuals with lower tinnitus distress. Subsequent exploratory analyses were conducted to investigate the role physical activity may have on the observed results between high and low distress groups. The purpose of the experiment was to identify brain regions to be targeted in future intervention studies for tinnitus. A total of 32 individuals with varying levels of tinnitus severity were recruited from the Urbana-Champaign area. Volunteers were divided into higher tinnitus distress (HD) and lower tinnitus distress (LD) groups. Note that these groups also significantly differed based on physical activity level and were subsequently stratified into higher and lower physical activity level subgroups for exploratory analysis. While in a functional magnetic resonance imaging (fMRI) scanner, subjects listened to affective sounds classified as pleasant, neutral or unpleasant from the International Affective Digital Sounds database. The HD group recruited amygdala and parahippocampus to a greater extent than the LD group when listening to affective sounds. The LD group engaged frontal regions to a greater extent when listening to the affective stimuli compared to the HD group. Both higher physical activity level subgroups recruited more frontal regions, and both lower levels of physical activity subgroups recruited more limbic regions respectively. Individuals with lower tinnitus distress may utilize frontal regions to better control their emotional response to affective sounds. Our analysis also suggests physical activity may contribute to lower tinnitus severity and greater engagement of the frontal cortices. We suggest that future intervention studies focus on changes in the function of limbic and frontal regions when evaluating the efficacy of treatment. Additionally, we recommend further investigation concerning the impact of physical activity level on tinnitus distress.


Ultrasound Assisted 1,4-diazabicyclo[2.2.2] Octaniumdiacetate Multicomponent Synthesis of Benzodiazepines: A Novel, Highly Efficient and Green Protocol.
A simple and efficient method is presented for the synthesis of benzodiazepines through the multicomponent reaction of o-phenylenediamine, various aldehydes and 5,5-dimethylcyclohexane-1,3-dione (dimedone) in the presence of the acidic bis ionic liquid 1,4-diazabicyclo[2.2.2]octanium diacetate under ultrasound irradiation. The ionic liquid used is recoverable and reusable. This procedure is simple and environmentally friendly, and offers easy work-up, mild conditions and excellent yield in a short reaction time. All of the synthesized compounds were characterized by IR, 1H NMR, mass spectrometry and elemental analysis.


A 5-item scale to predict stroke outcome after cortical middle cerebral artery territory infarction: validation from results of the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study.
Various clinical, laboratory, and radiographic parameters have been identified as predictors of outcome for ischemic stroke. The purpose of this study was to combine these parameters into a validated scale for outcome prognostication in patients with a middle cerebral artery territory infarction. We retrospectively reviewed 129 patients over a 2-year period and considered demographic, clinical, laboratory, and radiographic parameters as potential predictors of outcome. Inclusion criteria were unilateral hemispheric infarcts within the middle cerebral artery territory >15 mm in diameter. Our primary outcome measure was a favorable recovery defined as a modified Rankin Score was ≤2 at 30 days. A multivariable model was used to determine independent predictors of outcome and weighted to create a 5-item scale to predict stroke recovery. External validation of this model was done using data from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. The 5 independent predictors of outcome were as follows: age (OR, 1.09; 95% CI, 1.03 to 1.14; P=0.001), National Institutes of Health Stroke Scale score (OR, 1.17; 95% CI, 1.06 to 1.30; P=0.003), infarct volume (OR, 1.01; 95% CI, 1.00 to 1.02; P=0.03), admission white blood cell count (8.5×10(3)/mm(3); OR, 1.16; 95% CI, 1.03 to 1.27; P=0.04), and presence of hyperglycemia (OR, 4.2; 95% CI, 1.1 to 16.4; P=0.04). Combining these variables into a point scale significantly improved prediction over the individual variables accounted alone as evidenced by the area underneath the receiver operating curve (OR, 0.91; 95% CI, 0.87 to 0.96; P=0.0001). When applied to the DEFUSE study population for validation, the model achieved a sensitivity of 83% and specificity of 86%. With validation from a prospective study of similar patients, this model serves as a useful clinical and research tool to predict stroke recovery after cortical middle cerebral artery territory infarction.


Wideband generation of pulses in dual-pump optical parametric amplifier: theory and experiment.
The generation of pulses in dual-pump fiber optical parametric amplifier is investigated. Theoretically, it is shown that in an analogical manner to pulse generation in single-pump fiber optical parametric amplifiers, the generated pulse shape depends on the linear phase mismatch between the interacting waves. However the dual-pump architecture allows for the bounding of the phase mismatch over a wide bandwidth. This feature permits the generation of uniform pulses over a wide bandwidth, contrary to the single-pump architecture. Using the developed theory, a pulse source with uniform pulses at 5 GHz repetition rate and duty cycle of 0.265 over 40 nm is demonstrated.


Gaussian Processes for Data-Efficient Learning in Robotics and Control.
Autonomous learning has been a promising direction in control and robotics for more than a decade since data-driven learning allows to reduce the amount of engineering knowledge, which is otherwise required. However, autonomous reinforcement learning (RL) approaches typically require many interactions with the system to learn controllers, which is a practical limitation in real systems, such as robots, where many interactions can be impractical and time consuming. To address this problem, current learning approaches typically require task-specific knowledge in form of expert demonstrations, realistic simulators, pre-shaped policies, or specific knowledge about the underlying dynamics. In this paper, we follow a different approach and speed up learning by extracting more information from data. In particular, we learn a probabilistic, non-parametric Gaussian process transition model of the system. By explicitly incorporating model uncertainty into long-term planning and controller learning our approach reduces the effects of model errors, a key problem in model-based learning. Compared to state-of-the art RL our model-based policy search method achieves an unprecedented speed of learning. We demonstrate its applicability to autonomous learning in real robot and control tasks.


Sensors vs. experts - a performance comparison of sensor-based fall risk assessment vs. conventional assessment in a sample of geriatric patients.
Fall events contribute significantly to mortality, morbidity and costs in our ageing population. In order to identify persons at risk and to target preventive measures, many scores and assessment tools have been developed. These often require expertise and are costly to implement. Recent research investigates the use of wearable inertial sensors to provide objective data on motion features which can be used to assess individual fall risk automatically. So far it is unknown how well this new method performs in comparison with conventional fall risk assessment tools. The aim of our research is to compare the predictive performance of our new sensor-based method with conventional and established methods, based on prospective data. In a first study phase, 119 inpatients of a geriatric clinic took part in motion measurements using a wireless triaxial accelerometer during a Timed Up&Go (TUG) test and a 20 m walk. Furthermore, the St. Thomas Risk Assessment Tool in Falling Elderly Inpatients (STRATIFY) was performed, and the multidisciplinary geriatric care team estimated the patients' fall risk. In a second follow-up phase of the study, 46 of the participants were interviewed after one year, including a fall and activity assessment. The predictive performances of the TUG, the STRATIFY and team scores are compared. Furthermore, two automatically induced logistic regression models based on conventional clinical and assessment data (CONV) as well as sensor data (SENSOR) are matched. Among the risk assessment scores, the geriatric team score (sensitivity 56%, specificity 80%) outperforms STRATIFY and TUG. The induced logistic regression models CONV and SENSOR achieve similar performance values (sensitivity 68%/58%, specificity 74%/78%, AUC 0.74/0.72, +LR 2.64/2.61). Both models are able to identify more persons at risk than the simple scores. Sensor-based objective measurements of motion parameters in geriatric patients can be used to assess individual fall risk, and our prediction model's performance matches that of a model based on conventional clinical and assessment data. Sensor-based measurements using a small wearable device may contribute significant information to conventional methods and are feasible in an unsupervised setting. More prospective research is needed to assess the cost-benefit relation of our approach.


Primary Care Physician Perspectives about Antipsychotics and Other Medications for Symptoms of Dementia.
Guidelines, policies, and warnings have been applied to reduce the use of medications for behavioral and psychological symptoms of dementia (BPSD). Because of rare dangerous side effects, antipsychotics have been singled out in these efforts. However, antipsychotics are still prescribed "off label" to hundreds of thousands of seniors residing in nursing homes and communities. Our objective was to evaluate how and why primary-care physicians (PCPs) employ nonpharmacologic strategies and drugs for BPSD. Semi-structured interviews analyzed via template, immersion and crystallization, and thematic development of 26 PCPs (16 family practice, 10 general internal medicine) in full time primary-care practice for at least 3 years in Northwestern Virginia. PCPs described 4 major themes regarding BPSD management: (1) nonpharmacologic methods have substantial barriers; (2) medication use is not constrained by those barriers and is perceived as easy, efficacious, reasonably safe, and appropriate; (3) pharmacologic policies decrease the use of targeted medications, including antipsychotics, but also have unintended consequences such as increased use of alternative risky medications; and (4) PCPs need practical evidence-based guidelines for all aspects of BPSD management. PCPs continue to prescribe medications because they meet patient-oriented goals and because PCPs perceive drugs, including antipsychotics and their alternatives, to be more effective and less dangerous than evidence suggests. To optimally treat BPSD, PCPs need supportive verified prescribing guidelines and access to nonpharmacologic modalities that are as affordable, available, and efficacious as drugs; these require and deserve significant additional research and payer support. Community PCPs should be included in BPSD policy and guideline development.


Mutator genes and selection for the mutation rate in bacteria.
Gene frequencies in populations of haploid, asexual organisms are described by linear recurrence equations. Several models in which the mutation rate is controlled by one locus and the fitness is controlled at one or more other loci are developed. It is shown that good approximations can be introduced to give explicit solutions for the course of selection in these models. It is shown that a strong non-equilibrium selection for mutator genes is possible even when the presence of such a gene decreases the fitness of an individual. Experiments that corroborate these conclusions are discussed along with the effects of population size that determine the applicability of these results to natural populations.


Research Into the Effect of Proton Pump Inhibitors on Lungs and Leukocytes.
Proton pump inhibitors (PPI) are the most commonly used medication in the world. They are prescribed as an effective treatment choice for gastrointestinal system diseases linked to hyperacidity, especially. Additionally, non-indication and unnecessary use are very common. Many publications in recent times have reported significant side effects. However, there are insufficient studies about the mechanism for these side effects. Twenty-four Wistar albino rats were used in this study. Rats were divided into 3 groups of control, group-administered H2 receptor blockers and a group-administered PPI. Medications were administered for 30 days intraperitoneal. After 30 days, rats were euthanized and lung tissue was obtained. Lung was stained for immunohistochemical catalase, superoxide dismutase, Glutathione peroxidase, myeloperoxidase, and toluidine blue and investigated with a light microscope. Transmission electron microscopy (TEM) was used to investigate lung tissues and neutrophil leukocytes. Additionally, lung tissue had biochemical hydrogen peroxide (H2O2) levels researched. H2O2 amounts, produced by lysosomes with important duties for neutrophil functions in lung tissues, were found to be statistically significantly reduced in the group-administered PPI. Results from investigations of specimens obtained with immunohistochemical staining observed increases in antioxidant amounts in the PPI group. Investigation with TEM identified more inflammation findings in the lung tissue from the group-administered PPI compared to the control group and the group-administered H2 receptors. In conclusion, we identified long-term PPI use disrupts neutrophil leukocyte functions in the lung. All clinicians should be much more careful about PPI use.


Histone deacetylase activity is required for full transcriptional repression by mSin3A.
Members of the Mad family of bHLH-Zip proteins heterodimerize with Max to repress transcription in a sequence-specific manner. Transcriptional repression by Mad:Max heterodimers is mediated by ternary complex formation with either of the corepressors mSin3A or mSin3B. We report here that mSin3A is an in vivo component of large, heterogeneous multiprotein complexes and is tightly and specifically associated with at least seven polypeptides. Two of the mSin3A-associated proteins, p50 and p55, are highly related to the histone deacetylase HDAC1. The mSin3A immunocomplexes possess histone deacetylase activity that is sensitive to the specific deacetylase inhibitor trapoxin. mSin3A-targeted repression of a reporter gene is reduced by trapoxin treatment, suggesting that histone deacetylation mediates transcriptional repression through Mad-Max-mSin3A multimeric complexes.


S-[2-[(2'-carbamoylethyl)amino]ethyl] phosphorothioate and related compounds as potential antiradiation agents.
A reinvestigation of the radiation protection activity of S-[2-[(2'-carbamylethyl)amino]ethyl] lithium hydrogen phosphorothioate (4a) revealed that this compound possessed good (70% protection at a dose of 600 mg/kg) activity. The thione and imino bioisosteres of 4, S-[2-(2'-thiocarbamylethylamino)ethyl] lithium hydrogen phosphorothioate (13a) and S-[2-(2'-amidinoethylamino)ethyl] phosphorothioic acid (18b) showed 100% protection at doses of 300 and 150 mg/kg, respectively. The N-methyl (4b) and tert-butyl (4c) analogues of amide 4a, the N-methyl (13b) analogue of the thioamide 13a, the N-methyl (18a) analogue of amidine (18b), and the cyclic amidine S-[2-[[2'-(4,5-dihydroimidozoyl)ethyl]amino]ethyl] lithium hydrogen phosphorothioate (21) all showed 80% protection at the highest dose tested.


Prevalence of ataxia in children: a systematic review.
To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes. A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia. One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ∼26/100,000 children and likely reflects a minimum prevalence worldwide. The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted.


Stepwise group sparse regression (SGSR): gene-set-based pharmacogenomic predictive models with stepwise selection of functional priors.
Complex mechanisms involving genomic aberrations in numerous proteins and pathways are believed to be a key cause of many diseases such as cancer. With recent advances in genomics, elucidating the molecular basis of cancer at a patient level is now feasible, and has led to personalized treatment strategies whereby a patient is treated according to his or her genomic profile. However, there is growing recognition that existing treatment modalities are overly simplistic, and do not fully account for the deep genomic complexity associated with sensitivity or resistance to cancer therapies. To overcome these limitations, large-scale pharmacogenomic screens of cancer cell lines--in conjunction with modern statistical learning approaches--have been used to explore the genetic underpinnings of drug response. While these analyses have demonstrated the ability to infer genetic predictors of compound sensitivity, to date most modeling approaches have been data-driven, i.e. they do not explicitly incorporate domain-specific knowledge (priors) in the process of learning a model. While a purely data-driven approach offers an unbiased perspective of the data--and may yield unexpected or novel insights--this strategy introduces challenges for both model interpretability and accuracy. In this study, we propose a novel prior-incorporated sparse regression model in which the choice of informative predictor sets is carried out by knowledge-driven priors (gene sets) in a stepwise fashion. Under regularization in a linear regression model, our algorithm is able to incorporate prior biological knowledge across the predictive variables thereby improving the interpretability of the final model with no loss--and often an improvement--in predictive performance. We evaluate the performance of our algorithm compared to well-known regularization methods such as LASSO, Ridge and Elastic net regression in the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (Sanger) pharmacogenomics datasets, demonstrating that incorporation of the biological priors selected by our model confers improved predictability and interpretability, despite much fewer predictors, over existing state-of-the-art methods.


Docetaxel (Taxotere) in combination with platinums in patients with non-small cell lung cancer: trial data and implications for clinical management.
Docetaxel (Taxotere; Aventis, Antony, France) is among the most effective agents for the treatment of non-small cell lung cancer and its use in combination with cisplatin is a logical development. Docetaxel has been combined with cisplatin and is well-tolerated with promising activity in phase II studies. Extensive phase II investigations in the first-line setting recorded response rates of 32% to 52% survival (median, 8 to 12 months) with 33% to 48% of patients alive at 1 year. Neutropenia is dose-limiting. However, the incidence of severe neuropathy is low and clinically significant nephrotoxicity is uncommon. Following these encouraging findings, the combination of docetaxel with cisplatin has been studied in two randomized phase III trials that compare the new combination against reference regimens. These studies have completed accrual and data are expected shortly. The combination of docetaxel with carboplatin is also active and feasible. Neutropenia is the main adverse event and grade II or III neurotoxicity is uncommon. In phase II trials combining doses of 65 to 100 mg/m2 docetaxel with doses of carboplatin designed to maintain an area under the curve of 5 to 7.5 mg/mL/min, response rates have ranged from 30% to 67%.


Associations of aspirin, nonsteroidal anti-inflammatory drug and paracetamol use with PSA-detected prostate cancer: findings from a large, population-based, case-control study (the ProtecT study).
Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti-inflammatory drugs may protect against prostate cancer development. We analysed data from a cross-sectional case-control study (n(cases) = 1,016; n(controls) = 5,043), nested within a UK-wide population-based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to investigate the relationship of aspirin, nonsteroidal anti-inflammatory drug (NSAID) and paracetamol use with prostate cancer. In conditional logistic regression models accounting for stratum matching on age (5-year age bands) and recruitment centre, use of non-aspirin NSAIDs [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.04-1.67] or all NSAIDs (OR = 1.25; 95% CI = 1.07-1.47) were positively associated with prostate cancer. There were weaker, not conventionally statistically significant, positive associations of aspirin (OR = 1.13; 95% CI = 0.94-1.36) and paracetamol (OR = 1.20; 95% CI = 0.90-1.60) with prostate cancer. Mutual adjustment for aspirin, non-aspirin NSAIDs or paracetamol made little difference to these results. There was no evidence of confounding by age, family history of prostate cancer, body mass index or self-reported diabetes. Aspirin, NSAID and paracetamol use were associated with reduced serum PSA concentrations amongst controls. Our findings do not support the hypothesis that NSAIDs reduce the risk of PSA-detected prostate cancer. Our conclusions are unlikely to be influenced by PSA detection bias because the inverse associations of aspirin, NSAID and paracetamol use with serum PSA would have attenuated (not generated) the observed positive associations.


Effects of Balloon Dilation for Idiopathic Laryngotracheal Stenosis on Voice Production.
To evaluate the effects of balloon dilation for idiopathic laryngotracheal stenosis on voice production. Retrospective review of 10 female patients with idiopathic laryngotracheal stenosis undergoing balloon dilation. Voice outcomes were evaluated by comparing pre- and posttreatment patient-reported, perceptual, aerodynamic, and acoustic parameters. Complete data sets were not available for all subjects; sample size for each parameter is reported with the corresponding result. Total Voice Handicap Index (VHI) decreased significantly (22.9 ± 13.5 to 6.8 ± 6.5; n = 8; p = .015), as did glottal function index (7.2 ± 4.9 to 1.5 ± 2.0; n = 6; p = .022). No changes were observed in the GRBAS (grade, roughness, breathiness, asthenia, strain) scale. Changes in aerodynamic parameters were not statistically significant. Percent jitter decreased (1.32 ± 1.37 to 0.60 ± 0.29; n = 7; P = .078), and fundamental frequency range was preserved (507 ± 325 to 612 ± 281; n = 7; P = .309). Our sample of patients with idiopathic laryngotracheal stenosis had a mild-moderate dysphonia that improved with balloon dilation. Importantly, adverse effects on voice that can occur with open procedures were not observed. Patient perception of dysphonia improved while fundamental frequency range was maintained and aerodynamic parameters remained within or moved toward the normal range. Larger prospective studies are warranted to further evaluate changes in voice production associated with balloon dilation.


The cognitive foundations of cultural stability and diversity.
The existence and diversity of human cultures are made possible by our species-specific cognitive capacities. But how? Do cultures emerge and diverge as a result of the deployment, over generations and in different populations, of general abilities to learn, imitate and communicate? What role if any do domain-specific evolved cognitive abilities play in the emergence and evolution of cultures? These questions have been approached from different vantage points in different disciplines. Here we present a view that is currently developing out of the converging work of developmental psychologists, evolutionary psychologists and cognitive anthropologists.


Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials(†).
Therapeutic drug monitoring (TDM) for tacrolimus (Tac) is universally applied. However, the concentration-effect relationship for Tac is poorly defined. This study investigated whether Tac concentrations are associated with acute rejection in kidney transplant recipients. Data from three large trials were pooled. We used univariate and multivariate analysis to investigate the relationship between biopsy-proven acute rejection (BPAR) and Tac predose concentration at five time points (day 3, 10 and 14, and month 1 and 6 after transplantation). A total of 136/1304 patients experienced BPAR, giving an overall incidence of 10.4%. We did not find any significant correlations between Tac predose concentrations and the incidence of BPAR at the different time points. In the multivariate analysis, only delayed graft function (DGF) and the use of induction therapy were independently correlated with BPAR, with an odds ratio of 2.7 [95% CI: 1.8-4.0; p < 0.001] for DGF and 0.66 [95% CI: 0.44-0.99; p = 0.049] for induction therapy. The other variables, including the Tac predose concentrations, were not statistically significantly associated with BPAR. We did not find an association between the Tac predose concentrations measured at five time points after kidney transplantation and the incidence of acute rejection occurring thereafter. Based on this study it is not possible to define the optimal target concentrations for Tac.


The Preoperative Assessment and Optimization of Patients Undergoing Major Urological Surgery.
Improving patient outcomes from major urological surgery requires not only advancement in surgical technique and technology, but also the practice of patient-centered, multidisciplinary, and integrated medical care of these patients from the moment of contemplation of surgery until full recovery. This review examines the evidence for recent developments in preoperative assessment and optimization that is of relevance to major urological surgery. Current perioperative medicine recommendations aim to improve the short-term safety and long-term effectiveness of surgical treatments by the delivery of multidisciplinary integrated medical care. New strategies to deliver this aim include preoperative risk stratification using a frailty index and cardiopulmonary exercise testing for patients undergoing intra-abdominal surgery (including radical cystectomy), preoperative management of iron deficiency and anemia, and preoperative exercise intervention. Proof of the utility and validity for improving surgical outcomes through advances in preoperative care is still evolving. Evidence-based developments in this field are likely to benefit patients undergoing major urological surgery, but further research targeted at high-risk patients undergoing specific urological operations is required.


A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.


Combined effect of erythromycin, tetracycline and sulfamethoxazole on performance of anaerobic sequencing batch reactors.
The combined effects of erythromycin-tetracycline-sulfamethoxazole (ETS) and sulfamethoxazole-tetracycline (ST) antibiotics on the performance of anaerobic sequencing batch reactors were studied. A control reactor was fed with wastewater that was free of antibiotics, while two additional reactors were fed with ETS and ST. The way in which the ETS and ST mixtures impact COD removal, VFA production, antibiotic degradation, biogas production and composition were investigated. The effects of the ETS mixtures were different from the ST mixtures, erythromycin can have an antagonistic effect on sulfamethoxazole and tetracycline. The anaerobic pre-treatment of these antibiotics can represent a suitable alternative to the use of chemical treatments for concentrations at 10 mg/L of S and 1 mg/L of T; 2 mg/L of E, 2 mg/L of T and 20 mg/L of S for the ST and ETS reactors respectively, which corresponds to min 70% COD removal efficiency.


Age-related references in national public health, technology appraisal and clinical guidelines and guidance: documentary analysis.
older people may be less likely to receive interventions than younger people. Age bias in national guidance may influence entire public health and health care systems. We examined how English National Institute for Health & Care Excellence (NICE) guidance and guidelines consider age. we undertook a documentary analysis of NICE public health (n = 33) and clinical (n = 114) guidelines and technology appraisals (n = 212). We systematically searched for age-related terms, and conducted thematic analysis of the paragraphs in which these occurred ('age-extracts'). Quantitative analysis explored frequency of age-extracts between and within document types. Illustrative quotes were used to elaborate and explain quantitative findings. 2,314 age-extracts were identified within three themes: age documented as an a-priori consideration at scope-setting (518 age-extracts, 22.4%); documentation of differential effectiveness, cost-effectiveness or other outcomes by age (937 age-extracts, 40.5%); and documentation of age-specific recommendations (859 age-extracts, 37.1%). Public health guidelines considered age most comprehensively. There were clear examples of older-age being considered in both evidence searching and in making recommendations, suggesting that this can be achieved within current processes. we found inconsistencies in how age is considered in NICE guidance and guidelines. More effort may be required to ensure age is consistently considered. Future NICE committees should search for and document evidence of age-related differences in receipt of interventions. Where evidence relating to effectiveness and cost-effectiveness in older populations is available, more explicit age-related recommendations should be made. Where there is a lack of evidence, it should be stated what new research is needed.


Microstructure based prediction of the deformation behavior of soft collagenous membranes.
The response of human amnion (HA) and bovine Glisson's capsule (GC) to uniaxial and biaxial tensile loading is analyzed on tissue (∼mm) and collagen fiber (∼μm) length scales. The mechanical behavior of the membranes is rationalized based on a discrete fiber network model that relates model parameters with microstructural features of the tissues. Parameters were first determined for GC based on the quantity and organization of collagen fibers in the tissue. Next, parameters for HA were defined by comparing the microstructures of the two membranes, which differ in fiber organization in that collagen forms μm-thick fiber bundles in GC while 50 nm-thin fibrils constitute the network in HA. The flexural behavior of these structures is phenomenologically represented in the model, indicating that shear forces are transmitted through fibrils within GC bundles, but to a much lesser extent than in a corresponding solid cross section. The model provides excellent predictions of the uniaxial and biaxial mechanical response, as well as of the progressive reorientation of fibers associated with uniaxial loading. The results are particularly relevant since model parameters were not obtained through a fitting procedure of the tissue's tension-stretch curve. Furthermore, simulations of representative in vivo deformation states indicated that a large part of the fibers are expected to be un-crimped under physiological loading conditions. Thus, the crimped shape of collagen fibers in the initial test configuration, and typically observed in histological analyses, might be a consequence of the contraction occurring when membranes are extracted from their environment in the body.


Chelant-enhanced washing of CCA-contaminated soil: Coupled with selective dissolution or soil stabilization.
Remediation of CCA-contaminated soil (Cr, Cu, and As) by biodegradable chelant-enhanced washing (EDDS, S,S-ethylene-diamine-disuccinic-acid) needs further enhancement. This study investigated the effectiveness of coupling with pre-treatment by selective dissolution and post-treatment by soil amendments, respectively. Three groups of reagents (reductants, alkaline solvents, and organic ligands) were adopted in the pre-treatment to dissolve the oxide minerals before EDDS extraction. In the post-treatment, soil amendments (coal fly ash (CFA), acid mine drainage sludge (AMDS), green waste compost (GWC)), and their mixtures) were used for a 2-month stabilization after 2-h EDDS washing. Multi-endpoint evaluation was performed by assessing the chemical state, leachability, mobility, bioaccessibility, and plant-availability of residual metal(loid)s as well as the cytotoxicity, enzyme activities, and available nutrients of the treated soils. Pre-treatment by dithionite-citrate-bicarbonate significantly enhanced extraction efficiency, but also increased the leachability of As and Cr and bioaccessibility of Cr in the treated soils. While sodium hydroxide removed the majority of As without increasing its leachability and bioaccessibility, it increased the cytotoxicity and inhibited the acid phosphatase activity. Post-treatment with AMDS and CFA effectively controlled the mobility and leachability of residual As and Cr after EDDS washing. However, destabilized Cu was only marginally immobilized by GWC due to strong Cu-EDDS complexation. The bioaccessibility and phytoavailability of Cu was primarily reduced by EDDS washing, while those of As and Cr could be attenuated by AMDS and CFA. This study indicates that coupling chemical extraction with subsequent soil amendment plays complementary roles in mitigating effects of residual metal(loid)s and improving environmental quality.


[Medical auditing: procedures assessment in the women's integral health care program in the Vila Municipal Health Clinic, Pelotas, Rio Grande do Sul, Brazil]
This study is based on a medical audit of the Vila Municipal Health Clinic, Pelotas, Rio Grande do Sul. We collected data from family medical records in 1992,1993, and 1994. The data concerned the Women's Integral Health Care Program. We collected information on age, visits for medical and non-medical reasons, blood pressure, breast examination, coverage of Pap smear testing, and contraceptive methods. On average, women visited the clinic 3.5 to 4 times a year; 53% of the women were between 20 and 39 years of age; 42.5% of the women had had a Pap smear in the previous three years; 19% of the women had had their breasts examined. Blood pressure measurement was the most common procedure recorded in this clinic. We believe quality of medical records is a factor in patient care. We expect a critique of the low-quality medical records found in this audit can serve as the basis for a discussion among the health care team, with a view towards improving medical care, thereby benefiting patients.


Detection of bisphenol A using palm-size NanoAptamer analyzer.
We have demonstrated a palm-size NanoAptamer analyzer capable of detecting bisphenol A (BPA) at environmentally relevant concentrations (<1ng/mL or ppb). It is designed for performing reaction and fluorescence measurement on single cuvette sample. Modified NanoGene assay was used as the sensing mechanism where signaling DNA and QD655 was tethered to QD565 and magnetic bead via the aptamer. Aptamer affinity with BPA resulted in the release of the signaling DNA and QD655 from the complex and hence corresponding decrease in QD655 fluorescence measurement signal. Baseline characterization was first performed with empty cuvettes, quantum dots and magnetic beads under near-ideal conditions to establish essential functionality of the NanoAptamer analyzer. Duration of incubation time, number of rinse cycles, and necessity of cuvette vibration were also investigated. In order to demonstrate the capability of the NanoAptamer analyzer to detect BPA, samples with BPA concentrations ranging from 0.0005 to 1.0ng/mL (ppb) were used. The performance of the NanoAptamer analyzer was further examined by using laboratory protocol and commercial spectrofluorometer as reference. Correlation between NanoAptamer analyzer and laboratory protocol as well as commercial spectrofluorometer was evaluated via correlation plots and correlation coefficients.


Discrimination of phytoplankton functional groups using an ocean reflectance inversion model.
Ocean reflectance inversion models (ORMs) provide a mechanism for inverting the color of the water observed by a satellite into marine inherent optical properties (IOPs), which can then be used to study phytoplankton community structure. Most ORMs effectively separate the total signal of the collective phytoplankton community from other water column constituents; however, few have been shown to effectively identify individual contributions by multiple phytoplankton groups over a large range of environmental conditions. We evaluated the ability of an ORM to discriminate between Noctiluca miliaris and diatoms under conditions typical of the northern Arabian Sea. We: (1) synthesized profiles of IOPs that represent bio-optical conditions for the Arabian Sea; (2) generated remote-sensing reflectances from these profiles using Hydrolight; and (3) applied the ORM to the synthesized reflectances to estimate the relative concentrations of diatoms and N. miliaris. By comparing the estimates from the inversion model with those from synthesized vertical profiles, we identified those conditions under which the ORM performs both well and poorly. Even under perfectly controlled conditions, the absolute accuracy of ORM retrievals degraded when further deconstructing the derived total phytoplankton signal into subcomponents. Although the absolute magnitudes maintained biases, the ORM successfully detected whether or not Noctiluca miliaris appeared in the simulated water column. This quantitatively calls for caution when interpreting the absolute magnitudes of the retrievals, but qualitatively suggests that the ORM provides a robust mechanism for identifying the presence or absence of species.


Pharmacists' knowledge and attitudes about natural health products: a mixed-methods study.
To explore knowledge and attitude of pharmacists in Qatar towards natural health products (NHPs). The quantitative component of this study consisted of an anonymous, online, self-administered questionnaire to assess knowledge about NHPs among pharmacists in Qatar. Descriptive statistics and inferential analysis were conducted using Statistical Package of Social Sciences (SPSS®). Means and standard deviation were used to analyze descriptive data, and statistical significance was expressed as P-value, where P≤0.05 was considered statistically significant. Associations between variables were measured using Pearson correlation. The qualitative component utilized focus group (FG) meetings with a purposive sample of community pharmacists. Meetings were conducted until a point of saturation was reached. FG discussions were audio-taped and transcribed verbatim. Data were analyzed using a framework approach to sort the data according to emerging themes. The majority of participants had average to poor knowledge about NHPs while only around 7% had good knowledge. In the FG meetings, participants considered the media, medical representatives, and old systems of natural health as major source of their knowledge. They criticized undergraduate pharmacy courses (for inadequately preparing pharmacists to deal with NHPs) and the pharmacy regulations (for being irrelevant). A perception of NHPs as being "safe" still exists among pharmacists. Pharmacists' ability to provide effective services associated with NHPs is limited by poor access to evidence-based information and poor knowledge. A perception of NHPs and CAM as 'safe' still exists among pharmacists, and regulations related to NHPs require addressing to follow best practice and ensure patient safety.


Potential relationship between gastroesophageal reflux disease and atrial arrhythmias.
A potential reduction in symptoms related to atrial fibrillation after treatment of gastroesophageal reflux disease symptoms with proton pump inhibitor therapy has been previously described. However, illustration of this relationship by combined 24-hour pH and ambulatory Holter monitoring has not been performed. We report 3 patients with symptoms of both palpitations and reflux who underwent simultaneous Holter and 24-hour ambulatory pH monitoring off of antireflux therapy. All of the patients reported a reduction in arrhythmia symptoms on proton pump inhibitor therapy. The findings from this preliminary series suggest a potential relationship between gastroesophageal reflux disease and atrial arrhythmias that might improve with antireflux therapy. Patients with documentation of both atrial arrhythmias and reflux should have a trial of aggressive acid suppressive therapy To further confirm this relationship, larger prospective studies are needed to assess whether maximal acid suppression improves arrhythmias.


Clostridium perfringens tpeL is expressed during sporulation.
Clostridium perfringens TpeL belongs to the family of large clostridial toxins. Although recent studies demonstrated the expression of tpeL during vegetative growth nothing is known about tpeL expression during sporulation. Our current study demonstrated that tpeL: (i) is also expressed during sporulation; (ii) expression is dependent on the master regulator of sporulation, Spo0A, and the sporulation-specific sigma factor, SigE; and (iii) is localized to the mother cell compartment of the sporulating cell. In summary, these results indicate that TpeL is a sporulation-regulated C. perfringens toxin.


Multilocus sequence typing.
Multilocus sequence typing (MLST) was first proposed in 1998 as a typing approach that enables the unambiguous characterization of bacterial isolates in a standardized, reproducible, and portable manner using the human pathogen Neisseria meningitidis as the exemplar organism. Since then, the approach has been applied to a large and growing number of organisms by public health laboratories and research institutions. MLST data, shared by investigators over the world via the Internet, have been successfully exploited in applications ranging from molecular epidemiological investigations to population biology and evolutionary analyses. This chapter describes the practical steps in the development and application of an MLST scheme and some of the common tools and techniques used to obtain the maximum benefit from the data. Considerations pertinent to the implementation of high-capacity MLST projects (i.e., those involving thousands of isolates) are discussed.


Laser resurfacing and remodeling of hypertrophic burn scars: the results of a large, prospective, before-after cohort study, with long-term follow-up.
Hypertrophic burn scars produce significant morbidity, including itching, pain, stiffness, and contracture, but best management practices remain unclear. We present the largest study to date that examines long-term impact of laser therapies, a potentially transformative technology, on scar remodeling. We conducted a prospective, before-after cohort study in burn patients with hypertrophic scars. Pulsed-dye laser was used for pruritus and erythema; fractional CO2 laser was used for stiffness and abnormal texture. Outcomes included (1) Vancouver Scar Scale (VSS), which documents pigmentation, erythema, pliability, and height, and (2) University of North Carolina "4P" Scar Scale (UNC4P), which rates pain, pruritus, paresthesias, and pliability. A total of 147 burn patients (mean age, 26.9 years; total body surface area, 16.1%) received 415 laser sessions (2.8 sessions/patient), 16 months (median) after injury, including pulsed dye laser (n = 327) and CO2 (n = 139). Laser treatments produced rapid, significant, and lasting improvements in hypertrophic scar. Provider-rated VSS dropped from 10.43 [standard deviation (SD) 2.37] to 5.16 (SD 1.92), by the end of treatments, and subsequently decreased to 3.29 (SD 1.24), at a follow-up of 25 months. Patient-reported UNC4P fell from 5.40 (SD 2.54) to 2.05 (SD 1.67), after the first year, and further decreased to 1.74 (SD 1.72), by the end of the study period. For the first time, ever, in a large prospective study, laser therapies have been shown to dramatically improve both the signs and symptoms of hypertrophic burn scars, as measured by objective and subjective instruments. Laser treatment of burn scars represents a disruptive innovation that can yield results not previously possible and may displace traditional methods of operative intervention.


Aminoglycoside antibiotics and renal function: changes in urinary gamma-glutamyltransferase excretion.
The urinary excretion of the renal proximal tubular enzyme, gamma-glutamyltransferase (gamma-GT), has been studied in 41 patients receiving tobramycin, gentamicin or streptomycin for a variety of infections. All patients receiving tobramycin or gentamicin have shown increased excretion of gamma-GT in the urine. Only 46% of those receiving streptomycin have shown an increase in gamma-GT excretion and this is of a lesser degree. A change in creatinine clearance which could only be explained by antibiotic administration was detected in three patients (2 on gentamicin, 1 on streptomycin). The degree of elevation of urinary gamma-GT activity was greater when the initial creatinine clearance was lower, and it is therefore suggested that those patients with pre-existing renal dysfunction should be monitored particularly carefully for signs of nephrotoxicity from these antibiotics. Urinary gamma-GT is a useful enzyme in the investigation of renal drug effects.


3D object watermarking by a 3D hidden object.
In this paper we present a method to watermark a 3D object with another hidden 3D object using digital holography. The watermark or the hidden information is a 3D object that is embedded in the digital hologram of a 3D host object. The digital holograms are obtained optically by phase shift interferometery. The hologram of the hidden 3D object is double phase encoded before embedding it to the host 3D object hologram. Then, the watermarked hologram is double phase encoded again using different set of codes. The resultant watermarked hologram is very secure because of the multi-key nature of the watermarking process. We discuss the effect of distortion caused by hologram quantization and occlusion of some of the hologram pixels. We present tests to illustrate the effect of using a window of the hologram to reconstruct the hidden 3D object and the host 3D object. Both mathematical analysis and simulations are presented to illustrate the system performance. To the best of our knowledge, this is the first report of embedding a 3D objects within another 3D object.


Prevalence and socio-demographic distribution of eating, physical activity and sedentary behaviours among Australian adolescents.
To examine the prevalence and socio-demographic distribution of adherence to national dietary and physical activity recommendations among Australian secondary school students. Cross-sectional survey of 12,188 students in Years 8 to 11 (aged 12-17 years). Students' self-reported eating, physical activity and sedentary behaviours were assessed using validated instruments administered via an online questionnaire. Less than one-quarter of students (24%) reported meeting the daily requirement of at least four serves of vegetables, while 41% reported consuming the recommended three or more daily serves of fruit. Just 15% of students reported engaging in at least 60 minutes of moderate-to-vigorous activity every day, and only one in five students met the recommendation of spending no more than two hours per day in small screen recreation. Males were performing better than females in terms of fruit intake and physical activity, but worse in relation to frequency of consumption of sugary drinks and fast food, and time spent using electronic media. The proportion of students meeting fruit and vegetable recommendations declined with advancing year level, while lower socio-economic position (SEP) students were faring less well than those from high SEP neighbourhoods, particularly with regards to healthy eating. There is considerable scope for improving young people's health behaviours in line with national dietary and physical activity recommendations.


Cardiac pacing in left bundle branch/bifascicular block patients.
The primary concern in patients with bifascicular block is the increased risk of progression to complete heart block. Further, an additional first-degree A-V block in patients with bifascicular block or LBBB might increase the risk of block progression. Anesthesia, monitoring and surgical techniques can induce conduction defects and bradyarrhythmias in patients with pre-existing bundle branch block. In the setting of an acute MI, several different types of conduction disturbance may become manifest and complete heart block occurs usually in patients with acute myocardial infarction more commonly if there is pre-existing or new bundle branch block. The question that arises is whether it is necessary to insert a temporary pacing catheter in patients with bifascicular block undergoing anesthesia. It is important that an anesthesiologist should be aware of the indications for temporary cardiac pacing as well as the current recommendations for permanent pacing in patients with chronic bifascicular and trifascicular block. This article also highlights the recent guidelines for temporary transvenous pacing in the setting of acute MI and the different pacing modalities that are available for an anesthesiologist.


Feasibility and Acceptability of a Positive Psychological Intervention for Patients With Type 2 Diabetes.
Positive psychological attributes (eg, optimism) have been associated with a healthier lifestyle and superior medical outcomes in patients with type 2 diabetes; however, there has been minimal study of behavioral interventions that target positive psychological constructs in this population. Accordingly, we developed a novel, telephone-based, 12-week positive psychology intervention and assessed its feasibility and short-term impact in adults with type 2 diabetes and suboptimal health behavior adherence. This was a pilot and feasibility study in adult inpatients and outpatients at an urban academic medical center recruited between December 2013 and December 2014. Adult patients with (1) type 2 diabetes (meeting American Diabetes Association criteria, eg, glycated hemoglobin A1c [HbA1c] > 6.5% or fasting glucose > 126 mg/dL) and (2) suboptimal adherence (score < 15/18 on the Medical Outcomes Study Specific Adherence Scale items for medication, diet, and exercise) were eligible. Participants received a positive psychology manual, completed exercises (eg, writing a gratitude letter, performing acts of kindness), and reviewed these activities by phone with a study trainer over the 12-week study period. Feasibility and acceptability were assessed via exercise completion rates and postexercise ratings of ease/utility on 0-10 Likert scales. Longer-term efficacy was explored by examining changes in psychological states and health behaviors from baseline to 12 weeks using random-effects regression models and estimates of effect size. A total of 15 participants enrolled; 12 participants provided complete baseline and follow-up data and were included in the analyses. Over 90% of these participants completed at least 2 exercises, and 75% completed a majority of the exercises. Participants rated the exercises as helpful (mean = 7.8/10) and easy to complete (mean = 7.1/10), and they reported improvements in optimism, gratitude, depression, anxiety, physical function, self-care, and health behaviors (Cohen d = 0.28-1.00). A positive psychology intervention for suboptimally adherent patients with type 2 diabetes was feasible, acceptable, and associated with broad pre-post psychological and health behavior improvement in a small initial study. Further testing of this promising intervention is warranted. ClinicalTrials.gov identifier: NCT02736084.


Asthma caused by potassium aluminium tetrafluoride: a case series.
The objective of this study is to describe a case-series of potassium aluminium tetrafluoride (KAlF(4))-induced occupational asthma (OA) and/or occupational rhinitis (OR). The study involves five patients from a heat-exchanger production line who were examined (including specific inhalation challenge tests) for suspected OA and/or OR caused by a flux containing almost 100% KAlF(4) - with fluorides' workplace air concentrations ranging between 1.7 and 2.8 mg/m(3). No subject had a previous history of asthma. All five patients had a positive specific challenge test (three patients were diagnosed with OA alone, one with OR and one with both OR and OA). At the follow-up visit, after three years on average, all patients needed permanent corticosteroid therapy (four topical, one oral). After elimination from the exposure, only one of the observed subjects gave an indication of an improvement, two subjects stabilized and two worsened. Our case series focuses on the correlation between patients' exposure to fluorides in air-conditioner production and the subsequent occurrence of OR/OA. Currently, it is uncertain whether these OR/OA were caused by hypersensitivity or irritation.


Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance.
SLC7A11 (xCT), together with SLC3A2 (4F2hc), encodes the heterodimeric amino acid transport system x(c)-, which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. We used microarrays to analyze gene expression of transporters in 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60). The expression of SLC7A11 showed significant correlation with that of SLC3A2 (r = 0.66), which in turn correlated with SLC7A5 (r = 0.68), another known partner for SLC3A2, and with T1A-2 (r = 0.60; all P < 0.0001). Linking expression of SLC7A11 with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue, L-alanosine, and 296 with negative correlations, e.g., geldanamycin. However, no significant correlation was observed with the geldanamycin analogue 17-allylamino, 17-demethoxygeldanamycin (17-AAG). Inhibition of transport system x(c)- with glutamate or (S)-4-carboxyphenylglycine in lung A549 and HOP-62, and ovarian SK-OV-3 cells, reduced the potency of L-alanosine and lowered intracellular glutathione levels. This further resulted in increased potency of geldanamycin, with no effect on 17-AAG. Down-regulation of SLC7A11 by small interfering RNA affected drug potencies similarly to transport inhibitors. The inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine, also decreased intracellular glutathione levels and enhanced potency of geldanamycin, but did not affect L-alanosine. These results indicate that SLC7A11 mediates cellular uptake of L-alanosine but confers resistance to geldanamycin by supplying cystine for glutathione maintenance. SLC7A11 expression could serve as a predictor of cellular response to L-alanosine and glutathione-mediated resistance to geldanamycin, yielding a potential target for increasing chemosensitivity to multiple drugs.


CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.
Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype.


Intensive group training protocol versus guideline physiotherapy for patients with chronic low back pain: a randomised controlled trial.
Intensive group training using principles of graded activity has been proven to be effective in occupational care for workers with chronic low back pain. Objective of the study was to compare the effects of an intensive group training protocol aimed at returning to normal daily activities and guideline physiotherapy for primary care patients with non-specific chronic low back pain. The study was designed as pragmatic randomised controlled trial with a setup of 105 primary care physiotherapists in 49 practices and 114 patients with non-specific low back pain of more than 12 weeks duration participated in the study. In the intensive group training protocol exercise therapy, back school and operant-conditioning behavioural principles are combined. Patients were treated during 10 individual sessions along 20 group sessions. Usual care consisted of physiotherapy according to the Dutch guidelines for Low Back Pain. Main outcome measures were functional disability (Roland Morris disability questionnaire), pain intensity, perceived recovery and sick leave because of low back pain assessed at baseline and after 6, 13, 26 and 52 weeks. Both an intention-to-treat analysis and a per-protocol analysis were performed. Multilevel analysis did not show significant differences between both treatment groups on any outcome measures during the complete follow-up period, with one exception. After 26 weeks the protocol group showed more reduction in pain intensity than the guideline group, but this difference was absent after 52 weeks. We finally conclude that an intensive group training protocol was not more effective than usual physiotherapy for chronic low back pain.


Directed evolution of phenylacetone monooxygenase as an active catalyst for the Baeyer-Villiger conversion of cyclohexanone to caprolactone.
Phenylacetone monooxygenase (PAMO) is an exceptionally robust Baeyer-Villiger monooxygenase, which makes it ideal for potential industrial applications. However, its substrate scope is limited, unreactive cyclohexanone being a prominent example. Such a limitation is unfortunate, because this particular transformation in an ecologically viable manner would be highly desirable, the lactone and the respective lactam being of considerable interest as monomers in polymer science. We have applied directed evolution in search of an active mutant for this valuable C-C activating reaction. Using iterative saturation mutagenesis (ISM), several active mutants were evolved, with only a minimal trade-off in terms of stability. The best mutants allow for quantitative conversion of 2 mM cyclohexanone within 1 h reaction time. In order to circumvent the NADP(+) regeneration problem, whole E. coli resting cells were successfully applied. Molecular dynamics simulations and induced fit docking throw light on the origin of enhanced PAMO activity. The PAMO mutants constitute ideal starting points for future directed evolution optimization necessary for an industrial process.


Recent advances in search of oral heparin therapeutics.
Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant.


Optimum bile acid treatment for rapid gall stone dissolution.
To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.


Comparative study of acetylcholinesterase and glutathione S-transferase activities of closely related cave and surface Asellus aquaticus (Isopoda: Crustacea).
The freshwater isopod crustacean Asellus aquaticus has recently been developed as an emerging invertebrate cave model for studying evolutionary and developmental biology. Mostly morphological and genetic differences between cave and surface A. aquaticus populations have been described up to now, while scarce data are available on other aspects, including physiology. The purpose of this study was to advance our understanding of the physiological differences between cave A. aquaticus and its surface-dwelling counterparts. We sampled two surface populations from the surface section of the sinking Pivka River (central Slovenia, Europe), i.e. locality Pivka Polje, and locality Planina Polje, and one cave population from the subterranean section of the sinking Pivka River, i.e. locality Planina Cave. Animals were sampled in spring, summer and autumn. We measured the activities of acetylcholinesterase (AChE) and glutathione S-transferase (GST) in individuals snap-frozen in the field immediately after collection. Acetylcholinesterase is likely related to animals' locomotor activity, while GST activity is related to the metabolic activity of an organism. Our study shows significantly lower AChE and GST activities in the cave population in comparison to both surface A. aquaticus populations. This confirms the assumption that cave A. aquaticus have lower locomotor and metabolic activity than surface A. aquaticus in their respective natural environments. In surface A. aquaticus populations, seasonal fluctuations in GST activity were observed, while these were less pronounced in individuals from the more stable cave environment. On the other hand, AChE activity was generally season-independent in all populations. To our knowledge, this is the first study of its kind conducted in A. aquaticus. Our results show that among closely related cave and surface A. aquaticus populations also physiological differences are present besides the morphological and genetic. These findings contribute to a better understanding of the biology of A. aquaticus and cave crustaceans in general.


Walking the Line: Conducting Transect Walks in Burkina Faso.
In this article we present results from transect walks and participatory mapping done in Burkina Faso. Since the Sahelian drought of the 1970s, researchers have continued to depict the Sahelian region of West Africa as an environment experiencing severe degradation; a narrative that persists over time. Recently, however, analyses of satellite imagery have identified remarkable patterns of greening across the Sahel. The causes of this greening are hotly debated. Through this project we aim to inform these debates with on-the-ground perceptions of local farmers and pastoralists. The transect walk method is a community-based process that collects information on the land-use/land-cover (LULC) features across villages. Transects help triangulate data by combining high-resolution satellite imagery, firsthand observations, and local experiences of ecological processes. We describe the methodology behind transects and discuss how they contextualize an otherwise removed process of environmental analysis. We also describe the challenges that arise throughout the fieldwork process.


Copper(I)-catalyzed amination of aryl halides in liquid ammonia.
The amination of aryl halides in liquid ammonia (LNH(3)) is catalyzed by a copper(I) salt/ascorbate system to yield primary aromatic amines in good to excellent yields. The low concentrations of catalyst required and the ease of product isolation suggest that this process has potential industrial applications. Commonly used ligands for analogous metal-catalyzed reactions are not effective. The rate of amination of iodobenzene in liquid ammonia is first order in copper(I) catalyst concentration. The small Hammett ρ = 0.49 for the amination of 4-substituted iodobenzenes in liquid ammonia at 25 °C indicates that the C-I bond is not significantly broken in the transition state structure and that there is a small generation of negative charge in the aryl ring, which is compatible with the oxidative addition of the copper ion being rate limiting.


Physical Activity Patterns Among Women and Men During Pregnancy and 8 Months Postpartum Compared to Pre-pregnancy: A Longitudinal Study.
Background: Realizing the essential prerequisite of regular physical activity (PA) it is essential to have knowledge about how different life change events may influence individual's participation. Many studies have documented that pregnancy and the transition to parenthood are life change events associated with decreased PA among women however, the examination of changes of PA in the male parent during this major life change event has been largely neglected in scientific literature and a significant research gap can be found. In the light of this, this longitudinal study aimed to follow changing PA patterns among women and men during pregnancy and 8 months postpartum compared to pre-pregnancy. Methods: In this study, 123 women and 112 men (partners of the women) that lived in the municipality of Karlskrona, Sweden, were included. Data were collected between 2008 and 2010. The self-reported amount of PA performed outdoors and indoors before pregnancy throughout the entire pregnancy, and 8 months postpartum, were measured. Results: We found similar changes in PA patterns among both women and men during pregnancy and 8 months postpartum when compared to pre-pregnancy. In almost all the activities studied except for walking/strolling, a significant decline was found. Conclusions: Our findings contribute new knowledge about changes in men's PA patterns from pre-pregnancy to pregnancy and postpartum. As couples seem to change activity patterns similarly, it is important to promote family-based PA initiatives and encourage couples to be active together during pregnancy and postpartum.


Optical density changes of Gafchromic MD-55 film resulting from laser light exposure at wavelengths of 671 nm and 633 nm.
Laser-based scanners provide a sensitive means for measuring optical density (OD) of Gafchromic films. Such instruments were reviewed in a recent AAPM report (task group 55) which provided recommendations and information on OD measurements (effect of wavelength, temperature, etc.). The present article reports that variable rate scanners and spot densitometers using laser diodes (671 nm) and HeNe lasers (633 nm) can cause polymerization of Gafchromic film. The light induced polymerization depends on light power, wavelength, beam spot size, dwell time, and prior radiation dose of the film. Measurements were made with a custom built scanner that provided accurate control of light power, light polarization, dwell time, and film position in relation to the beam focus. The results demonstrate that lasers operating with powers of 0.1, 0.5, 1.0, and 1.5 mW produce a nonlinear increase in OD of Gafchromic film. The measured change in OD after 1 min of exposure ranges from 0.150 to 0.244 for a laser diode operating at 0.5 and 1.5 mW, respectively. Tables are included that tabulate the increase in OD for laser power, dwell time, and prior dose. Laser light induced polymerization can have a significant impact on dosimetry measurements acquired using these laser-based systems.


Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor.
The periodic destruction of mitotic cyclins is triggered by the activation of the anaphase-promoting complex/cyclosome (APC/C) in mitosis. Although the ability of the APC/C to recognize destruction box (D-box) substrates oscillates throughout the cell cycle, the mechanism regulating APC/C binding to D-box substrates remains unclear. Here, we show that the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding. Emi1 itself contains a conserved C-terminal D-box, which provides APC/C-binding affinity, and a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding. Mutation of the ZBR converts Emi1 into a D-box-dependent APC/C substrate. The identification of a direct Emi1-APC/C complex further explains how Emi1 functions as a stabilizing factor for cyclin accumulation and the need to destroy Emi1 for APC/C activation in mitosis. The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors.


New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance.
Unlike Plasmodium falciparum, Plasmodium vivax rarely causes severe disease in healthy travellers or in temperate endemic regions and has been regarded as readily treatable with chloroquine. However, in tropical areas, recent reports have highlighted severe and fatal disease associated with P. vivax infection. We review the evidence for severe disease and the spread of drug-resistant P. vivax and speculate how these maybe related. Studies from Indonesia, Papua New Guinea, Thailand and India have shown that 21-27% of patients with severe malaria have P. vivax monoinfection. The clinical spectrum of these cases is broad with an overall mortality of 0.8-1.6%. Major manifestations include severe anaemia and respiratory distress, with infants being particularly vulnerable. Most reports of severe and fatal vivax malaria come from endemic regions where populations have limited access to healthcare, a high prevalence of comorbidity and where drug-resistant P. vivax strains and partially effective primaquine regimens significantly undermine the radical cure and control of this relapsing infection. The mechanisms underlying severe disease in vivax malaria remain poorly defined. Severe, fatal and multidrug-resistant vivax malaria challenge our perception of P. vivax as a benign disease. Strategies to understand and address these phenomena are needed urgently if the global elimination of malaria is to succeed.


Patient survival after the diagnosis of cancer in renal transplant recipients: a nested case-control study.
Malignancy is a well-known complication after renal transplantation. We studied the influence of cancer on patient survival in the Dutch renal transplant population in a nested case-controlled analysis. Between March 1966 and May 2008, 15,227 renal transplantations in 12,805 recipients were registered in the Netherlands Organ Transplant Registry database. Total follow-up was 89,651 person years. We performed an analysis of patient and graft survival both from the day of transplantation and the diagnosis of cancer in recipients with invasive cancer. Recipients without invasive cancer, matched for gender, age, and year of transplantation, served as a control group. For the survival analysis after the diagnosis of cancer, the matched control group consisted of patients with a functioning graft at the moment the index patient was diagnosed with cancer. Cancer had been registered in 908 (7.1%) patients, 630 (69%) of them died with functioning kidney, 510 (81%) because of their malignancy (at 8.2 years after transplantation, median). The median patient survival after transplantation was 11.9 vs. 16.8 years in the study and control group, respectively (P<0.001). The median patient and graft survival after the diagnosis of cancer was 2.1 vs. 8.3 (P<0.001) and 25 vs. 22.4 (P<0.001) years in the study and control group, respectively. Mortality because of cancer is observed at a significantly later time after transplantation compared with mortality because of the other main lethal complications. It significantly affects life expectancy and carries a poor prognosis with a limited survival after diagnosis.


Percutaneous absorption, biotransformation, and systemic disposition of parathion in vivo in swine. I. Comprehensive pharmacokinetic model.
Topical exposure to pesticides is a common route of entry for systemic effects. To quantify disposition of parathion (PA) and its major metabolites in a widely accepted animal model for human dermal risk assessment, a comprehensive pharmacokinetic model was formulated following [ring-UL-14C]PA topical (occluded and non-occluded dose of 300 micrograms, 40 micrograms/cm2 on the abdomen and back) and intravenous (300 micrograms) administration in vivo in female weanling pigs. The model was then confirmed with an intravenous p-nitrophenol (PNP) study. Total 14C as well as HPLC-separated PA, paraoxon (PO), PNP, and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles in plasma and urine, and 14C in blood, stratum corneum, dosed tissues, dosing device, and evaporative loss were determined. The model quantitates the evaporative loss, dosing device binding, percutaneous absorption, first-pass metabolism and its impact on the systemic metabolic profile of PA, as well as the distribution and excretion kinetics of both the parent compound and its metabolites. Model parameters and the simulated amount-time profiles were reported. Occlusion not only enhanced the partition of both PA and PNP into the stratum corneum from the dosed skin surface, but also slowed down the distribution of PA and PNP in the local dosed tissues. A significant finding was that occlusion also altered the first pass biotransformation of PA in the epidermis. PA, PO, and PNP were more easily absorbed into blood from the back than from the abdomen skin. The rate-limiting process in PA percutaneous absorption is the partitioning from skin surface into the stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)


First Report of Erwinia amylovora Causing Fire Blight on Plum (Prunus domestica) in Hungary.
During July 2011, a severe, unusual disease symptom was observed on young shoots on a 10-year old plum tree (Prunus domestica L. 'd'Agen') in the city of Budaörs, near Budapest. The naturally infected shoots showed typical symptoms of fire blight including terminal shoots with brown-to-black necrotic lesions and later, shepherd's crook deformation. Symptoms were the same as fire blight, symptoms reported from other hosts and locations. The first occurrence of fire blight on European plum was recorded in Germany in 2002 (4). Shoots containing regions of dead and healthy tissue were surface sterilized with ethanol (50-mg sample homogenized with 500 μl of sterile water and 50 μl of the homogenate streaked to King's B agar medium). After 48 h of incubation at 26°C, the medium contained pure cultures of a bacterium with white mucoid colonies, which is morphologically consistent with E. amylovora (1). Isolates were gram negative and induced a hypersensitive reaction in tobacco (Nicotiana tabacum L. 'White Burley') leaves (2). Biochemical tests were also used for identification, and the results of API 20E and API 50 CH kits (Biomérieux, Marcy l'Etoile, France), demonstrated that the bacterium belongs to Enterobacteriaceae. Pathogenicity was tested by injecting five healthy young plum shoots from the same tree with a 10-μl bacterial suspension of 107 CFU/ml. Controls were injected with sterile distilled water. Shoots were kept at 26°C and 80 to 100% relative humidity. Five days after inoculation, dark brown-to-black lesions and shepherd's crook symptoms were observed only on inoculated shoots. The bacterium was reisolated from lesions on inoculated shoots, fulfilling Koch's postulates. No lesions were observed on controls. For molecular identification of the pathogen, the 16S rDNA region was amplified from isolate EA-PlumBo1 with a general bacterial primer pair (63f forward and 1389r reverse) (3). The PCR products were cloned into a pGEM T-Easy plasmid vector (Promega, Madison, WI) and were transformed into Escherichia coli DH5α cells. A recombinant plasmid (2A2.5) was sequenced by M13 forward and reverse primers. The sequence was deposited in GenBank (Accession No. HE610678) and showed 99 to 100% sequence homology with a number of E. amylovora isolates, including type strain AJ233410 with 99% similarity and 100% homology with sequences FN434113 and FN666575, where the complete genomes are known. On the basis of the symptoms, colony morphology, biochemical tests, and 16S rDNA sequence homology, the pathogen was identified as E. amylovora. To our knowledge, this is the first report of a natural outbreak of fire blight on plum in Hungary and the presence of the pathogen may seriously influence local stone fruit production in the future. References: (1) E. O. King et al. J. Lab. Clin. Med. 44:301, 1954. (2) Z. Klement. Nature 199:299, 1963. (3) A. M. Osborn et al. Environ. Microbiol. 2:39, 2000. (4) J. L. Vanneste et al. Acta Hortic. 590:89, 2002.


Risk stratification in differentiated thyroid cancer with RAI-avid lung metastases.
Radioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification. This retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan-Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve. Age ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors. The high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.


The dual-porosity structure of peat and the extremely high organic matter content give rise to a complex medium that typically generates prolonged tailing and early 50% concentration breakthrough in the breakthrough curves (BTCs) of chloride (Cl-) and other anions. Untangling whether these observations are due to rate-limited (physical) diffusion into inactive pores, (chemical) adsorption or anion exclusion remains a critical question in peat hydrogeochemistry. This study aimed to elucidate whether Cl- is truly conservative in peat, as usually assumed, and whether the prolonged tailing and early 50% concentration breakthrough of Cl- observed is due to diffusion, adsorption, anion exclusion or a combination of all three. The mobile-immobile (MiM) dual-porosity model was fit to BTCs of Cl- and deuterated water measured on undisturbed cores of the same peat soils, and equilibrium Cl- adsorption batch experiments were conducted. Adsorption of Cl- to undecomposed and decomposed peat samples in batch experiments followed Freundlich isotherms but did not exhibit any trends with the degree of peat decomposition and sorption became negligible below aqueous Cl- concentrations of ~310 mg L-1. The dispersivity determined by fitting the Cl- BTCs whether assuming adsorption or no adsorption were significantly different than determined by the deuterated water (p < .0001). However, no statistical differences in dispersivity (p = .27) or immobile water content (p = .97) was observed between deuterated water and Cl- when accounting for anion exclusion. A higher degree of decomposition significantly increased anion exclusion (p < .0001) but did not influence the diffusion of either tracer into the immobile porosity. Contrary to previous assumptions, Cl- is not truly conservative in peat due to anion exclusion, and adsorption at higher aqueous concentrations, but the overall effect of anion exclusion on transport is likely minimal.


T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.


Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane.
Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis that in many cases is caused by mutations of the ELANE gene, which encodes neutrophil elastase (NE). Recent data suggest a model in which ELANE mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately a block in granulocytic differentiation. To test this model, we generated transgenic mice carrying a targeted mutation of Elane (G193X) reproducing a mutation found in SCN. The G193X Elane allele produces a truncated NE protein that is rapidly degraded. Granulocytic precursors from G193X Elane mice, though without significant basal UPR activation, are sensitive to chemical induction of ER stress. Basal and stress granulopoiesis after myeloablative therapy are normal in these mice. Moreover, inaction of protein kinase RNA-like ER kinase (Perk), one of the major sensors of ER stress, either alone or in combination with G193X Elane, had no effect on basal granulopoiesis. However, inhibition of the ER-associated degradation (ERAD) pathway using a proteosome inhibitor resulted in marked neutropenia in G193X Elane. The selective sensitivity of G913X Elane granulocytic cells to ER stress provides new and strong support for the UPR model of disease patho-genesis in SCN.


Response requirements modulate tactile spatial congruency effects.
Several recent studies have provided support for the view that tactile stimuli/events are remapped into an abstract spatial frame of reference beyond the initial somatotopic representation present in the primary somatosensory cortex. Here, we demonstrate for the first time that the extent to which this remapping of tactile stimuli takes place is dependent upon the particular demands imposed by the task that participants have to perform. Participants in the present study responded to either the elevation (up vs. down) or to the anatomical location (finger vs. thumb) of vibrotactile targets presented to one hand, while trying to ignore distractors presented simultaneously to the other hand. The magnitude and direction of the target-distractor congruency effect was measured as participants adopted one of two different postures with each hand (palm-up or palm-down). When the participants used footpedal responses (toe vs. heel; Experiment 1), congruency effects were determined by the relative elevation of the stimuli in external coordinates (same vs. different elevation), regardless of whether the relevant response feature was defined externally or anatomically. Even when participants responded verbally (Experiment 2), the influence of the relative elevation of the stimuli in external space, albeit attenuated, was still observed. However, when the task involved responding with the stimulated finger (four-alternative forced choice; Experiment 3), congruency effects were virtually eliminated. These findings support the view that tactile events can be remapped according to an abstract frame of reference resulting from multisensory integration, but that the frame of reference that is used while performing a particular task may depend to a large extent on the nature of the task demands.


Photosynthetic Metabolism and Nitrogen Reshuffling Are Regulated by Reversible Cysteine Thiol Oxidation Following Nitrogen Deprivation in Chlamydomonas.
As global temperatures climb to historic highs, the far-reaching effects of climate change have impacted agricultural nutrient availability. This has extended to low latitude oceans, where a deficit in both nitrogen and phosphorus stores has led to dramatic decreases in carbon sequestration in oceanic phytoplankton. Although Chlamydomonas reinhardtii, a freshwater model green alga, has shown drastic systems-level alterations following nitrogen deprivation, the mechanisms through which these alterations are triggered and regulated are not fully understood. This study examined the role of reversible oxidative signaling in the nitrogen stress response of C. reinhardtii. Using oxidized cysteine resin-assisted capture enrichment coupled with label-free quantitative proteomics, 7889 unique oxidized cysteine thiol identifiers were quantified, with 231 significantly changing peptides from 184 proteins following 2 h of nitrogen deprivation. These results demonstrate that the cellular response to nitrogen assimilation, photosynthesis, pigment biosynthesis, and lipid metabolism are regulated by reversible oxidation. An enhanced role of non-damaging oxidative pathways is observed throughout the photosynthetic apparatus that provides a framework for further analysis in phototrophs.


Structurally robust biological networks.
The molecular circuitry of living organisms performs remarkably robust regulatory tasks, despite the often intrinsic variability of its components. A large body of research has in fact highlighted that robustness is often a structural property of biological systems. However, there are few systematic methods to mathematically model and describe structural robustness. With a few exceptions, numerical studies are often the preferred approach to this type of investigation. In this paper, we propose a framework to analyze robust stability of equilibria in biological networks. We employ Lyapunov and invariant sets theory, focusing on the structure of ordinary differential equation models. Without resorting to extensive numerical simulations, often necessary to explore the behavior of a model in its parameter space, we provide rigorous proofs of robust stability of known bio-molecular networks. Our results are in line with existing literature. The impact of our results is twofold: on the one hand, we highlight that classical and simple control theory methods are extremely useful to characterize the behavior of biological networks analytically. On the other hand, we are able to demonstrate that some biological networks are robust thanks to their structure and some qualitative properties of the interactions, regardless of the specific values of their parameters.


Radiographic measures of chronic periodontitis and carotid artery plaque.
Chronic periodontitis (CP) is associated with stroke and subclinical atherosclerosis, but clinical measurement of CP can be time consuming and invasive. The purpose of this study was to determine whether radiographically assessed CP is associated with nonstenotic carotid artery plaque as an ultrasound measure of subclinical atherosclerosis. Panoramic oral radiographs were obtained from 203 stroke-free subjects ages 54 to 94 during the baseline examination of the Oral Infections and Vascular Disease Epidemiology Study (INVEST). CP exposure among dentate subjects was defined either categorically (periodontal bone loss > or =50% [severe] versus <50% bone loss) or via tertile formation (for dose-response investigation), with edentulous subjects categorized separately. In all subjects, high-resolution B-mode carotid ultrasound was performed. Carotid plaque thickness (CPT) and prevalence (present/absent) were recorded. Covariates included age, sex, smoking, diabetes, hypertension, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein cholesterol. Among dentate subjects with severe periodontal bone loss, mean CPT was significantly greater (1.20+/-1.00 mm versus 0.73+/-0.89 mm; P=0.003). CPT increased with more severe bone loss (upper versus lower tertile bone loss; P=0.049; adjusted for age, sex, and hypertension). This apparent dose-response effect was more evident among never-smokers. In a fully adjusted multivariate logistic regression model, severe periodontal bone loss was associated with a nearly 4-fold increase in risk for the presence of carotid artery plaque (adjusted odds ratio, 3.64; CI, 1.37 to 9.65). Severe periodontal bone loss is associated independently with carotid atherosclerosis. Panoramic oral radiographs may thus provide an efficient means to assess CP in studies of atherosclerosis risk.