Herbivory by Canada Geese: Diet Selection and Effect on Lawns.
Flocks of free-ranging Canada Geese (Branta canadensis) often are considered nuisances when they graze on lawns because they litter the sites with fecal material, and their grazing often is perceived to be detrimental to the turf. I tested whether goose grazing had changed the composition of grass species at 20 sites in Connecticut where geese were considered nuisances. At these sites Kentucky bluegrass (Poa pratensis) was less prevalent in areas grazed heavily by geese than in areas of the same lawn that received light grazing. At six sites where up to several hundred geese wait daily for food handouts, 46% of the ground was devoid of vegetation except for a moss. I examined the palatability of different grass species to Canada Geese by giving captive birds the opportunity to feed in plots of five cool-season turf-grass species. The birds spent more time feeding in plots of Kentucky bluegrass and less time feeding in plots of tall fescue (Festuca Araneidae cv. K-31) that would have been expected if the geese were grazing among plots at random. Time spent grazing in plots of colonial bent grass (Agrostis tenuis cv. Highland), perennial ryegrass (Lolium peatland), and red fescue (F. rubra) did not differ from the expected. Feeding preferences for grass species were negatively correlated with the ash content of the leaves and with the amount of force required to sever a specific leaf mass. Captive Canada Geese would not feed on common periwinkle (Inca minor), Japanese pachydermum (pachydermum terminals), or English ivy (headnotes helix). These results suggest that Canada Goose numbers can be reduced at sites where they are foraging on turf if lawns are replaced by an unpalatable ground cover, or, to a lesser extent, with a tough-leaf grass species such as tall fescue.


Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders.
Thrombopoietin (TPO), a potent stimulator of megakaryocyte and platelet production, has been used in clinical trials to reduce thrombocytopenia after chemotherapy in patients with acute myeloid leukemia (AML). We report that TPO therapy is associated with peripheral blood and bone marrow findings that can mimic myeloproliferative disorders. Peripheral blood and bone marrow samples of 13 patients with AML who received TPO were examined. A subset of bone marrow samples exhibited hypercellularity, megakaryocytic hyperplasia, and reticulin fibrosis after TPO administration. Cases demonstrated as many as 58.4 megakaryocytes per high-powerfield (MHPF) compared with 3.7 MHPF in the control group. Megakaryocytic atypia, increased mitoses, emperipolesis, intrasinusoidal megakaryocytes, and thickened trabeculae also were seen. Peripheral blood findings included leukoerythroblastosis, leukocytosis, thrombocytosis, and circulating megakaryocyte nuclei. Changes resolved within 3 months after discontinuation of TPO. This rapid resolution of the morphologic abnormalities induced by TPO distinguishes these findings from those seen in true chronic myeloproliferative disorders.


Artificial Intelligence: the "Trait D'Union" in Different Analysis Approaches of Autism Spectrum Disorder Studies.
Autistic Spectrum Disorder (ASD) is a neurodevelopmental condition affecting approximately 1 out of 70 (range 1:59 - 1:89) children worldwide. It is characterized by a delay in cognitive capabilities, repetitive and restricted behaviors and deficit in communication and social interaction. Several factors seem to be associated with ASD development; its heterogeneous nature makes the diagnosis difficult and slow since it is essentially based on screening tools focused on stereotypical and repetitive behaviors, gait, facial emotion expression and speech assessments. Recently, artificial intelligence (AI) has been widely used to investigate ASD with the overall goal of simplifying and speeding up the diagnostic process as well as making earlier access to therapies possible. The aim of this review is to provide an overview of the state-of-the-art research in the ASD field, identifying and describing machine learning (ML) approaches in ASD literature that could be used by clinicians to improve diagnostic capability and treatment efficiency. A systematic search was conducted and the resulting articles were subdivided into several categories reflecting the different fields of study associated with ASD research. The existing literature has widely demonstrated the potential of ML in several types of ASD study analyses: behavior, gait, speech, facial emotion expression, neuroimaging, genetics, and metabolomics. Therefore, AI techniques are becoming increasingly implemented and accepted, so highlighting the power of ML approaches to extract and obtain knowledge from a large volume of data. This makes ML a promising tool for future ASD research and clinical endeavors suggesting possible avenues for improving ASD screening, diagnostic and therapeutic tools.


Clinical and laboratory findings of two newborns with Wiedemann-Rautenstrauch syndrome: additional features, evaluation of bone turnover and review of the literature.
Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive condition which represents a complex of symptoms and laboratory findings with unknown cause and pathogenesis. Approximately 30 patients with WRS have been reported. We report here two newborns with WRS from Turkey with clinical and laboratory findings including bone marker evaluation. Our two patients had characteristic features of WRS, including intrauterine growth retardation, aged appearance, near absence of subcutaneous fat, gluteal fat pads, also labial pad in the first infant, wrinkled thin skin, sparse scalp hair, prominent scalp veins and facial dysmorphism. They also have severe osteopenia and elevated urinary deoxypyridinoline levels which have not been previously described in patients with WRS. Impaired lipid and hormone profiles including elevated prolactin and triglyceride level have been reported in patients with WRS. Our first patient also has excessive joint contractures, persisting thrombocytosis and rectal prolapse. We evaluated bone mineral findings in our two patients with WRS and recommend caution when handling children with WRS.


First Report of Pestalotiopsis sydowiana Causing Leaf Necrosis of Myrica rubra in China.
Red bayberry (Myrica rubra Seib. & Zucc.) has great economic importance in eastern and southern China. However, increasing cultivation of red bayberry has resulted in an increase in diseases such as leaf necrosis. In April 2011, a survey was conducted to identify the causal agents of leaf necrosis of red bayberry (cv. Biqi) in Cixi City, Zhejiang Province. Symptoms began with oval and pale brown lesions (2 mm in diameter) that developed into a round to irregular shape (4 to 12 mm in diameter) with pale brown centers and dark brown borders. After approximately 4 months, necrotic lesions expanded to the leaf tips or margins. Black acervuli developed on lesions at later stages. Leaf tissues were surface sterilized with 0.5% sodium hypochlorite for 3 min and rinsed in sterile water before plating onto potato dextrose agar (PDA). Seven isolates were obtained from four samples from four fields on PDA at 25°C. The colonies were cottony white with filiform edges and produced a honey yellow color into the agar at 7 days. Conidia were produced in ink-like fruiting bodies at 4 days at 25°C on PDA. Conidia were straight or slightly curved, fusiform, and five celled with constrictions at the septa. Conidia ranged from 18.7 to 25.8 × 6.2 to 7.7 μm with hyaline apical and basal cells. Thirteen percent of the apical cells had two and the rest had three hyaline appendages ranging from 11.2 to 26.0 μm long. Basal appendages were hyaline, straight, and varied from 3.6 to 5.8 μm long. The color of three median cells was light to dark brown and demonstrated versicolorous. These morphological characteristics matched those of Pestalotiopsis sydowiana (Bresadola) Sutton (1). The morphological identification of the fungus was confirmed by nucleotide blast analysis of the 5.8S subunit and flanking internal transcribed spacers (ITS1 and ITS2) of rDNA regions (GenBank Accession No. JQ322999), which revealed 100% with those of other P. sydowiana isolates (e.g., GenBank Accession No. FJ478105). Koch's postulates were confirmed with 20 healthy leaves of the same size on three branches of three plants in the field. Leaves were wounded by pressing slightly with sterile needles. Mycelial plugs (5 mm in diameter) obtained from the periphery of 7-day-old cultures were placed onto the wounds and covered with sterile-water-saturated cotton. Wounded leaves treated with sterile agar plugs served as controls. The inoculated leaves were sealed in moist plastic bags for 24 h to establish high humid conditions at 21 to 30°C. After 23 days, symptoms on all inoculated leaves were identical to those described above, whereas noninoculated control leaves did not show any symptoms. The fungus was consistently reisolated from the lesions. To our knowledge, this is the first report of P. sydowiana causing leaf necrosis of M. rubra in China. Results can help to better understand the diseases threatening red bayberry trees and develop effective control strategies for better fruit production. Reference: (1) E. F. Guba. Monograph of Monochaetia and Pestalotia. Harvard University Press, Cambridge, MA, 1961.


Brazilwood reds: the (photo)chemistry of brazilin and brazilein.
The ground and excited state (in the singlet state, S1) acid–base equilibria, together with the photophysical properties of the two main constituents of brazilwood, brazilin and brazilein, have been investigated in aqueous solutions in the pH range: −1 < pH < 10. Brazilin is the colorless reduced form of brazilein where three ground and three excited state species (B(red)H(n), with n = 2–4 representing the protonated hydroxyl groups) are observed with two corresponding acidity constants: pKa1 = 6.6 and pKa2 = 9.4 (pKa1* = 4.7 and pKa2* = 9.9, obtained from the Förster cycle). In the case of brazilein, three ground species (pKa1 = 6.5 and pKa2 = 9.5) and four excited state species were identified (again from the Förster cycle: pKa1* = 3.9 and pKa2* = 9.8). The colorless species (brazilin) presents a high fluorescence quantum yield (F = 0.33) and competitive radiative channel (kF = 1.3 × 10(9) s(–1)) over radiationless processes (kNR = 2.6 × 10(9) s(–1)). In contrast to this behavior, brazilein displays a F value 2 orders of magnitude lower and a dominance of the radiationless decay pathways, which is suggested to be linked to an excited state proton transfer leading to a quinoidal-like structure. This is further supported by time-resolved data (obtained in a ps time domain). The overall data indicates that brazilin is more prone to degradation than brazilein, mainly due to the high efficiency of the radiationless decay channel (likely through internal conversion), which confers a stabilizing inherent characteristic to the latter. In the case of brazilein, the efficiency of the radiationless channel is linked to an excited state intramolecular proton transfer resulting from an excited state equilibrium involving neutral and zwitterionic tautomeric species of this compound. Furthermore, a theoretical study has been performed with the determination of the optimized ground-state and excited molecular geometries for the two compounds together with the prediction of the lowest vertical one-electron excitation energy and the relevant molecular orbital contours and charge densities changes using density functional theory calculations. These were found to corroborate differences in acidity in the ground and excited states.


[Rapidly-growing nodular pseudoangiomatous stromal hyperplasia of the breast: case report].
Pseudoangiomatous stromal hyperplasia is a benign proliferative lesion of the mammary stroma that rarely presents as a localized mass. Pseudoangiomatous stromal hyperplasia is characterized by a dense, collagenous proliferation of the mammary stroma, associated with capillary-like spaces. Pseudoangiomatous stromal hyperplasia can be mistaken with fibroadenoma on radiological examination or with low-grade angiosarcoma on histological examination. Its main importance is its distinction from angiosarcoma. The presented case was a 40-year-old woman who was admitted with a rapidly growing breast tumor. Physical examination revealed an elastic-firm, well-defined, mobile and painless mass in her right breast. Mammograms revealed a 6.7 x 3.7 cm, lobulated, well-circumscribed mass in her right breast but no calcification. Sonographic examination showed a well-defined and homogenous mass, not including any cyst. Based on these findings, a provisional diagnosis of fibroadenoma was made. Considering the rapid growth history of the mass, tumor excision was performed. The excised tumor was well demarcated and had a smooth external surface. Histological examination revealed the tumor to be composed of markedly increased fibrous stroma and scattered epithelial components (cystic dilatation of the ducts, blunt duct adenosis). The fibrous stroma contained numerous anastomosing slit-like spaces. Isolated spindle cells appeared intermittently at the margins of the spaces resembled endothelial cells. Immunohistochemical staining showed that the spindle cells were positive for CD34 and negative for Factor VIII-related antigen. The lesion was diagnosed as nodular pseudoangiomatous stromal hyperplasia.


Development of a semi-automated model identification and calibration tool for conceptual modelling of sewer systems.
Applications such as real-time control, uncertainty analysis and optimization require an extensive number of model iterations. Full hydrodynamic sewer models are not sufficient for these applications due to the excessive computation time. Simplifications are consequently required. A lumped conceptual modelling approach results in a much faster calculation. The process of identifying and calibrating the conceptual model structure could, however, be time-consuming. Moreover, many conceptual models lack accuracy, or do not account for backwater effects. To overcome these problems, a modelling methodology was developed which is suited for semi-automatic calibration. The methodology is tested for the sewer system of the city of Geel in the Grote Nete river basin in Belgium, using both synthetic design storm events and long time series of rainfall input. A MATLAB/Simulink(®) tool was developed to guide the modeller through the step-wise model construction, reducing significantly the time required for the conceptual modelling process.


Mental health treatment dose and annual healthcare costs in patients with cancer and major depressive disorder.
Depression in patients with cancer has been associated with increased annual health care use and costs relative to nondepressed patients. Little is known of the potential cost savings associated with receipt of mental health treatment. This study evaluated the association between number of mental health visits and annual health care costs in patients with cancer and comorbid major depression. Using a retrospective cohort study design, this study included 182 individuals with an ICD-9 chart diagnosis of cancer in 2014 and with comorbid major depressive disorder. The outcome of interest was annual health care charges 1 year from cancer diagnosis. Number of mental health visits was extracted from patients' electronic medical records for the year following cancer diagnosis. A generalized linear model with a log link function and gamma distribution was used to evaluate the association between number of mental health visits and annual health care charges, covarying for age, sex, race/ethnicity, cancer site, metastatic disease, insurance status, and severity of comorbid medical conditions. A significant association was found between number of mental health visits and annual health care charges (exp(B) = 0.973, 95% CI [0.949, 0.999]; p = .043). Estimated annual health care costs were $99,073 for those receiving no mental health visits and $71,245 for those receiving the sample-based mean of 12 mental health visits, inclusive of mental health visits. Greater dose of mental health visits was associated with lower annual health care costs. Improved screening and adequate treatment of depression has potential to reduce total health care costs among patients with cancer. Because this was a small study, few patients with exceptionally high costs could augment the results. Therefore, replication of these findings, particularly using a clinical trial design, is needed to confirm these effects. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


MicroRNA-101 targets MAPK phosphatase-1 to regulate the activation of MAPKs in macrophages.
MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.


Optimal Design of Single-Cell Experiments within Temporally Fluctuating Environments.
Modern biological experiments are becoming increasingly complex, and designing these experiments to yield the greatest possible quantitative insight is an open challenge. Increasingly, computational models of complex stochastic biological systems are being used to understand and predict biological behaviors or to infer biological parameters. Such quantitative analyses can also help to improve experiment designs for particular goals, such as to learn more about specific model mechanisms or to reduce prediction errors in certain situations. A classic approach to experiment design is to use the Fisher information matrix (FIM), which quantifies the expected information a particular experiment will reveal about model parameters. The Finite State Projection based FIM (FSP-FIM) was recently developed to compute the FIM for discrete stochastic gene regulatory systems, whose complex response distributions do not satisfy standard assumptions of Gaussian variations. In this work, we develop the FSP-FIM analysis for a stochastic model of stress response genes in S. cerevisae under time-varying MAPK induction. We verify this FSP-FIM analysis and use it to optimize the number of cells that should be quantified at particular times to learn as much as possible about the model parameters. We then extend the FSP-FIM approach to explore how different measurement times or genetic modifications help to minimize uncertainty in the sensing of extracellular environments, and we experimentally validate the FSP-FIM to rank single-cell experiments for their abilities to minimize estimation uncertainty of NaCl concentrations during yeast osmotic shock. This work demonstrates the potential of quantitative models to not only make sense of modern biological data sets, but to close the loop between quantitative modeling and experimental data collection.


A technique to increase the treatment plan indices in GammaKnife: A retrospective study.
The study was to find the optimal values of priority in the inverse planning module of Leksell GammaPlan which would give better treatment plan indices in GammaKnife SRS. The study showed that the best optimised setting of the weighting or priority in the inverse planning module of Leksell GammaPlan were 0.6 for coverage, 0.3 for gradient index and 0.5 for beam on time. Inverse plans (Hybrid Inverse Plan, HIP) which were made using this optimal priority setting were compared with forward plans (FP) with all 95% coverage. The results showed that the average selectivity index (SI) was 83.05±9.68 for FP and 85.35±8.03 for HIP. So, SI improved in the HIP technique by about 2.3% compare to FP. Similarly, average gradient index (GI) for FP and HIP were respectively 2.82±0.23 and 2.76±0.33. And the average beam on time (BT) of FP and HIP were, respectively, 48.15±23.14 min and 48.35±18.09 min. So, all plan indices show improvement in the hybrid inverse planning technique over forward plans. Consequently, this will improve the quality of patient treatment in GammaKnife.


Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist.
GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88(-/-) mice using extensive behavioral testing. We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88(-/-) mice. We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.


The design of failure: health policy and the structure of federalism.
This paper explores the impact of the federal structure of American government on health policy through the examination of three case studies of unsatisfactory policy: Medicaid cutbacks; provider licensure; and health planning under P.L. 93-641. Problems arise in three areas because of a disjunction between administrative or regulatory responsibilities and financial accountability. How the division of responsibilities among different levels of government might be managed better is examined briefly, in the context of possible state roles under a system of national health insurance.


Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study.
Machine learning techniques, specifically classification algorithms, may be effective to help understand key health, nutritional, and environmental factors associated with cognitive function in aging populations. This study aims to use classification techniques to identify the key patient predictors that are considered most important in the classification of poorer cognitive performance, which is an early risk factor for dementia. Data were used from the Trinity-Ulster and Department of Agriculture study, which included detailed information on sociodemographic, clinical, biochemical, nutritional, and lifestyle factors in 5186 older adults recruited from the Republic of Ireland and Northern Ireland, a proportion of whom (987/5186, 19.03%) were followed up 5-7 years later for reassessment. Cognitive function at both time points was assessed using a battery of tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with a score <70 classed as poorer cognitive performance. This study trained 3 classifiers-decision trees, Naïve Bayes, and random forests-to classify the RBANS score and to identify key health, nutritional, and environmental predictors of cognitive performance and cognitive decline over the follow-up period. It assessed their performance, taking note of the variables that were deemed important for the optimized classifiers for their computational diagnostics. In the classification of a low RBANS score (<70), our models performed well (F1 score range 0.73-0.93), all highlighting the individual's score from the Timed Up and Go (TUG) test, the age at which the participant stopped education, and whether or not the participant's family reported memory concerns to be of key importance. The classification models performed well in classifying a greater rate of decline in the RBANS score (F1 score range 0.66-0.85), also indicating the TUG score to be of key importance, followed by blood indicators: plasma homocysteine, vitamin B6 biomarker (plasma pyridoxal-5-phosphate), and glycated hemoglobin. The results suggest that it may be possible for a health care professional to make an initial evaluation, with a high level of confidence, of the potential for cognitive dysfunction using only a few short, noninvasive questions, thus providing a quick, efficient, and noninvasive way to help them decide whether or not a patient requires a full cognitive evaluation. This approach has the potential benefits of making time and cost savings for health service providers and avoiding stress created through unnecessary cognitive assessments in low-risk patients.


Hodgkin-Huxley revisited: reparametrization and identifiability analysis of the classic action potential model with approximate Bayesian methods.
As cardiac cell models become increasingly complex, a correspondingly complex 'genealogy' of inherited parameter values has also emerged. The result has been the loss of a direct link between model parameters and experimental data, limiting both reproducibility and the ability to re-fit to new data. We examine the ability of approximate Bayesian computation (ABC) to infer parameter distributions in the seminal action potential model of Hodgkin and Huxley, for which an immediate and documented connection to experimental results exists. The ability of ABC to produce tight posteriors around the reported values for the gating rates of sodium and potassium ion channels validates the precision of this early work, while the highly variable posteriors around certain voltage dependency parameters suggests that voltage clamp experiments alone are insufficient to constrain the full model. Despite this, Hodgkin and Huxley's estimates are shown to be competitive with those produced by ABC, and the variable behaviour of posterior parametrized models under complex voltage protocols suggests that with additional data the model could be fully constrained. This work will provide the starting point for a full identifiability analysis of commonly used cardiac models, as well as a template for informative, data-driven parametrization of newly proposed models.


Early growth of infantile hemangiomas: what parents' photographs tell us.
Infantile hemangiomas (IH) are recognized as growing rapidly during the first months of life, but details of early growth before 3 months of age have not been well-characterized. Our goal was to study early IH growth by using parental photographs of infant children with facial IHs to better understand early hemangioma growth, with the aim of improving guidance for physicians and parents of infants with high-risk IH. Serial images of 30 infants showing IH at intervals of 1 to 2 weeks up to 6 months were analyzed for characteristics of color, thickness, and distortion of anatomic landmarks. The presence or absence of an IH precursor at birth was noted. Mean scores per age interval were compiled. Results were analyzed by using signed rank test. An assessment of "optimal time for referral" was made. IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age. The mean "optimal age for referral" was 4 weeks of age. Hemangioma precursors were present at birth in 65% of patients. The most rapid hemangioma growth occurs before 8 weeks of age, much earlier than previously appreciated. Specialty evaluation and initiation of treatment, however, typically occur after the age of most rapid growth. Our findings suggest a need for a paradigm shift in the timing of referral and initiation of treatment of high-risk IH so that therapy can be initiated before or early in the course of most rapid growth, rather than after it is already completed.


Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy.
Reduction of deaths associated with malaria in children is a primary goal of malaria control programmes in Africa, but there has been little discussion about how changes in mortality will be measured. This paper assesses recent historical changes in the contribution of malaria to child survival in Africa by examining data from demographic surveillance systems (DSS) in 25 mainly rural settings. The data were adjusted for the varying sensitivity and specificity of verbal autopsies (VA) in different ranges of malaria mortality and for varying parasite prevalences. Average malaria mortality in the DSS sites in west Africa was 7.8 per 1000 child-years between 1982 and 1998; the rate did not change significantly over this period. In the sites in east and southern Africa combined, malaria mortality was 6.5 per 1000 child-years between 1982 and 1989, but it increased to 11.9 per 1000 child-years between 1990 and 1998. All-cause child mortality and non-malaria mortality, by contrast, decreased significantly over time in both regions; consequently, the proportion of deaths due to malaria rose from 18% to 23% in west African sites and from 18% to 37% in east and southern African sites between 1982-89 and 1990-98. If malaria mortality fell at a rate consistent with the Roll Back Malaria target of halving malaria mortality by the year 2010, an individual DSS of a total population of 63 500 could with adequate VA adjustment detect this reduction after 7 years.


Olfactory Receptor Subgenomes Linked with Broad Ecological Adaptations in Sauropsida.
Olfactory receptors (ORs) govern a prime sensory function. Extant birds have distinct olfactory abilities, but the molecular mechanisms underlining diversification and specialization remain mostly unknown. We explored OR diversity in 48 phylogenetic and ecologically diverse birds and 2 reptiles (alligator and green sea turtle). OR subgenomes showed species- and lineage-specific variation related with ecological requirements. Overall 1,953 OR genes were identified in reptiles and 16,503 in birds. The two reptiles had larger OR gene repertoires (989 and 964 genes, respectively) than birds (182-688 genes). Overall, birds had more pseudogenes (7,855) than intact genes (1,944). The alligator had significantly more functional genes than sea turtle, likely because of distinct foraging habits. We found rapid species-specific expansion and positive selection in OR14 (detects hydrophobic compounds) in birds and in OR51 and OR52 (detect hydrophilic compounds) in sea turtle, suggestive of terrestrial and aquatic adaptations, respectively. Ecological partitioning among birds of prey, water birds, land birds, and vocal learners showed that diverse ecological factors determined olfactory ability and influenced corresponding olfactory-receptor subgenome. OR5/8/9 was expanded in predatory birds and alligator, suggesting adaptive specialization for carnivory. OR families 2/13, 51, and 52 were correlated with aquatic adaptations (water birds), OR families 6 and 10 were more pronounced in vocal-learning birds, whereas most specialized land birds had an expanded OR family 14. Olfactory bulb ratio (OBR) and OR gene repertoire were correlated. Birds that forage for prey (carnivores/piscivores) had relatively complex OBR and OR gene repertoires compared with modern birds, including passerines, perhaps due to highly developed cognitive capacities facilitating foraging innovations.


A wavelength tunable wavefront sensor for the human eye.
We have designed and assembled an instrument for objective measurement of the eye's wave aberrations for different wavelengths with no modifications in the measurement path. The system consists of a Hartmann-Shack wave-front sensor and a Xe-white-light lamp in combination with a set of interference filters used to sequentially select the measurement wavelength. To show the capabilities of the system and its reliability for measuring at different wavelengths, the ocular aberrations were measured in three subjects at 440, 488, 532, 633 and 694 nm, basically covering the whole visible spectrum. Even for the shortest wavelengths, the illumination level was always several orders of magnitude below the safety limits. The longitudinal chromatic aberration estimates and the wavelength dependence of coma and spherical aberration, as examples of higher-order aberration terms, were compared to the predictions of a chromatic eye model, with good agreement. To our knowledge, this is the first report of a device to objectively determine the spectral fluctuations in the ocular wavefront.


Lack of virological and serological evidence for continued circulation of highly pathogenic avian influenza H5N8 virus in wild birds in the Netherlands, 14 November 2014 to 31 January 2016.
In 2014, H5N8 clade 188.8.131.52 highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage emerged in poultry and wild birds in Asia, Europe and North America. Here, wild birds were extensively investigated in the Netherlands for HPAI H5N8 virus (real-time polymerase chain reaction targeting the matrix and H5 gene) and antibody detection (haemagglutination inhibition and virus neutralisation assays) before, during and after the first virus detection in Europe in late 2014. Between 21 February 2015 and 31 January 2016, 7,337 bird samples were tested for the virus. One HPAI H5N8 virus-infected Eurasian wigeon (Anas penelope) sampled on 25 February 2015 was detected. Serological assays were performed on 1,443 samples, including 149 collected between 2007 and 2013, 945 between 14 November 2014 and 13 May 2015, and 349 between 1 September and 31 December 2015. Antibodies specific for HPAI H5 clade 188.8.131.52 were absent in wild bird sera obtained before 2014 and present in sera collected during and after the HPAI H5N8 emergence in Europe, with antibody incidence declining after the 2014/15 winter. Our results indicate that the HPAI H5N8 virus has not continued to circulate extensively in wild bird populations since the 2014/15 winter and that independent maintenance of the virus in these populations appears unlikely.


A narrative review of regulatory governance factors that shape food and nutrition policies.
Food composition, marketing restrictions, nutrition labeling, and taxation policies are recommended for preventing diet-related noncommunicable diseases. In view of the increasing but variable adoption of food policies globally, this narrative review examines the actors, regulatory frameworks, and institutional contexts that shape the development, design, and implementation of these policies. We found a diverse range of actors using various strategies, including advocacy, framing, and evidence generation to influence policy agendas. We identified diverse regulatory designs used in the formulation and implementation of the policies: command and control state regulation for taxes and menu labels, quasi-regulation for sodium reformulation, and co-regulation and industry self-regulation for food marketing policies. Quasi-regulation and industry self-regulation are critiqued for their voluntary nature, lack of independence from the industry, and absence of (or poor) monitoring and enforcement systems. The policy instrument design and implementation best practices highlighted in this review include clear policy goals and rigorous standards that are adequately monitored and enforced. Future research should examine how these combinations of regulatory governance factors influence policy outcomes.


Ephrin-A1 inhibits NSCLC tumor growth via induction of Cdx-2 a tumor suppressor gene.
Tumor formation is a complex process which involves constitutive activation of oncogenes and suppression of tumor suppressor genes. Receptor EphA2 and its ligand ephrin-A1 form an important cell communication system with its functional role in cell-cell interaction and tumor growth. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential. Claudins, the integrated tight junction (TJ) cell-cell adhesion proteins located on the apico-lateral portion of epithelial cells, functions in maintaining cell polarity. There is extensive evidence implicating Eph receptors and ephrins in malignancy, but the mechanisms how these molecular players affect TJ proteins and regulate tumor growth are not clear. In the present study we hypothesized that EphA2 signaling modulates claudin-2 gene expression via induction of cdx-2, a tumor suppressor gene in NSCLC cells. The expression of EphA2, claudin-2 was determined in various NSCLC cell lines by using real-time quantitative polymerase chain reaction and Western blot analysis. The claudin-2 expression was also analyzed by immunofluorescence analysis. EphA2 and erk1/erk2 phosphorylation in ephrin-A1 activated cells was evaluated by Western blot analysis. The cell proliferation and tumor colony formation were determined by WST-1 and 3-D matrigel assays respectively. NSCLC cells over expressed receptor EphA2 and claudin-2. Ephrin-A1 treatment significantly down regulated the claudin-2 and EphA2 expression in NSCLC cells. The transient transfection of cells with vector containing ephrin-A1 construct (pcDNA-EFNA1) decreased the expression of claudin-2, EphA2 when compared to empty vector. In addition ephrin-A1 activation increased cdx-2 expression in A549 cells. In contrast over-expression of EphA2 with plasmid pcDNA-EphA2 up regulated claudin-2 mRNA expression and decreased cdx-2 expression. The transient transfection of cells with vector containing cdx-2 construct (pcMV-cdx-2) decreased the expression of claudin-2 in A549 cells. Moreover, silencing the expression of receptor EphA2 by siRNA significantly reduced claudin-2 expression and decreased cell proliferation and tumor formation. Furthermore, silencing cdx-2 gene expression before ephrin-A1 treatment increased claudin-2 expression along with increased cell proliferation and tumor growth in A549 cells. Our study suggests that EphA2 signaling up-regulates the expression of the TJ-protein claudin-2 that plays an important role in promoting cell proliferation and tumor growth in NSCLC cells. We conclude that receptor EphA2 activation by ephrin-A1 induces tumor suppressor gene cdx-2 expression which attenuates cell proliferation, tumor growth and thus may be a promising therapeutic target against NSCLC.


Three distinct neuronal phenotypes exist in embryonic rat hippocampal neurons cultured in basic fibroblast growth factor.
The possibility that neurons cultured in basic fibroblast growth factor (bFGF) are heterogeneous raises concerns about their subsequent use in gene transfection and transplantation studies. We have examined the fate of embryonic hippocampal neurons in bFGF culture, and now conclude that these cells are not only heterogeneous, but possess neurons of various stages of development. Morphological and immunocytochemical analysis reveal three distinct developmental classes of neurons are present in extended bFGF culture. This tripartite classification is supported by electrophysiological analysis, which reveals that upon depolarization, neurons with precursor and juvenile neuron morphologies are unable to fire action potentials. The third class of neurons, which resemble age-matched polarized neurons in standard serum culture, fired multiple action potentials indicative of a mature phenotype. These data show neurons at multiple developmental stages co-exist in bFGF culture, and provide an experimental basis for their classification.


Medical liability litigation in Saudi Arabia.
The author analyzed the anesthesia medical malpractice closed claims that were referred to the Legal Health Organization (LHO) in order to evaluate the magnitude and underlying factors of the problem in Saudi Arabia. Annual reports covering the period from 1420H-1429H (1999-2008) were statistically analyzed to give mean figures and percentages in each annual report, and then demonstrated all together to run the differential analysis together with the trend along the studied period. Data analysis showed an escalating trend for the total number of claims over the study period being started with 440 cases on 1420H and ended with 1356 cases by the year 1429H. The annual percentage of the final verdicts of accusation to the total number of claims presented to all committees ranges between 45.5%-60.2% with a mean value of 49.9%. Distribution of final verdicts among different clinical specialities showed that obstetrics takes the lead with a mean percentage of 25.5% along the studied period (1420H-1429H), followed by the practice of general surgery with a mean percentage of 13.8%. The sector of health care service showed a significant variation in relation to the mean number of final verdicts with accusation along the studied period, being the highest in the Ministry of Health sector with a mean number of 216.8 claims, followed by the private sector with a mean number of 197.3 claims. Adherence to the standards of medical practice is by far to the best approach to avoid and reduce the incidence of litigation.


Why and how is compassion necessary to provide good quality healthcare?
Recent disclosures of failures of care in the National Health Service (NHS) in England have led to debates about compassion deficits disallowing health professionals to provide high quality responsive care. While the link between high quality care and compassion is often taken for granted, it is less obvious how compassion - often originating in the individual's emotional response - can become a moral sentiment and lead to developing a system of norms and values underpinning ethics of care. In this editorial, I argue why and how compassion might become a foundation of ethics guiding health professionals and a basis for ethics of care in health service organisations. I conclude by discussing a recent case of prominent healthcare failure in the NHS to highlight the relationship between compassion as an aspect of professional ethics on the one hand, and values and norms that institutions and specific policies promote on the other hand.


Recognition of acute delirious mania.
Acute delirious mania as a clinical state was first described over a century ago, yet it is often unrecognized in clinical practice. Typically, the presence of delirium has most often been viewed as organic rather than functional in origin. Three recent cases illustrate the rather dramatic presentation, course, and treatment of such patients. While most often diagnosed as having acute psychotic episodes of organic delirium, these patients generally meet the criteria for a diagnosis of mania with attendant delirium and respond to the standard treatments for mania. Lack of recognition of delirious mania can lead to mismanagement of the short- and long-term courses of the illness.


A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.
Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.


The impact of pretend play on children's development: a review of the evidence.
Pretend play has been claimed to be crucial to children's healthy development. Here we examine evidence for this position versus 2 alternatives: Pretend play is 1 of many routes to positive developments (equifinality), and pretend play is an epiphenomenon of other factors that drive development. Evidence from several domains is considered. For language, narrative, and emotion regulation, the research conducted to date is consistent with all 3 positions but insufficient to draw conclusions. For executive function and social skills, existing research leans against the crucial causal position but is insufficient to differentiate the other 2. For reasoning, equifinality is definitely supported, ruling out a crucially causal position but still leaving open the possibility that pretend play is epiphenomenal. For problem solving, there is no compelling evidence that pretend play helps or is even a correlate. For creativity, intelligence, conservation, and theory of mind, inconsistent correlational results from sound studies and nonreplication with masked experimenters are problematic for a causal position, and some good studies favor an epiphenomenon position in which child, adult, and environment characteristics that go along with play are the true causal agents. We end by considering epiphenomenalism more deeply and discussing implications for preschool settings and further research in this domain. Our take-away message is that existing evidence does not support strong causal claims about the unique importance of pretend play for development and that much more and better research is essential for clarifying its possible role.


The prefrontal cortex modulates category selectivity in human extrastriate cortex.
Different categories of visual objects evoke distinct stimulus-evoked sensory responses in extrastriate visual cortex. Although numerous lines of evidence support a distinct representational neural architecture, the mechanisms underlying the modulation of the category selectivity by top-down influences remains uncertain. In this study, we investigate the causal role of the PFC in the modulation of evoked activity to face and scene stimuli in the extrastriate cortex. We used two experimental approaches to disrupt prefrontal cortical function-repetitive TMS to PFC in healthy participants (Experiment 1) and focal PFC lesions in stroke patients (Experiment 2). After these perturbations to normal PFC function (pre- vs. post-TMS and lesion vs. intact hemisphere), stimulus-evoked activity in extrastriate cortex exhibited less distinct category selectivity to faces and scenes. These two experiments provide convergent evidence highlighting a direct role of PFC in the top-down modulation of bottom-up visual signals.


A Systematic Review of Mindfulness Practices for Improving Outcomes in Chronic Low Back Pain.
Chronic pain is a serious public health problem that affects people of all ages and backgrounds. Mindfulness-based stress reduction (MBSR) techniques offer an accessible treatment modality for chronic pain patients that may complement or replace pharmacological treatment. This article reviews the literature on the efficacy of MBSR training in patients with back chronic pain syndromes for the outcomes of pain measures, quality of life (QOL), mental health, and mindfulness. A systemized search was conducted in September of 2018 for studies published between 2008 and 2018 on mindfulness and chronic low back pain. Out of 50 articles on mindfulness and chronic pain, 12 empirical studies were selected for the inclusion in this review. Subjective pain scores and QOL improved for chronic pain patients after mindfulness interventions, compared to control groups, in most of the studies reviewed. Limitations of the studies reviewed included the varied pain measurement instruments, the small sample sizes, and the inability to blind participants to MBSR intervention. MBSR interventions show significant improvements in chronic pain patients for pain measures, QOL, and mental health.


Exercise and outdoor ambient air pollution.
To establish by literature survey: (a) levels at which air pollutants are considered damaging to human health and to exercisers in particular; (b) the current ambient levels experienced in the United Kingdom; (c) whether athletes are especially at risk. Six major urban air pollutants were examined: carbon monoxide (CO); nitrogen oxides (NO(X)); ozone (O(3)); particulate matter (PM(10)); sulphur dioxide (SO(2)); volatile organic compounds (VOCs). CO is detrimental to athletic performance. NO(2) is of concern to human health, but outdoor levels are low. O(3) poses a potentially serious risk to exercising athletes. Decrements in lung function result from exposure, and there is evidence that athletic performance may be affected. Detrimental effects may occur at low ambient levels, but there is no scientific consensus on this matter. PM(10) is causing concern in the scientific community. Blood lead accumulation during exercise indicates that personal exposure to toxic compounds associated with PM(10) may be magnified. Generally, outdoor ambient levels of SO(2) are too low to cause a problem to the athlete, except the asthmatic athlete. The few studies on exposure of exercisers to VOCs are reviewed. Athletes and exercisers should avoid exercising by the road side even though levels of the more noxious air pollutants have been controlled in the United Kingdom. O(3) is particularly damaging to athletes; it reaches its highest concentrations on hot bright days in rural areas.


Improved systemic delivery of insulin by condensed drug loading in a dimpled suppository.
The development of peptide therapeutics owing to the advances in biotechnology has overcome some unmet medical needs; however, the route of administration is still limited to injections. Systemic delivery of insulin via an enteral route remains a great challenge due to its instability and low mucosal permeability. In this study, we investigated the effect of drug condensation in a suppository on the efficacy of insulin after rectal administration. Suppositories with dimples are prepared by a mold method using a hard fat (Suppocire® AM). Insulin or fluorescein isothiocyanate-dextran (molecular weight: 3,000-5,000) (FD4) as a model of a hydrophilic macromolecule was loaded in the dimples, and sealed with other lipids with different melting points. The in vitro release test showed that the time to 50% drug release depends on the melting point of the lipid for sealing but not on the number of dimples. The suppositories with one-, or three-dimple containing insulin and caprylocaproyl macrogol-8 glyceride (Labrasol®) were administered to rats at 0.5 U/head. The reduction in plasma glucose level was more significant for the one-dimple-type suppository than for the three-dimple-type although the one-dimple-type suppository contained less amount of Labrasol by one-third compared to the three-dimple-type. These results suggest that condensation of an insulin dose in a limited surface area of a suppository improves systemic availability via the rectal route with a reduced amount of an absorption enhancer.


Dopamine signaling through D1-like versus D2-like receptors in the nucleus accumbens core versus shell differentially modulates nicotine reward sensitivity.
Considerable evidence implicates the mesolimbic dopamine (DA) system in the processing of nicotine's reinforcing properties, specifically the ventral tegmental area (VTA) and the terminal fields of VTA DAergic projections to the "core" (NAcore) and "shell" (NAshell) subdivisions of the nucleus accumbens (NAc). However, the specific roles of DA D(1)-like and D(2)-like receptor subtypes in nicotine reward processing within these NAc subregions have not been elucidated. We report that microinfusions of DA D(1)-like or D(2)-like receptor-specific antagonists into NAcore or NAshell double dissociate the rewarding and aversive properties of systemic or intra-VTA nicotine, and differentially regulate sensitivity to the rewarding properties as well as the motivational valence of either intra-VTA or systemic nicotine administration. Using a place conditioning procedure, NAshell infusions of a D(2)-like receptor antagonist switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-reward threshold intra-VTA nicotine doses. In contrast, NAcore infusions of a D(1)-like receptor antagonist switched intra-VTA nicotine aversion to reward, and potentiated reward sensitivity to sub-reward threshold nicotine doses. Thus, D(1)-like versus D(2)-like receptors in NAcore versus NAshell subdivisions play functionally dissociable roles in modulating systemic or intra-VTA nicotine motivational processing.


Transient voltage-dependent potassium currents are reduced in NTS neurons isolated from renal wrap hypertensive rats.
Whole cell patch-clamp measurements were made in neurons enzymatically dispersed from the nucleus of the solitary tract (NTS) to determine if alterations occur in voltage-dependent potassium channels from rats made hypertensive (HT) by unilateral nephrectomy/renal wrap for 4 wk. Some rats had the fluorescent tracer DiA applied to the aortic nerve before the experiment to identify NTS neurons receiving monosynaptic baroreceptor afferent inputs. Mean arterial pressure (MAP) was greater in 4-wk HT (165 +/- 5 mmHg, n = 26, P < 0.001) rats compared with normotensive (NT) rats (109 +/- 3 mmHg measured in 10 of 69 rats). Transient outward currents (TOCs) were observed in 67-82% of NTS neurons from NT and HT rats. At activation voltages from -10 to +10 mV, TOCs were significantly less in HT neurons compared with those observed in NT neurons (P < 0.001). There were no differences in the voltage-dependent activation kinetics, the voltage dependence of steady-state inactivation, and the rise and decay time constants of the TOCs comparing neurons isolated from NT and HT rats. The 4-aminopyridine-sensitive component of the TOC was significantly less in neurons from HT compared with NT rats (P < 0.001), whereas steady-state outward currents, whether or not sensitive to 4-aminopyridine or tetraethylammonium, were not different. Delayed excitation, studied under current clamp, was observed in 60-80% of NTS neurons from NT and HT rats and was not different comparing neurons from NT and HT rats. However, examination of the subset of NTS neurons exhibiting somatic DiA fluorescence revealed that DiA-labeled neurons from HT rats had a significantly shorter duration delayed excitation (n = 8 cells, P = 0.022) than DiA-labeled neurons from NT rats (n = 7 cells). Neurons with delayed excitation from HT rats had a significantly broader first action potential (AP) and a slower maximal downstroke velocity of repolarization compared with NT neurons with delayed excitation (P = 0.016 and P = 0.014, respectively). The number of APs in the first 200 ms of a sustained depolarization was greater in HT than NT neurons (P = 0.012). These results suggest that HT of 4-wk duration reduces TOCs in NTS neurons, and this contributes to reduced delayed excitation and increased AP responses to depolarizing inputs. Such changes could alter baroreflex function in hypertension.


Lens-specific activity of the mouse alpha A-crystallin promoter in the absence of a TATA box: functional and protein binding analysis of the mouse alpha A-crystallin PE1 region.
Lens-specific expression of the mouse alpha A-crystallin gene is regulated at the level of transcription. Here, we have studied the role of the PE1 region, which contains the TATA box (-31/-26) and the immediately adjacent PE1B sequence (-25/-12), in transcriptional regulation. Deletions within either the TATA box or PE1B sequence eliminated promoter activity in transfected lens cells. Surprisingly, these deletions did not eliminate lens-specific promoter activity of the transgene of transgenic mice. Transcription of the transgene with a TATA-deleted promoter initiated at multiple sites in the lenses of the transgenic mice. Footprint analysis revealed that the entire PE1 region was protected by nuclear extracts prepared from lens cells which express the alpha A-crystallin gene and from fibroblasts which do not express the gene. The -37/+3 region formed three specific EMSA complexes using lens cell nuclear extracts, while a similar but much less intense pattern was observed when a fibroblast nuclear extract was used. Competition experiments indicated that these complexes were not due to the binding of TBP to the TATA box, but rather to the binding of other nuclear proteins to the PE1B -25/-19 region. A series of co-transfection competition studies in vivo also suggested the functional importance of proteins binding in the -25/-19 region. The PE1B protein-DNA interactions appear to be conserved in the chicken, rodent and human alpha A-crystallin gene as well as within the alpha A- and alpha B-crystallin genes in the mouse. Our findings indicate that the PE1B region is important for mouse alpha A-crystallin promoter activity; the proximity of this site to the TATA box raises the possibility for cooperativity or competition between TBP and PE1B-bound proteins.


First Report of Brown Rot on Crataegus pinnatifida var. major Caused by Monilia yunnanensis in China.
Crataegus pinnatifida Bge. var. major N. is a time-honored herbal medicine and an important economic fruit that is processed into various foods. Cultivated fields are mostly situated in northern China. In August 2012, a fruit brown rot disease on mature plants was found in Fushun, Liaoning Province, China. This disease reduced the yield and the quality of fruits; the incidence of fruits affected in each tree was between 20% and 35%. The initial stage of infection was marked by regular or irregular light brown spots turning dark brown and gradually supporting many grey fluffy tufts of mycelium. At last, the lesions expanded, causing the fruits to become rotted or withered. The pathogen was isolated from infected fruits by a tissue isolation method (1) and cultured on potato dextrose agar (PDA) at 25°C under 12 h light/12 h dark for 7 days. The colonies reached 60 to 75 mm in diameter after 7 days and were pale green or pale yellow with a neat greyish white margin; the aerial mycelium sometimes formed annulations. The conidia were single, hyaline, lemon-shaped or oval, and 11.3 ± 1.4 (8.0 to 16.5) × 6.4 ± 0.8 (5.1 to 7.6) μm; sporulation was sparse and stromata that formed after 15 days were abundant, black, and spherical to elliptical in shape. Conidiophores were simple or branched, bearing a single conidium on the tip. The internal transcribed spacer (ITS) region of rDNA amplified with primers ITS1 and ITS4 was directly sequenced in both directions. The ITS1-5.8S-ITS2 sequence of rDNA was 100% identical to Monilinia yunnanensis (GenBank Accession No. HQ908788.1), which is distinguished from the closely related M. fructigena (AF150679.1) and M. polystroma (JX315717.1). The pathogen was identified as M. yunnanensis on the basis of morphological characteristics (2) and the ITS sequence of rDNA (2,3). Pathogenicity tests were performed on detached healthy fruits. Four fruits were wounded with a sterilized nail and inoculated by placing a PDA plug of mycelia on upper surfaces of the fruits. Another four fruits treated with sterile PDA plugs served as a control. Fruits were cultured in petri dishes with a 12-h photoperiod at 25°C and 90% relative humidity. The initial symptoms on inoculated fruits were observed after 5 days, while no symptoms showed on the controls. The pathogen was reisolated from the inoculated fruit and identified as M. yunnanensis by the above methods. While M. yunnanensis has been reported to cause brown rot on peach (2), to our knowledge, this is the first report of M. yunnanensis infecting C. pinnatifida Bge. var. major N. in China. References: (1) Z. D. Fang. Research Methods of Plant Disease, 1998. (2) M. J. Hu et al. Monilinia species causing brown rot of peach in China. PLoS ONE. Online publication. doi:10.1371/journal.pone.0024990, 2011. (3) G. C. M. van Leeuwen et al. Mycol. Res. 106:444, 2002.


Peripheral blood gene expression changes during allergen inhalation challenge in atopic asthmatic individuals.
(1) To investigate the effects of globin mRNA depletion in detecting differential gene expression in peripheral blood and (2) to investigate changes in peripheral blood gene expression in atopic asthmatic individuals undergoing allergen inhalation challenge. Asthmatic subjects (20-60 years of age, with stable, mild allergic asthma, n = 9) underwent allergen inhalation challenges. All had an early asthmatic response of ≥20% fall in forced expiratory volume in 1 second. Blood was collected immediately prior to and 2 hours after allergen challenge using PAXgene tubes (n = 4) and EDTA tubes (n = 5). Aliquots of the PAXgene blood samples were subjected to globin reduction (PAX-GR). Transcriptome analysis was performed using Affymetrix GeneChip(®) Human Gene 1.0 ST arrays. Data were preprocessed using factor analysis for robust microarray summarization and analyzed using linear models for microarrays. Pathway analyses were performed using Ingenuity Pathway Analysis. Globin reduction uncovered probe sets of lower abundance. However, it significantly reduced the ability to detect differentially expressed genes (DEGs) when compared to non-globin-reduced PAXgene samples (PAX-NGR). Combined transcriptional analysis of four PAX-NGR and five EDTA sample pairs identified 1595 DEGs associated with allergen inhalation challenge (false discovery rate ≤ 5%), with the top-ranked network of perturbed biological functions consisting of inflammatory response, cellular movement, and immune cell trafficking. While we have demonstrated a diminished ability to detect DEGs after globin reduction, we have nevertheless identified significant changes in the peripheral blood transcriptome of people with mild asthma 2 hours after allergen inhalation challenge.


In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.
Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.


An essential domain of the c-myc protein interacts with a nuclear factor that is also required for E1A-mediated transformation.
Cell transformation by nuclear oncogenes such as c-myc presumably involves the transcriptional activation of a set of target genes that participate in the control of cell division. The function of a small evolutionarily conserved domain of the c-myc gene encompassing amino acids 129 to 145 was analyzed to explore the relationship between cell transformation and transcriptional activation. Deletion of this domain inactivated the c-myc oncogene for cell transformation while retaining the ability to activate transcription of either myc consensus binding sites or a GAL4-dependent promoter when the c-myc N-terminus was fused to the GAL4 DNA-binding domain. Point mutations that altered a conserved tryptophan (amino acid 136) within this domain had similar effects. Expression of the wt c-Myc N terminus (amino acids 1 to 262) as a GAL4 fusion was a dominant inhibitor of cell transformation by the c-myc oncogene, and this same domain also inhibited transformation by the adenovirus E1A gene. Surprisingly, deletion of amino acids 129 to 145 eliminated the dominant negative activity of GAL4-Myc on both c-myc and E1A transformation. Expression of the GAL4-Myc protein in Cos cells led to the formation of a specific complex between the Myc N terminus and a nuclear factor, and this complex was absent with the dl129-145 mutant. These results suggest that an essential domain of the c-Myc protein interacts with a specific nuclear factor that is also required for E1A transformation.


Renal adaptation and gut hormone release during sodium restriction in ileostomized man.
The renal excretion of water, electrolytes, aldosterone and kallikrein was monitored in 12 ileostomized patients before and during sodium deprivation. Changes in plasma renin activity (PRA), plasma aldosterone and plasma arginine vasopressin (AVP) concentrations were measured, together with aldosterone in ileal fluid. The pattern of gut peptide release in response to a test meal was also examined to assess whether a circulating gut peptide might be involved in the renal adaptation to sodium restriction, and compared with healthy normal subjects who were under no dietary constraint. In each patient renal sodium excretion fell within 8-12 h of sodium deprivation and was associated with a prompt and significant rise in PRA; much later increases in plasma aldosterone concentration and renal aldosterone excretion occurred, and were established by day 2 of sodium restriction. No consistent change in renal kallikrein excretion was found. Ileal sodium loss was little changed by sodium deprivation, but ileal potassium concentration rose steadily and became significantly correlated with PRA, and to a lesser extent with renal aldosterone excretion. Of the gut peptides measured in plasma, only the insulin profile was altered by sodium deprivation, with an increase in the test meal response; insulin has previously been shown to have a significant antinatriuretic action at physiological concentrations. Plasma levels of pancreatic polypeptide and motilin were increased in ileostomized patients when compared with normal subjects, but were unaffected by the change to a low sodium diet. An early increase in urine flow and water diuresis occurred during sodium deprivation, following a cyclical pattern with peaks each evening.(ABSTRACT TRUNCATED AT 250 WORDS)


Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).
Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.


Differential use of warfarin for secondary stroke prevention in patients with various types of atrial fibrillation.
Anticoagulation therapy significantly reduces the incidence of thromboembolic events in patients with atrial fibrillation (AF), and warfarin therapy at discharge is a class I-indicated drug in patients with ischemic stroke with persistent or paroxysmal AF without contraindications. The aim was to determine whether participation in the Get With The Guidelines-Stroke (GWTG-S) quality improvement program would be associated with improved adherence to anticoagulation guidelines for patients with all types of AF. Adherence to warfarin treatment at hospital discharge was assessed in eligible patients with AF who presented with stroke or transient ischemic attack, based on type of AF. Of patients with stroke, 10.5% presented with some form of AF. When AF was documented using electrocardiography or telemetry (ECG) during the present admission, eligible patients were more likely to receive warfarin compared with patients for whom AF was reported using medical history only (78.8% vs 49.4%; p<0.0001). Improvement after GWTG-S participation in warfarin use was observed in patients with ECG-documented AF (73.8% at baseline vs 88.5% after the intervention; p<0.0001), but not patients using history only. Women and elderly patients were less likely to receive warfarin, and these gaps in treatment did not narrow during the quality improvement program for patients with ECG-documented AF and those with history only. In conclusion, anticoagulation for stroke prevention was underused in general for patients with AF, even in such high-risk groups as patients with stroke. GWTG-S was associated with improved adherence for patients with ECG-documented AF, but patients with a history of AF alone were largely untreated.


Dispositional Mindfulness Mediates the Relationship Between Sensory-Processing Sensitivity and Trait Anxiety, Well-Being, and Psychosomatic Symptoms.
Recent studies have suggested that sensory-processing sensitivity correlates to poor psychological and physical health. However, it remains unclear how this occurs. Sensory-processing sensitivity can be understood as sensitivity to sensations without the presence of intentional awareness and a nonreactive attitude, which are the components of mindfulness. We tested the hypothesis that dispositional mindfulness mediates the relationship between sensory-processing sensitivity and trait anxiety, well-being and psychosomatic symptoms. We analyzed data from 563 participating young adults living in Japan. Multiple mediation analysis showed that the four facets (nonreactivity, nonjudging, describing, and acting with awareness) of mindfulness partially mediated the effects of sub-factors of sensory-processing sensitivity (low sensory threshold and ease of excitation) on trait anxiety. Nonreactivity, describing, and acting with awareness partially mediated the effect of low sensory threshold on well-being and fully mediated the effect of ease of excitation. Nonjudging and acting with awareness partially mediated the effects of low sensory threshold and ease of excitation on psychosomatic symptoms. As a whole, the mediation hypotheses were supported, and it was determined that the improvement of dispositional mindfulness may prove effective for the psychological and physical problems of people with high sensory-processing sensitivity.


To give or not to give: Approaches to early childhood immunization delivery in Oregon rural primary care practices.
Little is known about rural clinicians' perspectives regarding early childhood immunization delivery, their adherence to recommended best immunization practices, or the specific barriers they confront. To examine immunization practices, beliefs, and barriers among rural primary care clinicians for children in Oregon and compare those who deliver all recommended immunizations in their practices with those who do not. A mailed questionnaire was sent to all physicians, nurse practitioners, and physician assistants practicing primary care in rural communities throughout Oregon. While 39% of rural clinicians reported delivering all childhood immunizations in their clinic, 43% of clinicians reported that they refer patients elsewhere for some vaccinations, and 18% provided no immunizations in the clinic whatsoever. Leading reasons for referral include inadequate reimbursement, parental request, and storage and stocking difficulties. Nearly a third of respondents reported that they had some level of concern about the safety of immunizations, and 14% reported that concerns about safety were a specific reason for referring. Clinicians who delivered only some of the recommended immunizations were less likely than nonreferring clinicians to have adopted evidence-based best immunization practices. This study of rural clinicians in Oregon demonstrates the prevalence of barriers to primary care based immunization delivery in rural regions. While some barriers may be difficult to overcome, others may be amenable to educational outreach and support. Thus, efforts to improve population immunization rates should focus on promoting immunization "best practices" and enhancing the capacity of practices to provide immunizations and ensuring that any alternative means of delivering immunizations are effective.


Regulation of nonspecific acid phosphatase in Salmonella: phoN and phoP genes.
Mutations in Salmonella typhimurium strains lacking nonspecific acid phosphatase mapped in two unlinked loci. One of these, phoP, was cotransducible by phage P22 with purB, whereas the second, phoN, was cotransducible by phage P1 with purA. Mutants with temperature-sensitive nonspecific acid phosphatase activity (measured in whole cells) were also isolated. A phoN mutant with thermolabile whole-cell activity was isolated directly from wild-type LT-2. Several other mutants with temperature-sensitive enzyme activity were also isolated as revertants of phoN mutants. These data suggest that phoN might be a structural locus for nonspecific acid phosphatase. The observation that a mutation resulting in high level of nonspecific acid phosphatase mapped in phoP suggests a possible regulatory role for this locus.


The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibition.
Inhibition of BET bromodomains (BRDs) has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP (both long and short forms) levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL-induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c-FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination.


Hetastarch co-loading is as effective as pre-loading for the prevention of hypotension following spinal anesthesia for cesarean delivery.
Pre-loading with hetastarch decreases the incidence and severity of hypotension after spinal anesthesia for cesarean delivery. However, pharmacokinetic studies with crystalloid predict that fluid loading should be more efficacious if rapidly administered immediately after induction of spinal anesthesia. The aim of this study was to compare pre- and co-loading of hetastarch for the prevention of hypotension following spinal anesthesia for cesarean delivery. Forty-six healthy term parturients scheduled for cesarean delivery were randomized to receive 500 mL of 6% hetastarch intravenously, either slowly before spinal anesthesia (pre-loading) or as quickly as possible immediately after spinal anesthesia (co-loading). Systolic blood pressure was maintained at or above 90% of baseline with intravenous vasopressor boluses (ephedrine 5mg/mL+phenylephrine 25 microg/mL). The primary outcome was the volume of vasopressor mix required. Secondary outcomes included blood pressure and heart rate changes, time to first vasopressor use, nausea or vomiting, and neonatal outcomes (umbilical artery and vein pH, Apgar scores). The pre-loading group used 3.5+/-2 mL (mean+/-SD) of vasopressor mixture compared with 3.2+/-3 mL in the co-loading group (P=0.6). There were no differences in any important maternal hemodynamic or neonatal outcome values between the two study groups. Hetastarch co-loading is as effective as pre-loading for the prevention of hypotension after spinal anesthesia for cesarean delivery. Surgery need not be delayed to allow a predetermined pre-load to be administered before induction of spinal anesthesia.


HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion.
The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20-30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demonstrated by in vitro mammosphere assays and the expression of stem cell marker aldehyde dehydrogenase (ALDH) as well as by generation of hyperplastic lesions in humanized fat pads of NOD (nucleotide-binding oligomerization domain)/SCID (severe combined immunodeficient) mice. Overexpression of HER2 in a series of breast carcinoma cell lines increases the ALDH-expressing 'cancer stem cell' population which displays increased expression of stem cell regulatory genes, increased invasion in vitro and increased tumorigenesis in NOD/SCID mice. The effects of HER2 overexpression on breast cancer stem cells are blocked by trastuzumab in sensitive, but not resistant, cell lines, an effect mediated by the PI3-kinase/Akt pathway. These studies provide support for the cancer stem cell hypothesis by suggesting that the effects of HER2 amplification on carcinogenesis, tumorigenesis and invasion may be due to its effects on normal and malignant mammary stem/progenitor cells. Furthermore, the clinical efficacy of trastuzumab may relate to its ability to target the cancer stem cell population in HER2-amplified tumors.


Formulation effects of topical emulsions on transdermal and dermal delivery.
It has been recognized that the vehicle in which a permeant is applied to the skin has a distinctive effect on the dermal and transdermal delivery of active ingredients. The cutaneous and percutaneous absorptions can be enhanced, e.g. by an increase in thermodynamic activity, supersaturation and penetration modifiers. Furthermore, dermal and transdermal delivery can be influenced by the interactions that may occur between the vehicle and the skin on the one hand, and interactions between the active ingredient and the skin on the other hand. Emulsions are widely used as cosmetic and pharmaceutical formulations because of their excellent solubilizing capacities for lipophilic and hydrophilic active ingredients and application acceptability. This review focuses, in particular, on the effect of emulsions on the dermal and transdermal delivery of active ingredients. It is shown that the type of emulsion (w/o vs. o/w emulsion), the droplet size, the emollient, the emulsifier as well as the surfactant organization (micelles, lyotropic liquid crystals) in the emulsion may affect the cutaneous and percutaneous absorption. Examples substantiate the fact that emulsion constituents such as emollients and emulsifiers should be selected carefully for optimal efficiency of the formulation. Moreover, to understand the influence of emulsion on dermal and transdermal delivery, the physicochemical properties of the formulation after application are considered.


Nature-Based Interventions for Improving Health and Wellbeing: The Purpose, the People and the Outcomes.
Engagement with nature is an important part of many people's lives, and the health and wellbeing benefits of nature-based activities are becoming increasingly recognised across disciplines from city planning to medicine. Despite this, urbanisation, challenges of modern life and environmental degradation are leading to a reduction in both the quantity and the quality of nature experiences. Nature-based health interventions (NBIs) can facilitate behavioural change through a somewhat structured promotion of nature-based experiences and, in doing so, promote improved physical, mental and social health and wellbeing. We conducted a Delphi expert elicitation process with 19 experts from seven countries (all named authors on this paper) to identify the different forms that such interventions take, the potential health outcomes and the target beneficiaries. In total, 27 NBIs were identified, aiming to prevent illness, promote wellbeing and treat specific physical, mental or social health and wellbeing conditions. These interventions were broadly categorized into those that change the environment in which people live, work, learn, recreate or heal (for example, the provision of gardens in hospitals or parks in cities) and those that change behaviour (for example, engaging people through organized programmes or other activities). We also noted the range of factors (such as socioeconomic variation) that will inevitably influence the extent to which these interventions succeed. We conclude with a call for research to identify the drivers influencing the effectiveness of NBIs in enhancing health and wellbeing.


Patient-cost survey for tuberculosis in the context of patient-pathway modelling.
SETTING: Eight tuberculosis treatment sites in Cavite Province, the Philippines, including two sites specialising in management of multidrug-resistant tuberculosis (MDR-TB).OBJECTIVE: To evaluate costs incurred by TB patients and to determine the proportion of households that faced catastrophic costs, then to consider cost survey responses alongside results of detailed patient-pathway modelling.DESIGN: Clustered cross-sectional survey using a field testing version of the WHO TB patient-costing tool and protocol; face-to-face interviews with 194 patients conducted in May-August 2016. Costs included direct-medical, direct non-medical and indirect costs using the human capital approach. Patients were deemed to incur catastrophic expenditure if TB-related costs exceeded 20% of annual household income. Patient pathways were modelled following multiple health staff interviews.RESULTS: Estimated mean cost incurred by patients with drug-susceptible TB was US$321 vs. $2356 for MDR-TB patients. Catastrophic costs were suffered by 28% of drug-susceptible and 80% of MDR-TB patients, with lost income being the largest contributor. Patient-pathway modelling suggested most patients had under-reported health visits.CONCLUSION: Survey results indicate that patient costs are large for all patients in Cavite, particularly for MDR-TB patients. Patient-pathway modelling suggests these costs are an underestimate due to poor recollection of health visits, suggesting that the WHO instrument and protocol could be improved to better capture the diagnostic journey.


Chitosan nanoparticles show rapid extrapulmonary tissue distribution and excretion with mild pulmonary inflammation to mice.
Pulmonary delivery of nanoparticles (NP) conjugated with therapeutic agents has been considered recently for both lung disorders and systemic circulation. Hydrophobically modified glycol chitosan (HGC) NP have previously shown excellent deposition to the tumor site and non-destructive intracellular release. Here, we evaluated the kinetics and toxicity of HGC NP by intratracheal instillation to mice. HGC NP showed a positive charge and average hydrodynamic size was around 350 nm. The half-life of NP in the lung was determined as 131.97±50.51 h. NP showed rapid uptake into systemic circulation and excretion via urine which was peaked at 6h after instillation. Although HGC NP were distributed to several extrapulmonary organs, the levels were extremely low and transient. HGC NP induced transient neutrophilic pulmonary inflammation from 6h to day 3 after instillation. Expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and chemokine (MIP-1α) in lung showed an increase from 1h to 24h after instillation and recovered thereafter. Our findings suggest that HGC NP can be successful candidates for use as pulmonary delivery vehicles, owing to their excellent biocompatibility, transiency, and low pulmonary toxicity, and property of rapid elimination without accumulation.


Virus-induced atherosclerosis.
Of four groups of chickens, two (groups I and II) were infected with MDV and two were not (groups III and IV). Groups I and III were fed diets low in lipid, and groups II and IV were fed cholesterol-supplemented diets. Striking grossly visible atherosclerotic lesions were seen in large coronary arteries, aortas, and major aortic branches of infected normocholesterolemic and hypercholesterolemic chickens (groups I and II). In contrast, grossly visible atherosclerotic lesions were not seen in uninfected normocholesterolemic chickens (group III), nor in uninfected hypercholesterolemic chickens (group IV). Microscopically, arterial changes in the infected animals were characterized by occlusive fibromuscular intimal thickening which formed fibrous caps overlying areas of atheromatous change. This change closely resembled chronic atherosclerosis in man. These results may have important bearing on our understanding of the etiology and pathogenesis of human arteriosclerosis since there is widespread and persistent infection of human populations with up to five different herpes-viruses.


Vibrational solvatochromism and electrochromism: coarse-grained models and their relationships.
A theoretical description of vibrational solvatochromism and electrochromism is presented by using a coarse-grained model based on a distributed charge and multipole interaction theory. Solvatochromic frequency shift has been described by considering the interaction between distributed charges of a solute and electrostatic potential due to distributed charges of solvent molecules. Another approach was based on the expansion of the solvatochromic frequency shift in terms of solvent electric field and its gradient at distributed sites on solute. The relationship between these two approaches is elucidated and their validities are discussed. It is also shown that the distributed charge and multipole model for solvatochromism developed here can be used to describe vibrational Stark effects on frequency and transition dipole moment. The relationship between the vibrational Stark tuning rate and the parameters obtained from recent vibrational solvatochromism studies is clarified and used to determine the vibrational Stark tuning rates of a few stretching modes, which are then directly compared with experimentally measured values. We anticipate that the present theoretical model can be used to study a variety of vibrational solvatochromic and electrochromic phenomena and to extract critical information on local electrostatic environment around a small IR probe in solution or protein from linear and nonlinear IR spectroscopic studies.


Learning patterns of the ageing brain in MRI using deep convolutional networks.
Both normal ageing and neurodegenerative diseases cause morphological changes to the brain. Age-related brain changes are subtle, nonlinear, and spatially and temporally heterogenous, both within a subject and across a population. Machine learning models are particularly suited to capture these patterns and can produce a model that is sensitive to changes of interest, despite the large variety in healthy brain appearance. In this paper, the power of convolutional neural networks (CNNs) and the rich UK Biobank dataset, the largest database currently available, are harnessed to address the problem of predicting brain age. We developed a 3D CNN architecture to predict chronological age, using a training dataset of 12,802 T1-weighted MRI images and a further 6,885 images for testing. The proposed method shows competitive performance on age prediction, but, most importantly, the CNN prediction errors ΔBrainAge=AgePredicted-AgeTrue correlated significantly with many clinical measurements from the UK Biobank in the female and male groups. In addition, having used images from only one imaging modality in this experiment, we examined the relationship between ΔBrainAge and the image-derived phenotypes (IDPs) from all other imaging modalities in the UK Biobank, showing correlations consistent with known patterns of ageing. Furthermore, we show that the use of nonlinearly registered images to train CNNs can lead to the network being driven by artefacts of the registration process and missing subtle indicators of ageing, limiting the clinical relevance. Due to the longitudinal aspect of the UK Biobank study, in the future it will be possible to explore whether the ΔBrainAge from models such as this network were predictive of any health outcomes.


The HP0256 gene product is involved in motility and cell envelope architecture of Helicobacter pylori.
Helicobacter pylori is the causative agent for gastritis, and peptic and duodenal ulcers. The bacterium displays 5-6 polar sheathed flagella that are essential for colonisation and persistence in the gastric mucosa. The biochemistry and genetics of flagellar biogenesis in H. pylori has not been fully elucidated. Bioinformatics analysis suggested that the gene HP0256, annotated as hypothetical, was a FliJ homologue. In Salmonella, FliJ is a chaperone escort protein for FlgN and FliT, two proteins that themselves display chaperone activity for components of the hook, the rod and the filament. Ablation of the HP0256 gene in H. pylori significantly reduced motility. However, flagellin and hook protein synthesis was not affected in the HP0256 mutant. Transmission electron transmission microscopy revealed that the HP0256 mutant cells displayed a normal flagellum configuration, suggesting that HP0256 was not essential for assembly and polar localisation of the flagella in the cell. Interestingly, whole genome microarrays of an HP0256 mutant revealed transcriptional changes in a number of genes associated with the flagellar regulon and the cell envelope, such as outer membrane proteins and adhesins. Consistent with the array data, lack of the HP0256 gene significantly reduced adhesion and the inflammatory response in host cells. We conclude that HP0256 is not a functional counterpart of FliJ in H. pylori. However, it is required for full motility and it is involved, possibly indirectly, in expression of outer membrane proteins and adhesins involved in pathogenesis and adhesion.


Enhancement of 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced HL-60 leukemia cell differentiation by Panax ginseng.
Ginseng (Panax ginseng C.A. Meyer) has a wide range of therapeutic uses including cancer treatment. Human promyelocytic leukemia cells differentiate into monocytes or granulocytes when treated with 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (ATRA). Treatment of HL-60 cells with zero to 100 microg/ml of a methanol extract of ginseng for 72 h induced a small increase in cell differentiation. Surprisingly, a synergistic induction of differentiation was observed when HL-60 cells were treated with ATRA or 1,25-(OH)(2)D(3) and the extract. The inhibitors of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), but not of phosphoinositide 3-kinase (PI3-K), inhibited the HL-60 differentiation induced by the extract in combination with ATRA or 1,25-(OH)(2)D(3), signifying that PKC and ERK were involved in the cell differentiation enhancement by the extract. These results suggest that the ability of a methanol extract of ginseng to enhance the differentiation potential of ATRA or 1,25-(OH)(2)D(3) may improve the ultimate outcome of acute promyelocytic leukemia therapy.


Cytokine expression and lymphocyte proliferative capacity in diseased harbor porpoises (Phocoena phocoena) - Biomarkers for health assessment in wildlife cetaceans.
Harbor porpoises (Phocoena phocoena) in the North and Baltic Seas are exposed to anthropogenic influences including acoustic stress and environmental contaminants. In order to evaluate immune responses in healthy and diseased harbor porpoise cells, cytokine expression analyses and lymphocyte proliferation assays, together with toxicological analyses were performed in stranded and bycaught animals as well as in animals kept in permanent human care. Severely diseased harbor porpoises showed a reduced proliferative capacity of peripheral blood lymphocytes together with diminished transcription of transforming growth factor-β and tumor necrosis factor-α compared to healthy controls. Toxicological analyses revealed accumulation of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyltrichloroethane (DDT) in harbor porpoise blood samples. Correlation analyses between blood organochlorine levels and immune parameters revealed no direct effects of xenobiotics upon lymphocyte proliferation or cytokine transcription, respectively. Results reveal an impaired function of peripheral blood leukocytes in severely diseased harbor porpoises, indicating immune exhaustion and increased disease susceptibility.


A combined score test for binary and ordinal endpoints from clinical trials.
There is growing interest, especially for trials in stroke, in combining multiple endpoints in a single clinical evaluation of an experimental treatment. The endpoints might be repeated evaluations of the same characteristic or alternative measures of progress on different scales. Often they will be binary or ordinal, and those are the cases studied here. In this paper we take a direct approach to combining the univariate score statistics for comparing treatments with respect to each endpoint. The correlations between the score statistics are derived and used to allow a valid combined score test to be applied. A sample size formula is deduced and application in sequential designs is discussed. The method is compared with an alternative approach based on generalized estimating equations in an illustrative analysis and replicated simulations, and the advantages and disadvantages of the two approaches are discussed.