Executive Summary of the American Radium Society Appropriate Use Criteria for Local Excision in Rectal Cancer.
The goal of treatment for early stage rectal cancer is to optimize oncologic outcome while minimizing effect of treatment on quality of life. The standard of care treatment for most early rectal cancers is radical surgery alone. Given the morbidity associated with radical surgery, local excision for early rectal cancers has been explored as an alternative approach associated with lower rates of morbidity. The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines for the use of local excision in early stage rectal cancer that include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) used by a multidisciplinary expert panel to rate the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. These guidelines are intended for the use of all practitioners and patients who desire information regarding the use of local excision in rectal cancer.


Targeted RNA sequencing reveals the deep complexity of the human transcriptome.
Transcriptomic analyses have revealed an unexpected complexity to the human transcriptome, whose breadth and depth exceeds current RNA sequencing capability. Using tiling arrays to target and sequence select portions of the transcriptome, we identify and characterize unannotated transcripts whose rare or transient expression is below the detection limits of conventional sequencing approaches. We use the unprecedented depth of coverage afforded by this technique to reach the deepest limits of the human transcriptome, exposing widespread, regulated and remarkably complex noncoding transcription in intergenic regions, as well as unannotated exons and splicing patterns in even intensively studied protein-coding loci such as p53 and HOX. The data also show that intermittent sequenced reads observed in conventional RNA sequencing data sets, previously dismissed as noise, are in fact indicative of unassembled rare transcripts. Collectively, these results reveal the range, depth and complexity of a human transcriptome that is far from fully characterized.


H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression.
The human bacterial pathogen Helicobacter pylori exhibits genotoxic properties that promote gastric carcinogenesis. H. pylori introduces DNA double strand breaks (DSBs) in epithelial cells that trigger host cell DNA repair efforts. Here, we show that H. pylori-induced DSBs are repaired via error-prone, potentially mutagenic non-homologous end-joining. A genome-wide screen for factors contributing to DSB induction revealed a critical role for the H. pylori type IV secretion system (T4SS). Inhibition of transcription, as well as NF-κB/RelA-specific RNAi, abrogates DSB formation. DSB induction further requires β1-integrin signaling. DSBs are introduced by the nucleotide excision repair endonucleases XPF and XPG, which, together with RelA, are recruited to chromatin in a highly coordinated, T4SS-dependent manner. Interestingly, XPF/XPG-mediated DNA DSBs promote NF-κB target gene transactivation and host cell survival. In summary, H. pylori induces XPF/XPG-mediated DNA damage through activation of the T4SS/β1-integrin signaling axis, which promotes NF-κB target gene expression and host cell survival.


An integrative framework for Bayesian variable selection with informative priors for identifying genes and pathways.
The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS) framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS) g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed.


A systematic review of the benefits of physical therapy within a multidisciplinary care approach for people with schizophrenia: An update.
This systematic review summarizes the most recent evidence from randomized controlled trials (RCTs) considering the effectiveness of physical therapy interventions (aerobic exercises, strength exercises, relaxation training, basic body awareness exercises, or a combination of these) within the multidisciplinary management of schizophrenia. Two authors searched PubMed, PsycINFO, EMBASE, Web of Science, Physiotherapy Evidence Database (PEDro), and the Cochrane Library considering RCTs published from July 1, 2011-October 1, 2014. Thirteen RCTs representing 549 participants met the inclusion criteria. Overall, the results demonstrate that aerobic exercise significantly reduces psychiatric symptoms, potentially improves mental and physical quality of life and reduces metabolic risk and weight. Specifically, yoga reduces psychiatric symptoms, whilst Tai-chi and progressive muscle relaxation may also have benefits to patients. Two RCTs reported on adverse events. No adverse event was observed supporting the notion that physical therapy is safe in people with schizophrenia. There was considerable heterogeneity in the design, implementation and outcomes in the included studies precluding a meaningful meta-analysis. In general, the quality of physical therapy RCTS is improving and current research demonstrates that physical therapy approaches are valuable interventions and can help improve the psychiatric, physical and quality of life of people with schizophrenia.


Collagen metabolism and reversal of aortic medial hypertrophy in spontaneously hypertensive rats treated with methyldopa.
Collagen synthesis, content, and concentration were determined in the hypertrophied intima media of thoracic aortas from 10-, 15-, and 20-week-old spontaneously hypertensive rats (SHR). Although the rates of aortic collagen synthesis declined with age, the dry weight of the intima media and the total collagen content increased proportionally. Collagen concentration thus remained unchanged. Methyldopa was administered orally to SHR when they were 12 to 15 weeks of age, when their body weight were identical to the untreated group. Blood pressure and the degree of aortic medial hypertrophy, judged by medial dry weight per kilogram body weight, were significantly lower compared with untreated SHR. Collagen synthesis was likewise decreased to a mean rate not significantly higher than age-matched normotensive Wistar-Kyoto controls. This reduction in collagen synthesis, however, was not sufficient to decrease measurably the total collagen content of the aortas compared with untreated SHR. Since medial dry weights were lower in the treated rats, collagen concentration in aortas from SHR given methyldopa for 3 weeks was actually increased. The increase in collagen concentration also suggests that medial hypertrophy was reversed.


Mapping the genetic and tissular diversity of 64 phenolic compounds in Citrus species using a UPLC-MS approach.
Phenolic compounds contribute to food quality and have potential health benefits. Consequently, they are an important target of selection for Citrus species. Numerous studies on this subject have revealed new molecules, potential biosynthetic pathways and linkage between species. Although polyphenol profiles are correlated with gene expression, which is responsive to developmental and environmental cues, these factors are not monitored in most studies. A better understanding of the biosynthetic pathway and its regulation requires more information about environmental conditions, tissue specificity and connections between competing sub-pathways. This study proposes a rapid method, from sampling to analysis, that allows the quantitation of multiclass phenolic compounds across contrasting tissues and cultivars. Leaves and fruits of 11 cultivated citrus of commercial interest were collected from adult trees grown in an experimental orchard. Sixty-four phenolic compounds were simultaneously quantified by ultra-high-performance liquid chromatography coupled with mass spectrometry. Combining data from vegetative tissues with data from fruit tissues improved cultivar classification based on polyphenols. The analysis of metabolite distribution highlighted the massive accumulation of specific phenolic compounds in leaves and the external part of the fruit pericarp, which reflects their involvement in plant defence. The overview of the biosynthetic pathway obtained confirmed some regulatory steps, for example those catalysed by rhamnosyltransferases. The results suggest that three other steps are responsible for the different metabolite profiles in 'Clementine' and 'Star Ruby' grapefruit. The method described provides a high-throughput method to study the distribution of phenolic compounds across contrasting tissues and cultivars in Citrus, and offers the opportunity to investigate their regulation and physiological roles. The method was validated in four different tissues and allowed the identification and quantitation of 64 phenolic compounds in 20 min, which represents an improvement over existing methods of analysing multiclass polyphenols.


Cannabinoids and Opioids in the Treatment of Inflammatory Bowel Diseases.
In traditional medicine, Cannabis sativa has been prescribed for a variety of diseases. Today, the plant is largely known for its recreational purpose, but it may find a way back to what it was originally known for: a herbal remedy. Most of the plant's ingredients, such as Δ-tetrahydrocannabinol, cannabidiol, cannabigerol, and others, have demonstrated beneficial effects in preclinical models of intestinal inflammation. Endogenous cannabinoids (endocannabinoids) have shown a regulatory role in inflammation and mucosal permeability of the gastrointestinal tract where they likely interact with the gut microbiome. Anecdotal reports suggest that in humans, Cannabis exerts antinociceptive, anti-inflammatory, and antidiarrheal properties. Despite these reports, strong evidence on beneficial effects of Cannabis in human gastrointestinal diseases is lacking. Clinical trials with Cannabis in patients suffering from inflammatory bowel disease (IBD) have shown improvement in quality of life but failed to provide evidence for a reduction of inflammation markers. Within the endogenous opioid system, mu opioid receptors may be involved in anti-inflammation of the gut. Opioids are frequently used to treat abdominal pain in IBD; however, heavy opioid use in IBD is associated with opioid dependency and higher mortality. This review highlights latest advances in the potential treatment of IBD using Cannabis/cannabinoids or opioids.


Patients with brain contusions: predictors of outcome and relationship between radiological and clinical evolution.
Traumatic parenchymal mass lesions are common sequelae of traumatic brain injuries (TBIs). They occur in up to 8.2% of all TBI cases and 13%-35% of severe TBI cases, and they account for up to 20% of surgical intracranial lesions. Controversy exists concerning the association between radiological and clinical evolution of brain contusions. The aim of this study was to identify predictors of unfavorable outcome, analyze the evolution of brain contusions, and evaluate specific indications for surgery. In a retrospective, multicenter study, patients with brain contusions were identified in separate patient cohorts from 11 hospitals over a 4-year period (2008-2011). Data on clinical parameters and course of the contusion were collected. Radiological parameters were registered by using CT images taken at the time of hospital admission and at subsequent follow-up times. Patients who underwent surgical procedures were identified. Outcomes were evaluated 6 months after trauma by using the Glasgow Outcome Scale-Extended. Multivariate analysis revealed the following reliable predictors of unfavorable outcome: 1) increased patient age, 2) lower Glasgow Coma Scale score at first evaluation, 3) clinical deterioration in the first hours after trauma, and 4) onset or increase of midline shift on follow-up CT images. Further multivariate analysis identified the following as statistically significant predictors of clinical deterioration during the first hours after trauma: 1) onset of or increase in midline shift on follow-up CT images (p < 0.001) and 2) increased effacement of basal cisterns on follow-up CT images (p < 0.001). In TBI patients with cerebral contusion, the onset of clinical deterioration is predictably associated with the onset or increase of midline shift and worsened status of basal cisterns but not with hematoma or edema volume increase. A combination of clinical deterioration and increased midline shift/basal cistern compression is the most reasonable indicator for surgery.


Development and clinical implementation of an enhanced display algorithm for use in networked electronic portal imaging.
To introduce and clinically validate a preprocessing algorithm that allows clinical images from an electronic portal imaging device (EPID) to be displayed on any computer monitor, without loss of clinical usability. The introduction of such a system frees EPI systems from the constraints of fixed viewing workstations and increases mobility of the images in a department. The preprocessing algorithm, together with its variable parameters is introduced. Clinically, the algorithm is tested using an observer study of 316 EPID images of the pelvic region in the framework of treatment of carcinoma of the cervix and endometrium. Both anterior-posterior (AP/PA) and latero-lateral (LAT) images were used. The images scored were taken from six different patients, five of whom were obese, female, and postmenopausal. The result is tentatively compared with results from other groups. The scoring system, based on the number of visible landmarks in the port, is proposed and validated. Validation was performed by having the observer panel score images with artificially induced noise levels. A comparative study was undertaken with a standard automatic window and leveling display technique. Finally, some case studies using different image sites and EPI detectors are presented. The image quality for all images in this study was deemed to be clinically useful (mean score >1). Most of the images received a score which was second highest (AP/PA landmarks > or =6 and LAT landmarks > or =5). Obesity, which has been an important factor determining the image quality, was not seen to be a factor here. Compared to standard techniques a highly significant improvement was determined with regard to clinical usefulness. The algorithm performs fast (less than 9 seconds) and needs no additional user interaction in most of the cases. The algorithm works well on both direct detection portal imagers and camera-based imagers whether analog or digital cameras. We have demonstrated that it is possible to preprocess EPIs in such a way that the clinically relevant landmarks are easily detected on a generic computer screen. The algorithm is system-independent and fast. This allows for the encoding of EPIs in more generalized commercial formats so that distribution of images is facilitated.


Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome.
To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.


Questionnaire- and measurement-based individual thyroid doses in Ukraine resulting from the Chornobyl nuclear reactor accident.
The U.S. National Cancer Institute (NCI), in cooperation with the Ministries of Health of Belarus and of Ukraine, is involved in epidemiological studies of thyroid diseases presumably related to the Chornobyl accident, which occurred in Ukraine on 26 April 1986. Within the framework of these studies, individual thyroid absorbed doses, as well as uncertainties, have been estimated for all members of the cohorts (13,215 Ukrainians and 11,918 Belarusians), who were selected from the large group of children aged 0 to 18 whose thyroids were monitored for gamma radiation within a few weeks after the accident. Information on the residence history and dietary habits of each cohort member was obtained during personal interviews. The methodology used to estimate the thyroid absorbed doses resulting from intakes of (131)I by the Ukrainian cohort subjects is described. The model of thyroid dose estimation is run in two modes: deterministic and stochastic. In the stochastic mode, the model is run 1,000 times for each subject using a Monte Carlo procedure. The geometric means of the individual thyroid absorbed doses obtained in the stochastic mode range from 0.0006 to 42 Gy. The arithmetic and geometric means of these individual thyroid absorbed doses over the entire cohort are 0.68 and 0.23 Gy, respectively. On average, the individual thyroid dose estimates obtained in the deterministic mode are about the same as the geometric mean doses obtained in the stochastic mode, while the arithmetic mean thyroid absorbed doses obtained in the stochastic mode are about 20% higher than those obtained in the deterministic mode. The distributions of the 1000 values of the individual thyroid absorbed dose estimates are found to be approximately lognormal, with geometric standard deviations ranging from 1.6 to 5.0 for most cohort subjects. For the time being, only the thyroid doses resulting from intakes of (131)I have been estimated for all subjects. Future work will include the estimation of the contributions to the thyroid doses resulting from external irradiation and from intakes of short-lived ((133)I and (132)Te) and long-lived ((134)Cs and (137)Cs) radionuclides, as well as efforts to reduce the uncertainties.


Cannabinoids and inflammation: implications for people living with HIV.
: Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies. Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons. Δ-Tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the phytocannabinoids, which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators. CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication. Studies involving SIV-infected macaques have shown that Δ-THC can reduce morbidity and mortality and has favourable effects on gut mucosal immunity. Furthermore, ΔTHC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques. In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokine secretion, all of which are related to HIV disease progression and comorbidities. Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.


CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection.
HIV-1 frequently escapes from CD8 T cell responses via HLA-I restricted adaptation, leading to the accumulation of adapted epitopes (AE). We previously demonstrated that AE compromise CD8 T cell responses during acute infection and are associated with poor clinical outcomes. Here, we examined the impact of AE on CD8 T cell responses and their biological relevance in chronic HIV infection (CHI). In contrast to acute infection, the majority of AE are immunogenic in CHI. Longitudinal analyses from acute to CHI showed an increased frequency and magnitude of AE-specific IFNγ responses compared to NAE-specific ones. These AE-specific CD8 T cells also were more cytotoxic to CD4 T cells. In addition, AE-specific CD8 T cells expressed lower levels of PD1 and CD57, as well as higher levels of CD28, suggesting a more activated and less exhausted phenotype. During CHI, viral sequencing identified AE-encoding strains as the dominant quasispecies. Despite increased CD4 T cell cytotoxicity, CD8 T cells responding to AE promoted dendritic cell (DC) maturation and CD4 T cell trans-infection perhaps explaining why AE are predominant in CHI. Taken together, our data suggests that the emergence of AE-specific CD8 T cell responses in CHI confers a selective advantage to the virus by promoting DC-mediated CD4 T cell trans-infection.


Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs.
The present study was designed to determine the effects of glucocorticoid (GC) on bone turnover, minerals, structure, and bone mechanical properties in minipigs. Six 8-month-old Göttingen minipigs were subcutaneously injected with prednisolone (PN, 0.5 mg/kg body wt (BW)/day, 5 days/week for 26 weeks (Group GC)), 6 were treated with vehicle alone (Group VC), and 4 were sacrificed at start of the study for baseline controls (Group BC). The increase in BW was similar in all groups. PN significantly reduced serum osteocalcin and urinary type-1 collagen N-telopeptide levels at 13 weeks and thereafter, compared with baseline and control, and also reduced serum bone specific alkaline phosphatase levels relative to baseline. At 26 weeks, the longitudinal axis of the lumbar bone and length of femur were smaller in Group GC than Group VC. The total cross-sectional area of femur, but not the lumbar bone, in Group GC was significantly different from Group VC. BMD of the femur, but not L2, measured by DXA, was lower in Group GC than in Groups BC and VC. The cortical shell structure measured by 2D-micro-CT deteriorated and age-dependent increases in trabecular bone structure 3D micro-CT were reduced by PN. PN also caused deterioration of the cortical structure of the mid-femur. In L2 and femur, PN significantly reduced the ultimate load and maximum absorption energy of the femur and L2 compared with Group VC. The structural modulus in Group GC was lower than in Group BC. Regression analyses revealed that bone minerals, bone structure, and chemical markers correlated with mechanical properties of L2 and mid-femur. Our results indicate that PN reduced systemic bone formation and resorption and suppressed the age-dependent increases in bone minerals, structure, and mechanical properties of L2 and mid-femur. Reduced bone turnover seemed to be associated with a reduction in mechanical properties. The growing minipig could be a suitable model of GCs-induced osteoporosis in humans.


Widespread occurrence of small inversions in the chloroplast genomes of land plants.
Large inversions are well characterized in the chloroplast genomes of land plants. In contrast, reports of small inversions are rare and involve limited plant groups. In this study, we report the widespread occurrence of small inversions ranging from 5 to 50 bp in fully and partially sequenced chloroplast genomes of both monocots and dicots. We found that small inversions were much more common than large inversions. The small inversions were scattered over the chloroplast genome including the IR, SSC, and LSC regions. Several small inversions were uncovered in chloroplast genomes even though they shared the same overall gene order. The majority of these small inversions were located within 100 bp downstream of the 3' ends of genes. All had inverted repeat sequences, ranging from 11 to 24 bp, at their ends. Such small inversions form stem-loop hairpin structures that usually have the function of stabilizing the corresponding mRNA molecules. Intra-molecular recombination between the inverted sequences in the stem-forming regions are responsible for generating flip-flop orientations of the loops. The presence of two different orientations of the stem-loop in the trnL-F noncoding region of a single species of Jasminum elegans suggests that a short inversion can be generated within a short period of time. Small inversions of non-coding sequences may influence sequence alignment and character interpretation in phylogeny reconstructions, as shown in nine species of Jasminum. Many small inversions may have been generated by parallel or back mutation events during chloroplast genome evolution. Our data indicate that caution is needed when using chloroplast non-coding sequences for phylogenetic analysis.


Deciphering ionic current signatures of DNA transport through a nanopore.
Within just a decade from the pioneering work demonstrating the utility of nanopores for molecular sensing, nanopores have emerged as versatile systems for single-molecule manipulation and analysis. In a typical setup, a gradient of the electrostatic potential captures charged solutes from the solution and forces them to move through a single nanopore, across an otherwise impermeable membrane. The ionic current blockades resulting from the presence of a solute in a nanopore can reveal the type of the solute, for example, the nucleotide makeup of a DNA strand. Despite great success, the microscopic mechanisms underlying the functionality of such stochastic sensors remain largely unknown, as it is not currently possible to characterize the microscopic conformations of single biomolecules directly in a nanopore and thereby unequivocally establish the causal relationship between the observables and the microscopic events. Such a relationship can be determined using molecular dynamics-a computational method that can accurately predict the time evolution of a molecular system starting from a given microscopic state. This article describes recent applications of this method to the process of DNA transport through biological and synthetic nanopores.


Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project.
The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.


SU-E-T-603: Influence of PTV Delineation at Air Cavity Interface on Tomotherapy Plan Quality.
To determine if different ways in PTV delineation at an air cavity interface yield differences in overall plan quality and treatment efficiency Methods: Three different PTVs were used for treating a patient whose CTV surrounded a large air cavity created by a resected hard palate. The CTV lined the surface of the air cavity while PTV1 included the entire air cavity, PTV2 extended 4mm from the surface of the cavity into air, and PTV3 was reduced 4mm within the surface of the cavity. Tomotherapy plans were generated for all three PTVs. During each planning, all constraints to target and normal structures were kept constant along with the number of optimizations. Same planning process was repeated on a head and neck digital phantom with mock target, normal structures and cavity. Three treatment planning approaches showed no significantly different target coverage in terms of minimum or maximum dose to their respective PTVs. All plans attained 95% coverage of the CTV and PTV by 100% of the prescription. The conformity index (CI) of the plans delivered to PTV1, PTV2, and PTV3 were 1.09, 1.11, and 1.18, respectively. The skin, optic nerves, brainstem and spinal cord all received similar maximum dose to their respective volumes for each plan within 1Gy. The monitor units required for each treatment plan were all within 6% of one another with PTV1 having the highest. For head and neck phantom, the CIs of three plans were 1.05, 1.21, and 1.18, respectively. The coverage of the phantom CTV and sparing of normal structures were nearly equivalent. The total treatment times were identical. Tomotherapy planning is able to deliver dose to a head and neck PTV containing a large air cavity without compromising target coverage, sparing of normal tissues, or delivery time.


Systolic blood pressure estimation using PPG and ECG during physical exercise.
In this work, a model to estimate systolic blood pressure (SBP) using photoplethysmography (PPG) and electrocardiography (ECG) is proposed. Data from 19 subjects doing a 40 min exercise was analyzed. Reference SBP was measured at the finger based on the volume-clamp principle. PPG signals were measured at the finger and forehead. After an initialization process for each subject at rest, the model estimated SBP every 30 s for the whole period of exercise. In order to build this model, 18 features were extracted from PPG signals by means of its waveform, first derivative, second derivative, and frequency spectrum. In addition, pulse arrival time (PAT) was derived as a feature from the combination of PPG and ECG. After evaluating four regression models, we chose multiple linear regression (MLR) to combine all derived features to estimate SBP. The contribution of each feature was quantified using its normalized weight in the MLR. To evaluate the performance of the model, we used a leave-one-subject-out cross validation. With the aim of exploring the potential of the model, we investigated the influences of the inclusion of PAT, regression models, measurement sites (finger and forehead), and posture change (lying, sitting, and standing). The results show that the inclusion of PAT reduced the standard deviation (SD) of the difference from 14.07 to 13.52 mmHg. There was no significant difference in the estimation performance between the model using finger- and forehead-derived PPG signals. Separate models are necessary for different postures. The optimized model using finger-derived PPG signals during physical exercise had a performance with a mean difference of 0.43 mmHg, an SD of difference of 13.52 mmHg, and median correlation coefficients of 0.86. Furthermore, we identified two groups of features that contributed more to SBP estimation compared to other features. One group consists of our proposed features depicting beat morphology. The other comprises existing features depicting the dicrotic notch. The present work demonstrates promising results of the SBP estimation model during physical exercise.


Light scattering by donor lenses as a function of depth and wavelength.
To determine quantitatively dependence on the wavelength and angle, as a function of depth, of light scattering in the human lens. To compare the result for forward directions with psychophysical data. To derive candidate particle distributions that might be responsible for nuclear light scattering as significant in the psychophysical situation. The amount of light scattered by donor lenses (n = 15, ages 48 to 82 years) from a 1-mm x 0.1-mm white slit beam was measured as a function of depth in the lens for seven angles from 10 degrees to 165 degrees, and for four wavelengths from 400 to 700 nm. Absolute values for light scattering (Rayleigh ratios) were derived. The light-scattering data are confounded by the short wavelength-absorbing pigments in the lens. After correction, backward light scattering in the nucleus followed wavelength to a power of -4. In the superior layers and for forward directions in the nucleus, light scattering was less dependent on wavelength. The nuclear data could be explained on the basis of a bimodal protein particle distribution: particles much smaller than wavelength, in quantitative accordance with the literature, and particles larger than wavelength, which control forward light scattering. The particles of significance for forward light scattering have, on average, a mean radius of 692 nm and constitute only 0.000003 of the volume. The wavelength dependence of retinal stray light is lessened by: the large sizes, the contribution of superficial lenticular layers, the lenticular pigments, and the contribution of other components of the eye.


Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options.
Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given.


Amniotic membrane immobilized poly(vinyl alcohol) hybrid polymer as an artificial cornea scaffold that supports a stratified and differentiated corneal epithelium.
Poly(vinyl alcohol) (PVA) is a biocompatible, transparent hydrogel with physical strength that makes it promising as a material for an artificial cornea. In our previous study, type I collagen was immobilized onto PVA (PVA-COL) as a possible artificial cornea scaffold that can sustain a functional corneal epithelium. The cellular adhesiveness of PVA in vitro was improved by collagen immobilization; however, stable epithelialization was not achieved in vivo. To improve epithelialization in vivo, we created an amniotic membrane (AM)-immobilized polyvinyl alcohol hydrogel (PVA-AM) for use as an artificial cornea material. AM was attached to PVA-COL using a tissue adhesive consisting of collagen and citric acid derivative (CAD) as a crosslinker. Rabbit corneal epithelial cells were air-lift cultured with 3T3 feeder fibroblasts to form a stratified epithelial layer on PVA-AM. The rabbit corneal epithelial cells formed 3-5 layers of keratin-3-positive epithelium on PVA-AM. Occludin-positive cells were observed lining the superficial epithelium, the gap-junctional protein connexin43-positive cells was localized to the cell membrane of the basal epithelium, while both collagen IV were observed in the basement membrane. Epithelialization over implanted PVA-AM was complete within 2 weeks, with little inflammation or opacification of the hydrogel. Corneal epithelialization on PVA-AM in rabbit corneas improved over PVA-COL, suggesting the possibility of using PVA-AM as a biocompatible hybrid material for keratoprosthesis.


Comparing the efficacy of exercise, internal and external shoe modification in pes planus: A clinical and pedobarographic study.
Pes planus is a condition that can cause pain along the innerfoot due to the absence or abnormal depression of the longitudinal arch. There are few studies available that compare therapy modalities used in these patients. In our study, those treated with conservative therapies - internal and external shoe modifications and pes planus exercises - were compared clinically and pedobarographyically. 60 pes planus patients were included in the study. In the first group; internal modification was performed by placing a medial longitudinal arch support inside the shoe. In the second group, external shoe modification was performed using the Thomas heel. In the third group of patients however, only an exercise program was executed. The patients' foot pain levels, functional asssessment, satisfaction and quality of life were recorded. Pedobarography was used in measuring both static and dynamic plantar pressure. Assessments were carried out at baseline and at the end of the first and third months respectively where intra- and inter- group comparisons were performed. Each group was composed of 20 subjects. While improvement in terms of foot pain, foot function index and quality of life was observed in all the study groups (p< 0.05), the most improvement was observed in the group of patients treated with internal modification (p< 0.016). This was followed by the external modification and the exercise groups respectively. No difference was observed between the internal and external modification groups in terms of patient satisfaction. Cross-sectionally; clinical assessments, pedobarographic analysis were correlated. The changes observed after static and dynamic pedobarographic studies were not significantly different between the study groups. At the end of the study it was observed that internal modification yielded the most significant clinical improvement. In the literature, there are limited publications comparing the conservative treatments with each other. In this study we aimed to compare the conservative treatments for flatfoot.


Heterochronic faecal transplantation boosts gut germinal centres in aged mice.
Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.


Pathways to diagnosis of non-small cell lung cancer: a descriptive cohort study.
Little has been published on the diagnostic and referral pathway for lung cancer in Australia. This study set out to quantify general practitioner (GP) and lung specialist attendance and diagnostic imaging in the lead-up to a diagnosis of non-small cell lung cancer (NSCLC) and identify common pathways to diagnosis in New South Wales (NSW), Australia. We used linked health data for participants of the 45 and Up Study (a NSW population-based cohort study) diagnosed with NSCLC between 2006 and 2012. Our main outcome measures were GP and specialist attendances, X-rays and computed tomography (CT) scans of the chest and lung cancer-related hospital admissions. Among our study cohort (N = 894), 60% (n = 536) had ≥4 GP attendances in the 3 months prior to diagnosis of NSCLC, 56% (n = 505) had GP-ordered imaging (chest X-ray or CT scan), 39% (N = 349) attended a respiratory physician and 11% (N = 102) attended a cardiothoracic surgeon. The two most common pathways to diagnosis, accounting for one in three people, included GP and lung specialist (respiratory physician or cardiothoracic surgeon) involvement. Overall, 25% of people (n = 223) had an emergency hospital admission. For 14% of people (N = 129), an emergency hospital admission was the only event identified on the pathway to diagnosis. We found little effect of remoteness of residence on access to services. This study identified a substantial proportion of people with NSCLC being diagnosed in an emergency setting. Further research is needed to establish whether there were barriers to the timely diagnosis of these cases.


Compressive Sensing Inference of Neuronal Network Connectivity in Balanced Neuronal Dynamics.
Determining the structure of a network is of central importance to understanding its function in both neuroscience and applied mathematics. However, recovering the structural connectivity of neuronal networks remains a fundamental challenge both theoretically and experimentally. While neuronal networks operate in certain dynamical regimes, which may influence their connectivity reconstruction, there is widespread experimental evidence of a balanced neuronal operating state in which strong excitatory and inhibitory inputs are dynamically adjusted such that neuronal voltages primarily remain near resting potential. Utilizing the dynamics of model neurons in such a balanced regime in conjunction with the ubiquitous sparse connectivity structure of neuronal networks, we develop a compressive sensing theoretical framework for efficiently reconstructing network connections by measuring individual neuronal activity in response to a relatively small ensemble of random stimuli injected over a short time scale. By tuning the network dynamical regime, we determine that the highest fidelity reconstructions are achievable in the balanced state. We hypothesize the balanced dynamics observed in vivo may therefore be a result of evolutionary selection for optimal information encoding and expect the methodology developed to be generalizable for alternative model networks as well as experimental paradigms.


Mountains and arid climates of middle latitudes.
Simulations from a global climate model with and without orography have been used to investigate the role of mountains in maintaining extensive arid climates in middle latitudes of the Northern Hemisphere. Dry climates similar to those observed were simulated over central Asia and western interior North America in the experiment with mountains, whereas relatively moist climates were simulated in these areas in the absence of orography. The experiments suggest that these interior regions are dry because general subsidence and relatively infrequent storm development occur upstream of orographically induced stationary wave troughs. Downstream of these troughs, precipitation-bearing storms develop frequently in association with strong jet streams. In contrast, both atmospheric circulation and precipitation were more zonally symmetric in the experiment without mountains. In addition, orography reduces the moisture transport into the continental interiors from nearby oceanic sources. The relative soil wetness of these regions in the experiment without mountains is consistent with paleoclimatic evidence of less aridity during the late Tertiary, before substantial uplift of the Rocky Mountains and Tibetan Plateau is believed to have occurred.


The Effect of Acute Caffeine Ingestion on Cognitive Dual Task Performance during Assessment of Static and Dynamic Balance in Older Adults.
The present work aimed to evaluate the effect of 3 mg·kg-1 caffeine consumption on the standing and dynamic balance performance of older adults and sought to establish if caffeine ingestion can modulate the influence of a cognitive dual task on balance performance. Twelve apparently healthy participants (8 females) aged >65 years (72 ± 3.7 years) completed the study. Bipedal postural sway, four square step test, timed up and go, Y-balance (anterior reach only) and force-time characteristics of sit-to-stand performance were used to assess standing and dynamic balance. Attention and working memory were assessed using a serial 3s and 7s subtraction task during seated rest and completion of the bipedal standing assessment and Y-balance test. This battery of assessments was completed on two separate occasions, once following the consumption of a non-ergogenic placebo and again following the consumption of 3 mg·kg-1 caffeine. The administration of treatments was randomised, counterbalanced and double-blind. Caffeine reduced performance in the bipedal standing balance assessments, evidenced by an increase in COPML, COPPath, COPVelocity. Performance during the dynamic balance tests was unaffected, other than rate of force development during the sit-to-stand, which was improved following caffeine ingestion. The introduction of a cognitive dual task had either limited effects, or improved facets of bipedal standing balance, whilst performance during the dynamic balance task was significantly reduced. In both balance assessments, there was evidence for a reduction in the performance of the cognitive task when both the balance and cognitive tests were performed simultaneously, with this effect not modulated by caffeine consumption. These findings refute the idea that caffeine ingestion may have positive effects on balance performance. However, despite a caffeine-induced reduction in bipedal standing balance, it is unlikely that caffeine ingestion would exacerbate fall risk given the limited effects in the dynamic balance tests. Future work should establish if these effects are generalisable to older frail participants and if caffeine can modulate the detrimental effects of an acute exercise bout on balance performance.


Pemphigus mouse model as a tool to evaluate various immunosuppressive therapies.
Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3). We have generated an active disease mouse model for PV by adoptive transfer of Dsg3(-/-) lymphocytes. In this study, we investigated the benefits and limitations of this model as a tool to evaluate various immunosuppressive therapeutic strategies. We used the following three measurements to evaluate the effects of the drugs during the time course: Dsg3 enzyme-linked immunosorbent assay scores that represent the level of production of anti-Dsg3 IgG, body weight loss that reflects the severity of oral erosions and PV score that reflects the extent of skin lesions. We examined various immunosuppressive agents currently used to treat patients with PV model mice in preventive protocol. Cyclophosphamide almost completely suppressed the production of anti-Dsg3 IgG, development of body weight loss and the appearance of the PV phenotype in contrast with the control group without the drug. Azathioprine, cyclosporin A and tacrolimus hydrate also showed suppressive effects to various degrees. However, methylprednisolone and dexamethasone failed to show significant effects in contrast to the findings reported in humans. Knowing the advantages and limitations of this model will provide an important foundation for the future evaluation and development of novel therapeutic strategies.


Ipilimumab-induced colitis in patients with metastatic melanoma.
Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade≥2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1-4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1-2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9-12 mg daily) and one was treated with infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy. Ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy.


Kinetic and molecular identification of sodium-dependent glucose transporter in normal rat cholangiocytes.
While previous work has demonstrated that monosaccharides can be absorbed from bile, studies of sugar transport by the biliary, epithelia (i.e., cholangiocytes) are lacking. Using a novel model of polarized rat cholangiocytes in primary culture, designated normal rat cholangiocytes (NRC), we examined directly the uptake and transcellular transport of a nonmetabolizable monosaccharide, methyl alpha-D-glucopyranoside (AMG). When the apical or basolateral domain of cholangiocytes was exposed to radiolabeled AMG or sucrose (control), only apical absorption of AMG was evident. This apical uptake was time dependent, saturable, and significantly inhibited (> or = 90%) by removal of Na+ or in the presence of phlorizin (0.1 mM), a competitive inhibitor of the Na(+)-glucose cotransporter. The transcellular flux of AMG was also polar (i.e., apical to basolateral). Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the presence of the transcript for the specific Na(+)-glucose cotransporter SGLT1 in NRC and in freshly isolated cholangiocytes but not in purified hepatocytes; in contrast, the transcript for SGLT2 was absent in all liver samples. In situ RT-PCR on frozen sections of normal rat liver showed that SGLT1 was expressed exclusively in cholangiocytes. Immunoblot analysis using a specific polyclonal antibody for the facilitative glucose transporter GLUT1 demonstrated it to be present in vesicles derived from NRC enriched in basolateral plasma membrane domains. Our data are consistent with the concept that SGLT1 is present on the apical domain of biliary epithelia and, in conjunction with GLUT1 on the basolateral domain, accounts for glucose absorption from bile.


Constructing minimal models for complex system dynamics.
One of the strengths of statistical physics is the ability to reduce macroscopic observations into microscopic models, offering a mechanistic description of a system's dynamics. This paradigm, rooted in Boltzmann's gas theory, has found applications from magnetic phenomena to subcellular processes and epidemic spreading. Yet, each of these advances were the result of decades of meticulous model building and validation, which are impossible to replicate in most complex biological, social or technological systems that lack accurate microscopic models. Here we develop a method to infer the microscopic dynamics of a complex system from observations of its response to external perturbations, allowing us to construct the most general class of nonlinear pairwise dynamics that are guaranteed to recover the observed behaviour. The result, which we test against both numerical and empirical data, is an effective dynamic model that can predict the system's behaviour and provide crucial insights into its inner workings.


Effect of hypoxia on percent of arteriolar and capillary beds perfused in the rat brain.
The effects of moderate and severe hypoxia on quantitative regional morphometric indexes of the total and perfused arteriolar and capillary network were studied in the rat brain to determine whether diffusion distances were reduced in hypoxia. Fluorescein isothiocyanate (FITC)-labeled dextran was injected into the femoral vein of conscious control and hypoxic rats. After 20 s, the animal was decapitated and the head was frozen in liquid N2. Sections from eight brain regions were photographed to detect the perfused microvessels and then stained for alkaline phosphatase to visualize the total vascular network. There were significant increases in percent perfused arteriolar and capillary morphology between the two groups of hypoxic animals and control animals. In control rats, the percent of capillaries perfused averaged 45.6 +/- 0.6% (mean +/- SE). In moderate hypoxia 63.4 +/- 1.8% of the vessels were perfused and in severe hypoxia 89.4 +/- 0.1% were perfused. The percentage of arterioles perfused changed similarly. There were no significant differences in any index of total or percent perfused arteriolar or capillary morphometry among the regions within any group. During severe hypoxia, a greater percentage of the capillary reserves was utilized. These results demonstrate a uniform response to hypoxia in the capillary and arteriolar network of the conscious rat brain.


A single domain in human DNA polymerase iota mediates interaction with PCNA: implications for translesion DNA synthesis.
DNA polymerases (Pols) of the Y family rescue stalled replication forks by promoting replication through DNA lesions. Humans have four Y family Pols, eta, iota, kappa, and Rev1, of which Pols eta, iota, and kappa have been shown to physically interact with proliferating cell nuclear antigen (PCNA) and be functionally stimulated by it. However, in sharp contrast to the large increase in processivity that PCNA binding imparts to the replicative Pol, Poldelta, the processivity of Y family Pols is not enhanced upon PCNA binding. Instead, PCNA binding improves the efficiency of nucleotide incorporation via a reduction in the apparent K(m) for the nucleotide. Here we show that Poliota interacts with PCNA via only one of its conserved PCNA binding motifs, regardless of whether PCNA is bound to DNA or not. The mode of PCNA binding by Poliota is quite unlike that in Poldelta, where multisite interactions with PCNA provide for a very tight binding of the replicating Pol with PCNA. We discuss the implications of these observations for the accuracy of DNA synthesis during translesion synthesis and for the process of Pol exchange at the lesion site.


Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B.
Delayed ventricular arrhythmias during acute myocardial ischemia (1B arrhythmias) are associated with an increase in tissue impedance and are most likely sustained in a thin subepicardial layer. The goal of this study was to test the hypothesis that heterogeneous uncoupling between depolarized midmyocardium and surviving subepicardium results in heterogeneous refractoriness in the latter, providing the reentry substrate after a premature beat. A 3-dimensional bidomain slab was constructed comprising a normal subepicardial layer coupled to a slightly depolarized (-80 to -60 mV) but inexcitable midmyocardium. Experimentally measured tissue impedance served as input for the model. Four stages of heterogeneous uncoupling between the 2 layers were simulated, each corresponding to an experimental ischemic impedance value. Effective refractory periods (ERP), conduction velocities, and inducibility of reentry were examined. Heterogeneous uncoupling resulted in subepicardial ERP dispersion, allowing reentry to occur. The minimum ERP dispersion needed to induce reentry was 28 ms. Reentry induction was only possible in this model at the 2 intermediate stages of uncoupling, and only when midmyocardial resting membrane potential was more negative than -60 mV. Complete uncoupling of the layers resulted in normal subepicardial conduction without arrhythmias. The minimum length of the reentrant pathway was 2.5 cm, comparable to 2.4 cm reported in previous experiments. Heterogeneous uncoupling to a negative sink such as depressed inexcitable midmyocardium may be a substrate for ischemia 1B arrhythmias. Total uncoupling removes the arrhythmogenic substrate.


Quantifying local and cooperative components in the ferroelectric distortion of BaTiO(3): learning from the off-center motion in the MnCl(6)(5-) complex formed in KCl:Mn(+).
The delicate balance between cooperative and local contributions in the ferroelectric distortions of BaTiO3 is explored by means of ab initio calculations. As a salient feature, it is found that a single Ti(4+) ion in BaTiO3 is not allowed to move off-center at ambient pressure, while this is no longer true if the lattice is expanded by only ∼5%, stressing the high sensitivity of the local contribution to chemical and hydrostatic pressures. In order to further understand the effect of local contributions on the phase transition mechanism of ferroelectrics, we have investigated the surprising C3v → C4v → Oh local transformations occurring in the 10-50 K temperature range for the MnCl6(5-) complex formed in KCl:Mn(+) that mimic the behavior of BaTiO3. From Boltzmann analysis of the vibronic levels derived from ab initio calculations and considering decoherence introduced by random strains, the present calculations reproduce the experimental phase sequence and transition temperatures. Furthermore, our calculations show that the off-center instability in KCl:Mn(+) would be suppressed by reducing by only 1% the lattice parameter, a situation that then becomes comparable to that found for BaTiO3 at ambient pressure. The present results thus stress the deep link between the structural phase transitions of ferroelectric materials and local phase transitions displayed by transition-metal impurities in insulators.


Neutrophil migration inhibitory properties of polyunsaturated fatty acids. The role of fatty acid structure, metabolism, and possible second messenger systems.
The n-3 polyunsaturated fatty acids (PUFA) appear to have antiinflammatory properties that can be partly explained by their biological activity on leukocytes. Since leukocyte emigration is an essential component of the inflammatory response, we have examined the effects of the n-3 PUFA (eicosapentaenoic and docosahexaenoic acids) on neutrophil random and chemotactic movement. Preexposure of neutrophils for 15-30 min to 1-10 micrograms/ml PUFA reduced the random and chemotactic migration to both FMLP- and fungi-activated complement. The inhibitory effect diminished with increasing saturation and carbon chain length, and methylation abolished this activity. Arachidonic and docosahexaenoic acids were the most active fatty acids. The PUFA concentration required to inhibit migration was dependent on cell number, suggesting that the fatty acid effects on leukocyte migration in vivo may be governed by the stage of the inflammatory response. It was concluded that the PUFA rather than their metabolites were responsible for the inhibition since: (a) antioxidants did not prevent the PUFA-induced migration inhibition and the hydroxylated intermediates were less active, and (b) inhibitors of the cyclooxygenase and lipoxygenase pathways were without effect. Inhibitors of protein kinases and calmodulin-dependent enzyme system did not prevent the PUFA-induced migration inhibition, which was also independent of phospholipase D-catalyzed hydrolysis of phospholipids. It is also shown that PUFA decrease the FMLP-induced Ca2+ mobilization.


Neural basis of interaction between target presence and display homogeneity in visual search: an fMRI study.
The functional magnetic resonance imaging (fMRI) technique was used to investigate the functional neuroanatomy of the attention mechanisms employed in visual search with homogeneous or heterogeneous displays. Participants were asked to search for a vertically oriented bar among distractor bars with the same or different orientations, with half of the trials being target-present and the other half being target-absent. Behaviorally, RTs were slower for target-absent than for -present trials when the distractors were heterogeneous, but were faster for target-absent than for -present trials when the distractors were homogeneous. At the neural level, a widely distributed brain network was involved in this interaction. The bilateral frontal eye field, intraparietal sulcus, precentral gyrus and supplementary eye field may play a role in representing the target against distractors and further in detecting and responding to the presence of the target. The right superior frontal gyrus and the bilateral temporal-parietal junction may play a role in filtering distracting information in the search process.


Evidence for sexual transmission of genital herpes in children.
Genital herpes in a prepubertal child presents a child protection clinician with a difficult problem: how likely is it that transmission occurred as a consequence of sexual abuse? Published guidelines on the management of sexually transmitted infections in children provide varying recommendations and refer to a limited literature. To review the evidence for the likelihood of sexual transmission in a child with proven genital herpes. Structured literature search for reports of series of children presenting with genital herpes where an assessment for possible sexual transmission or child sexual abuse had been made. Five suitable papers were identified. Although just over half of reported cases of genital herpes in children had evidence suggestive of a sexual mode of transmission, the quality of assessment of possible sexual abuse was too weak to enable any reliable estimation of its likelihood. Sexual transmission is reported more commonly in older children (aged > or =5 years), in children presenting with genital lesions alone and where type 2 herpes simplex virus is isolated. Child protection clinicians should be aware of the weakness of the evidence on the likelihood of sexual transmission of genital herpes in prepubertal children. The US guidance that child sexual abuse is "suspicious" reflects the evidence better than the UK guidance that it is "probable". A larger, more up-to-date, methodologically sound, population based study is required.


Serum CYFRA 21-1 but not Vimentin is Associated with Poor Prognosis in Advanced Lung Cancer Patients.
Cytokeratins and Vimentin are intermediate filament proteins. Vimentin expression in tissue samples has been reported to be associated with a poor prognosis in non-small cell lung cancer patients who underwent surgery. CYFRA 21-1 (Cytokeratin 19 Fragment) is a well known tumor marker. This study aimed to investigate the usefulness of serum vimentin as a tumor marker and significance of CYFRA 21-1 and vimentin expression on prognosis of advanced lung cancer patients. One hundred and four advanced lung cancer patients and 19 non-lung cancer patients were included. A total of 157 clinical samples obtained from 113 patients was used for immunostaining of vimentin and measurements of CYFRA 21-1 and vimentin concentrations. Compared to low concentration, high concentration of serum CYFRA 21-1 was associated with shorter overall survival in lung cancer patients. However, there was no difference in the serum vimentin concentration between the patients with lung cancer and those with non-lung cancer. No difference in vimentin concentration was observed between the malignant and non-malignant pleural effusions. Immunostaining revealed that of the 43 tumor samples, 21 were positive and 22 were negative for vimentin. No significant difference was found in overall survival between patients with positive and negative for vimentin. An elevated serum CYFRA 21-1 concentration was associated with shorter overall survival in advanced lung cancer patients. However, serum vimentin was not as useful as a tumor marker of lung cancer. The vimentin positivity in tumor samples might not predict patients' prognosis in patients with advanced lung cancer.


Bone mass, size and previous fractures as predictors of prospective fractures in an osteoporotic referral population.
The influence of bone mass, bone size and previous low energy fractures upon prospective fractures has not been investigated in a referral osteoporotic population. We investigated the association between bone mass, bone size, previous fractures, body constitution, and prospective validated fractures in 5701 women and 1376 men, aged 30 years and older. Bone mass measurements of the femoral neck were collected at a single study center in Sweden. Most of the subjects were measured on suspicion of osteoporosis. Data on validated low energy retrospective and prospective fractures in the cohort were collected from the corresponding health care district. Bone mineral density (BMD, g/cm(2)) and estimated volumetric BMD (vBMD, g/cm(3)) were shown to be good independent predictors for fracture in both women and men (Hazard ratio per standard deviation decrease (HR)=1.27-1.52, p<0.05). Bone size did not predict prospective fractures in either sex (HR=0.91-0.99, p>0.05), and bone size completely explained the higher BMD in men than in women. In women, retrospective low energy fractures (HR=1.78, p<0.001) and height (HR=1.02, p=0.006) were additional independent predictors of osteoporotic fractures after adjusting for age and BMD. In conclusion, we show that in a large osteoporotic referral population, age, BMD and previous fractures are independent predictors of prospective low energy fractures. These results add additional strength to the recent change in focus towards a multivariate analysis when assessing the future risk of fracture.


Synchronized personalized music audio-playlists to improve adherence to physical activity among patients participating in a structured exercise program: a proof-of-principle feasibility study.
Preference-based tempo-pace synchronized music has been shown to reduce perceived physical activity exertion and improve exercise performance. The extent to which such strategies can improve adherence to physical activity remains unknown. The objective of the study is to explore the feasibility and efficacy of tempo-pace synchronized preference-based music audio-playlists on adherence to physical activity among cardiovascular disease patients participating in a cardiac rehabilitation. Thirty-four cardiac rehabilitation patients were randomly allocated to one of two strategies: (1) no music usual-care control and (2) tempo-pace synchronized audio-devices with personalized music playlists + usual-care. All songs uploaded onto audio-playlist devices took into account patient personal music genre and artist preferences. However, actual song selection was restricted to music whose tempos approximated patients' prescribed exercise walking/running pace (steps per minute) to achieve tempo-pace synchrony. Patients allocated to audio-music playlists underwent further randomization in which half of the patients received songs that were sonically enhanced with rhythmic auditory stimulation (RAS) to accentuate tempo-pace synchrony, whereas the other half did not. RAS was achieved through blinded rhythmic sonic-enhancements undertaken manually to songs within individuals' music playlists. The primary outcome consisted of the weekly volume of physical activity undertaken over 3 months as determined by tri-axial accelerometers. Statistical methods employed an intention to treat and repeated-measures design. Patients randomized to personalized audio-playlists with tempo-pace synchrony achieved higher weekly volumes of physical activity than did their non-music usual-care comparators (475.6 min vs. 370.2 min, P < 0.001). Improvements in weekly physical activity volumes among audio-playlist recipients were driven by those randomized to the RAS group which attained weekly exercise volumes that were nearly twofold greater than either of the two other groups (average weekly minutes of physical activity of 631.3 min vs. 320 min vs. 370.2 min, personalized audio-playlists with RAS vs. personalized audio-playlists without RAS vs. non-music usual-care controls, respectively, P < 0.001). Patients randomized to music with RAS utilized their audio-playlist devices more frequently than did non-RAS music counterparts (P < 0.001). The use of tempo-pace synchronized preference-based audio-playlists was feasibly implemented into a structured exercise program and efficacious in improving adherence to physical activity beyond the evidence-based non-music usual standard of care. Larger clinical trials are required to validate these findings. ClinicalTrials.gov ID (NCT01752595).


An Information-Theoretic Approach to Self-Organisation: Emergence of Complex Interdependencies in Coupled Dynamical Systems.
Self-organisation lies at the core of fundamental but still unresolved scientific questions, and holds the promise of de-centralised paradigms crucial for future technological developments. While self-organising processes have been traditionally explained by the tendency of dynamical systems to evolve towards specific configurations, or attractors, we see self-organisation as a consequence of the interdependencies that those attractors induce. Building on this intuition, in this work we develop a theoretical framework for understanding and quantifying self-organisation based on coupled dynamical systems and multivariate information theory. We propose a metric of global structural strength that identifies when self-organisation appears, and a multi-layered decomposition that explains the emergent structure in terms of redundant and synergistic interdependencies. We illustrate our framework on elementary cellular automata, showing how it can detect and characterise the emergence of complex structures.


A model of spindle rhythmicity in the isolated thalamic reticular nucleus.
1. The oscillatory properties of the isolated reticular (RE) thalamus were modeled with the use of compartmental models of RE cells. Hodgkin-Huxley type kinetic models of ionic channels were derived from voltage- and current-clamp data from RE cells. Interactions between interconnected RE cells were simulated with the use of a kinetic model of gamma-aminobutyric acid (GABA) inhibitory synapses. 2. The intrinsic bursting properties of RE cells in the model were due to the presence of a low-threshold Ca2+ current and two Ca(2+)-activated currents. The properties of these model RE cells were compared with RE neurons recorded intracellularly in vivo in cats. 3. Model RE cells densely interconnected with GABAA synapses produced synchronous oscillations at a frequency close to that of spindles (7-14 Hz). Networks of RE neurons organized in a two-dimensional array with only proximal connectivity also exhibited synchronized oscillations in the spindle range. In addition, the proximally connected network showed periods of high and low synchronicity, giving rise to waxing and waning oscillations in the population of RE cells. 4. The spatiotemporal behavior of the network was investigated during waxing and waning oscillations. The waxing and waning emerged as an alternation between periods of desynchronized and synchronized activity, corresponding to periods of irregular and coherent spatial activity. During synchronized periods, the network displayed propagating coherent waves of synchronous activity that had a tendency to form spirals. 5. Networks of model RE neurons fully connected through GABAB synapses exhibited perfectly synchronous oscillations at lower frequencies (0.5-1 Hz), but two-dimensional networks with proximal GABAB connectivity failed to synchronize. 6. These simulations demonstrate that networks of model neurons that include the main intrinsic currents found in RE cells can generate waxing and waning oscillatory activity similar to the spindle rhythmicity observed in the isolated RE nucleus in vivo. The model reveals the interplay between the intrinsic rhythmic properties of RE cells and the fast synaptic interactions in organizing synchronized rhythmicity.


Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.
Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.


Supramolecular polymerization provides non-equilibrium product distributions of imine-linked macrocycles.
Supramolecular polymerization of imine-linked macrocycles has been coupled to dynamic imine bond exchange within a series of macrocycles and oligomers. In this way, macrocycle synthesis is driven by supramolecular assembly, either into small aggregates supported by π-π interactions, or high-aspect ratio nanotubes stabilized primarily by electrostatic and solvophobic interactions. For the latter, supramolecular polymerization into nanotubes restricts imine exchange, thereby conferring chemical stability to the assemblies and their constituent macrocycles. Competition in the formation and component exchange among macrocycles favored pyridine-2,6-diimine-linked species due to their rapid synthesis, thermodynamic stability, and assembly into high-aspect ratio nanotubes under the reaction conditions. In addition, the pyridine-containing nanotubes inhibit the formation of similar macrocycles containing benzene-1,3-diimine-linkages, presumably by disrupting their assembly and templation. Finally, we exploit rapid imine exchange within weak, low-aspect ratio macrocycle aggregates to carry out monomer exchange reactions to macrocycles bearing pyridine moieties. Once a pyridine-containing dialdehyde has exchanged into a macrocycle, the macrocycle becomes capable of nanotube formation, which dramatically slows further imine exchange. This kinetic trap provides chemically diverse macrocycles that are not attainable by direct synthetic methods. Together these findings provide new insights into coupling supramolecular polymerization and dynamic covalent bond-forming processes and leverages this insight to target asymmetric nanotubes. We envision these findings spurring further research efforts in the synthesis of nanostructures with designed and emergent properties.


Comparative Survey of Holding Positions for Reducing Vaccination Pain in Young Infants.
Background. Infant holding position may reduce vaccination pain. However, the optimal position for young infants remains controversial. Objectives. To compare the effectiveness of holding infants in the supine position and the effectiveness of holding infants in upright position for relieving acute pain from vaccine injection. Methods. This prospective cohort study enrolled 6-12-week-old healthy infants. We examined infant pain responses by evaluating the following three categories: (1) crying, (2) irritability, and (3) facial expression. Results. In total, 282 infants were enrolled, with 103 and 179 held in the supine and upright positions, respectively. At 30 s after vaccination, the infants in the supine position showed a larger decrease in crying (p < 0.001), irritability (p = 0.002), and pained facial expression (p = 0.001) than did those in the upright position. However, there was no significant difference in pain response between two groups at 180 s after intervention. Conclusion. In 2-month-old infants, the supine position may reduce acute pain more effectively than does the upright position. Our findings provide a clinical strategy for relieving vaccination pain in young infants.


Genomic investigation of alpha-synuclein multiplication and parkinsonism.
Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the alpha-synuclein gene (SNCA). A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild-type alpha-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication.


In vitro communities derived from oral and gut microbial floras inhibit the growth of bacteria of foreign origins.
The gastrointestinal (GI) tract is home to trillions of microbes. Within the same GI tract, substantial differences in the bacterial species that inhabit the oral cavity and intestinal tract have been noted. While the influence of host environments and nutritional availability in shaping different microbial communities is widely accepted, we hypothesize that the existing microbial flora also plays a role in selecting the bacterial species that are being integrated into the community. In this study, we used cultivable microbial communities isolated from different parts of the GI tract of mice (oral cavity and intestines) as a model system to examine this hypothesis. Microbes from these two areas were harvested and cultured using the same nutritional conditions, which led to two distinct microbial communities, each with about 20 different species as revealed by PCR-based denaturing gradient gel electrophoresis analysis. In vitro community competition assays showed that the two microbial floras exhibited antagonistic interactions toward each other. More interestingly, all the original isolates tested and their closely related species displayed striking community preferences: They persisted when introduced into the bacterial community of the same origin, while their viable count declined more than three orders of magnitude after 4 days of coincubation with the microbial flora of foreign origin. These results suggest that an existing microbial community might impose a selective pressure on incoming foreign bacterial species independent of host selection. The observed inter-flora interactions could contribute to the protective effect of established microbial communities against the integration of foreign bacteria to maintain the stability of the existing communities.


A randomized study of three interventions for aspiration of thin liquids in patients with dementia or Parkinson's disease.
This study was designed to identify which of 3 treatments for aspiration on thin liquids-chin-down posture, nectar-thickened liquids, or honey-thickened liquids-results in the most successful immediate elimination of aspiration on thin liquids during the videofluorographic swallow study in patients with dementia and/or Parkinson's disease. This randomized clinical trial included 711 patients ages 50 to 95 years who aspirated on thin liquids as assessed videofluorographically. All patients received all 3 interventions in a randomly assigned order during the videofluorographic swallow study. Immediate elimination of aspiration on thin liquids occurred most often with honey-thickened liquids for patients in each diagnostic category, followed by nectar-thickened liquids and chin-down posture. Patients with most severe dementia exhibited least effectiveness on all interventions. Patient preference was best for chin-down posture followed closely by nectar-thickened liquids. To identify best short-term intervention to prevent aspiration of thin liquid in patients with dementia and/or Parkinson's disease, a videofluorographic swallow assessment is needed. Evidence-based practice requires taking patient preference into account when designing a dysphagic patient's management plan. The longer-term impact of short-term prevention of aspiration requires further study.


Analysis of Three Epoetin Alpha Products by LC and LC-MS Indicates Differences in Glycosylation Critical Quality Attributes, Including Sialic Acid Content.
Erythropoietin (EPO) is one of the main therapeutics used to treat anemic patients, greatly improving their quality of life. In this study, biosimilars Binocrit and a development product, called here CIGB-EPO, were compared to the originator product, Eprex. All three are epoetin alpha products, reputed to have similar glycosylation profiles. The quality, safety, and efficacy of this biotherapeutic depend on the following glycosylation critical quality attributes (GCQAs): sialylation, N-glycolyl-neuraminic acid (Neu5Gc) content, branching, N-acetyl-lactosamine (LacNAc) extensions, and O-acetylation pattern. Reverse-phase ultra-high-pressure liquid chromatography (RP-UHPLC) analysis of acid-released, 1,2-diamino-4,5-methylenedioxybenzene (DMB) labeled sialic acid derivatives and hydrophilic interaction liquid chromatography (HILIC) in combination with mass spectrometry (HILIC-UHPLC-MS) of procainamide (PROC) labeled N-glycans were the analytical tools used. An automated method for enzymatic release and PROC labeling was applied for the first time to the erythropoiesis stimulating agent (ESA) products, which facilitated novel, in-depth characterization, and allowed identification of precise structural features including the location of O-acetyl groups on sialic acid (SA) moieties. Samples were digested by a sialate-O-acetylesterase (NanS) to confirm the presence of O-acetyl groups. It was found that Eprex contained the greatest relative abundance of O-acetylated derivatives, Binocrit expressed the least Neu5Gc, and CIGB-EPO showed the greatest variety of high-mannose-phosphate structures. The sialylation and LacNAc extension patterns of the three ESAs were similar, with a maximum of four N-acetyl-neuraminic acid (Neu5Ac) moieties detected per glycan. Such differences in SA derivatization, particularly O-acetylation, could have consequences for the quality and safety of a biotherapeutic, as well as its efficacy.


Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group.
The Age-Related Macular Degeneration Study-Krypton Laser (AMDS-K) is a multicenter controlled clinical trial designed to determine whether krypton red laser photocoagulation is of value in preventing visual acuity loss in eyes with macular degeneration that have either choroidal neovascularization 1 to 199 microns from the center of the foveal avascular zone or choroidal neovascularization 200 microns or farther from the foveal avascular zone center with blood and/or blocked fluorescence extending within 200 microns of the foveal avascular zone center. Recruitment ended in December 1987 after 247 patients had been assigned to photocoagulation and 249 patients had been assigned to no treatment. At 3 years after randomization, 49% (86/174) of treated eyes, in contrast to 58% (98/169) of untreated eyes, had lost six or more lines of visual acuity. The average visual acuity of treated and untreated eyes at that time was 20/200 and 20/250, respectively. The benefit of laser treatment was largest among patients without evidence of hypertension and diminished to no apparent benefit among patients who had highly elevated blood pressure and/or used antihypertensive medication. Treatment of lesions meeting the AMDS-K eligibility criteria in eyes of patients with no hypertension is recommended. However, treatment cannot be recommended uniformly for patients with definite hypertension having lesions similar to those of patients enrolled in the AMDS-K.


Light-induced charged and trap states in colloidal nanocrystals detected by variable pulse rate photoluminescence spectroscopy.
Intensity instabilities are a common trademark of the photoluminescence of nanoemitters. This general behavior is commonly attributed to random fluctuations of free charges and activation of charge traps reducing the emission yield intermittently. However, the actual physical origin of this phenomenon is actively debated. Here we devise an experiment, variable pulse rate photoluminescence, to control the accumulation of charges and the activation of charge traps. The dynamics of these states is studied, with pulse repetition frequencies from the single-pulse to the megahertz regime, by monitoring photoluminescence spectrograms with picosecond temporal resolution. We find that both photocharging and charge trapping contribute to photoluminescence quenching, and both processes can be reversibly induced by light. Our spectroscopic technique demonstrates that charge accumulation and trap formation are strongly sensitive to the environment, showing different dynamics when nanocrystals are dispersed in solution or deposited as a film.


CgGCS, Encoding a Glucosylceramide Synthase, Is Required for Growth, Conidiation and Pathogenicity in Colletotrichum gloeosporioides.
Fungal glucosylceramide plays important role in cell division, hyphal formation and growth, spore germination and the modulation of virulence and has recently been considered as target for small molecule inhibitors. In this study, we characterized CgGCS, a protein encoding a glucosylceramide synthase (GCS) in Colletotrichum gloeosporioides. Disruption of CgGCS resulted in a severe reduction of mycelial growth and defects in conidiogenesis. Sphingolipid profile analysis revealed large decreases in glucosylceramide production in the mutant strains. Pathogenicity assays indicated that the ability of the ΔCgGCS mutants to invade both tomato and mango hosts was almost lost. In addition, the expression levels of many genes, especially those related to metabolism, were shown to be affected by the mutation of CgGCS via transcriptome analysis. Overall, our results demonstrate that C. gloeosporioides glucosylceramide is an important regulatory factor in fungal growth, conidiation, and pathogenesis in hosts.


Development of the FUN-1 family of fluorescent probes for vacuole labeling and viability testing of yeasts.
A new family of fluorescent probes has been developed for assessing the viability and metabolic activity of yeasts. This class of halogenated unsymmetric cyanine dyes is exemplified by the FUN-1 [2-chloro-4-(2,3-dihydro-3-methyl-(benzo-1,3-thiazol-2-yl)- methylidene)-1-phenylquinolinium iodide] stain, a membrane-permeant nucleic acid-binding dye that has been found to give rise to cylindrical intravacuolar structures (CIVS) in Saccharomyces cerevisiae. Biochemical processing of the dye by active yeasts yielded CIVS that were markedly red shifted in fluorescence emission and therefore spectrally distinct from the nucleic acid-bound form of the dye. The formation of CIVS occurred under both aerobic and anaerobic conditions and was highly temperature dependent. Treatment of yeasts with the nonmetabolizable glucose analog 2-deoxy-D-glucose reduced cellular ATP levels approximately 6-fold and completely inhibited CIVS formation. Under aerobic conditions, the formation of CIVS was abrogated by the cytochrome oxidase inhibitors azide and cyanide; however, the H+ transport uncoupler carbonyl cyanide m-chlorophenylhydrazone inhibited CIVS formation under both aerobic and anaerobic conditions. Depletion of cellular thiols, including glutathione, with millimolar concentrations of N-ethylmaleimide, iodoacetamide, or allyl alcohol completely inhibited CIVS production. Marked reduction in the formation of CIVS by ethacrynic acid and sulfobromophthalein, inhibitors of glutathione S-transferase, suggested that dye processing can involve enzyme-mediated formation of glutathione conjugates. The conversion of FUN-1 by S. cerevisiae was studied quantitatively by using several techniques, including fluorometry, flow cytometry, and wide-field and confocal laser scanning fluorescence microscopy.


Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.
Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.


Review of Pharmacological Properties and Chemical Constituents of Pimpinella anisum.
Pimpinella anisum (anise), belonging to Umbelliferae family, is an aromatic plant which has been used In Iranian traditional medicine (especially its fruits) as carminative, aromatic, disinfectant, and galactagogue. Because the wide traditional usage of Pimpinella anisum for treatment of diseases, in this review published scientific reports about the composition and pharmacological properties of this plant were collected with electronic literature search of GoogleScholar, PubMed, Sciencedirect, Scopus, and SID from 1970 to 2011. So far, different studies were performed on aniseeds and various properties such as antimicrobial, antifungal, antiviral, antioxidant, muscle relaxant, analgesic and anticonvulsant activity as well as different effects on gastrointestinal system have been reported of aniseeds. It can also reduce morphine dependence and has beneficial effects on dysmenorrhea and menopausal hot flashes in women. In diabetic patients, aniseeds showed hypoglycemic and hypolipidemic effect and reduce lipid peroxidation. The most important compounds of aniseeds essential oil were trans-anetole, estragole, γ-hymachalen, para-anisaldehyde and methyl cavicol. Due to broad spectrum of pharmacological effects, and very few clinical studies of Pimpinella anisum, more clinical trials are recommended to evaluate the beneficial effects of this plant in human models and synthesis of new drugs from the active ingredients of this plant in future.


Reactivity of bulky Ln(ii) amidinates towards P4, As4, and As4S4.
The reduction of P4, As4 and As4S4 (realgar) with the sterically encumbered reductants [(DippForm)2Ln(thf)2] (Ln = Sm, Yb; DippForm = {(2,6-iPr2C6H3)NC(H) = N(2,6-iPr2C6H3)}-) is reported. For the first time, purely f-element containing inverse inorganic sandwich complexes [{(DippForm)2Sm}2(μ2-η4:η4-E4)] (E = P, As), featuring a π-aromatic cyclo [E4]2- middle deck, were obtained upon reaction with P4 and As4. The reaction with realgar leads to a cage disruption and the formation of the unusual species [{(DippForm)(DippForm-AsS2)}Ln(thf)]. The reactivity of divalent Ln amidinates towards main group molecules is in comparison to metallocenes faster, more efficient and thus significantly influenced by the ligand environment. Experimental results are supported by DFT calculations.