Probing Interactions between AuNPs/AgNPs and Giant Unilamellar Vesicles (GUVs) Using Hyperspectral Dark-field Microscopy.
Noble metallic nanoparticles (NPs) such as gold and silver nanoparticles (AuNPs and AgNPs) have been shown to exhibit anti-tumor effect in anti-angiogenesis, photothermal and radio therapeutics. On the other hand, cell membranes are critical locales for specific targeting of cancerous cells. Therefore, NP-membrane interactions need be studied at molecular level to help better understand the underlying physicochemical mechanisms for future applications in cancer nanotechnology. Herein, we report our study on the interactions between citrate stabilized colloidal AuNPs/AgNPs (10 nm in size) and giant unilamellar vesicles (GUVs) using hyperspectral dark-field microscopy. GUVs are large model vesicle systems well established for the study of membrane dynamics. GUVs used in this study were prepared with dimyristoyl phosphatidylcholine (DMPC) and doped with cholesterol at various molar concentrations. Both imaging and spectral results support that AuNPs and AgNPs interact very differently with GUVs, i.e., AuNPs tend to integrate in between the lipid bilayer and form a uniform golden-brown crust on vesicles, whereas AgNPs are bejeweled on the vesicle surface as isolated particles or clusters with much varied configurations. The more disruptive capability of AuNPs is hypothesized to be responsible for the formation of golden brown crusts in AuNP-GUV interaction. GUVs of 20 mol% CHOL:DMPC were found to be a most economical concentration for GUVs to achieve the best integrity and the least permeability, consistent with the finding from other phase studies of lipid mixture that the liquid-ordered domains have the largest area fraction of the entire membrane at around 20 mol% of cholesterol.


Patient Choice in Depression Psychotherapy: Outcomes of Patient-Preferred Therapy Versus Randomly Allocated Therapy.
Patient choice is recognized as a factor that influences clinical outcomes and treatment evaluation in mental health care. However, research on how having a choice affects patients with depression has been rare. This Dutch study examined whether patients randomly selected to choose between two types of depression psychotherapy benefited more from treatment than patients randomly assigned to an intervention. Data were derived from a trial of outpatients with depression who were randomly assigned to cognitive therapy (CT), interpersonal psychotherapy (IPT), or a 2-month waitlist control condition followed by the patient's choice of CT or IPT. Treatment groups were combined into a no-choice condition (N=151), with the waitlist as the choice condition (N=31). Multilevel regression was used to compare depression severity (measured with the Beck Depression Inventory-II [BDI-II]) and general psychological distress (measured with the Brief Symptom Inventory [BSI]) posttreatment and at the 5-month follow-up. Differences in patients' pretreatment expectations, beliefs about treatment credibility, and posttreatment evaluation were examined. No significant differences in clinical outcomes were found between the choice and no-choice conditions (mean difference: BDI-II posttreatment=-0.55, 95% confidence interval [CI]=-5.25 to 4.15; follow-up=2.10, 95% CI=-4.01 to 8.20; BSI posttreatment=-1.89, 95% CI=-15.35 to 11.58; follow-up=3.13, 95% CI=-12.32 to 18.57). Patients in both groups reported comparable scores on pretreatment expectations, credibility beliefs, and posttreatment evaluation. Neither expectations nor credibility beliefs were predictive of clinical outcomes. Our findings did not support the value of patient choice. Considering the exploratory nature of the trial, future studies designed to examine the effects of choice in depression treatment are recommended.


Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo.
Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the Magnolia officinalis and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC.


Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis.
To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition-mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.


Stability properties of underdominance in finite subdivided populations.
IN ISOLATED populations underdominance leads to bistable evolutionary dynamics: below a certain mutant allele frequency the wildtype succeeds. Above this point, the potentially underdominant mutant allele fixes. In subdivided populations with gene flow there can be stable states with coexistence of wildtypes and mutants: polymorphism can be maintained because of a migration-selection equilibrium, i.e., selection against rare recent immigrant alleles that tend to be heterozygous. We focus on the stochastic evolutionary dynamics of systems where demographic fluctuations in the coupled populations are the main source of internal noise. We discuss the influence of fitness, migration rate, and the relative sizes of two interacting populations on the mean extinction times of a group of potentially underdominant mutant alleles. We classify realistic initial conditions according to their impact on the stochastic extinction process. Even in small populations, where demographic fluctuations are large, stability properties predicted from deterministic dynamics show remarkable robustness. Fixation of the mutant allele becomes unlikely but the time to its extinction can be long.


Comparison of anastomotic microcirculation in coloanal J-pouches versus straight and side-to-end coloanal reconstruction: an experimental study in the pig.
Several studies have shown a lower rate of anastomotic leakages in patients with coloanal J-pouch reconstruction than in those with straight coloanal anastomosis following anterior resection of the rectum. This study investigated whether this difference is due to a better anastomotic microcirculation. Thirty-two healthy, adult Göttinger mini-pigs underwent anterior rectal resection. They were subsequently randomized to following four groups (eight pigs per group): straight end-to-end, side-to-end, small pouch (4 cm), and large pouch (8 cm) coloanal anastomosis. Bowel perfusion was measured before and after vessel ligature at predefined locations using laser Doppler flowmetry. After completion of the anastomosis microcirculation was investigated 1 cm above, below, and directly at the anastomotic site. Following vessel ligature there was a 25% drop in blood flow. After completion of the anastomosis there was a further decrease of 25% in the distal segment, while no changes were observed above the anastomosis. There were no statistical differences either before or after completion of the anastomosis between the various groups. It is concluded that anastomotic blood flow does not depend on the type of coloanal reconstruction in healthy pigs.


Building a Stronger System for Tracking Nutrition-Sensitive Spending: A Methodology and Estimate of Global Spending for Nutrition-Sensitive Foreign Aid.
There is growing awareness that the necessary solutions for improving nutrition outcomes are multisectorial. As such, investments are increasingly directed toward "nutrition-sensitive" approaches that not only address an underlying or basic determinant of nutrition but also seek to achieve an explicit nutrition goal or outcome. Understanding how and where official development assistance (ODA) for nutrition is invested remains an important but complex challenge, as development projects components vary in their application to nutrition outcomes. Currently, no systematic method exists for tracking nutrition-sensitive ODA. To develop a methodology for classifying and tracking nutrition-sensitive ODA and to produce estimates of the amount of nutrition-sensitive aid received by countries with a high burden of undernutrition. We analyzed all financial flows reported to the Organization for Economic Co-Operation and Development's Development Assistance Committee Creditor Reporting Service in 2010 to estimate these investments. We assessed the relationships between national stunting prevalence, stunting burden, under-5 mortality, and the amount of nutrition-specific and nutrition-sensitive ODA. We estimate that, in 2010, a total of $379·4 million (M) US dollars (USD) was committed to nutrition-specific projects and programs of which 25 designated beneficiaries (countries and regions) accounted for nearly 85% ($320 M). A total of $1.79 billion (B) was committed to nutrition-sensitive spending, of which the top 25 countries/regions accounted for $1.4 B (82%). Nine categories of development activities accounted for 75% of nutrition-sensitive spending, led by Reproductive Health Care (30·4%), Food Aid/Food Security Programs (14·1%), Emergency Food Aid (13·2%), and Basic Health Care (5·0%). Multivariate linear regression models indicate that the amount of nutrition-sensitive (P = .001) and total nutrition ODA was significantly predicted by stunting prevalence (P = .001). The size of the total population of stunted children significantly predicted the amount of nutrition-specific ODA (P < .001). The recipient profile of nutrition-specific and nutrition-sensitive ODA is related but distinct. Nutrition indicators are associated with the level of nutrition-related ODA commitments to recipient countries. A reliable estimate of nutrition spending is critical for effective planning by both donors and recipients and key for success, as the global development community recommits to a new round of goals to address the interrelated causes of undernutrition in low-income countries.


Brain-Wide Genome-Wide Association Study for Alzheimer's Disease via Joint Projection Learning and Sparse Regression Model.
Brain-wide and genome-wide association (BW-GWA) study is presented in this paper to identify the associations between the brain imaging phenotypes (i.e., regional volumetric measures) and the genetic variants [i.e., single nucleotide polymorphism (SNP)] in Alzheimer's disease (AD). The main challenges of this study include the data heterogeneity, complex phenotype-genotype associations, high-dimensional data (e.g., thousands of SNPs), and the existence of phenotype outliers. Previous BW-GWA studies, while addressing some of these challenges, did not consider the diagnostic label information in their formulations, thus limiting their clinical applicability. To address these issues, we present a novel joint projection and sparse regression model to discover the associations between the phenotypes and genotypes. Specifically, to alleviate the negative influence of data heterogeneity, we first map the genotypes into an intermediate imaging-phenotype-like space. Then, to better reveal the complex phenotype-genotype associations, we project both the mapped genotypes and the original imaging phenotypes into a diagnostic-label-guided joint feature space, where the intraclass projected points are constrained to be close to each other. In addition, we use l2,1-norm minimization on both the regression loss function and the transformation coefficient matrices, to reduce the effect of phenotype outliers and also to encourage sparse feature selections of both the genotypes and phenotypes. We evaluate our method using AD neuroimaging initiative dataset, and the results show that our proposed method outperforms several state-of-the-art methods in term of the average root-mean-square error of genome-to-phenotype predictions. Besides, the associated SNPs and brain regions identified in this study have also been shown in the previous AD-related studies, thus verifying the effectiveness and potential of our proposed method in AD pathogenesis study.


Towards a methanol economy based on homogeneous catalysis: methanol to H2 and CO2 to methanol.
The possibility to implement both the exhaustive dehydrogenation of aqueous methanol to hydrogen and CO2 and the reverse reaction, the hydrogenation of CO2 to methanol and water, may pave the way to a methanol based economy as part of a promising renewable energy system. Recently, homogeneous catalytic systems have been reported which are able to promote either one or the other of the two reactions under mild conditions. Here, we review and discuss these developments.


Brain and cognitive correlates of sleep fragmentation in elderly subjects with and without cognitive deficits.
Sleep disturbances are increasingly recognized as a risk factor for Alzheimer's disease. However, no study has assessed the relationships between objective sleep fragmentation (SF) and brain and cognitive integrity across different cognitive stages, from cognitively unimpaired elderly subjects to patients with subjective cognitive decline and/or mild cognitive impairment. 30 cognitively unimpaired elderly participants and 36 patients with subjective cognitive decline and/or mild cognitive impairment underwent a neuropsychological evaluation, structural MRI, 18F-fluorodeoxyglucose, and 18F-florbetapir-PET scans, and an actigraphy recording over a minimum of six consecutive nights. Multiple regression and mediation analyses were performed between SF parameters, neuroimaging data, and cognitive scores. In cognitively unimpaired elderly participants, SF intensity mediated the association between frontohippocampal hypometabolism and lower executive functioning. Moreover, to a lower extent, increased SF variability was related to thalamic atrophy and ventromedial prefrontal amyloid burden. However, in patients with subjective cognitive decline and/or mild cognitive impairment, SF no longer contributed to the expression of cognitive deficits. These findings suggest that SF may directly contribute to lower cognitive performance in cognitively unimpaired elderly subjects. Therefore, treating sleep disturbances before the onset of cognitive deficits may help to cope with brain alterations and maintain cognitive functioning.


Anthocyanin fraction from potato extracts is cytotoxic to prostate cancer cells through activation of caspase-dependent and caspase-independent pathways.
Polyphenols from fruits and vegetables exhibit anticancer properties both in vitro and in vivo and specialty potatoes are an excellent source of dietary polyphenols, including phenolic acids and anthocyanins. This study investigated the effects of specialty potato phenolics and their fractions on LNCaP (androgen dependent) and PC-3 (androgen independent) prostate cancer cells. Phenolic extracts from four specialty potato cultivars CO112F2-2, PATX99P32-2, ATTX98462-3 and ATTX98491-3 and organic acid, phenolic acid and anthocyanin fractions (AF) were used in this study. CO112F2-2 cultivar extracts and their AF at 5 mug chlorogenic acid eq/ml were more active and inhibited cell proliferation and increased the cyclin-dependent kinase inhibitor p27 levels in both LNCaP and PC-3 cells. Potato extract and AF induced apoptosis in both the cells and, however, the effects were cell context dependent. Cell death pathways induced by potato extract and AF were associated with mitogen-activated protein kinase and c-jun N-terminal kinase activation and these kinases activated caspase-independent apoptosis through nuclear translocation of endonuclease G (Endo G) and apoptosis-inducing factor in both cell lines. Induction of caspase-dependent apoptosis was also kinase dependent but was observed only in LNCaP cells. Kinase inhibitors reversed this nuclear translocation of endonuclease G and apoptosis-inducing factor. This is the first report showing that the cytotoxic activities of potato extract/AF in cancer cells were due to activation of caspase-independent apoptosis. Current studies are focused on identifying individual components of the AF responsible for the induction of cell death pathways in prostate and other cancer cell lines and developing potato cultivars that overexpress these active compounds.


Developing interpretation bias modification as a "cognitive vaccine" for depressed mood: imagining positive events makes you feel better than thinking about them verbally.
Two interpretation bias modification experiments found that mental imagery vs. verbal processing of positive material have differential emotional effects. In Experiment 1, participants were instructed to imagine positively resolved auditory descriptions or to listen to the same events while thinking about their verbal meaning. Increases in positive mood and bias were greater in the imagery than in the verbal condition, replicating E. A. Holmes, A. Mathews, T. Dalgleish, and B. Mackintosh (2006). An emotional vulnerability test showed that imagery (relative to the verbal condition) protected against a later negative mood induction. Experiment 2 created 2 new verbal conditions aimed to increase or reduce verbal comparisons. Results suggest making unfavorable comparisons with the highly positive material might be partially responsible for the inferiority of the verbal condition in Experiment 1. The findings demonstrate that imagery can play a key role in cognitive bias modification procedures and thus that task instructions are crucial. Imagining a positive event can make you feel better than thinking about the same event verbally. The authors propose that recruiting imagery will be useful in therapeutic innovations to develop a "cognitive vaccine" for depressed mood.


Neuronal filtering of multiplexed odour representations.
Neuronal activity patterns contain information in their temporal structure, indicating that information transfer between neurons may be optimized by temporal filtering. In the zebrafish olfactory bulb, subsets of output neurons (mitral cells) engage in synchronized oscillations during odour responses, but information about odour identity is contained mostly in non-oscillatory firing rate patterns. Using optogenetic manipulations and odour stimulation, we found that firing rate responses of neurons in the posterior zone of the dorsal telencephalon (Dp), a target area homologous to olfactory cortex, were largely insensitive to oscillatory synchrony of mitral cells because passive membrane properties and synaptic currents act as low-pass filters. Nevertheless, synchrony influenced spike timing. Moreover, Dp neurons responded primarily during the decorrelated steady state of mitral cell activity patterns. Temporal filtering therefore tunes Dp neurons to components of mitral cell activity patterns that are particularly informative about precise odour identity. These results demonstrate how temporal filtering can extract specific information from multiplexed neuronal codes.


The effect of aging on low-fat, reduced-fat, and full-fat Cheddar cheese texture.
This study investigated the effects of aging and fat content on the texture of Cheddar cheese, both mechanical and sensory aspects, over a 9-mo aging period. Cheeses of 6, 16, and 33% fat were tested at 0.5, 3, 6, and 9 mo of aging. Cheeses were evaluated by a trained sensory panel using an established texture lexicon as well as instrumental methods, which were used to probe cheese structure. Sensory analysis showed that low-fat cheeses were differentiated from full-fat cheeses by being more springy and firm and this difference widened as the cheeses aged. In addition, full-fat cheeses broke down more during chewing than the lower fat cheeses and the degree of breakdown increased with aging. Mechanical properties were divided by magnitude of deformation during the test and separated into 3 ranges: the linear viscoelastic region, the nonlinear region, and fracture point. These regions represent a stress/strain response from low to high magnitude, respectively. Strong relationships between sensory terms and rheological properties determined in the linear (maximum compliance) and nonlinear (critical stress and strain and a nonlinear shape factor) regions were revealed. Some correlations were seen with fracture values, but these were not as high as terms related to the nonlinear region of the cheeses. The correlations pointed to strain-weakening behavior being the critical mechanical property. This was associated with higher fat content cheeses breaking down more as strain increased up to fracture. Increased strain weakening associated with an increase in fat content was attributed to fat producing weak points in the protein network, which became initiation sites for fracture within the structure. This suggests that fat replacers need to serve this functional role.


Peak flow as a predictor of cause-specific mortality in China: results from a 15-year prospective study of ~170,000 men.
Forced expiratory volume in one second (FEV1) is inversely associated with mortality in Western populations, but few studies have assessed the associations of peak expiratory flow (PEF) with subsequent cause-specific mortality, or have used populations in developing countries, including China, for such assessments. A prospective cohort study followed ~ 170,000 Chinese men ranging in age from 40-69 years at baseline (1990-1991) for 15 years. In the study, height-adjusted PEF (h-PEF), which was uncorrelated with height, was calculated by dividing PEF by height. Hazard ratios (HR) for cause-specific mortality and h-PEF, adjusted for age, area of residence, smoking, and education, were calculated through Cox regression analyses. Of the original study population, 7068 men died from respiratory causes (non-neoplastic) and 22 490 died from other causes (including 1591 from lung cancer, 5469 from other cancers, and 10 460 from cardiovascular disease) before reaching the age of 85 years. Respiratory mortality was strongly and inversely associated with h-PEF. For h-PEF ≥ 250 L/min, the association was log-linear, with a hazard ratio (HR) of 1.29 (95% CI: 1.25-1.34) per 100 L/min reduction in h-PEF. The association was stronger but not log-linear for lower values of h-PEF. Mortality from combined other causes was also inversely associated with h-PEF, and the association was log-linear for all values of h-PEF, declining with follow-up, with HRs per 100 L/min reduction in h-PEF of 1.13 (1.10-1.15), 1.08 (1.06-1.11), and 1.06 (1.03-1.08) in three consecutive 5-year follow-up periods. Specifically, lower values of h-PEF were associated with higher mortality from cardiovascular disease and lung cancer, but not from other cancers. A lower value of h-PEF was associated with increased mortality from respiratory and other causes, including lung cancer and cardiovascular disease, but its associations with the other causes of death declined across the follow-up period.


Initiation of high-frequency oscillatory ventilation and its effects upon cerebral circulation in pigs: an experimental study.
Current practice at high-frequency oscillatory ventilation (HFOV) initiation is a stepwise increase of the constant applied airway pressure to achieve lung recruitment. We hypothesized that HFOV would lead to more adverse cerebral haemodynamics than does pressure controlled ventilation (PCV) in the presence of experimental intracranial hypertension (IH) and acute lung injury (ALI) in pigs with similar mean airway pressure settings. In 12 anesthetized pigs (24-27 kg) with IH and ALI, mean airway pressure (P(mean)) was increased (to 20, 25, 30 cm H(2)O every 30 min), either with HFOV or with PCV. The order of the two ventilatory modes (cross-over) was randomized. Mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF) (fluorescent microspheres), cerebral metabolism, transpulmonary pressures (P(T)), and blood gases were determined at each P(mean) setting. Our end-points of interest related to the cerebral circulation were ICP, CPP and CBF. CBF and cerebral metabolism were unaffected but there were no differences between the values for HFOV and PCV. ICP increased slightly (HFOV median +1 mm Hg, P<0.05; PCV median +2 mm Hg, P<0.05). At P(mean) setting of 30 cm H(2)O, CPP decreased during HFOV (median -13 mm Hg, P<0.05) and PCV (median -17 mm Hg, P<0.05) paralleled by a decrease of MAP (HFOV median -11 mm Hg, P<0.05; PCV median -13 mm Hg, P<0.05). P(T) increased (HFOV median +8 cm H(2)O, P<0.05; PCV median +8 cm H(2)O, P<0.05). Oxygenation improved and normocapnia maintained by HFOV and PCV. There were no differences between both ventilatory modes. In animals with elevated ICP and ALI, both ventilatory modes had effects upon cerebral haemodynamics. The effects upon cerebral haemodynamics were dependent of the P(T) level without differences between both ventilatory modes at similar P(mean) settings. HFOV seems to be a possible alternative ventilatory strategy when MAP deterioration can be avoided.


Bok Is Not Pro-Apoptotic But Suppresses Poly ADP-Ribose Polymerase-Dependent Cell Death Pathways and Protects against Excitotoxic and Seizure-Induced Neuronal Injury.
Bok (Bcl-2-related ovarian killer) is a Bcl-2 family member that, because of its predicted structural homology to Bax and Bak, has been proposed to be a pro-apoptotic protein. In this study, we demonstrate that Bok is highly expressed in neurons of the mouse brain but that bok was not required for staurosporine-, proteasome inhibition-, or excitotoxicity-induced apoptosis of cultured cortical neurons. On the contrary, we found that bok-deficient neurons were more sensitive to oxygen/glucose deprivation-induced injury in vitro and seizure-induced neuronal injury in vivo Deletion of bok also increased staurosporine-, excitotoxicity-, and oxygen/glucose deprivation-induced cell death in bax-deficient neurons. Single-cell imaging demonstrated that bok-deficient neurons failed to maintain their neuronal Ca(2+)homeostasis in response to an excitotoxic stimulus; this was accompanied by a prolonged deregulation of mitochondrial bioenergetics.bok deficiency led to a specific reduction in neuronal Mcl-1 protein levels, and deregulation of both mitochondrial bioenergetics and Ca(2+)homeostasis was rescued by Mcl-1 overexpression. Detailed analysis of cell death pathways demonstrated the activation of poly ADP-ribose polymerase-dependent cell death in bok-deficient neurons. Collectively, our data demonstrate that Bok acts as a neuroprotective factor rather than a pro-death effector during Ca(2+)- and seizure-induced neuronal injury in vitro and in vivo Bcl-2 proteins are essential regulators of the mitochondrial apoptosis pathway. The Bcl-2 protein Bok is highly expressed in the CNS. Because of its sequence similarity to Bax and Bak, Bok has long been considered part of the pro-apoptotic Bax-like subfamily, but no studies have yet been performed in neurons to test this hypothesis. Our study provides important new insights into the functional role of Bok during neuronal apoptosis and specifically in the setting of Ca(2+)- and seizure-mediated neuronal injury. We show that Bok controls neuronal Ca(2+)homeostasis and bioenergetics and, contrary to previous assumptions, exerts neuroprotective activities in vitro and in vivo Our results demonstrate that Bok cannot be placed unambiguously into the Bax-like Bcl-2 subfamily of pro-apoptotic proteins.


Glucose- but not rice-based oral rehydration therapy enhances the production of virulence determinants in the human pathogen Vibrio cholerae.
Despite major attempts to prevent cholera transmission, millions of people worldwide still must address this devastating disease. Cholera research has so far mainly focused on the causative agent, the bacterium Vibrio cholerae, or on disease treatment, but rarely were results from both fields interconnected. Indeed, the treatment of this severe diarrheal disease is mostly accomplished by oral rehydration therapy (ORT), whereby water and electrolytes are replenished. Commonly distributed oral rehydration salts also contain glucose. Here, we analyzed the effects of glucose and alternative carbon sources on the production of virulence determinants in the causative agent of cholera, the bacterium Vibrio cholerae during in vitro experimentation. We demonstrate that virulence gene expression and the production of cholera toxin are enhanced in the presence of glucose or similarly transported sugars in a ToxR-, TcpP- and ToxT-dependent manner. The virulence genes were significantly less expressed if alternative non-PTS carbon sources, including rice-based starch, were utilized. Notably, even though glucose-based ORT is commonly used, field studies indicated that rice-based ORT performs better. We therefore used a spatially explicit epidemiological model to demonstrate that the better performing rice-based ORT could have a significant impact on epidemic progression based on the recent outbreak of cholera in Haiti. Our results strongly support a change of carbon source for the treatment of cholera, especially in epidemic settings.


Investigating the association between severity of COVID-19 infection during pregnancy and neonatal outcomes.
Pregnant women with COVID-19 require special attention and care, since the infection does not only affect the mother, but also her neonate and adversely affects pregnancy outcomes. The main goal of this retrospective cohort study is to investigate association between the maternal COVID-19 severity and risk of developing adverse neonatal outcomes. Patients were stratified into asymptomatic/mild and moderate to severe COVID-19. The following neonatal outcomes were assessed: gestational age at the time of delivery, birth weight, neonatal infection, neonatal intensive care unit (NICU) admission. The average age of patients was 28.5 ± 1.4 years old and majority were multigravida (74.0%, n = 148). Of total 200 pregnant women with COVID-19, 26.5% (n = 53) had moderate/severe disease and presented with higher incidence of preterm delivery and low birth weight (88.7%, n = 47; p < 0.001). In addition, more than half of the newborns delivered by mothers with severe disease were infected by SARS-COV-2 (58.5%, n = 31) and majority were admitted to the NICU (95.0%, n = 52). Based on the multivariate logistic regression analysis, pregnant women with moderate to severe COVID-19 were at much higher risk of preterm delivery, lower birth weight, neonatal infection, as well as neonatal ICU admission (p < 0.001). In addition, multigravida women were at higher risk for preterm delivery and lower birth weight (p = 0.017 and p = 0.02; respectively). Appropriate protective measures and early detection of suspected COVID-19 should be addressed for more favorable obstetric outcomes.


Total sleep deprivation reduces top-down regulation of emotion without altering bottom-up affective processing.
Sleep loss is reported to influence affective processing, causing changes in overall mood and altering emotion regulation. These aspects of affective processing are seldom investigated together, making it difficult to determine whether total sleep deprivation has a global effect on how affective stimuli and emotions are processed, or whether specific components of affective processing are affected selectively. Sixty healthy adults were recruited for an in-laboratory study and, after a monitored night of sleep and laboratory acclimation, randomly assigned to either a total sleep deprivation condition (n = 40) or a rested control condition (n = 20). Measurements of mood, vigilant attention to affective stimuli, affective working memory, affective categorization, and emotion regulation were taken for both groups. With one exception, measures of interest were administered twice: once at baseline and again 24 hours later, after the sleep deprived group had spent a night awake (working memory was assessed only after total sleep deprivation). Sleep deprived individuals experienced an overall reduction in positive affect with no significant change in negative affect. Despite the substantial decline in positive affect, there was no evidence that processing affectively valenced information was biased under total sleep deprivation. Sleep deprived subjects did not rate affective stimuli differently from rested subjects, nor did they show sleep deprivation-specific effects of affect type on vigilant attention, working memory, and categorization tasks. However, sleep deprived subjects showed less effective regulation of negative emotion. Overall, we found no evidence that total sleep deprivation biased the processing of affective stimuli in general. By contrast, total sleep deprivation appeared to reduce controlled processing required for emotion regulation.


Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.
Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.


North American ginseng exerts a neutral effect on blood pressure in individuals with hypertension.
An early observational study suggested that ginseng could elevate blood pressure. This caused concern because 4.5% of American adults use ginseng, with a popular choice being North American ginseng. To date, North American ginseng lacks hemodynamic evaluation; therefore, we conducted a randomized, double-blinded, controlled trial to investigate its effect on blood pressure in 16 hypertensive individuals (mean+/-SD age 61.1+/-8.1 years; systolic/diastolic blood pressure 132.4+/-12.8/83.3+/-8.1 mm Hg; 13 on antihypertensives). We used 6 batches of North American ginseng root that varied in quality and ginsenoside content, representing the spectrum of this ginseng on the market. On 8 mornings, each participant was fitted with an ambulatory blood pressure monitor, which measured blood pressure during a 30-minute baseline period. Each participant then consumed in a randomized and double-blind fashion 3 g of encapsulated treatment: placebo (on 2 mornings) or powdered North American ginseng (on 6 mornings). After treatment, blood pressure was measured every 10 minutes for 160 minutes, and its change at each post-treatment time point relative to baseline was determined per individual and averaged, and the mean was obtained for the overall 160-minute period. None of the North American ginsengs or their mean differed from placebo in their effect on overall (160 minutes) mean blood pressure change. None affected blood pressure versus placebo at the 10-minute intervals; but their mean versus placebo increased systolic and diastolic blood pressure at 140 and 160 minutes, respectively, and lowered diastolic blood pressure at 100 minutes. The findings together suggested that North American ginseng exerts a neutral acute effect on blood pressure in hypertensive individuals.


Evaluation of effectiveness of survivorship programmes: how to measure success?
Although the number of cancer survivors has increased substantially in the past two decades, the evidence base regarding the effectiveness of cancer survivorship programmes is inadequate. Survivorship programmes tend to evaluate their effectiveness by assessing changes in patient-reported outcomes, symptoms and health status, knowledge, and receipt of cancer surveillance in programme participants. However, more comprehensive and high-quality evaluations of survivorship programmes are needed, including assessments using a broader set of measures. These expanded evaluations can include assessments of programme structure; long-term outcomes, such as survival, quality-adjusted life-years, and functional status; receipt of social support, nutritional, rehabilitative, and fertility preservation services; programme value, including costs and avoidance of inappropriate resource utilisation; and ability of programmes to increase access to needed survivorship care services and health equity. In this Series paper, we provide examples of assessment measures for currently used survivorship programmes, discuss the rationale for and potential benefits of expanded types of evaluation measures, and identify how these measures correspond to several evaluation frameworks. We conclude that use of a common, expanded set of measures to facilitate broad comparisons across survivorship programmes and thorough and systematic evaluations will help to identify the optimal programmes for individual survivors, improve outcomes, and prove the value of survivorship care.


Psychotic experiences from preadolescence to adolescence: when should we be worried about adolescent risk behaviors?
Psychotic experiences (PE), below the threshold of psychotic disorder, are common in the general population. PE are associated with risk behaviors such as suicidality, non-suicidal self-injury (NSSI) and substance use. However, PE as specific or causal phenomena of these risk behaviors are still debated. We aimed to examine the longitudinal trajectories of PE from preadolescence to adolescence and their associated risk behaviors in adolescence. A total of 1138 adolescents from the Copenhagen Child Cohort 2000 were assessed for PE and risk behaviors (NSSI, suicide ideation and -attempts and substance use) at age 11 and 16 years, along with measures of general psychopathology and depressive symptoms specifically. Self-reported impact of general psychopathology tended to be associated with more PE persistence. PE were associated with all risk behaviors in cross section at both follow-ups. Persistent PE from ages 11 to 16 and incident PE at age 16 were associated with risk behaviors at age 16, whereas remitting PE from age 11 to 16 were not. After adjustment for co-occurring depressive symptoms and general psychopathology, all associations were markedly reduced. After exclusion of preadolescents who already had expressed risk behavior at age 11, PE in preadolescence did not stand out as an independent predictor of incident adolescent risk behaviors. The current study suggests that PE in preadolescence and adolescence may not play a direct causal role regarding NSSI, suicidality, and substance use. However, PE are still useful clinical markers of severity of psychopathology and associated risk behaviors.


TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.
Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.


Culture and teasing: the relational benefits of reduced desire for positive self-differentiation.
The authors hypothesized that teasing, a social interaction that benefits relational bonds at the expense of the self, should be viewed as more affiliative, and experienced as more pleasurable, by members of cultures that deemphasize positive self-differentiation. In four multimethod studies, Asian Americans attributed more affiliative intent to teasers and reported more positive target experience than did European Americans. Teaser behavior, attribution biases, and personality did not account for culture-related differences in teasing experience. Rather, childhood teasing may better prepare Asian American children to overlook a tease's affront to the self in favor of its relational rewards. Implications of deemphasizing positive self-differentiation in social interaction are discussed.


Australian monocot-infecting mastrevirus diversity rivals that in Africa.
Monocotyledonous plant infecting mastreviruses (family Geminiviridae) have been found in the Old World. The greatest diversity of these viruses has been found in Africa but this may simply reflect the more extensive sampling that has been done there. To provide a better understanding of mastrevirus diversity in Australia, we have sequenced the genomes of 41 virus isolates found in naturalised and native grasses and identified four new species in addition to the four previously characterised species. Two of these species, which were recovered from a single Sporobolus plant, are highly divergent and are most closely related to the African streak viruses. This, coupled with the discovery of divergent dicotyledonous plant infecting mastreviruses in Australia brings into question the hypothesis that mastreviruses may have originated in Africa. We found that the patterns of inter- and intra-species recombination and the recombination hotspots mirror those found in both their African monocot-infecting counterparts and dicot-infecting mastrevirus.


The modifying effect of the building envelope on population exposure to PM2.5 from outdoor sources.
A number of studies have estimated population exposure to PM2.5 by examining modeled or measured outdoor PM2.5 levels. However, few have taken into account the mediating effects of building characteristics on the ingress of PM2.5 from outdoor sources and its impact on population exposure in the indoor domestic environment. This study describes how building simulation can be used to determine the indoor concentration of outdoor-sourced pollution for different housing typologies and how the results can be mapped using building stock models and Geographical Information Systems software to demonstrate the modifying effect of dwellings on occupant exposure to PM2.5 across London. Building archetypes broadly representative of those in the Greater London Authority were simulated for pollution infiltration using EnergyPlus. In addition, the influence of occupant behavior on indoor levels of PM2.5 from outdoor sources was examined using a temperature-dependent window-opening scenario. Results demonstrate a range of I/O ratios of PM2.5 , with detached and semi-detached dwellings most vulnerable to high levels of infiltration. When the results are mapped, central London shows lower I/O ratios of PM2.5 compared with outer London, an apparent inversion of exposure most likely caused by the prevalence of flats rather than detached or semi-detached properties. Population exposure to air pollution is typically evaluated using the outdoor concentration of pollutants and does not account for the fact that people in London spend over 80% of their time indoors. In this article, building simulation is used to model the infiltration of outdoor PM2.5 into the domestic indoor environment for dwellings in a London building stock model, and the results mapped. The results show the variation in relative vulnerability of dwellings to pollution infiltration, as well as an estimated absolute indoor concentration across the Greater London Authority (GLA) scaled by local outdoor levels. The practical application of this work is a better understanding of the modifying effect of the building geometry and envelope design on pollution exposure, and how the London building stock may alter exposure. The results will be used to inform population exposure to PM2.5 in future environmental epidemiological studies.


Stable interactions between DNA polymerase δ catalytic and structural subunits are essential for efficient DNA repair.
Eukaryotic DNA polymerase δ (Pol δ) activity is crucial for chromosome replication and DNA repair and thus, plays an essential role in genome stability. In Saccharomyces cerevisiae, Pol δ is a heterotrimeric complex composed of the catalytic subunit Pol3, the structural B subunit Pol31, and Pol32, an additional auxiliary subunit. Pol3 interacts with Pol31 thanks to its C-terminal domain (CTD) and this interaction is of functional importance both in DNA replication and DNA repair. Interestingly, deletion of the last four C-terminal Pol3 residues, LSKW, in the pol3-ct mutant does not affect DNA replication but leads to defects in homologous recombination and in break-induced replication (BIR) repair pathways. The defect associated with pol3-ct could result from a defective interaction between Pol δ and a protein involved in recombination. However, we show that the LSKW motif is required for the interaction between Pol3 C-terminal end and Pol31. This loss of interaction is relevant in vivo since we found that pol3-ct confers HU sensitivity on its own and synthetic lethality with a POL32 deletion. Moreover, pol3-ct shows genetic interactions, both suppression and synthetic lethality, with POL31 mutant alleles. Structural analyses indicate that the B subunit of Pol δ displays a major conserved region at its surface and that pol31 alleles interacting with pol3-ct, correspond to substitutions of Pol31 amino acids that are situated in this particular region. Superimposition of our Pol31 model on the 3D architecture of the phylogenetically related DNA polymerase α (Pol α) suggests that Pol3 CTD interacts with the conserved region of Pol31, thus providing a molecular basis to understand the defects associated with pol3-ct. Taken together, our data highlight a stringent dependence on Pol δ complex stability in DNA repair.


Does management really work?
HBR's 90th anniversary is a sensible time to revisit a basic question: Are organizations more likely to succeed if they adopt good management practices? The answer may seem obvious to most HBR readers, but these three economists cast their net much wider than that. In a decadelong study of thousands of organizations in 20 countries, they and their interview teams assessed how well manufacturers, schools, and hospitals adhere to three management basics: targets, incentives, and monitoring. They found that huge numbers of companies follow none of those fundamentals, that adopting the basics yields big improvements in outcomes such as productivity and longevity, and that good nuts-and-bolts management at individual firms shapes national performance. At 14 textile manufacturers in India, for example, an intervention--involving free, high-quality advice from a consultant who was on-site half-time for five months--cut defects by half, reduced inventory by 20%, and raised output by 10%. A control group saw no such gains. The authors' global data set suggests that implementing good management at schools and hospitals yields change more slowly than at manufacturers--but it does come eventually. And the macroeconomic potential--for incomes, productivity, and delivery of critically needed services--is huge. A call for "better management" may sound prosaic, but given the global payoffs, it's actually quite radical.


Double insertion of transposable elements provides a substrate for the evolution of satellite DNA.
Eukaryotic genomes are replete with repeated sequences in the form of transposable elements (TEs) dispersed across the genome or as satellite arrays, large stretches of tandemly repeated sequences. Many satellites clearly originated as TEs, but it is unclear how mobile genetic parasites can transform into megabase-sized tandem arrays. Comprehensive population genomic sampling is needed to determine the frequency and generative mechanisms of tandem TEs, at all stages from their initial formation to their subsequent expansion and maintenance as satellites. The best available population resources, short-read DNA sequences, are often considered to be of limited utility for analyzing repetitive DNA due to the challenge of mapping individual repeats to unique genomic locations. Here we develop a new pipeline called ConTExt that demonstrates that paired-end Illumina data can be successfully leveraged to identify a wide range of structural variation within repetitive sequence, including tandem elements. By analyzing 85 genomes from five populations of Drosophila melanogaster, we discover that TEs commonly form tandem dimers. Our results further suggest that insertion site preference is the major mechanism by which dimers arise and that, consequently, dimers form rapidly during periods of active transposition. This abundance of TE dimers has the potential to provide source material for future expansion into satellite arrays, and we discover one such copy number expansion of the DNA transposon hobo to approximately 16 tandem copies in a single line. The very process that defines TEs-transposition-thus regularly generates sequences from which new satellites can arise.


Overcoming the matched-sample bottleneck: an orthogonal approach to integrate omic data.
MicroRNAs (miRNAs) are small non-coding RNA molecules whose primary function is to regulate the expression of gene products via hybridization to mRNA transcripts, resulting in suppression of translation or mRNA degradation. Although miRNAs have been implicated in complex diseases, including cancer, their impact on distinct biological pathways and phenotypes is largely unknown. Current integration approaches require sample-matched miRNA/mRNA datasets, resulting in limited applicability in practice. Since these approaches cannot integrate heterogeneous information available across independent experiments, they neither account for bias inherent in individual studies, nor do they benefit from increased sample size. Here we present a novel framework able to integrate miRNA and mRNA data (vertical data integration) available in independent studies (horizontal meta-analysis) allowing for a comprehensive analysis of the given phenotypes. To demonstrate the utility of our method, we conducted a meta-analysis of pancreatic and colorectal cancer, using 1,471 samples from 15 mRNA and 14 miRNA expression datasets. Our two-dimensional data integration approach greatly increases the power of statistical analysis and correctly identifies pathways known to be implicated in the phenotypes. The proposed framework is sufficiently general to integrate other types of data obtained from high-throughput assays.


Predicted complementarity determining regions of the T cell antigen receptor determine antigen specificity.
The antigen receptor on T cells (TCR) has been predicted to have a structure similar to a membrane-anchored form of an immunoglobulin F(ab) fragment. Virtually all of the conserved amino acids that are important for inter- and intramolecular interactions in the VH-VL pair are also conserved in the TCR V alpha and V beta chains. A molecular model of the TCR has been constructed by homology and we have used the information from this, as well as the earlier structural predictions of others, to study the basis for specificity. Specifically, regions of a TCR cloned from an antigen-specific T cell were stitched into the corresponding framework of a second TCR. Results indicate that the substitution of amino acid sequences corresponding to the complementarity determining regions (CDRs) of immunoglobulin can convey the specificity for antigen and major histocompatibility complex molecules. These data are consistent with a role, but not an exclusive role, for CDR3 in antigen peptide recognition.


Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.
Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: β estimate, 0.29; P = .001; global composite scores: β estimate, -0.11; P = .001; episodic memory scores: β estimate, -0.18; P < .001; and semantic memory scores: β estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.


Occurrence and Prognosis of Symptomatic Venous Thromboembolism in Colorectal Cancer Surgery Patients.
Colorectal cancer (CRC) has a high risk for postoperative thromboembolic complications such as venous thromboembolism (VTE) compared to other surgical diseases, but the relationship between VTE and CRC in Asian patients remains poorly understood. The present study examined the incidence of symptomatic VTE in Korean patients who underwent surgery for CRC. We also identified risk factors, incidence and survival rate for VTE in these patients. The patients were identified from the CRC database treated from January 2011 to December 2012 in a single institution. These patients were classified into VTE and non-VTE groups, their demographic features were compared, and the factors which had significant effects on VTE and mortality between the two groups were analyzed. We analyzed retrospectively a total of 840 patients and the incidence of VTE was 3.7% (31 patients) during the follow-up period (mean, 17.2 months). Histologic subtype (mucinous adenocarcinoma) and previous history of VTE affected the incidence of VTE on multivariate analysis. There was a statistically significant difference in survival rate between the VTE and non-VTE group, but VTE wasn't the factor affecting survival rate on multivariate analysis. Comparing differences in survival rate for each pathologic stage, there was only a significant difference in stage II patients. Among CRC patients after surgery, the incidence of VTE was approximately 3% within 1 year and development of VTE wasn't a significant risk factor for death in our study but these findings are not conclusive due to our small sample size.


Seismic signals in a courting male jumping spider (Araneae: Salticidae).
Visual displays in jumping spiders have long been known to be among the most elaborate animal communication behaviours. We now show that one species, Habronattus dossenus, also exhibits an unprecedented complexity of signalling behaviour in the vibratory (seismic) modality. We videotaped courtship behaviour and used laser vibrometry to record seismic signals and observed that each prominent visual signal is accompanied by a subsequent seismic component. Three broad categories of seismic signals were observed ('thumps', 'scrapes' and 'buzzes'). To further characterize these signals we used synchronous high-speed video and laser vibrometry and observed that only one seismic signal component was produced concurrently with visual signals. We examined the mechanisms by which seismic signals are produced through a series of signal ablation experiments. Preventing abdominal movements effectively 'silenced' seismic signals but did not affect any visual component of courtship behaviour. Preventing direct abdominal contact with the cephalothorax, while still allowing abdominal movement, only silenced thump and scrape signals but not buzz signals. Therefore, although there is a precise temporal coordination of visual and seismic signals, this is not due to a common production mechanism. Seismic signals are produced independently of visual signals, and at least three independent mechanisms are used to produce individual seismic signal components.


Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells.
In vivo, endothelial cells (ECs) are subjected to a complex mechanical environment composed of shear stress, pressure, and circumferential stretch. The aim of this study was to subject bovine aortic ECs to a pulsatile pressure oscillating from 70 to 130 mm Hg (mean of 100 mm Hg) in combination with pulsatile shear stresses from 0.1 to 6 dyne/cm2 (1 dyne/cm2=0.1 N/m2) with or without a cyclic circumferential stretch of 4% for 1, 4, and 24 hours. The effect of highly reversing oscillatory shear stress (range -3 to +3 dyne/cm2, mean of 0.3 dyne/cm2) typical of regions prone to the development of atherosclerotic plaques was also studied at 4 and 24 hours. Endothelin-1 (ET-1) and endothelial constitutive nitric oxide synthase (ecNOS) mRNA expression was time and mechanical force dependent. ET-1 mRNA was maximal at 4 hours and decreased to less than static culture expression at 24 hours, whereas ecNOS mRNA increased over time. Pressure combined with low shear stress upregulated ET-1 and ecNOS mRNA compared with static control. Additional increase in expression for both genes was observed under a combination of higher shear stress and pressure. A cyclic circumferential stretch of 4% did not induce a further increase in ET-1 and ecNOS mRNA at either low or high shear stress. Oscillatory shear stress with pressure induced a higher expression of ET-1 mRNA but lower expression of ecNOS mRNA compared with unidirectional shear stress and pressure. We have shown that the combination of pressure and oscillatory shear stress can downregulate ecNOS levels, as well as upregulate transient expression of ET-1, compared with unidirectional shear stress. These results provide a new insight into the exact role of mechanical forces in endothelial dysfunction in regions prone to the development of atherosclerosis.


Childhood adrenocortical tumors: case series and reevaluation of prognosis--a 24-year experience.
Adrenocortical neoplasms are rare in childhood and adolescence. The prognostic significance of tumor size, weight, and histological grade are still very much unclear. Eleven patients, (3 boys, 8 girls), with a median presentation age of 7 years (range, 0.8 to 16 years) were identified. Six presented with virilizing symptoms, two with cushingoid symptoms, one with both, and two others had nonspecific symptoms. The interval between onset of symptoms and diagnosis was an average of 18 months (median, 8 months). Hormonal profile correlated well with clinical presentation in nine patients. Two patients with nonspecific symptoms had an aldosterone-producing lesion and an androgen-secreting tumor. Ten patients underwent complete surgical excision, with one intraoperative spillage. Median tumor weight was 94.5 g (range, 4 to 750 g). Three lesions were less than 5 cm in maximal width, six were between 5 and 10 cm, and two were greater than 10 cm. Two tumors had capsular or vascular invasion. Three patients received chemotherapy: one who had inoperable metastatic disease, and two based on clinical and histopathologic findings. Ten patients are doing well, without evidence of recurrent disease with a median follow-up of 3 years (range, 9 months to 15 years), eight patients have been followed up for more than 2 years. The medically treated patient who had metastatic disease died 3 years after diagnosis. A review of the pediatric literature, in some cases, indicates that larger tumors have a worse prognosis, while other investigators claim histological grade is more important. The authors' results do not support these conclusions, but rather suggest that in the pediatric population, when excision is complete, guarded optimism is warranted even with tumors larger than 5 cm. Addendum: Since submission of the manuscript, patient 4 has been operated on twice for local recurrences 13 and 16 months after the initial surgery. She was the only patient in the series to have an intraoperative capsular tear. All other surgical patients remain free of disease.


Inhibitor affinity chromatography: profiling the specific reactivity of the proteome with immobilized molecules.
An inhibitor affinity chromatography (IAC) method has been developed for the analysis of inhibitor-protein interactions as a complementary approach to two-dimensional electrophoresis for functional proteomics studies. The procedure was developed utilizing a cyclin-dependent kinase 2 (Cdk2) inhibitor coupled to a polymeric resin and validated using a number of proteins interacting with the inhibitor with different specificities. Cdk2 and the other kinases bound and eluted from the resin in accordance with the relative in vitro potency of the inhibitor for each enzyme. Molecular interactions with the Cdk2 inhibitor were compared for HCT116 cancer cells versus rat pancreatic acinar cells. Proteins interacting with the ligand on the IAC matrix were identified by mass spectrometry. Isothermal calorimetry was used to confirm and quantitatively evaluate the binding affinity of some of the interacting proteins. Heat-shock protein (Hsp) 70 and Hsp27 were the strongest interactors with the inhibitor, displaying binding affinities comparable to those of Cdk2. These results support the use of IAC as a general method for the rapid identification and qualitative evaluation of the in vivo targets and potential side effects of a given drug.


Plasmacytoid dendritic cells play a key role in tumor progression in lipopolysaccharide-stimulated lung tumor-bearing mice.
The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1-10 μg/mouse) in a mouse model of B16-F10-induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 μg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells. In contrast, high-dose LPS (10 μg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic-polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8(+) T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4(+) T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice.


Multilocus sequence typing as a tool for studying the molecular epidemiology and population structure of Brachyspira hyodysenteriae.
The purpose of this study was to develop and apply a multilocus sequence typing (MLST) scheme to study the molecular epidemiology of Brachyspira hyodysenteriae, the aetiological agent of swine dysentery. Sequences of seven conserved genomic loci were examined in 111 B. hyodysenteriae strains. Fifty-eight of these previously had been analysed by multilocus enzyme electrophoresis (MLEE), and for some the results of pulsed field gel electrophoresis (PFGE), restriction endonuclease analysis (REA) and/or serotyping also were available. The discriminatory power of these methods was compared. The strains were divided into 67 sequence types (STs) and 46 amino acid types (AATs) by MLST. The Index of Association value was significantly different from zero, indication that the population was clonal. Eleven clonal complexes (Cc) comprising between 2 and 10 STs were recognised. A population snapshot based on AATs placed 77.5% of the isolates from 30 of the AATs into one major cluster. The founder type AAT9 included 13 strains from nine STs that were isolated in Australia, Sweden, Germany and Belgium, including one from a mallard. The MLST results were generally comparable to those produced by MLEE. The MLST system had a similar discriminatory power to PFGE, but was more discriminatory than REA, MLEE or serotyping. MLST data provided evidence for likely transmission of strains between farms, but also for the occurrence of temporal "micro-evolution" of strains on individual farms. Overall, the MLST system proved to be a useful new tool for investigating the molecular epidemiology and diversity of B. hyodysenteriae.


Community concepts of malaria-related illness with and without convulsions in southern Ghana.
Malaria, both with or without convulsions, is a serious hardship for people living in endemic areas, especially in sub-Saharan Africa. Community references to malaria, however, may encompass other conditions, which was collectively designated malaria-related illness (MRI). Inasmuch as the presence or absence of convulsions reportedly affects timely help-seeking for malaria, a local comparison of these conditions is needed to inform malaria control. Vignette-based EMIC interviews (insider-perspective interviews) for MRI with convulsions (convulsion positive, MRI-CP) and without convulsions (convulsion negative, MRI-CN) were developed to study relevant features of MRI-related experience, meaning and behaviour in two rural communities in Ghana. These semi-structured interviews elicited both qualitative narrative and categorical codes for quantitative analysis. Interviews with 201 respondents were conducted. The conditions depicted in the vignettes were well recognized by respondents and named with various local terms. Both presentations were considered serious, but MRI-CP was more frequently regarded potentially fatal than MRI-CN. More than 90.0% of respondents in both groups acknowledged the need to seek outside help. However, significantly more respondents advised appropriate help-seeking within 24 (p = 0.01) and 48 (p = 0.01) hours for MRI-CP. Over 50.0% of respondents responding to questions about MRI-CP identified MRI-CN as a cause of convulsions. Local comparison of MRI-CP and MRI-CN based on vignettes found a similar profile of reported categories of perceived causes, patterns of distress, help-seeking and preventive measures for both presentations. This differs from previous findings in sub-Saharan Africa, which assert communities regard the two conditions to be unrelated. The perceived relationships should be acknowledged in formulating strategies to control malaria through timely help-seeking and treatment to reduce childhood mortality.


IgA and secretory component (SC) in the third eyelid of domestic animals: a comparative study.
The third eyelid of domestic animals is important for the production and distribution of tears, in removing ocular debris and in protection of the globe, and has significant immunologic functions. Although it is known that tears contain antibodies of the immunoglobulin A (IgA) isotype which are produced mainly by plasma cells of the lacrimal gland, very little is known about the antibody repertoires in the third eyelid of domestic animals. To assess whether IgA is derived from local synthesis, we analyzed the location of IgA-producing cells and the cellular distribution of secretory component (SC) in the third eyelid of domestic animals in a comparative study. A total of 83 third eyelids of dogs, cats, pigs, cows, sheep, goats and horses were investigated in the course of this study. Third eyelids were obtained immediately after death, cut length-wise, fixed overnight and processed for immunohistochemical detection of IgA and SC by the ABC technique. The results show that IgA-producing plasma cells are densely populated in subepithelial spaces of the surface epithelium as well as in the nictitating gland in a species-specific manner. In contrast, the SC could be demonstrated exclusively in glandular acinar and ductal epithelial cells and in different cell types of the surface epithelium, preferentially located on the bulbar side of the nictitating membrane. It is suggested that most of the SC is locally produced by resident plasma cells and subsequently transferred through the surface epithelium and glandular duct cells by transcytosis. This indicates that the third eyelid is an important member of the secretory immune system in domestic animals.


Mechanism of delayed double ionization in a strong laser field.
When intense laser pulses release electrons nonsequentially, the time delay between the last recollision and the subsequent ionization may last longer than what is expected from a direct impact scenario [recollision excitation with subsequent ionization (RESI)]. We show that the resulting delayed ionization stems from the inner electron being promoted to a sticky region. We identify the mechanism that traps and releases the electron from this region. As a signature of this mechanism, we predict oscillations in the ratio of RESI to double ionization yields versus laser intensity.


Preventive Neuromuscular Training for Young Female Athletes: Comparison of Coach and Athlete Compliance Rates.
Fewer athletic injuries and lower anterior cruciate ligament injury incidence rates were noted in studies of neuromuscular-training (NMT) interventions that had high compliance rates. However, several groups have demonstrated that preventive NMT interventions were limited by low compliance rates. To descriptively analyze coach and athlete compliance with preventive NMT and compare the compliance between study arms as well as among school levels and sports. Randomized, controlled clinical trial. Middle and high school athletic programs. Participants or Other Participants: A total of 52 teams, comprising 547 female athletes, were randomly assigned to the experimental or control group and followed for 1 athletic season. The experimental group (n = 30 teams [301 athletes]: 12 basketball teams [125 athletes], 6 soccer teams [74 athletes], and 12 volleyball teams [102 athletes]) participated in an NMT program aimed at reducing traumatic knee injuries through a trunk-stabilization and hip-strengthening program. The control group (n = 22 teams [246 athletes]: 11 basketball teams [116 athletes], 5 soccer teams [68 athletes], and 6 volleyball teams [62 athletes]) performed a resistive rubber-band running program. Compliance with the assigned intervention protocols (3 times per week during the preseason [mean = 3.4 weeks] and 2 times per week in-season [mean = 11.9 weeks] of coaches [coach compliance] and athletes [athlete compliance]) was measured descriptively. Using an independent t test, we compared coach and athlete compliance between the study arms. A 2-way analysis of variance was calculated to compare differences between coach and athlete compliance by school level (middle and high schools) and sport (basketball, soccer, and volleyball). The protocols were completed at a mean rate of 1.3 ± 1.1 times per week during the preseason and 1.2 ± 0.5 times per week in-season. A total of 88.4% of athletes completed 2/3 of the intervention sessions. Coach compliance was greater in the experimental group than in the control group (P = .014). Coach compliance did not differ by sport but was greater at the high school than the middle school (P = .001) level. Athlete compliance did not differ by study arm, sport, or school level. Athletes received instruction in about 50% of each protocol. Nearly 90% of athletes performed more than 2/3 of the assigned NMT interventions. The assigned intervention was performed more often in the experimental arm compared with the control arm. Coaches at the high school level complied with the given protocol more than middle school coaches did. Athletes complied well with the protocol, but coaches did not, especially at the middle school level.


Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?
The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level.


Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.
Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.


Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers.
This study was designed to clarify discrepancies concerning the effects of droperidol on cardiac repolarization. Myocardial electrical activity was recorded by using microelectrode technique in rabbit Purkinje fibers and guinea pig ventricular muscle. In Purkinje fibers stimulated at 60 pulses/min, low concentrations (0.01-0.3 microM) of droperidol increased in a dose-dependent fashion action potential duration (APD) without altering the other parameters. At 1 and 3 microM, droperidol led to the reversal of the prolonging effect. The highest concentrations used (10 and 30 microM), produced shortening in APD at 50% repolarization concomitantly with a significant decrease in Vmax, action potential amplitude and resting membrane potential. Inexcitability occurred in 4 of 15 preparations exposed to 30 microM. In 8 of 15 Purkinje fibers, the prolonging effect induced by low concentrations was so important that APD exceeded the 1000-msec period of basal stimulation and early afterdepolarizations (EADs) and triggered activity developed. In guinea pig ventricular muscle, these effects were notably less pronounced. Prolongation of action potential showed a reverse use-dependence (i.e., much greater at the lowest stimulation frequencies), whereas Vmax depression was use-dependent. Decreasing extracellular K concentration from 4.0 to 2.7 mM enhanced the incidence of EADs in Purkinje fibers, whereas elevating the K concentration from 2.7 to 5.4 mM abolished them completely and shortened drastically APD. EADs were also eliminated by increasing magnesium concentration from 1 to 5 mM. Addition of isoproterenol favored EADs, whereas these were suppressed at plateau level by exposure to 0.3 microM nifedipine. The results indicate that in rabbit Purkinje fibers, droperidol exerts a dual effect on repolarization, prolongation with low concentrations with development of EADs and subsequent triggered activity. These abnormalities were suppressed at high concentrations concomitantly with a marked depression of other characteristics. These observations suggest multiple ionic channel activities and further studies are required to precise the underlying mechanisms at channel level.


Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients.
Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFα, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFα, 7.0 [4.8-11.7]; IL-6, 9.2 [3.8-17.2]; MCP-1, 109 [65-142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFα, 3.0 [2.0-3.6]; IL-6, 1.7 [0.5-7.2]; MCP-1, 79 [49-93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients.


Clopidogrel and proton pump inhibitors--where do we stand in 2012?
Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.


Predicting cancer therapy-induced cardiotoxicity: the role of troponins and other markers.
Several anticancer drugs have been associated with cardiac toxicity, especially the anthracyclines and trastuzumab. The pathogenesis of anthracycline-associated toxicity has been well described, whereas the mechanism of trastuzumab-associated toxicity is unknown. Although routine cardiac imaging studies (e.g. echocardiogram or multiple gated acquisition scans) may identify subclinical evidence of myocardial dysfunction, available data do not support their routine use for monitoring asymptomatic patients undergoing cancer therapy. Other modalities such as nuclear medicine scintigraphy with indium-111-antimyosin antibody and endomyocardial biopsy have been shown to be useful in identifying early cardiac damage, but their routine use is limited by practical considerations such as feasibility and cost. Consequently, there is significant interest in developing simple and reproducible methods for identifying patients at risk for treatment-induced myocardial damage. Available data suggest that circulating markers such as troponins and natriuretic peptides could potentially be useful for this purpose. Measurement of plasma troponin levels are commonly used in clinical practice in order to provide diagnostic and prognostic information in patients with myocardial ischaemia. Elevated levels may likewise correlate with anthracycline-induced cardiac damage, although plasma levels are only minimally elevated (well below that associated with ischaemia), and elevations may persist for weeks or months after anthracycline exposure. Clinical trials are currently evaluating the role of these markers in predicting both early and late, clinical and subclinical damage associated with anthracyclines and trastuzumab.


Attitudes of patients and surgeons towards sham surgery trials: a protocol for a scoping review of attributes to inform a discrete choice experiment.
In order to properly evaluate the efficacy of orthopaedic procedures, rigorous, randomised controlled sham surgery trial designs are necessary. However, randomised controlled trials (RCTs) for surgery involving a placebo are ethically debated and difficult to conduct with many failing to reach their desired sample size and power. A review of the literature on barriers and enablers to recruitment, and patient and surgeon attitudes and preferences towards sham surgery trials, will help to determine the characteristics necessary for successful recruitment. This review will scope the diverse literature surrounding sham surgery trials with the aim of informing a discrete choice experiment to empirically test patient and surgeon preferences for different sham surgery trial designs. The scoping review will be conducted in accordance with the methodological framework described in Arksey and O'Malley (2005) and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols extension for Scoping Reviews. The review will be informed by a systematic search of Medline, Embase, PsycInfo, CINAHL and EconLit databases (from database inception to 21 June 2019), a Google Scholar search, and hand searching of reference lists of relevant studies or reviews. Studies or opinion pieces that involve patient, surgeon or trial characteristics, which influence the decision to participate in a trial, will be included. Study selection will be carried out independently by two authors with discrepancies resolved by consensus among three authors. Data will be charted using a standardised form, and results tabulated and narratively summarised with reference to the research questions of the review. The findings from this review will inform the design of a discrete choice experiment around willingness to participate in surgical trials, the outcomes of which can inform decision and cost-effectiveness models of sham surgery RCTs. The qualitative information from this review will also inform patient-centred outcomes research. The review will be published in a peer-reviewed journal. CRD42019133296.


First Report of the Giant Stem Nematode, Ditylenchus gigas, from Broad Bean in Iran.
The giant stem nematode, Ditylenchus gigas (Nematoda: Tylenchida) has been recorded from several European and African countries mainly bordering the Mediterranean Sea (2). This nematode causes considerable yield loss of broad bean, Vicia faba, and it may induce more severe damage than the typical faba bean race of D. dipsaci. Spread of infestation through seed limits export of broad bean and has made these nematodes quarantine pests in many countries (2). Broad bean is cultivated in the north, west, southwest, and central parts of Iran. Although D. dipsaci has been reported from different crops and regions in Iran, there is no record of broad bean infection by this nematode. A survey of broad bean fields was conducted in the north and west provinces in a continuation of a study on different populations of D. dipsaci in Iran in May to July of 2007 and 2008 and resampling from some farms in June 2012. The sampling was performed at flowering stage and after. The aboveground plant samples were collected and cut into pieces of 2 to 3 cm, then incubated for 5 to 6 h in Whitehead trays. Morphological and molecular analysis of isolated nematodes from Kermanshah and Lorestan provinces revealed the presence of D. gigas in the samples. Of the 23 plant samples of cv. Barekat collected from Mazandaran and Golestan provinces in the north, 47.8% were infected with stem nematode, mostly with high population density of over 20,000 nematodes per 5 plant stems. The percentage of infected samples of broad bean cv. Shakhbozy collected in Lorestan and Kermanshah provinces in the west was 76.5%. The symptoms of infection were observed as necrotic lesions on the stem surface and reduction of internode distances in severe infection. The giant stem nematode population from Kermanshah showed the following characters: females (n = 20), L = 1,650 ± 140 (1,270 to 1,875) μm; b' = 8.6 ± 0.6 (7.7 to 10.0), c = 19.0 ± 1.3 (19.2 to 21.2), c' = 4.7 ± 0.5 (1.1 to 5.3), stylet = 11.6 ± 0.5 (11 to 12) μm; post vulval sac = 96 ± 16 (58 to 140) μm; vulval-anus distance = 217.0 ± 21.0 (178 to 272) μm, tail = 86.4 ± 9.4 (66 to 102) μm; males (n = 10), L = 1,495 ± 148 (1,236 to 1,636) μm; b' = 7.7 ± 0.3 (7.3 to 8.1), c = 17.3 ± 0.7 (16.3 to 18.6), stylet = 11.3 ± 0.5 (11 to 12) μm, tail = 86.5 ± 8.5 (71 to 95) μm, spicules = 24.8 ± 1.7 (23 to 28) μm. The morphological and morpohometric features were generally in agreement with those published for D. gigas (2). The morphological identification of D. gigas from Iran was supported by the analyses of the ITS rRNA and the D2-D3 expansion segments of the 28S rRNA gene sequences. The rRNA gene of D. gigas from broad bean and D. dipsaci from garlic were amplified and sequenced using two primer sets: (i) the TW81 and AB28 for the ITS-rRNA and (ii) D2A and D3B for partly 28S rRNA gene, as described by (2). New sequences were deposited in the GenBank under accession numbers KC310732 through KC310735. The Iranian D. gigas sequences showed 100% similarity with those of the Italian D. gigas isolates (ITS rRNA: HQ219231, HQ219232; D2-D3 of 28S rRNA: HQ219217 and HQ219216). The identification was further supported by PCR with species specific SCAR (sequence characterized amplified region) primers for this species (1). The specimens from broad bean generated a specific fragment ∼200 bp for D. gigas, whereas the samples with D. dipsaci from garlic and alfalfa produced one fragment ∼250 bp specific for this species. To our knowledge, this is the first report of D. gigas from broad bean in Iran. References: (1) M. Esquibet et al. Genome 46:1077, 2003. (2) N. Vovlas et al. Plant Pathol. 60:762, 2011.


Cancer rehabilitation services: an Italian population-based cohort study.
In Italy more than 55% of cancer patients live for more than 5 years after diagnosis, sometimes with several cancer-related sequelae. For this reason rehabilitation must offer not only physical interventions but also psychological, clinical, social and nutritional support. The CAREMORE pilot study was designed to assess whether cancer registries could serve to collect information on rehabilitation services, to describe and quantify the services provided by the National Health Service, and to examine the allocation of rehabilitation services to cancer patients. This was a pilot population-based cohort study. A sample of 1200 patients was identified from the databases of the Varese, Genoa, Reggio Emilia, Sassari and Ragusa cancer registries, all diagnosed in 2002 and followed for 5 years. For 4 cancer sites a list of rehabilitation items to be collected was drafted by a joint community of researchers and voluntary associations, with variables regarding rehabilitation data and follow-up. Data were analyzed by groups of patients, vital status, sex, and age. This pilot study suggested it is useful to collect information on several rehabilitation services: disability benefits, home care, aids and other support; it was not possible to collect reliable information on nutritional and psychological rehabilitation. In all, 36% of the sample applied for disability benefits, but with important differences between cancer sites. Eleven percent of the sample obtained home care, with no substantial differences between cancer sites, and 16% received at least one aid, with percentages varying from 27% for rectal cancer to 8% for lymphoma patients. The pilot study indicated that cancer registries could collect information on rehabilitation services. In the future it would be interesting to expand the roles of these registries to factors that influence quality of life, taking into account the possibility of collecting more information by actually interviewing patients.