WITHDRAWN: Proton pump inhibitor treatment for acute peptic ulcer bleeding.
Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer (PU) bleeding yield conflicting results. To evaluate the efficacy of PPIs in acute bleeding from PU using evidence from RCTs. We searched CENTRAL, The Cochrane Library (Issue 4, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), proceedings of major meetings to November 2004, and reference lists of articles. We contacted pharmaceutical companies and experts in the field. RCTs of PPI treatment (oral or intravenous) compared with placebo or H(2)-receptor antagonist (H(2)RA) in acute bleeding from PU. Two reviewers extracted data independently, assessed study validity, summarised studies and undertook meta-analysis. The influence of study characteristics on the outcomes was examined by subgroup analyses and meta-regression. Twenty-four RCTs comprising 4373 participants in total were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.04), but not for all-cause mortality (P = 0.24) or surgery (P = 0.45). There was no significant difference in all-cause mortality rates between PPI and control treatment; pooled rates were 3.9% on PPI versus 3.8% on control (odds ratio (OR) 1.01; 95% CI 0.74 to 1.40). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI versus 17.3% with control treatment (OR 0.49; 95% CI 0.37 to 0.65). PPI treatment significantly reduced surgery compared with control; pooled rates were 6.1% on PPI versus 9.3% on control (OR 0.61; 95% CI 0.48 to 0.78). There was no evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. PPIs significantly reduced surgery compared with placebo but not when compared with H(2)RA. There was no evidence to suggest that study quality, route of PPI administration or application of initial endoscopic haemostatic treatment influenced results on surgery. PPI treatment appeared more efficacious in studies conducted in Asia compared to studies conducted elsewhere. All-cause mortality was reduced only in Asian studies; reductions in rebleeding and surgery were quantitatively greater in Asian studies. Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery. PPI treatment in PU bleeding reduces rebleeding and surgery compared with placebo or H(2)RA, but there is no evidence of an overall effect on all-cause mortality.


Structural divisions and functional fields in the human cerebral cortex.
The question of what is a cortical area needs a thorough definition of borders both in the microstructural and the functional domains. Microstructural parcellation of the human cerebral cortex should be made on multiple criteria based on quantitative measurements of microstructural variables, such as neuron densities, neurotransmitter receptor densities, enzyme densities, etc. Because of the inter-individual variations of extent and topography of microstructurally defined areas, the final microstructurally defined areas appear as population maps. In the functional domain, columns, patches and blobs signifying synaptically active parts of the cortex appear as cortical functional fields. These fields are the largest functional entities of the cerebral cortex according to the cortical field hypothesis. In its strong version, the cortical field hypothesis postulates that all neurons and synapses within the fields perform a co-operative computation. A number of such fields together provide the functional contribution of the cerebral cortex. The functional parcellation of the human cerebral cortex must be based on field population maps, which after intersection analysis appear as functional domains. The major structural-functional hypothesis to be examined is whether these functional domains are equi-territorial to the microstructurally defined meta-maps. The cortical hypothesis predicts that, if two brain tasks make use of one or several identical or largely overlapping fields, they cannot be performed simultaneously without errors or increases in latency. Evidence for such interference is presented. This evidence represents a restriction in the parallel processing of the human brain. In the posterior part of the brain not only visual cortical areas may qualify for parallel processing, but also the somatosensory cortices appear to have separate functional streams for the detection of microgeometry and macrogeometry.


Multiple ART Programs Create a Dilemma for Providers to Monitor ARV Adherence in Uganda.
Increased availability and accessibility of antiretroviral therapy (ART) has improved the length and quality of life amongst people living with HIV/AIDS. This has changed the landscape for care from episodic to long-term care that requires more monitoring of adherence. This has led to increased demand on human resources, a major problem for most ART programs. This paper presents experiences and perspectives of providers in ART facilities, exploring the organizational factors affecting their capacity to monitor adherence to ARVs. From an earlier survey to test adherence indicators and rank facilities as good, medium or poor adherence performances, six facilities were randomly selected, two from each rank. Observations on facility set-up, provider-patient interactions and key informant interviews were carried out. The strengths, weaknesses, opportunities and threats identified by health workers as facilitators or barriers to their capacity to monitor adherence to ARVs were explored during group discussions. Findings show that the performance levels of the facilities were characterized by four different organizational ART programs operating in Uganda, with apparent lack of integration and coordination at the facilities. Of the six facilities studied, the two high adherence performing facilities were Non-Governmental Organization (NGO) programs, while facilities with dual organizational programs (Governmental/NGO) performed poorly. Working conditions, record keeping and the duality of programs underscored the providers' capacity to monitor adherence. Overall 70% of the observed provider-patient interactions were conducted in environments that ensured privacy of the patient. The mean performance for record keeping was 79% and 50% in the high and low performing facilities respectively. Providers often found it difficult to monitor adherence due to the conflicting demands from the different organizational ART programs. Organizational duality at facilities is a major factor in poor adherence monitoring. The different ART programs in Uganda need to be coordinated and integrated into a single well resourced program to improve ART services and adherence monitoring. The focus on long-term care of patients on ART requires that the limitations to providers' capacity for monitoring adherence become central during the planning and implementation of ART programs.


Americans' experiences in the health insurance marketplaces: results from the first month.
Conducted October 9-27, 2013, the Commonwealth Fund Affordable Care Act Tracking Survey interviewed a nationally representative sample of adults who are potentially eligible for the health reform law's new insurance coverage options, whether private plans or expanded Medicaid. Among the survey's key findings: 60 percent of potentially eligible adults are aware of the new marketplaces as a place where they might shop for coverage; 17 percent reported visiting the marketplaces in October to shop for a health plan; about one of five visitors were ages 19 to 29; and one of five visitors enrolled in a plan. Reflecting the technical problems that have plagued the federal marketplace and some state marketplace websites, 37 percent of those who did not enroll in coverage cited those technical difficulties as a reason. A majority of survey respondents, however, appear determined to gain coverage over the next few months.


Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182,780.
Both primary and acquired resistance to the growth-inhibitory effects of anti-estrogens (e.g., tamoxifen) limits the clinical usefulness of these drugs in the treatment of breast cancer. The new, steroidal anti-estrogen ICI 182,780 was tested for its ability to inhibit the proliferation of a tamoxifen-resistant variant of the parental MCF-7 human breast-cancer cell line. Two cell lines cloned from the MCF-7 line were used for these experiments: a tamoxifen-sensitive line, MCF 5-21, and a tamoxifen-resistant line, MCF 5-23. Compared with tamoxifen, ICI 182,780 appeared to be 150 and 1540 times more effective in inhibiting cell growth in the 5-21 and 5-23 sub-lines respectively. ICI 182,780 completely circumvented tamoxifen resistance at a concentration of (5 to 10) x 10(-9) M in this model. Based on IC50 concentrations, the 5-23 line was 22-fold more resistant to tamoxifen than the 5-21 line, but only 2-fold more resistant to ICI 182,780, reducing relative resistance by 10-fold in the resistant line. There were no differences in ER parameters between the 2 lines. ER numbers/cell were: 40500 and 34800 and the KD 0.48 and 0.15 x 10(-9) M in the 5-21 and 5-23 cells respectively. In the 5-23 cells, the concentrations of ICI 182,780 and tamoxifen resulting in a 50% inhibition of 3H-estradiol binding were 2.3 x 10(-8) M and 1 x 10(-6) M, respectively (cf. estradiol 0.89 x 10(-9) M). Thus, one potential mechanism for the increased effectiveness of ICI 182,780 may relate to the increased affinity of this drug for the estrogen receptor as compared with tamoxifen.


Bisphosphonates are incorporated into adenine nucleotides by human aminoacyl-tRNA synthetase enzymes.
Bisphosphonates are synthetic pyrophosphate analogues and are therapeutic inhibitors of bone resorption, although their exact mechanisms of action are unclear. Some bisphosphonates can be metabolised into non-hydrolysable ATP analogues by Dictyostelium discoideum amoebae, in a back-reaction catalysed by several Class II aminoacyl-tRNA synthetases. We have found that the same enzymes in cell-free extracts of several human cell lines are also capable of metabolising in vitro the same bisphosphonates that are metabolised by Dictyostelium. These results indicate that human cells, following drug internalisation, should be capable of metabolising certain bisphosphonates. The toxic effects of these bisphosphonates towards bone-resorbing osteoclasts may therefore be due to accumulation of non-hydrolysable ATP analogues or inhibition of aminoacyl-tRNA synthetase enzymes.


Relating neural processing of reward and loss prospect to risky decision-making in individuals with and without Gambling Disorder.
Neuroimaging studies demonstrate alterations in fronto-striatal neurocircuitry in gambling disorder (GD) during anticipatory processing, which may influence decision-making impairments. However, to date little is known about fronto-striatal anticipatory processing and emotion-based decision-making. While undergoing neuroimaging, 28 GD and 28 healthy control (HC) participants performed the Monetary Incentive Delay Task (MIDT). Pearson correlation coefficients assessed out-of-scanner Iowa Gambling Task (IGT) performance with the neural activity during prospect (A1) processing on the MIDT across combined GD and HC groups. The HC and GD groups showed no significant difference in out-of-scanner IGT performance, although there was a trend for higher IGT scores in the HC group on the last two IGT trial blocks. Whole-brain correlations across combined HC and GD groups showed that MIDT BOLD signal in the ventral striatum/caudate/ventromedial prefrontal cortex and anterior cingulate regions during the prospect of winning positively correlated with total IGT scores. The GD group also contained a higher proportion of tobacco smokers, and correlations between neural activations in prospect on the MIDT may relate in part to gambling and/or smoking pathology. In this study, fronto-striatal activity during the prospect of reward and loss on the MIDT was related to decision-making on the IGT, with blunted activation linked to disadvantageous decision-making. The findings from this work are novel in linking brain activity during a prospect-of-reward phase with performance on a decision-making task in individuals with and without GD.


"With a little help from my friends...": the role of co-witness relationship in susceptibility to misinformation.
Inaccuracies in eyewitness accounts can occur when witnesses are exposed to post-event misinformation via discussion with a co-witness. The current study examined the role of co-witness relationship by comparing the memory performance of pairs of romantic couples, friends and previously unacquainted strangers with that of individuals. Ninety-six participants viewed an event and then discussed the witnessed event with a stranger, a romantic partner or a friend. One member of each pair saw a theft take place during the witnessed event. Individual group participants did not discuss the witnessed event with anyone. Results indicate that all co-witness dyads produced less accurate recall accounts than participants who did not interact with another witness. However, witnesses who were previously acquainted with their co-witness (either in a friendship or romantic relationship) were significantly more likely to report information obtained from their co-witness that they had not seen themselves. Prior acquaintance also led to an increased number of incorrect attributions of both guilt and innocence.


TRA1: A Locus Responsible for Controlling Agrobacterium-Mediated Transformability in Barley.
In barley (Hordeum vulgare L.), Agrobacterium-mediated transformation efficiency is highly dependent on genotype with very few cultivars being amenable to transformation. Golden Promise is the cultivar most widely used for barley transformation and developing embryos are the most common donor tissue. We tested whether barley mutants with abnormally large embryos were more or less amenable to transformation and discovered that mutant M1460 had a transformation efficiency similar to that of Golden Promise. The large-embryo phenotype of M1460 is due to mutation at the LYS3 locus. There are three other barley lines with independent mutations at the same LYS3 locus, and one of these, Risø1508 has an identical missense mutation to that in M1460. However, none of the lys3 mutants except M1460 were transformable showing that the locus responsible for transformation efficiency, TRA1, was not LYS3 but another locus unique to M1460. To identify TRA1, we generated a segregating population by crossing M1460 to the cultivar Optic, which is recalcitrant to transformation. After four rounds of backcrossing to Optic, plants were genotyped and their progeny were tested for transformability. Some of the progeny lines were transformable at high efficiencies similar to those seen for the parent M1460 and some were not transformable, like Optic. A region on chromosome 2H inherited from M1460 is present in transformable lines only. We propose that one of the 225 genes in this region is TRA1.


Direction selective habituation of motion adaptation.
Both adaptation and perceptual learning can change how we perceive the visual environment, reflecting the plasticity of the visual system. Our previous work has investigated the interaction between the two aspects of visual plasticity. One of the main findings is that multiple days of repeated motion adaptation attenuates motion aftereffect, which is explained by habituation of motion adaptation. Interestingly, there was almost no transfer of the effect to the untrained adapter, which differed from the trained adapter in the features including retinotopic location, spatiotopic location, and motion direction. Given that the reference frame of motion aftereffect is proposed to be retinotopic, it remains unclear whether the effect we refer to as habituation effect of motion adaptation is more like a special type of motion adaptation or not. Therefore, in three experiments, we examined the role of retinotopic location, spatiotopic location, and motion direction on the transfer of habituation, respectively. In each experiment, only one of the features was kept the same for the trained and untrained conditions. We found that the habituation effect transferred across both the retinotopic and spatiotopic locations as long as the adapting direction remained the same. The findings indicate that the effect we refer to as habituation of motion adaptation is anchored neither in eye-centered (retinotopic) nor world-centered (spatiotopic) coordinates. Rather, it is specific to the direction of the adapter. Therefore, the habituation effect of motion adaptation cannot be ascribed to a variant of motion adaptation.


The HSP90AA1 sperm content and the prediction of the boar ejaculate freezability.
In a previous study we reported that the immunolabelling of GLUT3, HSP90AA1, and Cu/ZnSOD proteins on boar sperm did not show differences between good and poor freezability ejaculates, in terms of a qualitative analysis based on location and reactivity of these proteins at 17 degrees C and at 240 min post-thaw. Since predicting the ejaculate freezability is considerably important in sperm cryopreservation procedures, the objective of the present study was to quantify the expression of these three proteins in good and poor freezability ejaculates. For this purpose, 10 ejaculates from 9 Piétrain boars were cryopreserved and their sperm quality assessed in the three main steps of the freezing process (17 degrees C, 5 degrees C, and 240 min post-thaw). After this assessment, the 10 ejaculates were clustered for freezability on the basis of their sperm progressive motility and membrane integrity at 240 min post-thaw. From the whole ejaculates, only four good and four poor freezability ejaculates displaying the most divergent values were selected for a western blot assay using sperm samples coming from the three mentioned freezing steps. Protein levels through densitometry were significantly different between good and poor freezability ejaculates for Cu/ZnSOD at 240 min post-thaw (P <or= 0.01) and for HSP90AA1 at 17 degrees C and 5 degrees C (P <or= 0.05). This last finding claims the introduction of tests based on molecular markers in spermatozoa to accurately predict the freezability of ejaculates in order to promote the use of frozen semen on artificial insemination programmes.


Enhancing safety and aroma appealing of fresh-cut fruits and vegetables using the antimicrobial and aromatic power of essential oils.
Microbial and aroma attributes are within the most decisive factors limiting safety and sensory appealing of fresh-cut fruits and vegetables. Alternatively, several plant essential oils (EOs) are constituted of several volatile active compounds and most of them present antimicrobial potential and had different aroma profile. Considering these premises, this hypothesis article states that safety and aroma appealing of fresh-cut produce could be improved with EO treatment. EOs could prevent fresh-cut fruit decay; however, their volatile constituents could be sorbed by the produce, and according to the aroma notes of the antimicrobial oil, sensorial appealing of odor, and flavor of the treated produce might be affected positively or negatively. Specifically, garlic oil is a natural antimicrobial constituted by sulfur compounds, which are responsible for its odor and antimicrobial properties. Besides, fresh-cut tomato is a highly perishable product that needs antimicrobial agents to preserve its quality and safety for a longer period of time. From the sensorial point of view, aroma combination of garlic and tomato is a common seasoning practice in Europe and America and well accepted by consumers. Once the right combination of flavors between the EOs and the fresh-cut produce has been selected, safety and quality of the treated fruit could be improved by adding antimicrobial protection and extra aroma. Therefore, other combinations between EOs and fresh-cut produce are discussed. This approximation could reinforce the trends of natural food preservation, accomplishing the demands of the increasing sector of consumers demanding tasty and convenient fresh-cut produce, containing only natural ingredients.


Improving diabetes management with electronic health records and patients' health records.
The lack of patient engagement and clinical inertia both contribute to suboptimal diabetes care. However, both obstacles are amenable to informatics- and Internet-based interventions. The use of electronic medical records (EMRs) is now established as being useful for improving diabetes care. Intelligent records that integrate computerized decision-support systems are now able to recommend care protocols tailored to risk levels. Web-based personal health record (PHR) systems, shared with healthcare providers, could also provide added value by promoting self-management of the behaviours related to diabetes. These Web-based programmes include patients' access to EMRs, uploading of glucose monitoring results, a glucose diary, secure e-mail with providers, manual or automated feedback on blood glucose readings and other risk factors, an educational website, and an online diary for entering personal information on exercise, diet and medication. The integration of Web-based patients' systems into the EMR used by physicians is the next frontier. In addition, the input from "smartphones" that are able to provide real-time support to patients could contribute to the reorganization of diabetes care. Convincing data on HbA(1c) improvements with such systems are available for type 2 diabetes, but are still equivocal for type 1 diabetes. Obstacles include patients' compliance with the technology, their ergonomic design and the need to reimburse providers for their care. Designing appropriate electronic tools and tailoring them to the conditions in France merits our attention.


The use of a Cissus quadrangularis/Irvingia gabonensis combination in the management of weight loss: a double-blind placebo-controlled study.
To evaluate the effects of two formulations, Cissus quadrangularis-only and a Cissus quadrangularis/Irvingia gabonensis combination, on weight loss in overweight and obese human subjects. The study was a 10 week randomized, double-blind, placebo-controlled design involving 72 obese or overweight participants (45.8% male; 54.2% female; ages 21-44; mean age = 29.3). The participants were randomly divided into three equal (n = 24) groups: placebo, Cissus quadrangularis-only, and Cissus quadrangularis/Irvingia gabonensis combination. Capsules containing the placebo or active formulations were administered twice daily before meals; no major dietary changes nor exercises were suggested during the study. A total of six anthropomorphic and serological measurements (body weight, body fat, waist size; total plasma cholesterol, LDL cholesterol, fasting blood glucose level) were taken at baseline and at 4, 8 and 10 weeks. Compared to the placebo group, the two active groups showed a statistically significant difference on all six variables by week 10. The magnitude of the differences was noticeable by week 4 and continued to increase over the trial period. Although the Cissus quadrangularis-only group showed significant reductions on all variables compared to the placebo group, the Cissus quadrangularis/Irvingia gabonensis combination resulted in even larger reductions. This apparently synergistic formulation should prove helpful in the management of obesity and its related complications.


The role of phosphagen specificity loops in arginine kinase.
Phosphagen kinases catalyze the reversible transfer of a phosphate between ATP and guanidino substrates, a reaction that is central to cellular energy homeostasis. Members of this conserved family include creatine and arginine kinases and have similar reaction mechanisms, but they have distinct specificities for different guanidino substrates. There has not been a full structural rationalization of specificity, but two loops have been implicated repeatedly. A small domain loop is of length that complements the size of the guanidino substrate, and is located where it could mediate a lock-and-key mechanism. The second loop contacts the substrate with a valine in the methyl-substituted guanidinium of creatine, and with a glutamate in the unsubstituted arginine substrate, leading to the proposal of a discriminating hydrophobic/hydrophilic minipocket. In the present work, chimeric mutants were constructed with creatine kinase loop elements inserted into arginine kinase. Contrary to the prior rationalizations of specificity, most had measurable arginine kinase activity but no creatine kinase activity or enhanced phosphocreatine binding. Guided by structure, additional mutations were introduced in each loop, recovering arginine kinase activities as high as 15% and 64% of wild type, respectively, even though little activity would be expected in the constructs if the implicated sites had dominant roles in specificity. An atomic structure of the mismatched complex of arginine kinase with creatine and ADP indicates that specificity can also be mediated by an active site that allows substrate prealignment that is optimal for reactivity only with cognate substrates and not with close homologs that bind but do not react.


Nitric oxide and autonomic control of heart rate: a question of specificity.
Despite its highly diffusible nature, the gaseous signalling molecule nitric oxide (NO) can exert specific effects within the CNS and PNS. To date, the specificity of the actions of NO remains an unsolved puzzle. There are several plausible mechanisms that might account for this specificity in the context of autonomic regulation of heart rate. NO acts at distinct levels within the autonomic nervous system to control cardiac rate, with opposing effects at different sites. We discuss factors that might contribute to this diversity of action, and conclude that the isoform of enzyme involved in producing NO, the spatial proximity of the NO source to the target, and differences in the intracellular coupling within the target cell are all crucial for encoding the functional action of NO.


Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.
Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.


Golgi-derived vesicles from developing epithelial cells bind actin filaments and possess myosin-I as a cytoplasmically oriented peripheral membrane protein.
In the intestinal brush border, the mechanoenzyme myosin-I links the microvillus core actin filaments with the plasma membrane. Previous immunolocalization shows that myosin-I is associated with vesicles in mature enterocytes (Drenckhahn, D., and R. Dermietzel. 1988. J. Cell Biol. 107:1037-1048) suggesting a potential role mediating vesicle motility. We now report that myosin-I is associated with Golgi-derived vesicles isolated from cells that are rapidly assembling brush borders in intestinal crypts. Crypt cells were isolated in hyperosmotic buffer, homogenized, and fractionated using differential- and equilibrium-density centrifugation. Fractions containing 50-100-nm vesicles, a similar size to those observed in situ, were identified by EM and were shown to contain myosin-I as demonstrated by immunoblotting and immunolabel negative staining. Galactosyltransferase, a marker enzyme for trans-Golgi membranes was present in these fractions, as was alkaline phosphatase, which is an apical membrane targeted enzyme. Galactosyltransferase was also present in vesicles immuno-purified with antibodies to myosin-I. Villin, a marker for potential contamination from fragmented microvilli, was absent. Myosin-I was found to reside on the vesicle "outer" or cytoplasmic surface for it was accessible to exogenous proteases and intact vesicles could be immunolabeled with myosin-I antibodies in solution. The bound myosin-I could be extracted from the vesicles using NaCl, KI and Na2CO3, suggesting that it is a vesicle peripheral membrane protein. These vesicles were shown to bundle actin filaments in an ATP-dependent manner. These results are consistent with a role for myosin-I as an apically targeted motor for vesicle translocation in epithelial cells.


A metagenomic library cloning strategy that promotes high-level expression of captured genes to enable efficient functional screening.
Functional screening of environmental DNA (eDNA) libraries is a potentially powerful approach to discover enzymatic "unknown unknowns", but is usually heavily biased toward the tiny subset of genes preferentially transcribed and translated by the screening strain. We have overcome this by preparing an eDNA library via partial digest with restriction enzyme FatI (cuts CATG), causing a substantial proportion of ATG start codons to be precisely aligned with strong plasmid-encoded promoter and ribosome-binding sequences. Whereas we were unable to select nitroreductases from standard metagenome libraries, our FatI strategy yielded 21 nitroreductases spanning eight different enzyme families, each conferring resistance to the nitro-antibiotic niclosamide and sensitivity to the nitro-prodrug metronidazole. We showed expression could be improved by co-expressing rare tRNAs and encoded proteins purified directly using an embedded His6-tag. In a transgenic zebrafish model of metronidazole-mediated targeted cell ablation, our lead MhqN-family nitroreductase proved ∼5-fold more effective than the canonical nitroreductase NfsB.


Silicosis at autopsy in platinum mine workers.
South Africa is the largest producer of platinum group metals in the world. Platinum is found in the Bushveld Complex in the north-east of the country. This volcanic intrusion contains many other minerals, including crystalline silica. Little is known about the health risks in the platinum mining industry. To explore the potential for platinum mine workers to develop silicosis. Autopsies are performed at the National Institute for Occupational Health, for compensation purposes. Platinum mine workers, who had worked for more than a year and had silicosis and/or fibrotic nodules in the lymph nodes, were identified from the autopsy database. An exhaustive search of other available data sources was undertaken to exclude exposure to silica dust in the gold mining industry. Eighty-five of 3863 (2.2%) platinum mine workers employed for more than a year had silicosis at autopsy; an additional 490 (12.7%) had fibrotic nodules in the lymph nodes. After reviewing all data sources, five mine workers with silicosis and 25 with fibrotic nodules in the lymph nodes fulfilled the study inclusion criteria. This case series supports the suggestion that there is a risk of silica exposure in platinum mine workers, a hypothesis supported by the few silica dust measurements taken in the platinum mines. The mining companies should be cognisant of this risk. The recording of comprehensive work histories and the routine measurement of silica dust levels should be enforced to enable risk of disease to be quantified in future studies.


Multiple Drug Resistant Urinary Tract Infection in Kidney Transplant Recipients: A Retrospective Cohort Study.
Urinary tract infection (UTI) is the most common infectious disease in post-kidney transplantation patients. The objective of the study was to investigate the prevalence, impact and risk factors of multiple drug resistant (MDR) UTI in kidney transplant recipients. This retrospective cohort study recruited 72 kidney transplant recipients between March 2017 and February 2018. Urine cultures performed during the 1st year of posttransplantation with reference to clinical data were evaluated. Predesigned questionnaire was used to collect data regarding demographic, transplant related, and microbiological information. Multivariate analysis was performed to ascertain risk factors of MDR UTI. Out of 72 patients, 28 (38.9%) had culture guided clinical UTI. Overall, 59 UTI episodes were noted throughout the duration of this study. Eschericia coli were found to be the most frequent uropathogen of UTI among kidney transplant recipients (n = 32, 54.2%). MDR bacteria were responsible for 27.1% (n = 16) of the post-transplantation UTI episodes among patients, with E. coli (n = 9, 56.3%) being the predominant bacterial pathogen. Most of the MDR strains of E. coli (n = 7, 77.8%) were extended spectrum beta-lactamase positive. Female gender (P <0.001), prolonged Foley's catheterization (P = 0.002), coexisting diabetes mellitus (DM) (P <0.001) and induction of anti-thymocyte globulin (ATG) therapy (P <0.001) were independently associated with high risk of MDR UTI. The allograft rejection was found to be significantly higher in patients of posttransplantation UTI with MDR uropathogen (P = 0.009). In conclusion, E. coli were the most prominent uropathogen of UTI with and without MDR pathogen in the present study. Female gender, prolonged Foley's catheterization, coexisting DM, and induction of ATG therapy were the risk factors independently associated with MDR UTI in kidney transplant recipients. MDR organisms were significantly associated with allograft rejection.


Genetics of HPA-axis, depression and suicidality.
The ultimate consequence of mental ill-health, suicidal behavior (SB), is a significant problem in most societies of the world. Suicide causes about one million deaths worldwide each year, and 10-20 times more people attempt suicide. The causes of why certain people engage in SB are complex, involving for e.g., both environmental and genetic factors, and interactions in-between. Well-established environmental risk factors are events causing significant psychological stress, which are particularly difficult to cope with, e.g. exposure to physical and sexual abuse. Excessive stress have the potential to induce unfavorable effects in a variety of higher brain-functions, incurred as side-effects to maladaptive responses in the genetically controlled stress-responsive neurosystems, e.g. the hypothalamic-pituitary-adrenal (HPA) axis; a major and systemic stress-modulator, which is mainly controlled by the regulatory corticotrophin releasing hormone receptor 1 (CRHR1) gene. Variation in-between individuals in such stress-regulatory genes such as CRHR1, may underlie the causes of the increased susceptibility of certain individuals towards SB. Here we review some of the current knowledge on what is known about the roles of the HPA axis in SB, with a focus on CRHR1.


Diversity and Ice Nucleation Activity of Microorganisms Collected With a Small Unmanned Aircraft System (sUAS) in France and the United States.
Many microbes relevant to crops, domestic animals, and humans are transported over long distances through the atmosphere. Some of these atmospheric microbes catalyze the freezing of water at higher temperatures and facilitate the onset of precipitation. We collected microbes from the lower atmosphere in France and the United States with a small unmanned aircraft system (sUAS). 55 sampling missions were conducted at two locations in France in 2014 (an airfield in Pujaut, and the top of Puy de Dôme), and three locations in the U.S. in 2015 (a farm in Blacksburg, Virginia, and a farm and a lake in Baton Rouge, Louisiana). The sUAS was a fixed-wing electric drone equipped with a remote-operated sampling device that was opened once the aircraft reached the desired sampling altitude (40-50 meters above ground level). Samples were collected on agar media (TSA, R4A, R2A, and CA) with and without the fungicide cycloheximide. Over 4,000 bacterial-like colonies were recovered across the 55 sUAS sampling missions. A positive relationship between sampling time and temperature and concentrations of culturable bacteria was observed for sUAS flights conducted in France, but not for sUAS flights conducted in Louisiana. A droplet freezing assay was used to screen nearly 2,000 colonies for ice nucleation activity, and 15 colonies were ice nucleation active at temperatures warmer than -8°C. Sequences from portions of 16S rDNA were used to identify 503 colonies from 54 flights to the level of genus. Assemblages of bacteria from sUAS flights in France (TSA) and sUAS flights in Louisiana (R4A) showed more similarity within locations than between locations. Bacteria collected with sUAS on TSA in France and Virginia were significantly different across all levels of classification tested (P < 0.001 for class, order, family, and genus). Principal Coordinates Analysis showed a strong association between the genera Curtobacterium, Pantoea, and Pseudomonas from sUAS flights in Virginia, and Agrococcus, Lysinibacillus, and Paenibacillus from sUAS flights in France. Future work aims to understand the potential origin of the atmospheric microbial assemblages collected with sUAS, and their association with mesoscale atmospheric processes.


Thermal variability increases the impact of autumnal warming and drives metabolic depression in an overwintering butterfly.
Increases in thermal variability elevate metabolic rate due to Jensen's inequality, and increased metabolic rate decreases the fitness of dormant ectotherms by increasing consumption of stored energy reserves. Theory predicts that ectotherms should respond to increased thermal variability by lowering the thermal sensitivity of metabolism, which will reduce the impact of the warm portion of thermal variability. We examined the thermal sensitivity of metabolic rate of overwintering Erynnis propertius (Lepidoptera: Hesperiidae) larvae from a stable or variable environment reared in the laboratory in a reciprocal common garden design, and used these data to model energy use during the winters of 1973-2010 using meteorological data to predict the energetic outcomes of metabolic compensation and phenological shifts. Larvae that experienced variable temperatures had decreased thermal sensitivity of metabolic rate, and were larger than those reared at stable temperatures, which could partially compensate for the increased energetic demands. Even with depressed thermal sensitivity, the variable environment was more energy-demanding than the stable, with the majority of this demand occurring in autumn. Autumn phenology changes thus had disproportionate influence on energy consumption in variable environments, and variable-reared larvae were most susceptible to overwinter energy drain. Therefore the energetic impacts of the timing of entry into winter dormancy will strongly influence ectotherm fitness in northern temperate environments. We conclude that thermal variability drives the expression of metabolic suppression in this species; that phenological shifts will have a greater impact on ectotherms in variable thermal environments; and that E. propertius will be more sensitive to shifts in phenology in autumn than in spring. This suggests that increases in overwinter thermal variability and/or extended, warm autumns, will negatively impact all non-feeding dormant ectotherms which lack the ability to suppress their overwinter metabolic thermal sensitivity.


Elucidation of the Strongest Factors Influencing Rapid Retinal Nerve Fiber Layer Thinning in Glaucoma.
To determine which groupings of prognostic factors best explain the rapid progressive retinal nerve fiber layer (RNFL) thinning in patients with primary open-angle glaucoma (POAG). Optic nerves of 111 POAG patients who were followed for at least 2.5 years, during which the RNFL thickness was measured by serial spectral-domain optical coherence tomography (OCT) were included. Eyes were imaged using enhanced depth-imaging spectral-domain OCT and swept-source OCT angiography to determine the lamina cribrosa curvature index (LCCI), and the presence of a choroidal microvasculature dropout (cMvD), respectively. The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements. A regression tree model was used to find groupings of factors that best explain the rate of future RNFL thinning. Disc hemorrhage, larger LCCI, and presence of cMvD were associated with faster global RNFL thinning in the multivariate regression analysis. The regression tree analysis revealed three stratified groups based on the rate of RNFL thinning, divided by the LCCI and the presence of cMvD. Eyes with LCCI ≥11.87 had the fastest RNFL thinning (-2.4 ± 0.8 μm/year, mean ± SD). Among eyes with LCCI <11.87, the presence of cMvD was the strongest factor influencing faster RNFL thinning (-1.5 ± 0.8 μm/year). Eyes with LCCI <11.87 and without a cMvD exhibited the slowest RNFL thinning (-0.8 ± 0.9 μm/year). Our regression tree model demonstrated that larger LCCI, and then the presence of cMvD were the first and second strongest prognostic factors for faster progressive RNFL thinning. Further studies may be needed to confirm these findings.


Evaluation of Suitable Internal Control Genes for RT-qPCR in Yak Mammary Tissue during the Lactation Cycle.
The yak is primarily found throughout the Tibetan high plateau and the surrounding mountainous area of south central Asia; among its others attributes, its milk is very important for the local population. A key concern in the field of yak research is the better understanding of which genes control the production and composition of milk. The most accurate and sensitive method for gene expression analysis is quantitative reverse transcription polymerase chain reaction (RT-qPCR). It is essential for reliable RT-qPCR to be able to the normalize the data using internal control genes (ICGs). However, it is critical to assess the reliability of the normalization by testing multiple ICGs. Our objective was to uncover a reliable normalization for RT-qPCR data obtained from yak mammary tissue during the lactation cycle. We assessed the reliability of 10 ICGs (ACTB, EIF6, GAPDH, LRP10, MRPL39, MRPS15, MTG1, RPS8, RPS23, and UXT) using geNorm. The analysis revealed that all of the tested ICGs can be considered to be reliable, but the use of the 6 most stable ICGs should be applied to yield a reliable normalization factor (NF). We compared the results of 3 target genes (CSN1S1, ESR1, and MYC) normalized using 6, 3, or 1 of the best ICGs. We did not observe overall differences between the 3 normalization strategies with the exception of 1 time point in MYC. The use of only a single ICG is not recommended; thus, we concluded that the calculation of the NF using the 3 best ICGs, MRPS15, RPS23, and UXT, is a reliable normalization strategy for RT-qPCR data obtained from yak mammary tissue during pregnancy and lactation. A dilution effect of the ICGs due to a large increase in the mRNA of abundantly expressed genes in bovine and porcine mammary tissue during the lactation cycle was previously observed. To test for the presence of a dilution effect in our study, we evaluated the pattern of non-normalized RT-qPCR data of ICGs from pregnancy to lactation and compared them with the total RNA concentration, milk yield, and non-normalized RT-qPCR data of 3 target genes. With a few exceptions, the non- normalized RT-qPCR data for the tested ICGs was significantly increased by lactation and had a positive correlation with total RNA and the non-normalized RT-qPCR data of CSN1S1. These data clearly indicated the presence of a "concentration effect" of single mRNA that remains unexplained but needs to be accounted for during the normalization of RT-qPCR data. Based on our findings, we recommend that the NF of the MRPS15, RPS23, and UXT genes should be used in the normalization of RT-qPCR data obtained from mammary tissue of lactating yaks during pregnancy and lactation.


Seasonality of sodium and potassium consumption in Switzerland. Data from three cross-sectional, population-based studies.
Blood pressure displays a seasonal pattern. Whether this pattern is related to high sodium and/or low potassium intakes has not been investigated. We assessed if sodium and potassium consumption present a seasonal pattern. We also simulated the impact of seasonality of sodium consumption on systolic blood pressure levels. Data from three Swiss population-based studies (n = 2845). Sodium and potassium consumption were assessed by urinary excretion using 24 h urine collection. Seasonality was assessed using the cosinor model and was adjusted for study, gender, age, body mass index, antihypertensive drug treatment, urinary creatinine and atmospheric relative humidity. The effect of sodium variation on blood pressure levels was estimated using data from a recent meta-analysis. Both sodium and potassium excretions showed a seasonal pattern. For sodium, the nadir occurred between August and October, and the peak between February and April, with a multivariate-adjusted seasonal variation (difference between peak and nadir) of 9.2 mmol. For potassium, the nadir occurred in October and the peak in April, with a multivariate-adjusted seasonal variation of 4.0 mmol. Excluding participants on antihypertensive drug treatment or stratifying the analysis by gender cancelled the seasonality of sodium consumption. The maximum impact of the seasonal variation in sodium consumption on systolic blood pressure ranged from 0.4 to 1.1 mm Hg, depending on the model considered. Sodium and potassium consumptions present specific seasonal variations. These variations do not explain the seasonal variations in blood pressure levels.


Protection against a fungal pathogen conferred by the aphid facultative endosymbionts Rickettsia and Spiroplasma is expressed in multiple host genotypes and species and is not influenced by co-infection with another symbiont.
Many insects harbour facultative endosymbiotic bacteria, often more than one type at a time. These symbionts can have major effects on their hosts' biology, which may be modulated by the presence of other symbiont species and by the host's genetic background. We investigated these effects by transferring two sets of facultative endosymbionts (one Hamiltonella and Rickettsia, the other Hamiltonella and Spiroplasma) from naturally double-infected pea aphid hosts into five novel host genotypes of two aphid species. The symbionts were transferred either together or separately. We then measured aphid fecundity and susceptibility to an entomopathogenic fungus. The pathogen-protective phenotype conferred by the symbionts Rickettsia and Spiroplasma varied among host genotypes, but was not influenced by co-infection with Hamiltonella. Fecundity varied across single and double infections and between symbiont types, aphid genotypes and species. Some host genotypes benefit from harbouring more than one symbiont type.


Gluten sensitivity: from gut to brain.
Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.


Picosecond fluorescence of intact and dissolved PSI-LHCI crystals.
Over the past several years, many crystal structures of photosynthetic pigment-protein complexes have been determined, and these have been used extensively to model spectroscopic results obtained on the same proteins in solution. However, the crystal structure is not necessarily identical to the structure of the protein in solution. Here, we studied picosecond fluorescence of photosystem I light-harvesting complex I (PSI-LHCI), a multisubunit pigment-protein complex that catalyzes the first steps of photosynthesis. The ultrafast fluorescence of PSI-LHCI crystals is identical to that of dissolved crystals, but differs considerably from most kinetics presented in the literature. In contrast to most studies, the data presented here can be modeled quantitatively with only two compartments: PSI core and LHCI. This yields the rate of charge separation from an equilibrated core (22.5 +/- 2.5 ps) and rates of excitation energy transfer from LHCI to core (k(LC)) and vice versa (k(CL)). The ratio between these rates, R = k(CL)/k(LC), appears to be wavelength-dependent and scales with the ratio of the absorption spectra of LHCI and core, indicating the validity of a detailed balance relation between both compartments. k(LC) depends slightly but nonsystematically on detection wavelength, averaging (9.4 +/- 4.9 ps)(-1). R ranges from 0.5 (<690 nm) to approximately 1.3 above 720 nm.


Non-tuberculous mycobacteria isolated from slaughter pigs in Mubende district, Uganda.
The importance of infections caused by non-tuberculous mycobacteria (NTM) in animals and humans has gained considerable recognition during the past few years. In the developed world, where pig production is extensively practiced, studies on mycobacterial infections and related control strategies have received increasing attention. The infections are reported to be caused by a wide spectrum of NTM. Unfortunately, these infections have been less recognized in sub-Saharan Africa owing to lack of awareness and systematic studies. In this study we aimed at isolating and identifying species of mycobacteria involved in causing infections in slaughter pigs in Mubende district of Uganda. Furthermore we wanted to identify factors associated with infection prevalence in the study area. A total of 363 lymph nodes were collected and cultured for the presence of mycobacteria. Isolates were identified by 16S rDNA gene sequencing. A questionnaire survey was administered to identify production related factors associated with infection prevalence. Data were assembled and analysed using descriptive statistics and mixed effects logistic regression analysis. Mycobacteria were detected in 39 % (143/363) of the examined lymph nodes, 63 % (59/93) of lymph nodes with gross lesions typical of mycobacteriosis and 31% (84/270) of lymph nodes with no visible lesions. Nineteen per cent of the isolated mycobacteria were identified as Mycobacterium (M) avium, of these 78% and 22% were M. avium sub sp. Hominissuis and avium respectively. Other mycobacterial species included M. senuense (16%), M. terrae (7%) and M. asiaticum (6%). This study found free range systems (OR = 3.0; P = 0.034) and use of water from valley dams (OR = 2.0; P = 0.049) as factors associated with high prevalence of mycobacteria in slaughter pigs. This study demonstrated a high prevalence of NTM infections among slaughter pigs in Mubende district of Uganda. M. avium was the most prevalent of all NTM isolated and identified. Free range system of pig management and valley dam water were the most significant factors associated with NTM prevalence in Mubende district. These findings could be of a major public health concern given that it is in a predominantly pork consuming population with 18% HIV/AIDS prevalence. Therefore, stringent post-mortem inspection at the slaughter houses is of paramount importance to reduce human exposure.


Selective cytotoxicity of oxysterols through structural modulation on rings A and B. Synthesis, in vitro evaluation, and SAR.
Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A and B was studied. Oxygen functionalities on ring B, such as oxo, oxime, acetamide, acetate, and alkoxy, were evaluated. Most oxysterols were cytotoxic in the low micromolar range, with emphasis to the tetrols 14 and 34, the 6β methoxy and acetoxy derivatives 21 and 45, and the oxime 28. In general, the oxysterols were more toxic to cancer cells and a set of compounds (9, 14, 21, 28, 45) with very high selectivity was identified. The cytotoxicity of 3β-acetates was lower than that of the parent alcohols, although incubation for a longer period rendered them equally cytotoxic, pointing them as potential prodrugs of oxysterols.


Community falls prevention for people who call an emergency ambulance after a fall: randomised controlled trial.
To evaluate whether a service to prevent falls in the community would help reduce the rate of falls in older people who call an emergency ambulance when they fall but are not taken to hospital. Randomised controlled trial. Community covered by four primary care trusts, England. 204 adults aged more than 60 living at home or in residential care who had fallen and called an emergency ambulance but were not taken to hospital. Referral to community fall prevention services or standard medical and social care. The primary outcome was the rate of falls over 12 months, ascertained from monthly diaries. Secondary outcomes were scores on the Barthel index, Nottingham extended activities of daily living scale, and falls efficacy scale at baseline and by postal questionnaire at 12 months. Analysis was by intention to treat. 102 people were allocated to each group. 99 (97%) participants in the intervention group received the intervention. Falls diaries were analysed for 88.6 person years in the intervention group and 84.5 person years in the control group. The incidence rates of falls per year were 3.46 in the intervention group and 7.68 in the control group (incidence rate ratio 0.45, 95% confidence interval 0.35 to 0.58, P<0.001). The intervention group achieved higher scores on the Barthel index and Nottingham extended activities of daily living and lower scores on the falls efficacy scale (all P<0.05) at the 12 month follow-up. The number of times an emergency ambulance was called because of a fall was significantly different during follow-up (incidence rate ratio 0.60, 95% confidence interval 0.40 to 0.92, P=0.018). A service to prevent falls in the community reduced the fall rate and improved clinical outcome in the high risk group of older people who call an emergency ambulance after a fall but are not taken to hospital. Current Controlled Trials ISRCTN67535605.


Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5.
Upon entry into a host cell, retroviruses direct the reverse transcription of the viral RNA genome and the establishment of an integrated proviral DNA. The retroviral integrase protein (IN) is responsible for the insertion of the viral DNA into host chromosomal targets. The two-hybrid system was used to identify a human gene product that binds tightly to the human immunodeficiency virus-type 1 (HIV-1) integrase in vitro and stimulates its DNA-joining activity. The sequence of the gene suggests that the protein is a human homolog of yeast SNF5, a transcriptional activator required for high-level expression of many genes. The gene, termed INI1 (for integrase interactor 1), may encode a nuclear factor that promotes integration and targets incoming viral DNA to active genes.


Beam-quality improvement of a passively Q-switched Nd:YAG laser with a core-doped rod.
We present experimental results that demonstrate the great efficiency of a core-doped Nd:YAG rod (a hexagonal Nd:YAG core surrounded by undoped YAG) in producing high output power and excellent beam quality. An additional improvement in beam quality is clearly observed when the core-doped rod is used in combination with a LiF:F(2)(-) crystal, which acts as a passive Q-switching element. This improvement is quantified by beam-propagation factors as low as M(2) approximately = at a maximum average output power of 9 W. We show that transversally pumped core-doped rods with the addition of LiF:F(2)(-) crystals fulfill the requirements for high-beam-quality, scalable, compact all-solid-state lasers in passively Q-switched operation.


Mechanistic insights of epithelial protein lost in neoplasm in prostate cancer metastasis.
EPLIN is frequently downregulated or lost in various cancers. The purpose of this study was to evaluate the importance of EPLIN in prostate cancer progression, with particular focus on the mechanistic implications to elucidate EPLIN's tumor suppressive function in cancer. EPLIN expression was evaluated in prostate cancer cell lines and tissues. PC-3 and LNCaP EPLINα overexpression models were generated through transfection with EPLINα sequence and EPLIN knockdown was achieved using shRNA in CA-HPV-10 cells. Functional assays were performed to evaluate cellular characteristics and potential mechanisms were evaluated using a protein microarray, and validated using western blot analysis. EPLIN expression was reduced in clinical prostate cancer sections, including hyperplasia (p ≤ 0.001) and adenocarcinoma (p = 0.005), when compared to normal prostate tissue. EPLINα overexpression reduced cell growth, migration and invasion, and influenced transcript, protein and phosphoprotein expression of paxillin, FAK and Src. EPLIN knockdown increased the invasive and migratory nature of CA-HPV-10 cells and also induced changes to FAK and Src total and/or phospho expression. Functional characterization of cellular migration and invasion in addition to FAK and Src inhibition demonstrated differential effects between control and EPLINα overexpression and EPLIN knockdown cell lines. This study highlights that EPLIN expression in prostate cancer is able to influence several aspects of cancer cell characteristics, including cell growth, migration and invasion. The mechanism of the tumor suppressive action of EPLIN remains to be fully elucidated; and this study proposes a role for EPLIN's ability to regulate the aggressive characteristics of prostate cancer cells partially through regulating FAK/Src signaling.


[Two cases of interstitial pneumonia with anti-PL-12 (alanyl tRNA synthetase) antibodies].
We present two cases of interstitial pneumonia (IP) whose sera contain autoantibodies to PL-12 (alanyl tRNA synthetase). The first patient is a 47-year-old female who was diagnosed as IP and treated with corticosteroid at another hospital. She was admitted to Keio University Hospital due to worsening of dyspnea and polyarthritis. Laboratory studies revealed elevation of LDH and CRP, and her chest radiography showed interstitial fibrosis. Because of clinical deterioration, the dose of corticosteroid was increased (prednisolone 40 mg/day) and her symptom was stabilized. The second patient, a 55 year-old female, was admitted to Tokyo Metropolitan Ohtsuka Hospital because of dyspnea on exertion and polyarthritis. She did not show any symptom of myositis and was diagnosed as IP with arthritis on the basis of her clinical and chest radiography. She was treated with oral corticosteroid (prednisolone 30 mg/day), which resulted in improvement of her respiratory symptom and arthritis. Both patients were found to have autoantibodies to the PL-12. Autoantibodies to aminoacyl tRNA synthetases have been recognized as having a linkage with myositis mainly because of observations of the Jo-1 specificity. There was one report on a North American population that most but not all patients with anti-PL-12 antibodies had myositis. However, the clinical significance of anti-PL-12 has not been examined in Japanese patients. These patients suggested that anti-PL-12 antibodies have a stronger association with IP than myositis in Japanese patients.


Attraction or repulsion: a matter of individual taste?
Cell migration along the correct paths is critical to normal organogenesis and tissue repair, and goes awry in tumor dissemination. Understanding the molecular cues that control such migration would provide opportunities to control these events. Recent findings in Drosophila highlight the role of the epidermal growth factor receptor (EGFR) in chemotaxis and pathfinding during development. These studies, and others performed in vertebrates, support a central role for EGFR-mediated chemotaxis. However, the signal or signals that then enable cells to further migrate independently of this chemotactic effect are not known. Three possible scenarios are discussed: that EGFR signaling sensitizes cells to new cues, that EGFR signaling is altered so that the cell responds predominantly to other motility signals that are now "unblinded," and that EGFR signaling still provides the motile signal but in a chemokinetic manner with matrix components providing the directionality. There are precedents for all three scenarios, but which one proves true will define the window of opportunity for regulating cell migration.


Bone marrow histochemical studies of fibrogenic cytokines and their receptors in myelodysplastic syndrome with myelofibrosis and related disorders.
Cellular and extracellular alterations of various fibrogenic cytokines have been described in a number of different chronic myeloid disorders that are associated with myelofibrosis. However, the available information related to both myelodysplastic syndrome with myelofibrosis (MDS-f) and bone marrow histochemical analysis is limited. In the current study, bone marrow immunohistochemical staining for platelet-derived growth factor, transforming growth factor (TGF)-beta, basic fibroblast growth factor (bFGF), and their receptors was performed in 9 patients with MDS-f, 9 patients with essential thrombocythemia (ET), 8 patients with 5q- syndrome, and 5 healthy control subjects. In addition, TGF-beta1 messenger RNA (mRNA) analysis was performed in 5 patients, each with MDS-f, myelofibrosis with myeloid metaplasia (MMM), polycythemia vera (PV), ET, and immune thrombocytopenic purpura, and in healthy control subjects. In general, protein and transcript expression patterns were similar to normal patterns and not significantly different among the various disease groups. The only exception was a reduced concentration of bFGF-expressing stromal cells in patients with PV, ET, and MMM.


Testing the genetics underlying the co-evolution of mate choice and ornament in the wild.
One of the most debated questions in evolutionary biology is whether female choice of males with exaggerated sexual displays can evolve as a correlated response to selection acting on genes coding for male attractiveness or high overall viability. To date, empirical studies have provided support for parts of this scenario, but evidence for all key genetic components in a natural population is lacking. Here we use animal-model quantitative genetic analysis on data from over 8,500 collared flycatchers (Ficedula albicollis) followed for 24 years to quantify all of the key genetic requirements of both fisherian and 'good-genes' models on sexual selection in the wild. We found significant additive genetic variances of all the main components: male ornament (forehead patch size), female mate choice for this ornament, male fitness and female fitness. However, when the necessary genetic correlations between these components were taken into account, the estimated strength of indirect sexual selection on female mate choice was negligible. Our results show that the combined effect of environmental influences on several components reduces the potential for indirect sexual selection in the wild. This study provides insight into the field of sexual selection by showing that genes coding for mate choice for an ornament probably evolve by their own pathways instead of 'hitchhiking' with genes coding for the ornament.


Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience.
Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were assessed in the elevated plus maze test for classifying rats as highly anxious 'affected' vs. 'non-affected', i.e. behaving as control animals. Analyzing the activation of specific interneuron subpopulations in the dorsal and ventral dentate gyrus (DG), the basolateral (BLA) and central amygdala by immunohistochemical double-labeling for cFos and different interneuron markers, revealed an increased activation of cholecystokinin (CCK)-positive interneurons in the ventral DG, together with increased activation of parvalbumin- and CCK-positive interneurons in the BLA of affected trauma-exposed rats. By contrast, increased activation of neuropeptide Y (NPY)-positive interneurons was observed in the dorsal DG of trauma-exposed, but non-affected rats. To test for a direct contribution of NPY in the dorsal DG to trauma resilience, a local shRNA-mediated knock down was performed after UWT. Such a treatment significantly reduced the prevalence of resilient animals. Our results suggest that distinct interneuron populations are associated with resilience or pathology in PTSD with high regional specificity. NPY within the dorsal DG was found to significantly contribute to trauma resilience.


Vector wave analysis for nonnormal incident rays in epimicroscopic refractive index profile measurements.
We have investigated the effects of nonnormal incident rays in calculating the refractive index profile of a dielectric sample using the reflectance measurement data obtained with a scanning confocal epimicroscope and also by solving three-dimensional vector wave equations for linearly polarized light. The numerically calculated reflection data of tightly focused Gaussian beams with different numerical apertures (NAs) on planar surfaces with various refractive indices confirm that the reflectance increases with an increase in the NA of a focusing objective lens. This is due to the nonnormal incident ray components of a Gaussian beam. We have found that the refractive index obtained with the assumption of a normal incident beam is far from the real value when the NA of a focusing lens becomes larger than 0.5, and thus the variation in the reflectance for different angular components in a Gaussian beam must be taken into consideration while using a larger NA lens. Errors in practical refractive index calculation for an optical fiber based on a normal incident beam in reflectance measurements can be as large as 1% in comparison to real values calculated by our three-dimensional vector wave equations.


Promoting reduced and discontinued substance use among adolescent substance users: effectiveness of a universal prevention program.
Efforts to address youth substance use have focused on prevention among non-users and treatment among severe users with less attention given to youth occupying the middle ground who have used substances but not yet progressed to serious abuse or addiction. Using a sample from 35 middle schools of 1,364 youth who reported using substances, this study examined the effectiveness of a universal youth substance use prevention program, the SAMHSA Model Program keepin' it REAL, in promoting reduced or recently discontinued alcohol, cigarette, and marijuana use. Discrete-time event history methods modeled the rates of reduced and recently discontinued use across four waves of data. Each substance (alcohol, cigarettes, and marijuana) was modeled separately. Beginning at the second wave, participants who reported use at wave 1 were considered at risk of reducing or discontinuing use. Since the data sampled students in schools, multi-level models accounted for the nesting of data at the school level. Results indicated that prevention program participation influenced the rates of reduced and recently discontinued use only for alcohol, controlling for baseline use severity, age, grades, socioeconomic status, ethnicity and gender. Among youth who reported use of alcohol in wave 1 (N=1,028), the rate of reducing use for program participants was 72% higher than the rate for control students. The rate of discontinuing use was 66% higher than the rate for control students. Among youth who reported use of one or more of the three substances in wave 1 (N=1,364), the rate of discontinuing all use was 61% higher for program participants than for control students. Limitations and implications of these findings and plans for further research are discussed.


Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model.
Periostin (PN), a secreted adhesion-related protein expressed in the periosteum and periodontal ligaments, acts as a critical regulator of the formation and maintenance of bone and teeth, and also plays an important role in tumorigenesis. Although PN is highly expressed in various types of human cancers, its function is still unclear. In this study, we focused on the exon 17 region of PN, which is alternatively spliced out. To investigate the function of full-length PN with exon 17, we produced a neutralizing antibody (PN1-Ab) against the peptide encoded by exon 17. In vivo, administration of PN1-Ab significantly inhibited the growth of primary tumors as well as metastatic tumors, associated with prevention of bone destruction, resulting in increased survival of mice. Consistent with in vivo data, the present in vitro study demonstrated that addition of full-length PN significantly inhibited cell adhesion and detached adherent cells, while PN1-Ab inhibited the action of PN in a dose-dependent manner. In addition, PN1-Ab significantly inhibited the proliferation, migration and invasion of 4T1 mouse breast cancer cells, which produced PN. Interestingly, PN1-Ab also inhibited the differentiation of osteoclasts. Overall, the present study demonstrated that PN plays a pivotal role in the progression and metastasis of breast cancer. Since administration of PN1-Ab prolonged cell survival through inhibition of the progression and metastasis of 4T1 cells, further development of the PN1-Ab such as generation of a humanized antibody may provide a new therapeutic agent against breast cancer.


Activation of cathepsin D by glycosaminoglycans.
We have previously shown that heparin can increase the activity of the proenzyme form of Alzheimer's beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Cathepsin D (CD) is a member of the aspartic protease family and has sequence similarity to BACE1. Therefore, we examined whether heparin and other glycosaminoglycans (GAGs) can influence the activity of CD. Heparin and other GAGs were found to stimulate the activity of recombinant proCD. Desulfation of heparin almost abolished the stimulation, indicating that sulfate groups were important for the stimulatory effect. In addition, the stimulation was dependent on the length of the GAG chain, as larger GAGs were more potent in their ability to stimulate proCD than shorter fragments. In the presence of heparin, limited autocatalytic proteolysis of the proenzyme was increased, suggesting that heparin increases the activity of proCD by accelerating the conversion of proCD, which has little activity, to pseudoCD, an active form lacking residues 1-26 of the prodomain. Furthermore, the activity of spleen-derived mature CD, which lacks the entire 44 amino acid residue prodomain, was also increased by heparin, indicating that the catalytic domain of CD contains at least one region to which GAGs bind and stimulate enzyme activity. Because heparin also stimulated the activity of pseudoCD, proenzyme activation was probably accelerated by the interaction of heparin with the catalytic domain of pseudoCD. However, it is possible that heparin may also activate the proenzyme directly. On the basis of this study, we propose that GAGs may regulate CD activity in vivo.


The Importance of Scabies Coinfection in the Treatment Considerations for Impetigo.
Skin infections account for a high disease burden in indigenous children living in northern Australia. Although the relationship between impetigo and scabies is recognized, the prevalence of scabies in children with impetigo is not well reported. We report the prevalence, demographics and treatment success outcomes of impetigo and scabies coinfection in indigenous children who were participants in a randomized controlled trial of impetigo treatment conducted in remote communities of the Northern Territory, Australia. Of 1715 screening episodes for impetigo, 508 children were randomized to receive intramuscular benzathine benzylpenicillin (BPG), twice daily co-trimoxazole (SXT) for 3 days (4 mg/kg trimethoprim plus 20 mg/kg sulfamethoxazole per dose) or once daily SXT for 5 days (8 mg/kg trimethoprim plus 40 mg/kg sulfamethoxazole per dose). A clinical diagnosis of scabies; tinea of the skin, scalp or nail; and head lice was made on all children. Scabies presence was not confirmed using diagnostic scrapings. In a post-hoc analysis, we determined whether coinfection with scabies had an impact on treatment success for impetigo. Of children randomized to receive treatment for impetigo, 84 of 508 (16.5%) had scabies. The presence of scabies ranged from 14.3% to 20.0% in the 3 treatment groups. Treatment success for impetigo with and without scabies coinfection, independent of the treatment groups, was 75.9% and 86.6%, respectively, absolute difference 10.7% [95% confidence interval (CI): +1% to +21%]. Treatment success for impetigo with and without scabies coinfection in the BPG group was 69.6% and 88.0%, respectively, absolute difference 18.4% (95% CI: -1% to +38%). In the pooled SXT groups, the treatment success for impetigo with and without scabies coinfection was 78.6% and 86.0%, respectively, with absolute difference 7.4% (95% CI: -4% to +18%). Treatment success in the pooled SXT group with scabies (78.6%) was higher than in the BPG group (69.6%) with scabies, absolute difference 9.0% (95% CI: +0.1% to +18%). Prediction of treatment success for impetigo is dependent on the presence or absence of scabies and for scabies coinfected impetigo it was higher in the group treated with SXT. The burden of scabies in an impetigo trial for Indigenous children was high. Treatment success for scabies coinfection was lower than for impetigo overall, with a higher success seen in the SXT group than the BPG group.


Thought disorder in alcoholics.
Research on cognitive impairment in chronic alcoholics has generally focused on pathology associated with organic brain damage. On the other hand, deficits more typical of the functional psychoses have been less explored, due to the absence of appropriate tests. By using the Thought Disorder Rating Scale (TDRS) recently developed at our Center, however, we have tested chronic alcoholics for the presence of classical symptoms of thought disorder. This test is based on the assessment of the patient's verbal behavior by an experienced clinician. Twenty subjects free of psychosis, severe withdrawal symptoms, and medical illness were, after detoxification, administered a test battery which included the TDRS, the Bender-Gestalt Test, and the Zung Self-rating Depression Scale (SDS). Five scored pathologically for thought disorder and of them four had abnormal Benders; whereas only two of 15 of those without thought disorder had abnormal Benders (t = 2.84, p < .01). Although SDS scores for both groups were in the depressed range, there was no significant difference between SDS means for the two groups. TDRS scores for these alcoholics are compared with those for other diagnosed groups, and implications for future investigation are discussed.


Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs.


Restoring oak forests through direct seeding or planting: Protocol for a continental-scale experiment.
The choice of revegetating via direct seeding or planting nursery-grown seedlings influences the potential stresses suffered by seedlings such as herbivory and drought. The outcome of the balance between both revegetation methods may ultimately depend on how species identity and traits such as seed and seedling size interact with environmental conditions. To test this, we will conduct a continental-scale experiment consisting of one mini-experiment replicated by multiple participants across Europe. Each participant will establish a site with seeded and planted individuals of one or more native, locally growing oak (Quercus) species; the selection of this genus aims to favour continental-scale participation and to allow testing the response of a widely distributed genus of broad ecological and economic relevance. At each site, participants will follow the present protocol for seed collection, seeding in the field, nursery cultivation, outplanting, protection against herbivores, site maintenance, and measurement of seedling performance and environmental variables. Each measurement on each species at each site will produce one effect size; the data will be analysed through mixed-effects meta-analysis. With this approach we will assess the main effect of revegetation method, species, plant functional traits, and the potential effect of site-specific effect moderators. Overall, we will provide a continental-scale estimate on the seeding vs. planting dilemma and analyse to what extent the differences in environmental conditions across sites, seed size, functional traits, and the phylogenetic relatedness of species can account for the differences in the effect of revegetation method on seedling performance across study sites and species.


Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial.
Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population. Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups: <65, 65-74 and ≥75 years. For men ≥75 years, these outcomes were compared between DPq3w, DPq1w, and mitoxantrone (MP) arms. Tolerability outcomes included dose delivery, grade 3/4 adverse events and quality of life. Efficacy outcomes included overall survival and tumor response. Of 1006 men with metastatic castrate-resistant prostate cancer (mCRPC) in the trial, 335 received DPq3w. Among these, 20% were age ≥75 years. For DPq3w, there were non-significant associations of worse tolerability and efficacy with advancing age. Twenty-eight percent of men age ≥75 years had an objective pain response, compared to 38% and 34% of patients 65-74 and <65 years, respectively. There were no significant differences in prostate-specific antigen (PSA) response (43-48%, p = 0.74) or measurable tumor response (7-17%, p = 0.30) according to age. Among men ≥75 years, DPq3w resulted in more dose reductions than DPq1w (22% versus 8%, p = 0.007), but tolerability was otherwise comparable. Both were associated with more favorable efficacy than mitoxantrone. Tolerability and efficacy of DPq3w appear less favorable with advancing age. Compared to DPq1w, DPq3w is associated with better survival outcomes, but similar tolerability, and remains the standard first-line chemotherapy option in mCRPC. Toxicity is substantial, therefore careful patient selection, close monitoring and early management of toxicities is advised.


Socioeconomic deprivation impact on meat intake and mortality: NIH-AARP Diet and Health Study.
Previous studies have not examined potential interactions between meat intake and characteristics of the local environment on the risk of mortality. This study examined the impact of area socioeconomic deprivation on the association between meat intake and all-cause and cause-specific mortality after accounting for individual-level risk factors. In the prospective NIH-AARP Diet and Health Study, we analyzed data from adults, ages 50-71 years at baseline (1995-1996). Individual-level dietary intake and health risk information were linked to the demographic and socioeconomic context of participants' local environment based on census tract data. Deaths (n = 33,831) were identified through December 2005. Multilevel Cox models were used to estimate hazard ratios and 95% confidence intervals for quintiles of area deprivation scores. Associations of red and processed meats with mortality were consistent across deprivation quintiles. Men residing in least-deprived neighborhoods had a stronger protective effect for white meat consumption. No differences by deprivation index were observed for women. Red and processed meat intake increases mortality risk regardless of level of deprivation within a given neighborhood suggesting biological mechanisms rather than neighborhood contextual factors may underlie these meat-mortality associations. The effect of white meat intake on cancer mortality was modified by area deprivation among men.


Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.
To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. Southern Australia. All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.


Forest malaria in Cambodia: the occupational and spatial clustering of Plasmodium vivax and Plasmodium falciparum infection risk in a cross-sectional survey in Mondulkiri province, Cambodia.
After a marked reduction in malaria burden in Cambodia over the last decades, case numbers increased again in 2017-2018. In light of the national goal of malaria elimination by 2025, remaining pockets of high risk need to be well defined and strategies well-tailored to identify and target the persisting burden cost-effectively. This study presents species-specific prevalence estimates and risk stratification for a remote area in Cambodia. A cross-sectional survey was conducted in 17 villages in the high-incidence province Mondulkiri in the dry season (December 2017 to April 2018). 4200 randomly selected participants (2-80 years old) were tested for Plasmodium infection by PCR. Risk of infection was associated with questionnaire-derived covariates and spatially stratified based on household GPS coordinates. The prevalence of PCR-detectable Plasmodium infection was 8.3% (349/4200) and was more than twice as high for Plasmodium vivax (6.4%, 268) than for Plasmodium falciparum (3.0%, 125, p < 0.001). 97.8% (262/268) of P. vivax and 92.8% (116/125, p < 0.05) of P. falciparum infections were neither accompanied by symptoms at the time of the interview nor detected by microscopy or RDT. Recent travels to forest sites (aOR 2.17, p < 0.01) and forest work (aOR 2.88, p < 0.001) were particularly strong risk factors and risk profiles for both species were similar. Large village-level differences in prevalence of Plasmodium infection were observed, ranging from 0.6% outside the forest to 40.4% inside. Residing in villages at the forest fringe or inside the forest compared to outside was associated with risk of infection (aOR 2.14 and 12.47, p < 0.001). Villages inside the forest formed spatial hotspots of infection despite adjustment for the other risk factors. Persisting pockets of high malaria risk were detected in forested areas and in sub-populations engaging in forest-related activities. High levels of asymptomatic infections suggest the need of better case detection plans and the predominance of P. vivax the implementation of radical cure. In villages inside the forest, within-village exposure was indicated in addition to risk due to forest activities. Village-level stratification of targeted interventions based on forest proximity could render the elimination efforts more cost-effective and successful.


Health literacy, self-perceived health and self-reported chronic morbidity among older people in Kosovo.
The aim was to describe health literacy among the older population of Kosovo, an Albanian speaking post-war country in the Western Balkans, in the context of self-perceived health status and self-reported chronic morbidity. A cross-sectional study was conducted in Kosovo in 2011 including 1753 individuals aged ≥ 65 years (886 men, 867 women; mean age 73.4 ± 6.3 years; response rate: 77%). Participants were asked to assess, on a scale from 1 to 5, their level of difficulty with regard to access, understanding, appraisal and application of health information. Sub-scale scores and an overall health literacy score were calculated for each participant. Information on self-perceived health status, presence and number of chronic diseases and socioeconomic characteristics was also collected. Mean values of the overall health literacy score and all sub-scale scores (access, understanding, appraisal and application) were lower among older people who reported a poorer health status or at least one chronic condition compared with individuals who perceived their health status as good or had no chronic conditions (p < 0.001 for all). Our findings provide valuable evidence on the independent and inverse association between health literacy levels and self-perceived health and chronic morbidity in this post-war European population. The putative link with chronic morbidity and lower adherence to health services is hard to establish through this cross-sectional study. Prospective population-based studies should be conducted in Kosovo and other transitional settings to replicate these findings and properly address the causal relationship between health literacy and health status.


Extending the host range of Listeria monocytogenes by rational protein design.
In causing disease, pathogens outmaneuver host defenses through a dedicated arsenal of virulence determinants that specifically bind or modify individual host molecules. This dedication limits the intruder to a defined range of hosts. Newly emerging diseases mostly involve existing pathogens whose arsenal has been altered to allow them to infect previously inaccessible hosts. We have emulated this chance occurrence by extending the host range accessible to the human pathogen Listeria monocytogenes by the intestinal route to include the mouse. Analyzing the recognition complex of the listerial invasion protein InlA and its human receptor E-cadherin, we postulated and verified amino acid substitutions in InlA to increase its affinity for E-cadherin. Two single substitutions increase binding affinity by four orders of magnitude and extend binding specificity to include formerly incompatible murine E-cadherin. By rationally adapting a single protein, we thus create a versatile murine model of human listeriosis.


Design of a novel small peptide targeted against a tumor-specific receptor.
EGFRvIII is the most common deletion variant of the epidermal growth factor receptor and is found in cancers of the brain, breast, ovary, and lung. The complete absence of the receptor in healthy tissues makes it an ideal tumor marker. We sought to design a peptide ligand against EGFRvIII for development as a diagnostic imaging agent. We used the concept of hydropathic complementarity to search for sequences whose amino acid sidechains display a reciprocal pattern of hydropathicity to those of the deletion junction of EGFRvIII. The resulting peptide (PEPHC1) was synthesized and tested for binding to EGFRvIII and EGFR. In in vitro assays, PEPHC1 bound the recombinant EGFRvIII extracellular domain or full-length EGFRvIII solubilized from cell membranes in preference to native EGFR. These results demonstrate the utility of hydropathic complementarity as a basis for the design of highly specific ligands that may prove useful as tumor-targeting agents.


Meta-analysis of probiotics for the treatment of irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a chronic condition affecting 3%-25% of the general population. As no curative treatment is available, therapy is aimed at reducing symptoms, often with little success. Because alteration of the normal intestinal microflora has been observed in IBS, probiotics (beneficial microbes taken to improve health) may be useful in reducing symptoms. This paper systematically reviews randomized, controlled, blinded trials of probiotics for the treatment of IBS and synthesizes data on efficacy across trials of adequate quality. PubMed, Medline, Google Scholar, NIH registry of clinical trials, metaRegister, and the Cochrane Central Register of Controlled Trials were searched from 1982-2007. We also conducted secondary searches of reference lists, reviews, commentaries, relevant articles on associated diseases, books and meeting abstracts. Twenty trials with 23 probiotic treatment arms and a total of 1404 subjects met inclusion criteria. Probiotic use was associated with improvement in global IBS symptoms compared to placebo [pooled relative risk (RR pooled) 0.77, 95% confidence interval (95% CI) 0.62-0.94]. Probiotics were also associated with less abdominal pain compared to placebo [RR pooled = 0.78 (0.69-0.88)]. Too few studies reported data on other IBS symptoms or on specific probiotic strains to allow estimation of a pooled RR. While our analyses suggest that probiotic use may be associated with improvement in IBS symptoms compared to placebo, these results should be interpreted with caution, given the methodological limitations of contributing studies. Probiotics warrant further study as a potential therapy for IBS.


Exposition to xenophobic content and support for right-wing populism: The asymmetric role of gender.
This paper studies whether exposure to anti-immigrant sentiment in the online context affects the willingness to support an openly anti-immigration party, and shows how gender moderates the effect. We designed an online experiment in which participants were invited to an online forum to discuss immigration issues. We manipulate the social acceptability of xenophobic views by exposing participants to an increasing proportion of comments with anti-immigrant content. As a proxy for open support for anti-immigrant policies, we ask participants to donate to a well-known German party with a strong anti-immigration discourse: Alternative für Deutschland (Alternative for Germany). We find no evidence that exposure to increasing social acceptability of xenophobic content affected the willingness to donate. In an exploratory analysis, we find that women are particularly reluctant to donate after the anti-immigrant comments raised normative concerns. The results can shed light on the heterogeneous effect of counter-normative discourses on support for anti-immigrant parties.


Palmitoylethanolamide Reverses Paclitaxel-Induced Allodynia in Mice.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a serious complication associated with antineoplastic drugs. Although there are no medications available that effectively prevent CIPN, many classes of drugs have been used to treat this condition, including anticonvulsants, serotonin and noradrenaline reuptake inhibitors, and opioids. However, these therapeutic options yielded inconclusive results in CIPN clinical trials and produced assorted side effects with their prolonged use. Thus, there is an urgent need to develop efficacious and safe treatments for CIPN. In this report, we tested whether the endogenous lipid palmitoylethanolamide (PEA) alone or in combination with the anticonvulsant gabapentin would reduce allodynia in a mouse paclitaxel model of CIPN. Gabapentin and PEA reversed paclitaxel-induced allodynia with respective ED50 doses (95% confidence interval) of 67.4 (61.52-73.94) and 9.2 (8.39-10.16) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. The PPAR-α antagonist receptor antagonist GW6471 [N-((2S)-2-(((1Z)-1-methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)phenyl)propyl)propanamide] completely blocked the antinociceptive effects of PEA. In addition, PEA administered via intraplantar injection into a paw, intrathecal injection, and intracerebroventricular injection reversed paclitaxel-induced allodynia, suggesting that it may act at multiple sites in the neuroaxis and periphery. Finally, repeated administration of PEA (30 mg/kg, 7 days) preserved the antiallodynic effects with no evidence of tolerance. These findings taken together suggest that PEA possesses potential to treat peripheral neuropathy in cancer patients undergoing chemotherapy.


Numerical cognition in bees and other insects.
The ability to perceive the number of objects has been known to exist in vertebrates for a few decades, but recent behavioral investigations have demonstrated that several invertebrate species can also be placed on the continuum of numerical abilities shared with birds, mammals, and reptiles. In this review article, we present the main experimental studies that have examined the ability of insects to use numerical information. These studies have made use of a wide range of methodologies, and for this reason it is striking that a common finding is the inability of the tested animals to discriminate numerical quantities greater than four. Furthermore, the finding that bees can not only transfer learnt numerical discrimination to novel objects, but also to novel numerosities, is strongly suggestive of a true, albeit limited, ability to count. Later in the review, we evaluate the available evidence to narrow down the possible mechanisms that the animals might be using to solve the number-based experimental tasks presented to them. We conclude by suggesting avenues of further research that take into account variables such as the animals' age and experience, as well as complementary cognitive systems such as attention and the time sense.