skn-1-Dependent and -independent regulation of aip-1 expression following metabolic stress in Caenorhabditis elegans.
Maintenance of a stable, properly folded, and catalytically active proteome is a major challenge to organisms in the face of multiple internal and external stresses which damage proteins and lead to protein misfolding. Here we show that internal metabolic stress produced by reactive intermediates resulting from tyrosine degradation triggers the expression of the aip-1 gene, which is critical in responses to the environmental toxin arsenic and the clearance of unstable polyglutamine and Abeta proteins. aip-1 acts via binding to the proteosome and enhancing proteosomal function. We find that full induction of aip-1 depends on the oxidative-stress-responsive skn-1 transcription factor but significant induction still occurs without skn-1. Importantly, activation of skn-1 with wdr-23(RNAi), which dramatically induces the expression of other skn-1 target genes, produces a minimal increase in aip-1 expression. This suggests that the previously demonstrated specificity in aip-1/AIRAP induction could reflect the actions of multiple synergistic activators, such as the heat shock factor homolog hsf-1, which we also find is required for full induction. These may be triggered by proteosome dysfunction, as we find that this event links the multiple inducers of aip-1. Together, our results show that cell stress triggers aip-1 expression by both skn-1-dependent and -independent pathways.


A novel peptide (GX1) homing to gastric cancer vasculature inhibits angiogenesis and cooperates with TNF alpha in anti-tumor therapy.
The discovery of the importance of angiogenesis in tumor growth has emphasized the need to find specific vascular targets for tumor-targeted therapies. Previously, using phage display technology, we identified the peptide GX1 as having the ability to target the gastric cancer vasculature. The present study investigated the bioactivities of GX1, as well as its potential ability to cooperate with recombinant mutant human tumor necrosis factor alpha (rmhTNFalpha), in gastric cancer therapy. Tetrazolium salt (MTT) assay showed that GX1 could inhibit cell proliferation of both human umbilical vein endothelial cells (HUVEC) (44%) and HUVEC with tumor endothelium characteristics, generated by culturing in tumor-conditioned medium (co-HUVEC) (62%). Flow-cytometry (FCM) and western blot assays showed that GX1 increased the rate of apoptosis from 11% to 31% (p < 0.01) by up-regulating caspase 3 expression level. A chorioallantoic membrane assay indicated that GX1 could suppress neovascularization in vivo, with the microvessel count decreasing from 21 to 11 (p < 0.05). When GX1 was fused to rmhTNFalpha, GX1-rmhTNFalpha selectively concentrated in the gastric cancer vasculature, as shown by enzyme-linked immunosorbent assay, immunofluorescence and emission-computed tomography. In vitro MTT and FCM assays showed that, compared to rmhTNFalpha alone, GX1-rmhTNFalpha was more effective at suppressing co-HUVEC proliferation (45% vs. 61%, p < 0.05) and inducing apoptosis (11% vs. 23%, p < 0.05). In a tumor formation test, GX1-rmhTNFalpha more effectively inhibited tumor growth than rmhTNFalpha (tumor volume: 271 mm3 vs. 134 mm3, p < 0.05), with less systemic toxicity as measured by body weight (20.57 g vs. 19.30 g, p < 0.05). These therapeutic effects may be mediated by selectively enhanced tumor vascular permeability, as indicated by Evan's blue assay. GX1 had both homing activity and the ability to inhibit vascular endothelial cell proliferation in vitro and neovascularization in vivo. Furthermore, when GX1 was conjugated to rmhTNFalpha, the fusion protein was selectively delivered to targeted tumor sites, significantly improving the anti-tumor activity of rmhTNFalpha and decreasing systemic toxicity. These results demonstrate the potential of GX1 as a homing peptide in vascular targeted therapy for gastric cancer.


Thromboembolism in inflammatory bowel disease: role of platelets.
Patients with inflammatory bowel disease are susceptible to thromboembolism and recently small vessel thrombosis has been implicated as an aetiological factor in Crohn's disease. This study therefore investigated platelet function in 104 patients with inflammatory bowel disease of whom eight had previous thromboembolism. Thirty five patients had reproducible spontaneous platelet aggregation of more than 30% (0 in controls) (p < 0.0001). A further 20 patients showed hypersensitivity of platelets to low concentrations of aggregating agents (p < 0.001). Plasma thromboxane B2 and beta thromboglobulin levels were significantly higher than controls (p < 0.001 and p < 0.001), but platelet lifespan studies were normal. There was no correlation with disease activity. Patients with inflammatory bowel disease have abnormal platelet activity, which may contribute to the inflammatory process.


"Found in Translation": predicting outcomes of complex organic chemistry reactions using neural sequence-to-sequence models.
There is an intuitive analogy of an organic chemist's understanding of a compound and a language speaker's understanding of a word. Based on this analogy, it is possible to introduce the basic concepts and analyze potential impacts of linguistic analysis to the world of organic chemistry. In this work, we cast the reaction prediction task as a translation problem by introducing a template-free sequence-to-sequence model, trained end-to-end and fully data-driven. We propose a tokenization, which is arbitrarily extensible with reaction information. Using an attention-based model borrowed from human language translation, we improve the state-of-the-art solutions in reaction prediction on the top-1 accuracy by achieving 80.3% without relying on auxiliary knowledge, such as reaction templates or explicit atomic features. Also, a top-1 accuracy of 65.4% is reached on a larger and noisier dataset.


Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma.
Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreER(T) line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury.


Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies.
Mesenchymal stem cells (MSCs) have potential for therapeutic application as an immunomodulatory and regenerative agent. The immunogenicity and survival of MSCs after infusion are, however, not clear and evidence suggests that allogeneic but also autologous MSCs disappear rapidly after infusion. This may be associated with the susceptibility of MSCs to lysis by natural killer (NK) cells, possibly a result of culture-induced stress. In the present study we examined whether NK cell-mediated lysis of MSCs could be inhibited by immunosuppressive drugs. Human MSCs were isolated from adipose tissue and expanded in culture. Peripheral blood mononuclear cells were activated with interleukin (IL)-2 (200 U/ml) and IL-15 (10 ng/ml) for 7 days. CD3(-)CD16(+)CD56(+) NK cells were then isolated by fluorescence-activated cell sorting and added to europium-labeled MSCs for 4 hr in the presence or absence of immunosuppressive drugs. Lysis of MSCs was determined by spectrophotometric measurement of europium release. Nonactivated NK cells were not capable of lysing MSCs. Cytokine-activated NK cells showed upregulated levels of granzyme B and perforin and efficiently lysed allogeneic and autologous MSCs. Addition of tacrolimus, rapamycin or sotrastaurin to the lysis assay did not inhibit MSC killing. Furthermore, preincubation of activated NK cells with the immunosuppressive drugs for 24 hr before exposure to MSCs had no effect on MSC lysis. Last, addition of the immunosuppressants before and during the activation of NK cells, reduced NK cell numbers but did not affect their capacity to lyse MSCs. We conclude that the immunosuppressive drugs tacrolimus, rapamycin, and sotrastaurin are not capable of inhibiting the lysis of allogeneic and autologous MSCs by activated NK cells. Other approaches to controlling lysis of MSCs should be investigated, as controlling lysis may determine the efficacy of MSC therapy.


Health care professionals' willingness to do mouth-to-mouth resuscitation.
To assess the willingness of physicians and nurses with training in basic cardiac life support to provide mouth-to-mouth resuscitation in both hospital and out-of-hospital settings, we surveyed all attendees at a monthly advanced life support course over a 1-year period. Of 622 attendees, 379 (61%) responded to our survey describing a variety of cardiac arrest scenarios. Less than half of the participants surveyed were willing to do mouth-to-mouth resuscitation on an unknown adult, male or female, who had collapsed in a supermarket. Overall, the group was willing to do mouth-to-mouth resuscitation on victims known to them: their neighbors (84%), children at a pool (88%), spouses (94%), and parents (93%). In the hospital setting, knowing a patient's human immunodeficiency virus (HIV) status greatly influenced the willingness to do mouth-to-mouth rescue. If a patient's HIV status was unknown, only a third of providers would do mouth-to-mouth resuscitation; if the HIV status was known to be negative, two thirds would do mouth-to-mouth resuscitation (P < 0.002), Children in the hospital whose HIV status was unknown would receive mouth-to-mouth resuscitation by 57% of the respondents. Children known to be HIV-negative would be resuscitated by 79% of the respondents. Co-workers were more willing to resuscitate a known physician or nurse than an unknown co-worker, with physicians more willing than nurses to do mouth-to-mouth resuscitation on an unknown co-worker. A third of the group has performed mouth-to-mouth resuscitation previously. Although an increased percentage of this subgroup was willing to provide mouth-to-mouth in all adult hospital scenarios, experienced providers of mouth-to-mouth wanted to receive mouth-to-mouth resuscitation less frequently (75%) than inexperienced providers (84%) (P = 0.02). The self-reported willingness to provide mouth-to-mouth resuscitation is influenced by patient characteristics; as the level of familiarity with the victim decreased, so did the willingness of the health care professional to do mouth-to-mouth.


Two halide-containing cesium manganese vanadates: synthesis, characterization, and magnetic properties.
Two new halide-containing cesium manganese vanadates have been synthesized by a high-temperature (580 °C) hydrothermal synthetic method from aqueous brine solutions. One compound, Cs3Mn(VO3)4Cl, (1) was prepared using a mixed cesium hydroxide/chloride mineralizer, and crystallizes in the polar noncentrosymmetric space group Cmm2, with a = 16.7820(8) Å, b = 8.4765(4) Å, c = 5.7867(3) Å. This structure is built from sinusoidal zig-zag (VO3)n chains that run along the b-axis and are coordinated to Mn2+ containing (MnO4Cl) square-pyramidal units that are linked together to form layers. The cesium cations reside between the layers, but also coordinate to the chloride ion, forming a cesium chloride chain that also propagates along the b-axis. The other compound, Cs2Mn(VO3)3F, (2) crystallizes in space group Pbca with a = 7.4286(2) Å, b = 15.0175(5) Å, c = 19.6957(7) Å, and was prepared using a cesium fluoride mineralizer. The structure is comprised of corner sharing octahedral Mn2+ chains, with trans fluoride ligands acting as bridging units, whose ends are capped by (VO3)n vanadate chains to form slabs. The cesium atoms reside between the manganese vanadate layers, and also play an integral part in the structure, forming a cesium fluoride chain that runs along the b-axis. Both compounds were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and single-crystal Raman spectroscopy. Additionally, the magnetic properties of 2 were investigated. Above 50 K, it displays behavior typical of a low dimensional system with antiferromagnetic interactions, as to be expected for linear chains of manganese(ii) within the crystal structure.


A Prospective Birth Cohort Study on Maternal Cholesterol Levels and Offspring Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences.
Growing evidence suggests that maternal cholesterol levels are important in the offspring's brain growth and development. Previous studies on cholesterols and brain functions were mostly in adults. We sought to examine the prospective association between maternal cholesterol levels and the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. We analyzed data from the Boston Birth Cohort, enrolled at birth and followed from birth up to age 15 years. The final analyses included 1479 mother-infant pairs: 303 children with ADHD, and 1176 neurotypical children without clinician-diagnosed neurodevelopmental disorders. The median age of the first diagnosis of ADHD was seven years. The multiple logistic regression results showed that a low maternal high-density lipoprotein level (≤60 mg/dL) was associated with an increased risk of ADHD, compared to a higher maternal high-density lipoprotein level, after adjusting for pertinent covariables. A "J" shaped relationship was observed between triglycerides and ADHD risk. The associations with ADHD for maternal high-density lipoprotein and triglycerides were more pronounced among boys. The findings based on this predominantly urban low-income minority birth cohort raise a new mechanistic perspective for understanding the origins of ADHD and the gender differences and future targets in the prevention of ADHD.


Parathyroid-hormone-related-protein-associated hypercalcemia in a patient with CLL-type low-grade leukemic B-cell lymphoma.
Humoral hypercalcemia of malignancy is a common metabolic disturbance associated with solid tumors, but it also occurs in lymphoma patients. Among these, low grade B-cell lymphoma accounts for only few cases, in which secretion of parathyroid hormone-related protein (PTHrP) remains even exceptional. We report the very rare case of a patient with a CLL type low grade leukemic B-cell lymphoma showing PTHrP-related hypercalcemia without evidence of bone lesions. Using immunohistochemistry, we demonstrate the cytoplasmic expression of PTHrP by the lymphoma cells in the bone marrow obtained at the onset of hypercalcemia. We postulate a pathogenetic role of leukemic cell production and secretion of PTHrP in hypercalcemia in low grade leukemic B-cell lymphoma.


Contact-line pinning controls how quickly colloidal particles equilibrate with liquid interfaces.
Previous experiments have shown that spherical colloidal particles relax to equilibrium slowly after they adsorb to a liquid-liquid interface, despite the large interfacial energy gradient driving the adsorption. The slow relaxation has been explained in terms of transient pinning and depinning of the contact line on the surface of the particles. However, the nature of the pinning sites has not been investigated in detail. We use digital holographic microscopy to track a variety of colloidal spheres-inorganic and organic, charge-stabilized and sterically stabilized, aqueous and non-aqueous-as they breach liquid interfaces. We find that nearly all of these particles relax logarithmically in time over timescales much larger than those expected from viscous dissipation alone. By comparing our results to theoretical models of the pinning dynamics, we infer the area per defect to be on the order of a few square nanometers for each of the colloids we examine, whereas the energy per defect can vary from a few kT for non-aqueous and inorganic spheres to tens of kT for aqueous polymer particles. The results suggest that the likely pinning sites are topographical features inherent to colloidal particles-surface roughness in the case of silica particles and grafted polymer "hairs" in the case of polymer particles. We conclude that the slow relaxation must be taken into account in experiments and applications, such as Pickering emulsions, that involve colloids attaching to interfaces. The effect is particularly important for aqueous polymer particles, which pin the contact line strongly.


Understanding of the aging pattern in quantum dot light-emitting diodes using low-frequency noise.
The negative and positive aging effects of quantum dot (QD) light-emitting diodes (QLEDs) have received considerable attention in recent years and various analysis methods have been discussed. Here, we introduce a new approach to understand the aging effect of QLEDs, which is to diagnose the behavior of carriers and traps at interfaces between each layer of the QLEDs and inside the layers themselves. In particular, low-frequency noise (LFN) measurement and the analysis of current in the QLEDs were introduced to investigate the trapping/de-trapping behaviors of carriers in the defect states in the devices. A flicker noise was observed before the carriers are injected into the QD emitting layer, while the exciton generation-recombination (G-R) noise and shot noise were observed when the electrons were injected. A correlated noise, which is the correlated model of the trapping/de-trapping of the carriers near and/or inside the QDs and the exciton recombination, was also observed above the turn-on voltage. In addition, when the devices were aged with a constant current source, rapid increases in the luminance and external quantum efficiency (EQE) were observed for up to 50 h. After 100 h of the current aging, however, the devices were negatively aged with the reduced EQE. The LFN analysis results imply that the aging phenomena mainly depend on the trapping/de-trapping of carriers. In addition to the LFN analysis, we also investigated the current density-voltage-luminance and capacitance-voltage characteristics of the devices to clarify the aging behaviors in QLEDs.


The Zarit Burden Interview: a new short version and screening version.
The purpose of the study was to develop a short and a screening version of the Zarit Burden Interview (ZBI) that would be suitable across diagnostic groups of cognitively impaired older adults, and that could be used for cross-sectional, longitudinal, and intervention studies. We used data from 413 caregivers of cognitively impaired older adults referred to a memory clinic. We collected information on caregiver burden with the 22-item ZBI, and information about dependence in activities of daily living (ADLs) and the frequency of problem behaviors among care recipients. We used factor analysis and item-total correlations to reduce the number of items while taking into consideration diagnosis and change scores. We produced a 12-item version (short) and a 4-item version (screening) of the ZBI. Correlations between the short and the full version ranged from 0.92 to 0.97, and from 0.83 to 0.93 for the screening version. Correlations between the three versions and ADL and problem behaviors were similar. We further investigated the behavior of the short version with a two-way analysis of variance and found that it produced identical results to the full version. The short and screening versions of the ZBI produced results comparable to those of the full version. Reducing the number of items did not affect the properties of the ZBI, and it may lead to easier administration of the instrument.


A cross-sectional study describing factors associated with utilisation of GP services by a cohort of people who inject drugs.
People who inject drugs (PWID) use healthcare services, including primary care, at a disproportionately high rate. We investigated key correlates of general practitioner (GP) related service utilisation within a cohort of PWID. Using baseline data from a cohort of 645 community-recruited PWID based in Melbourne, Victoria, we conducted a secondary analysis of associations between past month use of GP services unrelated to opioid substitution therapy (OST) and socio-demographic and drug use characteristics and self-reported health using multivariate logistic regression. Just under one-third (29%) of PWID had accessed GP services in the month prior to being surveyed. Participants who reported living with children (adjusted odds ratio, AOR 1.97, 95% CI 1.04 - 3.73) or having had contact with a social worker in the past month (AOR 1.92, 95% CI 1.24 - 2.98) were more likely to have seen a GP in the past month. Participants who were injecting daily or more frequently (AOR 0.50, 95% CI 0.30 - 0.83) or had a weekly income of less than $400 (AOR 0.59, 95% CI 0.38 - 0.91) were less likely to report having seen a GP in the past month. Our sample frequently attended GP services for health needs unrelated to OST. Findings highlight both the characteristics of PWID accessing GP services and also those potentially missing out on primary care and preventive services.


Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus.
Helicobacter hepaticus has been associated with naturally occurring hepatitis in certain inbred strains of mice, and in A/JCr mice it has been linked to the development of hepatic adenomas and adenocarcinomas. H. hepaticus was orally inoculated into 30 axenic, outbred female mice, and the mice were studied longitudinally to fulfill Koch's postulates and to ascertain the pathogenic potential of the organism under defined germfree conditions. Ten cage contact mice were also housed in the same germfree isolator to study transmission patterns, and 10 germfree mice were maintained in separate isolators as controls. Mice serially euthanized from 3 weeks through 24 months postinoculation (p.i.) were surveyed by culture and PCR for H. hepaticus in liver and intestinal tissues. Tissues were analyzed for histopathological changes, and sera were assayed for the presence of immunoglobulin G antibody to H. hepaticus and changes in the liver enzyme alanine aminotransferase. Inoculated mice and cage contact mice were persistently infected with H. hepaticus as identified by culture and PCR, in both the intestine and, less frequently, the liver, for the duration of the 2-year study. Animals developed persistent chronic hepatitis, and in some animals enterocolitis was noted. Hepatocellular carcinoma was diagnosed in one H. hepaticus-infected mouse. The level of H. hepaticus serum antibody was highest in experimentally infected mice at 12 to 18 months p.i.; this corresponded in general to the time interval when the highest levels of alanine aminotransferase were recorded. Although cage contact mice became persistently infected with H. hepaticus, lesions were less severe and the levels of serological biomarkers utilized in the study were lower. The H. hepaticus-infected mouse will provide an ideal model to study putative bacterial virulence determinants and how they interact with the host to induce chronic inflammation and tumorigenesis.


The effect of emergency department copayments for Medicaid beneficiaries following the Deficit Reduction Act of 2005.
High unemployment during the 2007-2009 Great Recession and eligibility expansions have increased the size and cost of Medicaid. To provide states with flexibility in administering the program while containing costs, the Deficit Reduction Act of 2005 (DRA) gave states the authority to impose cost-sharing strategies, including emergency department (ED) copayments for nonurgent visits. To our knowledge, there has been no previous longitudinal analysis of the effect of the DRA on health care utilization outcomes for Medicaid beneficiaries. To evaluate the effect of the DRA, which allowed states to enforce ED copayments for nonurgent visits, on ED utilization among Medicaid beneficiaries and to compare the effect among beneficiaries living in states that did and did not adopt ED copayments. A difference-in-difference quasi-experimental approach was used to compare trends in ED use among Medicaid beneficiaries from January 2001 to December 2010. Eight states with ED copayments for nonurgent ED visits (copayment states) were compared with 10 states with zero ED copayments (control states). The study cohort was the population of individuals 19 to 64 years old enrolled in Medicaid for a full calendar year as collected by the Medical Expenditure Panel Survey, a nationally representative survey of noninstitutionalized US civilians. The cohort consisted of 3122 adult Medicaid recipients in copayment states and 7433 adult Medicaid recipients in control states. The main exposure was the copayment enforcement authority of the DRA. The study controlled for sex, age, race, marital status, income relative to the federal poverty level, educational level, and self-reported health status. The primary outcome of this study was the change in the rate of ED utilization following the DRA. Additional outcomes included changes in the rate of outpatient medical provider visits and inpatient length of stay. Visits were not coded according to urgency, which prevented us from examining only nonurgent ED use. Estimates from a zero-inflated Poisson regression model detected no statistically significant change in annual ED admissions per Medicaid enrollee (change, 0.05; 95% CI, -0.05 to 0.16) in copayment states compared with control states following the DRA. There was also no change in the rate of outpatient medical provider visits (change, 0.02; 95% CI, -0.31 to 0.35) or in annual inpatient days (change, 0.13; 95% CI, -0.31 to 0.57) per Medicaid enrollee. Granting states permission to collect copayments for nonurgent visits under the DRA did not significantly change ED or outpatient medical provider use among Medicaid beneficiaries.


Experiences Building Globus Genomics: A Next-Generation Sequencing Analysis Service using Galaxy, Globus, and Amazon Web Services.
We describe Globus Genomics, a system that we have developed for rapid analysis of large quantities of next-generation sequencing (NGS) genomic data. This system achieves a high degree of end-to-end automation that encompasses every stage of data analysis including initial data retrieval from remote sequencing centers or storage (via the Globus file transfer system); specification, configuration, and reuse of multi-step processing pipelines (via the Galaxy workflow system); creation of custom Amazon Machine Images and on-demand resource acquisition via a specialized elastic provisioner (on Amazon EC2); and efficient scheduling of these pipelines over many processors (via the HTCondor scheduler). The system allows biomedical researchers to perform rapid analysis of large NGS datasets in a fully automated manner, without software installation or a need for any local computing infrastructure. We report performance and cost results for some representative workloads.


A double-blind study of citalopram versus placebo in the treatment of compulsive sexual behaviors in gay and bisexual men.
Compulsive sexual behavior (CSB) is a condition characterized by loss of control over sexual behavior and repeated negative consequences, including unsafe sex. Selective serotonin reuptake inhibitors have been found to reduce CSB symptomatology in open-label trials. The objective of this study was to conduct a preliminary double-blind, placebo-controlled evaluation of the efficacy, acceptability, and tolerability of citalopram in the treatment of CSB. Twenty-eight men who have sex with men who met the threshold for CSB on the basis of existing validated measures participated in a 12-week, double-blind trial of citalopram 20 to 60 mg/day to evaluate its effects on CSB symptoms. The primary efficacy measure was the Yale-Brown Obsessive Compulsive Scale-Compulsive Sexual Behavior. The study was conducted from June 2002 to April 2004. Significant treatment effects were obtained for sexual desire/drive (p < .05) and frequency of masturbation (p < .01) and pornography use (p < .05). Both groups reduced sexual risk, but did not differ significantly. This study provides partial support for the effectiveness of citalopram for reducing symptoms of CSB in this population. Larger-scale trials are recommended to determine the public health benefits of this treatment.


Meta-analysis of the acute effects of nicotine and smoking on human performance.
Empirical studies indicate that nicotine enhances some aspects of attention and cognition, suggesting a role in the maintenance of tobacco dependence. The purpose of this review was to update the literature since our previous review (Heishman et al. Exp Clin Psychopharmacol 2:345-395, 1994) and to determine which aspects of human performance were most sensitive to the effects of nicotine and smoking. We conducted a meta-analysis on the outcome measures of 41 double-blind, placebo-controlled laboratory studies published from 1994 to 2008. In all studies, nicotine was administered, and performance was assessed in healthy adult nonsmokers or smokers who were not tobacco-deprived or minimally deprived (<or=2 h). There were sufficient effect size data to conduct meta-analyses on nine performance domains, including motor abilities, alerting and orienting attention, and episodic and working memory. We found significant positive effects of nicotine or smoking on six domains: fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT (effect size range = 0.16 to 0.44). The significant effects of nicotine on motor abilities, attention, and memory likely represent true performance enhancement because they are not confounded by withdrawal relief. The beneficial cognitive effects of nicotine have implications for initiation of smoking and maintenance of tobacco dependence.


Tubular injury triggers podocyte dysfunction by β-catenin-driven release of MMP-7.
Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we used conditional knockout mice with tubule-specific ablation of β-catenin (Ksp-β-cat-/-) and subjected them to chronic angiotensin II (Ang II) infusion or Adriamycin. Compared with control mice, Ksp-β-cat-/- mice were dramatically protected from proteinuria and glomerular damage. MMP-7, a downstream target of β-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-β-cat-/- littermates. Incubation of isolated glomeruli with MMP-7 ex vivo led to nephrin depletion and impaired glomerular permeability. Furthermore, MMP-7 specifically and directly degraded nephrin in cultured glomeruli or cell-free systems, and this effect was dependent on its proteolytic activity. In vivo, expression or infusion of exogenous MMP-7 caused proteinuria, and genetic ablation of MMP-7 protected mice from Ang II-induced proteinuria and glomerular injury. Collectively, these results demonstrate that β-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.


Independent factor analysis.
We introduce the independent factor analysis (IFA) method for recovering independent hidden sources from their observed mixtures. IFA generalizes and unifies ordinary factor analysis (FA), principal component analysis (PCA), and independent component analysis (ICA), and can handle not only square noiseless mixing but also the general case where the number of mixtures differs from the number of sources and the data are noisy. IFA is a two-step procedure. In the first step, the source densities, mixing matrix, and noise covariance are estimated from the observed data by maximum likelihood. For this purpose we present an expectation-maximization (EM) algorithm, which performs unsupervised learning of an associated probabilistic model of the mixing situation. Each source in our model is described by a mixture of gaussians; thus, all the probabilistic calculations can be performed analytically. In the second step, the sources are reconstructed from the observed data by an optimal nonlinear estimator. A variational approximation of this algorithm is derived for cases with a large number of sources, where the exact algorithm becomes intractable. Our IFA algorithm reduces to the one for ordinary FA when the sources become gaussian, and to an EM algorithm for PCA in the zero-noise limit. We derive an additional EM algorithm specifically for noiseless IFA. This algorithm is shown to be superior to ICA since it can learn arbitrary source densities from the data. Beyond blind separation, IFA can be used for modeling multidimensional data by a highly constrained mixture of gaussians and as a tool for nonlinear signal encoding.


CLE14 peptide signaling in Arabidopsis root hair cell fate determination.
Morphological adjustment is a critical strategy for the survival of plant species in various environments. The CLE (CLAVATA3/EMBRYO SURROUNDING REGION) family of plant polypeptides is known to play important roles in various physiological and developmental processes and the relevant signaling pathways are conserved in diverse land plants. Previously, it has been suggested that overexpression of CLE14 promotes root hair cell differentiation in Arabidopsis roots. To clarify this suggested function of CLE14 peptide on root hair induction, we examined the effect of synthetic CLE14 peptide on Arabidopsis root hair development. Consistent with the results of previous overexpression analyses of CLE14, we demonstrated that application of synthetic CLE14 peptide induced excess root hair formation on CLE14-treated Arabidopsis roots. In addition, CLE14 reduced the expression of the non-hair cell fate determinant gene, GLABRA2. Our results thus indicate that CLE14 can activate the transcriptional regulatory cascade of root hair formation.


Comprehensive quantitative analysis of central carbon and amino-acid metabolism in Saccharomyces cerevisiae under multiple conditions by targeted proteomics.
Decades of biochemical research have identified most of the enzymes that catalyze metabolic reactions in the yeast Saccharomyces cerevisiae. The adaptation of metabolism to changing nutritional conditions, in contrast, is much less well understood. As an important stepping stone toward such understanding, we exploit the power of proteomics assays based on selected reaction monitoring (SRM) mass spectrometry to quantify abundance changes of the 228 proteins that constitute the central carbon and amino-acid metabolic network in the yeast Saccharomyces cerevisiae, at five different metabolic steady states. Overall, 90% of the targeted proteins, including families of isoenzymes, were consistently detected and quantified in each sample, generating a proteomic data set that represents a nutritionally perturbed biological system at high reproducibility. The data set is near comprehensive because we detect 95-99% of all proteins that are required under a given condition. Interpreted through flux balance modeling, the data indicate that S. cerevisiae retains proteins not necessarily used in a particular environment. Further, the data suggest differential functionality for several metabolic isoenzymes.


Recent advances in the pathogenesis and treatment of osteoporosis.
Over recent decades, the perception of osteoporosis has changed from that of an inevitable consequence of ageing, to that of a well characterised and treatable chronic non-communicable disease, with major impacts on individuals, healthcare systems and societies. Characterisation of its pathophysiology from the hierarchical structure of bone and the role of its cell population, development of effective strategies for the identification of those most appropriate for treatment, and an increasing armamentarium of efficacious pharmacological therapies, have underpinned this evolution. Despite this marked progress, individuals who experience a fragility fracture remain under-treated in many areas of the world, and there is substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and treatment.


Pneumoretroperitoneum after Attempted Epidural Anesthesia.
Air may extend to the retroperitoneal space from retroperitoneal perforation of a hollow viscus, infection of the anterior pararenal space with gas-forming organisms and from pneumothorax or pneumomediastinum [1]. Rare pathologies, such as open reduction and internal fixation of femoral fractures and anaerobic abscess of the hip joint have also been described in relation to this complication [1,2]. A rare case of pneumoretroperitoneum caused by insufflation of air during an attempt to achieve epidural anesthesia is described.


Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants.
To compare the efficacy and safety of 5%, 3%, and 0.9% saline solution for treating acute bronchiolitis in the prehospital setting. This was a double-blind trial including consecutive infants aged <18 months treated in an urban urgent care setting. A total of 165 patients were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline with epinephrine every 4 hours. The primary efficacy outcome was bronchiolitis severity score improvement at 48 hours (chi2 analysis). Scores and oxygen saturation immediately before and after each treatment were recorded to assess safety. A total of 187 previously healthy infants (median age, 3.1 months) diagnosed with bronchiolitis were enrolled. Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours, the mean severity score for the 5% saline group was 3.69+/-1.09, and that for the 0.9% saline group was 4.12+/-1.11 (P=.04; difference, 0.43, 95% confidence interval for the difference, 0.02-0.88). The mean severity score for the 3% saline group was intermediate at 4.00+/-1.22. Revisit rates after discharge were similar in the 3 treatment groups. No adverse reactions or other safety concerns were identified. Nebulization with 5% hypertonic saline is safe, can be widely generalizable, and may be superior to current treatment for early outpatient treatment of bronchiolitis.


Insulin resistance in idiopathic dilated cardiomyopathy: a possible etiologic link.
This study was designed to quantify the prevalence of abnormal glucose tolerance and insulin resistance in patients with idiopathic dilated cardiomyopathy (IDCM). Insulin resistance is an independent risk factor for mortality in patients with heart failure (HF) and is a known risk factor for ischemic cardiomyopathy. Though potential physiologic links between insulin resistance and HF have been hypothesized, the relationship between insulin resistance and IDCM remains unclear. A total of 230 consecutive patients from a university HF clinic were screened for IDCM, the absence of diabetes mellitus, and the lack of significant co-morbid conditions. Oral glucose tolerance tests were performed in the 43 patients with IDCM who met these criteria, and their plasma glucose and insulin responses were compared with those of 40 healthy volunteers, matched for age, gender, and body mass index. Plasma glucose responses were higher during the oral glucose tolerance tests in patients with IDCM (p < 0.01), associated with significantly higher plasma insulin concentrations following the oral glucose challenge (p < 0.01). In addition, abnormalities of glucose tolerance were significantly (p < 0.05) more common in patients with IDCM (49% vs. 23%). Insulin resistance and abnormal glucose tolerance are more prevalent in patients with IDCM and represent potentially reversible metabolic derangements in these individuals.


Evaluation of Acute 13-Week Subchronic Toxicity and Genotoxicity of the Powdered Root of Tongkat Ali (Eurycoma longifolia Jack).
Tongkat Ali (Eurycoma longifolia) is an indigenous traditional herb in Southern Asia. Its powdered root has been processed to produce health supplements, but no detailed toxicology report is available. In this study, neither mutagenicity nor clastogenicity was noted, and acute oral LD50 was more than 6 g/kg b.w. After 4-week subacute and 13-week subchronic exposure paradigms (0, 0.6, 1.2, and 2 g/kg b.w./day), adverse effects attributable to test compound were not observed with respect to body weight, hematology, serum biochemistry, urinalysis, macropathology, or histopathology. However, the treatment significantly reduced prothrombin time, partial thromboplastin time, blood urea nitrogen, creatinine, aspartate aminotransferase, creatine phosphate kinase, lactate dehydrogenase, and cholesterol levels, especially in males (P < 0.05). These changes were judged as pharmacological effects, and they are beneficial to health. The calculated acceptable daily intake (ADI) was up to 1.2 g/adult/day. This information will be useful for product development and safety management.


Long-Term Incidence and Predictors of Significant Hearing Loss Requiring Hearing Assistive Devices Among Childhood Cancer Survivors: A Population-Based Study.
Hearing loss is a significant late effect among childhood cancer survivors. Recent guidelines note insufficient evidence to quantify its natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HADs) using population-based health care data. In Ontario, Canada, HAD costs are subsidized by the Assistive Devices Program (ADP). Ontario children < 18 years of age at cancer diagnosis between 1987 and 2016 were identified and linked to ADP claims. Cumulative HAD incidence was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined. We identified 11,842 cases and 59,210 controls. Cases were at higher risk for HAD (hazard ratio [HR], 12.8; 95% CI, 9.8 to 16.7; P < .001). The cumulative incidence of HAD among survivors was 2.1% (95% CI, 1.7% to 2.5%) at 20 years and 6.4% (95% CI, 2.8% to 12.1%) at 30 years post-diagnosis. The 30-year incidence was highest in neuroblastoma (10.7%; 95% CI, 3.8% to 21.7%) and hepatoblastoma (16.2%; 95% CI, 8.6% to 26.0%) survivors. Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis (v 5-9 years; HR, 2.2; 95% CI, 1.4-3.3; P < .001). Relative to no cisplatin exposure, patients receiving < 200 mg/m2 were not at greater risk, unlike those receiving higher cumulative doses. Relative to no cranial or facial radiation, those who had received ≤ 32.00 Gy were at no higher risk, unlike those who had received > 32.00 Gy. Carboplatin exposure was not associated with HAD. Childhood cancer survivors are at elevated risk for requiring HAD, which continues to increase between 20 and 30 years after diagnosis. Thresholds of cisplatin and radiation exposure exist, above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations.


Toxicity of checkpoint inhibitors.
Immunologic checkpoint inhibitor is a new class of antineoplastic drugs which mechanism of action depends on the interaction with the immune system. The first in class was ipilimumab, anti-CTLA4, and soon the anti-PD1 (Programmed Death 1) and anti-PDL1 are expected to be available. Although the profile of adverse events is unique, they are predictable and, by complying with the guidelines available, the management of these drugs is safe in the great majority of patients. Here, it is provided a review of adverse events and their management.


Association between hours worked in paid employment and diet quality, frequency of eating out and consuming takeaways in the UK.
To examine associations between hours worked and diet quality, frequency of eating out and consuming takeaways. Data were taken from the National Diet and Nutrition Survey (2008-2014). Associations between hours worked in paid employment and diet quality, assessed using the Diet Quality Index (DQI) and selected foods and nutrients, were tested using linear regression models. Associations between hours worked and frequency of eating out and consuming takeaways were tested using ordinal logistic regression models. All models were adjusted for sex, age, equivalised household income, household composition and household food role. UK. Adults (n 2154) aged 19-64 years in employment. Mean (95 % CI) hours worked per week was 36·1 (35·6, 36·6) and mean DQI score was 41·9 (41·2, 42·5) %. Hours worked was not associated with DQI score, frequency of eating out or consuming takeaways. Hours worked was positively associated with consuming red meat, processed meat and alcohol intake. Adults working more hours had lower intake of fibre but higher total fat and saturated fat intakes if they lived in households with children. Working hours may not be the main factor driving poor-quality diets among this sample of UK adults in employment. Focusing on consumption of foods prepared outside the household may not be the most efficient way to improve diet quality as effort is needed at all levels. Although it is unclear what is driving the differences in nutrient intakes according to household composition, they are important to consider when developing interventions to improve healthy eating.


Disappearance of immunoglobulins from persistent renal amyloid deposits following stem cell transplantation for heavy-and light-chain amyloidosis.
Immunoglobulin (Ig)-related amyloidosis is the most common type of systemic amyloidosis in the developed countries and involves the kidney in most cases. Clinical remission can be achieved with chemotherapy and/or autologous stem cell transplantation (ASCT). Previous case reports have showed persistence of renal amyloid mass in light-chain amyloidosis (AL) even in the setting of hematologic and renal response. We report a novel finding in two cases of heavy- and light-chain amyloidosis (AHL) in which monoclonal Ig but not serum amyloid P (SAP), apolipoprotein E (ApoE) or amyloid bulk in the kidney regressed after successful therapy. In the pre-treatment renal biopsies, the amyloid deposits stained for one heavy and one light chains (IgG + λ in one case and IgA + κ in one case). Laser microdissection followed by mass spectrometry (LMD/MS) in both cases showed abundant spectra for Ig heavy and light chains, SAP and ApoE. Both patients achieved a hematologic response with disappearance of the monoclonal protein from serum and urine and normalization of serum-free light chain ratio, but renal response occurred in only one patient. Repeat kidney biopsies showed persistence of fibrillar amyloid deposits, but regression of Ig from the amyloid deposits based on immunofluorescence. LMD/MS on the repeat biopsy performed in one case also showed disappearance of Ig but not SAP or ApoE. Our finding suggests that effective chemotherapy and/or ASCT in some patients with AHL not only eliminates the circulating pathogenic monoclonal Ig but also the Ig component of amyloid deposits, which may translate into renal response. This, however, may not lead to regression of amyloid deposits themselves. The latter may require more time or addition of therapeutic agents that target amyloid-associated proteins such as SAP, which are not commercially available.


Peripheral bee venom's anti-inflammatory effect involves activation of the coeruleospinal pathway and sympathetic preganglionic neurons.
There are several reports indicating that the locus coeruleus (LC) is capable of altering immune responses. Moreover, it is well established that the LC is the major source of descending noradrenergic system. Recently we have demonstrated that subcutaneous bee venom (BV) injection dramatically suppressed peripheral inflammation through activation of sympathetic preganglionic neurons (SPNs) leading to release of adreno-medullary catecholamines. Importantly, this 'BV-induced anti-inflammatory effect' (BVAI) is also associated with an increase of the activity of LC. Based on these data, present study examined whether BV-induced LC activation increased the activity of SPNs and this pathway played a role in BVAI using a zymosan-induced inflammatory air pouch model in mice. Unilateral BV injection into left hind limb produced anti-inflammation and specifically increased Fos expression in SPNs of the T7-T11 (which mainly project to adrenal medulla), but not those of the T1-T6 or T12-L2 spinal cord. 6-Hydroxydopamine-induced unilateral lesion of the contralateral, but not ipsilateral (to the BV injection site) LC significantly blocked BVAI and BV-induced Fos expression in SPNs. Additionally, intrathecal administration of idazoxan (alpha2-adrenoceptor antagonist), blocked BVAI. These results indicate that BV-induced activation of the contralateral LC-descending noradrenergic pathway increased the activity of SPNs that project to the adrenal medulla and this pathway is necessary for BVAI.


Carbene stabilized interconnected bis-germylene and its silicon analogue with small methyl substituents.
The cyclic alkyl(amino) carbene (cAAC) [:C{N-C6H3(2,6-IPr2)}(CMe2)2CH2] stabilized MeGeGeMe has been isolated in the molecular form with composition (cAAC)MeGe-GeMe(cAAC) (1) at room temperature. Compound 1 was synthesized from the reduction of MeGeCl3 using three equivalents of KC8 in the presence of one equivalent of cAAC. The corresponding silicon compound (cAAC)MeSi-SiMe(cAAC) (2) was also prepared. Compounds 1 and 2 are the first examples of REER compounds (E = Ge, Si) carrying the smallest organic group. Furthermore the structures of compounds 1 and 2 have been investigated by using theoretical methods. The theoretical analysis of the structure of 1 is in agreement with the formation as an unprecedented carbene stabilized bis-germylene whereas compound 2 can be equally described as carbene stabilized bis-silylene with coordinate bonds as with classical double bonds of a 2,3-disila-1,3-butadiene. The compounds were also characterized by X-ray crystallography.


Infection by chikungunya virus modulates the expression of several proteins in Aedes aegypti salivary glands.
Arthropod-borne viral infections cause several emerging and resurging infectious diseases. Among the diseases caused by arboviruses, chikungunya is responsible for a high level of severe human disease worldwide. The salivary glands of mosquitoes are the last barrier before pathogen transmission. We undertook a proteomic approach to characterize the key virus/vector interactions and host protein modifications that occur in the salivary glands that could be responsible for viral transmission by using quantitative two-dimensional electrophoresis. We defined the protein modulations in the salivary glands of Aedes aegypti that were triggered 3 and 5 days after an oral infection (3 and 5 DPI) with chikungunya virus (CHIKV). Gel profile comparisons showed that CHIKV at 3 DPI modulated the level of 13 proteins, and at 5 DPI 20 proteins. The amount of 10 putatively secreted proteins was regulated at both time points. These proteins were implicated in blood-feeding or in immunity, but many have no known function. CHIKV also modulated the quantity of proteins involved in several metabolic pathways and in cell signalling. Our study constitutes the first analysis of the protein response of Aedes aegypti salivary glands infected with CHIKV. We found that the differentially regulated proteins in response to viral infection include structural proteins and enzymes for several metabolic pathways. Some may favour virus survival, replication and transmission, suggesting a subversion of the insect cell metabolism by arboviruses. For example, proteins involved in blood-feeding such as the short D7, an adenosine deaminase and inosine-uridine preferring nucleoside hydrolase, may favour virus transmission by exerting an increased anti-inflammatory effect. This would allow the vector to bite without the bite being detected. Other proteins, like the anti-freeze protein, may support vector protection.


Reduced head steadiness in whiplash compared with non-traumatic neck pain.
While sensorimotor alterations have been observed in patients with neck pain, it is uncertain whether such changes distinguish whiplash-associated disorders from chronic neck pain without trauma. The aim of this study was to investigate head steadiness during isometric neck flexion in subjects with chronic whiplash-associated disorders (WAD), those with chronic non-traumatic neck pain and healthy subjects. Associations with fatigue and effects of pain and dizziness were also investigated. Head steadiness in terms of head motion velocity was compared in subjects with whiplash (n=59), non-traumatic neck pain (n=57) and healthy controls (n=57) during 2 40-s isometric neck flexion tests; a high load test and a low load test. Increased velocity was expected to reflect decreased head steadiness. The whiplash group showed significantly decreased head steadiness in the low load task compared with the other 2 groups. The difference was explained largely by severe levels of neck pain and dizziness. No group differences in head steadiness were found in the high load task. Reduced head steadiness during an isometric holding test was observed in a group of patients with whiplash-associated disorders. Decreased head steadiness was related to severe pain and dizziness.


How wide is a stream? Spatial extent of the potential "stream signature" in terrestrial food webs using meta-analysis.
The magnitude of cross-ecosystem resource subsidies is increasingly well recognized; however, less is known about the distance these subsidies travel into the recipient landscape. In streams and rivers, this distance can delimit the "biological stream width," complementary to hydro-geomorphic measures (e.g., channel banks) that have typically defined stream ecosystem boundaries. In this study we used meta-analysis to define a "stream signature" on land that relates the stream-to-land subsidy to distance. The 50% stream signature, for example, identifies the point on the landscape where subsidy resources are still at half of their maximum (in- or near-stream) level. The decay curve for these data was best fit by a negative power function in which the 50% stream signature was concentrated near stream banks (1.5 m), but a non-trivial (10%) portion of the maximum subsidy level was still found > 0.5 km from the water's edge. The meta-analysis also identified explanatory variables that affect the stream signature. This improves our understanding of ecosystem conditions that permit spatially extensive subsidy transmission, such as in highly productive, middle-order streams and rivers. Resultant multivariate models from this analysis may be useful to managers implementing buffer rules and conservation strategies for stream and riparian function, as they facilitate prediction of the extent of subsidies. Our results stress that much of the subsidy remains near the stream, but also that subsidies (and aquatic organisms) are capable of long-distance dispersal into adjacent environments, and that the effective "biological stream width" of stream and river ecosystems is often much larger than has been defined by hydro-geomorphic metrics alone. Limited data available from marine and lake sources overlap well with the stream signature data, indicating that the "signature" approach may also be applicable to subsidy spatial dynamics across other ecosystems.


Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs.
Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and isolated deaths attributable to this emerging class of drugs.


Labral Reattachment in Femoroacetabular Impingement Surgery Results in Increased 10-year Survivorship Compared With Resection.
Since the importance of an intact labrum for normal hip function has been shown, labral reattachment has become the standard method for open or arthroscopic treatment of hips with femoroacetabular impingement (FAI). However, no long-term clinical results exist evaluating the effect of labral reattachment. A 2-year followup comparing open surgical treatment of FAI with labral resection versus reattachment was previously performed at our clinic. The goal of this study was to report a concise followup of these patients at a minimum of 10 years. We asked if patients undergoing surgical hip dislocation for the treatment of mixed-type FAI with labral reattachment compared with labral resection had (1) improved hip pain and function based on the Merle d'Aubigné-Postel score; and (2) improved survival at 10-year followup. Between June 1999 and July 2002, we performed surgical hip dislocation with femoral neck osteoplasty and acetabular rim trimming in 52 patients (60 hips) with mixed-type FAI. In the first 20 patients (25 hips) until June 2001, a torn labrum or a detached labrum in the area of acetabular rim resection was resected. In the next 32 patients (35 hips), reattachment of the labrum was performed. The same indications were used to perform both procedures during the periods in question. Of the 20 patients (25 hips) in the first group, 19 patients (95%) (24 hips [96%]) were available for clinical and/or radiographic followup at a minimum of 10 years (mean, 13 years; range, 12-14 years). Of the 32 patients (35 hips) in the second group, 29 patients (91%) (32 hips [91%]) were available for clinical and/or radiographic followup at a minimum of 10 years (mean, 12 years; range, 10-13 years). We used the anterior impingement test to assess pain. Function was assessed using the Merle d'Aubigné- Postel score and ROM. Survivorship calculation was performed using the method of Kaplan-Meier with failure defined as conversion to THA, progression of osteoarthritis (of one grade or more on the Tönnis score), and a Merle d'Aubigné-Postel score < 15. At the 10-year followup, hip pain in hips with labral reattachment was slightly improved for the postoperative Merle d'Aubigné-Postel pain subscore (5.0 ± 1.0 [3-6] versus 3.9 ± 1.7 [0-6]; p = 0.017). No difference existed for the prevalence of hip pain assessed using the anterior impingement test with the numbers available (resection group 52% [11 of 21 hips] versus reattachment group 27% [eight of 30 hips]; odds ratio, 3.03; 95% confidence interval [CI], 0.93-9.83; p = 0.062). Function was slightly better in the reattachment group for the overall Merle d'Aubigné-Postel score (16.7 ± 1.5 [13-18] versus 15.3 ± 2.4 [9-18]; p = 0.028) and hip abduction (45° ± 13° [range, 30°-70°] versus 38° ± 8° [range, 25°-45°]; p = 0.001). Hips with labral reattachment showed a better survival rate at 10 years than did hips that underwent labral resection (78%; 95% CI, 64%-92% versus 46%, 95% CI, 26%-66%; p = 0.009) with the endpoints defined as conversion to THA, progression of osteoarthritis, and a Merle d'Aubigné-Postel score < 15. With isolated endpoints, survival at 10 years was increased for labral reattachment and the endpoint Merle d'Aubigné score < 15 (83%, 95% CI, 70%-97% versus 48%, 95% CI, 28%-69%; p = 0.009) but did not differ for progression of osteoarthritis (83%, 95% CI, 68%-97% versus 81%, 95% CI, 63%-98%; p = 0.957) or conversion to THA (94%, 95% CI, 86%-100% versus 87%, 95% CI, 74%-100%; p = 0.366). The current results suggest the importance of preserving the labrum and show that resection may put the hip at risk for early deterioration. At 10-year followup, hips with labral reattachment less frequently had a decreased Merle d'Aubigné score but no effect on progression of osteoarthritis or conversion to THA could be shown. Level III, therapeutic study.


Systematic assessment of food item preference and reinforcer effectiveness: Enhancements in training laboratory-housed rhesus macaques.
The use of systematic preference assessments can enhance positive reinforcement training with captive animals. We found that the multiple stimulus without replacement (MSWO) technique identified food preferences in laboratory housed rhesus macaques, with raisins and grapes being ranked higher on average than dried apricot, pasta, and green beans (Friedman Test, χ2 (4) = 35.52, p < .001). Agreement between individuals (N = 21) was moderate (Kendall's W = 0.42), and consistency across time varied among individuals (W = .03-.90). Highly preferred items identified by the MSWO assessment were subsequently found to increase subjects' engagement in a husbandry task on which they were being trained (Mann-Whitney U = 6.00, p = .002) and to improve performance on a progressive ratio schedule (Wilcoxon signed-rank test, Z = -2.17, p = .03) when compared with low preference items. The progressive ratio technique supplements other preference assessment techniques by measuring the amount of work a subject will do to gain access to an item. The use of more effective reinforcers identified through systematic assessment has the potential to increase animal performance on husbandry and research tasks and to improve animal welfare in the laboratory setting.


White matter changes in patients with amnestic mild cognitive impairment detected by diffusion tensor imaging.
Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer's disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.


Stable room-temperature multi-wavelength lasing realization in ordinary erbium-doped fiber loop lasers.
A suppressant effect for mode competition of multi-wavelength lasing oscillations induced by deeply saturated effect in an ordinary erbium-doped fiber ring laser (EDFRL) was observed and experimentally investigated. Results show that the effect is helpful to obtain stable multi-wavelength lasing at room temperature in the EDFRL, which offers a new and simple approach to achieve stable multi-wavelength EDF lasing. Stable two- and three- wavelength lasing oscillations were achieved based on the effect in the ordinary EDFRL for the first time to our best knowledge. The multi-wavelength lasing oscillations were so stable integrated over smaller than 1 ms that the maximum power fluctuation over more than 30 minutes of observation was less than 0.1 dB and 0.5 dB for two-wavelength lasing with a spacing of 1.28 nm and 0.76 nm, respectively.


Development of flexible electrochemical impedance spectroscopy-based biosensing platform for rapid screening of SARS-CoV-2 inhibitors.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cells through the binding of its spike protein (S-protein) to the cell surface-expressing angiotensin-converting enzyme 2 (ACE2). Thus, inhibition of S-protein-ACE2 binding may impede SARS-CoV-2 cell entry and attenuate the progression of Coronavirus disease 2019 (COVID-19). In this study, an electrochemical impedance spectroscopy-based biosensing platform consisting of a recombinant ACE2-coated palladium nano-thin-film electrode as the core sensing element was fabricated for the screening of potential inhibitors against S-protein-ACE2 binding. The platform could detect interference of small analytes against S-protein-ACE2 binding at low analyte concentration and small volume (0.1 μg/mL and ~1 μL, estimated total analyte consumption < 4 pg) within 21 min. Thus, a few potential inhibitors of S-protein-ACE2 binding were identified. This includes (2S,3aS,6aS)-1-((S)-N-((S)-1-Carboxy-3-phenylpropyl)alanyl)tetrahydrocyclopenta[b] pyrrole-2-carboxylic acid (ramiprilat) and (2S,3aS,7aS)-1-[(2S)-2-[[(2S)-1-Carboxybutyl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid (perindoprilat) that reduced the binding affinity of S-protein to ACE2 by 72% and 67%; and SARS-CoV-2 in vitro infectivity to the ACE2-expressing human oral cavity squamous carcinoma cells (OEC-M1) by 36.4 and 20.1%, respectively, compared to the PBS control. These findings demonstrated the usefulness of the developed biosensing platform for the rapid screening of modulators for S-protein-ACE2 binding.


Towards the Development of a Diagnostic Test for Autism Spectrum Disorder: Big Data Meets Metabolomics.
Autism spectrum disorder (ASD) is defined as a neurodevelopmental disorder which results in impairments in social communications and interactions as well as repetitive behaviors. Despite current estimates showing that approximately 2.2% of children are affected in the United States, relatively little about ASD pathophysiology is known in part due to the highly heterogenous presentation of the disorder. Given the limited knowledge into the biological mechanisms governing its etiology, the diagnosis of ASD is performed exclusively based on an individual's behavior assessed by a clinician through psychometric tools. Although there is no readily available biochemical test for ASD diagnosis, multivariate statistical methods show considerable potential for effectively leveraging multiple biochemical measurements for classification and characterization purposes. In this work, markers associated with the folate dependent one-carbon metabolism and transulfuration (FOCM/TS) pathways analyzed via both Fisher Discriminant Analysis and Support Vector Machine showed strong capability to distinguish between ASD and TD cohorts. Furthermore, using Kernel Partial Least Squares regression it was possible to assess some degree of behavioral severity from metabolomic data. While the results presented need to be replicated in independent future studies, they represent a promising avenue for uncovering clinically relevant ASD biomarkers.


The effects of the Lactobacillus casei strain on obesity in children: a pilot study.
There are few data regarding the role of probiotics as a dietary intervention in the management of obesity in children. An open prospective examination was conducted to clarify the effects of Lactobacillus casei strain Shirota (LcS)-containing beverages in obese children. We compared the intestinal microbiota and organic acid levels between 12 obese (average age, 10.8 years; body mass index (BMI) Z score, 2.7±1.7) and 22 control children(average age, 8.5 years; BMI Z score, 0.1±0.7), and pre- and post-intervention in the obese children. The obese group underwent diet and exercise therapy for 6 months and then were given an LcS beverage daily for another 6 months and the body weight and serological markers were monitored. Significant reductions in the faecal concentrations of Bifidobacterium (obese group, 7.9±1.5 vs non-obese group, 9.8±0.5 Log10cells/g; P<0.01) along with a significant decline in the Bacteroides fragilis group, Atopobium cluster and Lactobacillus gasseri subgroup, and acetic acid (obese group, 45.1±16.9 vs non-obese group, 57.9±17.6 μmol/g; P<0.05) were observed in the obese group at baseline. A significant decline in body weight (-2.9±4.6%; P<0.05) and an elevation in the high density lipoprotein cholesterol level (+11.1±17.6%; P<0.05) were observed 6 months after ingestion of the LcS beverage compared to baseline. Furthermore, a significant increase in the faecal concentration of Bifidobacterium (7.0±1.2 before ingestion vs 9.1±1.2 Log10cells/g after ingestion; P<0.01) and an apparent increase in the acetic acid concentration (7.0±1.2 before ingestion vs 9.1±1.2 Log10cells/g after ingestion; P<0.01) were observed 6 months after ingestion. LcS contributed to weight loss while also improving the lipid metabolism in obese children via a significant increase in the faecal Bifidobacterium numbers and the acetic acid concentration.


[Deep Oscillation: therapeutic-rehabilitative experiences with a new electrostatic device].
Deep Oscillation® is an apparatus that produces low frequency electromagnetic radiations able to modulate immune reactions and, therefore, applicable to pain, tumour and inflammation treatments. The aim of this study is to evaluate how the Deep Oscillation® therapy works on conventional therapy resistant patients as the apparatus can be applied either to trauma derived fom surgical wounds or on sports post-traumatic oedema, low back pain and/or sciatalgic pain and cervicobrachial pain. In the first part of the study, 34 cases of recent surgical wounds have been treated with Deep Oscillation® with 3 times a week visits for 20 minutes. In the same way 30 cases of sports post-traumatic oedema, 20 cases of low back pain and/or sciatalgic pain and 10 cases of cervicobrachial pain were treated. Among these patients, 15 cases had also undergone contemporaneous nonsteroidal anti-inflammatory drugs intravenous drip, electrolytes and vitamins to verify the probable synergetic efficacy of both treatments. The results confirm that in some cases the Deep Oscillation® treatment is effective since the first/third therapy up to the restitutio ad integrum. It has also been demonstrated that the maximum efficiency of the Deep Oscillation® and nonsteroidal anti-inflammatory drugs synergetic treatment is probably due to the electromagnetic radiations able to facilitate the pharmacological uptake. This study confirms the capacity of the electrostatic energy, released by Deep Oscillation®, to stimulate the patient's neurosensory system, raising his pain threshold and facilitating his pharmacological uptake and restoring his functional recovery more quickly.


Early diagnosis of prostate cancer in the Western Cape.
Early stage prostate cancer does not cause symptoms, and even metastatic disease may exist for years without causing symptoms or signs. Whereas early stage prostate cancer can be cured with radical prostatectomy or radiotherapy, the prognosis of patients with locally advanced or metastatic cancer is significantly poorer. In view of the high incidence of advanced and therefore incurable prostate cancer seen at the oncology clinic of the Department of Urology, Tygerberg Hospital, we started a prostate clinic with the aim of detecting early stage prostate cancer which is potentially curable. A secondary objective was to investigate the question whether there is a higher incidence of prostate cancer among black African men. Men aged 50-70 years were invited by means of media communications (newspaper and radio) to attend our prostate clinic for a free physical examination, including a digital rectal examination (DRE) and serum prostate specific antigen (PSA) assay. If the DRE was clinically suspicious of malignancy and/or the serum PSA was > 4 ng/ml, the patient was appropriately counselled and referred for transrectal ultrasound (TRUS)-guided sextant prostate biopsy. In the period June 1997-September 1999 a total of 1,056 men attended the prostate clinic. Biopsies were indicated in 160 cases, and were obtained in 114 (71.3%, i.e. 10.8% of the entire cohort). Prostate cancer was detected on first biopsy in 3.5% of the entire group of men (in 35.9% of those with a clinically abnormal DRE, in 41.3% of those with a serum PSA > 4 ng/ml and in 88.6% of those with an abnormal DRE and serum PSA > 4 ng/ml. In the 37 men with prostate cancer, the clinical tumour stage was T1-2 in 83.8% and T3-4 in 16.2%. In the group of patients with clinical stage T1-2 tumours, the treatment was watchful waiting in 62.5% of cases, radiotherapy in 20.8% and radical prostatectomy in 16.7%. Analysis of the data according to race showed that in the group of 47 black men there was a higher percentage of clinically abnormal DRE, PSA > 4.0 ng/ml and biopsies showing malignancy, and a higher overall prostate cancer detection rate (8.5%). Our prostate cancer detection rate of 3.5% is slightly lower than that reported in larger studies (4.7%), which may be due to the fact that prostate biopsy was performed in only 71% of those who had an indication for biopsy. In the men diagnosed with clinically localised prostate cancer, potentially curative treatment was given in only 37.5% of cases. This compares unfavourably with the historical cohort of men seen at our oncology clinic, where 53% received potentially curative treatment, and a large European study where potentially curative treatment was given in 89% of cases. Our finding that black men had a higher percentage of clinically abnormal DRE, PSA > 4.0 ng/ml and biopsies showing malignancy and a higher overall detection rate of prostate cancer should be interpreted with caution, since black men comprised only 4.5% of our overall study cohort.


Treatment for intractable asthma: bronchial thermoplasty.
Bronchial Thermoplasty (BT) is an epoch-making treatment that reduces bronchial smooth muscle by using a bronchoscope to reach the basket catheter to the bronchus and directing high-frequency current directly into the bronchi. In GINA Guidelines 2019, BT is considered to be additional treatment at Step V (the most severe), and the evidence level is B. The Japanese guidelines (JGL) also added BT as a treatment for Step 4, but it is reserved because there are still unclear points regarding long-term efficacy and safety. In Japan, as of April 1, 2019, 672 treatments were performed at 123 institutions nationwide. The average age of patients was 54.1 years, but 84 cases were over 70 years old. The average value of %FEV1 was 78.2%, but there were 94 cases less than 60%. There were 32 cases that underwent BT treatment at our institution. Of them, 12 cases with progress up to one year later could be observed. The average age was 56.1 years old, and each of 6 men and women had a %FEV1 of 70.5%. One year later, AQLQ and %FEV1 improved, and the number of exacerbations decreased, but exhaled NO values increased. %FEV1 improvement might be due to poorer lung function (70.5% vs. 77.8%) and more BT activation (average 1.28 times AIR2) compared to the AIR2 trial. In terms of improvement in %FEV1, patients with moderate obstructive disorder from 50 to 80% responded well after BT treatment. In the near future, various new antibody preparations such as IL-4 / 13 antibody and anti-TSLP antibody are expected to be promoted. Therefore, we first consider whether these antibody preparations can be applied to patients with refractory asthma. We consider that BT is indicated only when there is no indication or no expected effect of antibody preparations. In other words, BT treatment is the last resort of intractable asthma, and it is the duty of medical professionals involved in BT treatment to be able to advocate when it is best to give BT to such patients.


Evaluation of the implementation of the Montreal At Home/Chez Soi project.
Homelessness and mental disorders constitute a major problem in Canada. The purpose of the At Home/Chez Soi pilot project was to house and provide supports to marginalised groups. Policymakers are in a better position to nurture new, complex interventions if they know which key factors hinder or enable their implementation. This paper evaluates the implementation process for the Montreal site of this project. We collected data from 62 individuals, through individual interviews, focus groups, questionnaires, observations and documentation. The implementation process was analysed using a conceptual framework with five constructs: Intervention Characteristics (IC), Context of Implementation (CI), Implementation Process (IP), Organizational Characteristics (OC) and Strategies of Implementation (SI). The most serious obstacle to the project came from the CI construct, i.e., lack of support from provincial authorities and key local resources in the homelessness field. The second was within the OC construct. The chief hindrances were numerous structures, divergent values among stakeholders, frequent turnover of personnel and team leaders; lacking staff supervision and miscommunication. The third is related to IC: the complex, unyielding nature of the project undermined its chances of success. The greatest challenges from IP were the pressure to perform, along with stress caused by planning, deadlines and tension between teams. Conversely, SI construct conditions (e.g., effective governing structures, comprehensive training initiatives and toolkits) were generally very positive even with problems in power sharing and local leadership. For the four other constructs, the following proved useful: evidence of the project's scope and quality, great needs of services consolidation, generous financing and status as a research pilot project, enthusiasm and commitment toward the project, substantially improved services, and overall user satisfaction. This study demonstrated the difficulty of implementing a complex project in the healthcare system. While the project faced many barriers, minimal conditions were also achieved. At the end of the study period, major tensions between organizations and teams were significantly reduced, supporting its full implementation. However, in late 2013, the project was unsustainable, calling into question the relevance of achieving a significant number of positive conditions in each area of the framework.


Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation.
Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1(+/-)) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury. However, the downstream Ras effector pathway responsible for this phenotype is unknown. Based on in vitro assays demonstrating enhanced extracellular signal-related kinase (Erk) signaling in Nf1(+/-) macrophages and vascular smooth muscle cells and in vivo evidence of Erk amplification without alteration of phosphatidylinositol 3-kinase signaling in Nf1(+/-) neointimas, we tested the hypothesis that Ras-Erk signaling regulates intimal proliferation in a murine model of NF1 arterial stenosis. By using a well-established in vivo model of inflammatory cell migration and standard cell culture, neurofibromin-deficient macrophages demonstrate enhanced sensitivity to growth factor stimulation in vivo and in vitro, which is significantly diminished in the presence of PD0325901, a specific inhibitor of Ras-Erk signaling in phase 2 clinical trials for cancer. After carotid artery injury, Nf1(+/-) mice demonstrated increased intimal proliferation compared with wild-type mice. Daily administration of PD0325901 significantly reduced Nf1(+/-) neointima formation to levels of wild-type mice. These studies identify the Ras-Erk pathway in neurofibromin-deficient macrophages as the aberrant pathway responsible for enhanced neointima formation.


Access to β-lactams by enantioselective palladium(0)-catalyzed C(sp3)-H alkylation.
β-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd(0)-catalyzed C-H functionalization for aryl-aryl couplings, related reactions involving the formation of saturated C(sp(3))-C(sp(3)) bonds are elusive. Reported here is an asymmetric C-H functionalization approach to β-lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp(3))-C(sp(3)) and strain-building reductive eliminations to for the four-membered ring. In general, the β-lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.


Fostering Effective Early Learning (FEEL) through a professional development programme for early childhood educators to improve professional practice and child outcomes in the year before formal schooling: study protocol for a cluster randomised controlled trial.
A substantial research base documents the benefits of attendance at high-quality early childhood education and care (ECEC) for positive behavioural and learning outcomes. Research has also found that the quality of many young children's experiences and opportunities in ECEC depends on the skills, dispositions and understandings of the early childhood adult educators. Increasingly, research has shown that the quality of children's interactions with educators and their peers, more than any other programme feature, influence what children learn and how they feel about learning. Hence, we sought to investigate the extent to which evidence-based professional development (PD) - focussed on promoting sustained shared thinking through quality interactions - could improve the quality of ECEC and, as a consequence, child outcomes. The Fostering Effective Early Learning (FEEL) study is a cluster randomised controlled trial for evaluating the benefits of a professional development (PD) programme for early childhood educators, compared with no extra PD. Ninety long-day care and preschool centres in New South Wales, Australia, will be selected to ensure representation across National Quality Standards (NQS) ratings, location, centre type and socioeconomic areas. Participating centres will be randomly allocated to one of two groups, stratified by centre type and NQS rating: (1) an intervention group (45 centres) receiving a PD intervention or (2) a control group (45 centres) that continues engaging in typical classroom practice. Randomisation to these groups will occur after the collection of baseline environmental quality ratings. Primary outcomes, at the child level, will be two measures of language development: verbal comprehension and expressive vocabulary. Secondary outcomes at the child level will be measures of early numeracy, social development and self-regulation. Secondary outcomes at the ECEC room level will be measures of environmental quality derived from full-day observations. In all cases, data collectors will be blinded to group allocation. This is the first randomised controlled trial of a new approach to PD, which is focussed on activities previously found to be influential in children's early language, numeracy, social and self-regulatory development. Results should inform practitioners, policy-makers and families of the value of specific professional development for early childhood educators. Australian New Zealand Clinical Trials Registry (ACTRN) identifier ACTRN12616000536460 . Registered on 27 April 2016. This trial was retrospectively registered, given the first participant (centre) had been enrolled at the time of registration.


Cryopreservation of Phaeocystis antarctica.
A large number of clonal isolates of the prymnesiophyte Phaeocystis antarctica have been established at the Alfred Wegener Institute in Bremerhaven, Germany, to address questions on the genetic diversity and ecological response patterns to climate change. However, at present the wider scientific community cannot access these strains and their long-term conservation, (currently by serial transfer), cannot be assured. Cryopreservation could provide the solution to these issues, as it would guarantee the long-term security of this genetically and ecological invaluable collection. This study outlines the successful application of conventional approaches and the use of novel, combined non-penetrating and penetrating cryoprotective strategies that have been successfully applied to the different life-stages of this alga.


AVR2 Targets BSL Family Members, Which Act as Susceptibility Factors to Suppress Host Immunity.
To be successful plant pathogens, microbes use "effector proteins" to manipulate host functions to their benefit. Identifying host targets of effector proteins and characterizing their role in the infection process allow us to better understand plant-pathogen interactions and the plant immune system. Yeast two-hybrid analysis and coimmunoprecipitation were used to demonstrate that the Phytophthora infestans effector AVIRULENCE 2 (PiAVR2) interacts with all three BRI1-SUPPRESSOR1-like (BSL) family members from potato (Solanum tuberosum). Transient expression of BSL1, BSL2, and BSL3 enhanced P. infestans leaf infection. BSL1 and BSL3 suppressed INFESTIN 1 elicitin-triggered cell death, showing that they negatively regulate immunity. Virus-induced gene silencing studies revealed that BSL2 and BSL3 are required for BSL1 stability and show that basal levels of immunity are increased in BSL-silenced plants. Immune suppression by BSL family members is dependent on the brassinosteroid-responsive host transcription factor CIB1/HBI1-like 1. The P. infestans effector PiAVR2 targets all three BSL family members in the crop plant S. tuberosum These phosphatases, known for their role in growth-promoting brassinosteroid signaling, all support P. infestans virulence and thus can be regarded as susceptibility factors in late blight infection.


An organisational analysis of the implementation of telecare and telehealth: the whole systems demonstrator.
To investigate organisational factors influencing the implementation challenges of redesigning services for people with long term conditions in three locations in England, using remote care (telehealth and telecare). Case-studies of three sites forming the UK Department of Health's Whole Systems Demonstrator (WSD) Programme. Qualitative research techniques were used to obtain data from various sources, including semi-structured interviews, observation of meetings over the course programme and prior to its launch, and document review. Participants were managers and practitioners involved in the implementation of remote care services. The implementation of remote care was nested within a large pragmatic cluster randomised controlled trial (RCT), which formed a core element of the WSD programme. To produce robust benefits evidence, many aspect of the trial design could not be easily adapted to local circumstances. While remote care was successfully rolled-out, wider implementation lessons and levels of organisational learning across the sites were hindered by the requirements of the RCT. The implementation of a complex innovation such as remote care requires it to organically evolve, be responsive and adaptable to the local health and social care system, driven by support from front-line staff and management. This need for evolution was not always aligned with the imperative to gather robust benefits evidence. This tension needs to be resolved if government ambitions for the evidence-based scaling-up of remote care are to be realised.


Testicular cancer and parental use of fertilizers in agriculture.
Testicular cancer incidence is increasing rapidly in several countries. Environmental causes acting early in life are suspected but have not yet been identified. We conducted a cohort study to identify parental risk factors for testicular cancer among farmers' sons. Children born in 1952-1991 to parents who were farm holders at the time of the agricultural censuses in 1969-1989 were identified in the Central Population Register (Oslo, Norway). The resulting cohort of male offspring (n = 166,291) were followed up in the Cancer Registry of Norway (Oslo, Norway) for 1965-1991. Exposure indicators were derived from census information on activities on the farm. The cancer incidence was compared with that of the total rural population, and potential risk factors were analyzed by Poisson regression. In a follow-up of 2,924,663 person-years, 158 incident cases of testicular cancer were identified. The study population had a higher incidence of testicular cancer than did the total rural population, particularly at ages 15-19 years and in western Norway. Specific fertilizer regimens on the farm were associated with testicular cancer (rate ratio = 2.44; 95% confidence interval = 1.66-3.56), in particular nonseminoma (rate ratio = 4.21; 95% confidence interval = 2.13-8.32). The rate ratio estimates were highest for boys ages 15-19 years and for a subset of study subjects who were considered more likely to have grown up on a farm. Nondifferential misclassification and bias toward unity are likely because exposure information was available only at the farm level and only for census years. The fertilizer indicators were not available early in life for most subjects, and precise interpretations are difficult. A hypothesis worth considering is that excess nutrient run-off from agriculture constitutes a risk. However, inferences concerning the biological basis of our observations can scarcely be made.


Frequent emergence and limited geographic dispersal of methicillin-resistant Staphylococcus aureus.
A small number of clonal lineages dominates the global population structure of methicillin-resistant Staphylococcus aureus (MRSA), resulting in the concept that MRSA has emerged on a few occasions after penicillinase-stable beta-lactam antibiotics were introduced to clinical practice, followed by intercontinental spread of individual clones. We investigated the evolutionary history of an MRSA clone (ST5) by mutation discovery at 108 loci (46 kb) within a global collection of 135 isolates. The SNPs that were ascertained define a radial phylogenetic structure within ST5 consisting of at least 5 chains of mutational steps that define geographically associated clades. These clades are not concordant with previously described groupings based on staphylococcal protein A gene (spa) typing. By mapping the number of independent imports of the staphylococcal cassette chromosome methicillin-resistance island, we also show that import has occurred on at least 23 occasions within this single sequence type and that the progeny of such recombinant strains usually are distributed locally rather than globally. These results provide strong evidence that geographical spread of MRSA over long distances and across cultural borders is a rare event compared with the frequency with which the staphylococcal cassette chromosome island has been imported.


The impact of obesity on perioperative complications in patients undergoing anterior lumbar interbody fusion.
Anterior approaches to the lumbar spine provide wide exposure that facilitates placement of large grafts with high fusion rates. There are limited data on the effects of obesity on perioperative complications. Data from consecutive patients undergoing anterior lumbar interbody fusion (ALIF) from 2007 to 2016 at a single academic center were analyzed. The primary outcome was any perioperative complication. Complications were divided into those occurring intraoperatively and those occurring postoperatively. Multivariate logistic regression was used to assess the association of obesity and other variables with these complications. An estimation table was used to identify a body mass index (BMI) threshold associated with increased risk of postoperative complication. A total of 938 patients were identified, and the mean age was 57 years; 511 were females (54.5%). The mean BMI was 28.7 kg/m2, with 354 (37.7%) patients classified as obese (BMI ≥ 30 kg/m2). Forty patients (4.3%) underwent a lateral transthoracic approach, while the remaining 898 (95.7%) underwent a transabdominal retroperitoneal approach. Among patients undergoing transabdominal retroperitoneal ALIF, complication rates were higher for obese patients than for nonobese patients (37.0% vs 28.7%, p = 0.010), a difference that was driven primarily by postoperative complications (36.1% vs 26.0%, p = 0.001) rather than intraoperative complications (3.2% vs 4.3%, p = 0.416). Obese patients had higher rates of ileus (11.7% vs 7.2%, p = 0.020), wound complications (11.4% vs 3.4%, p < 0.001), and urinary tract infections (UTI) (5.0% vs 2.5%, p = 0.049). In a multivariate model, age, obesity, and number of ALIF levels fused were associated with an increased risk of postoperative complication. An estimation table including 19 candidate cut-points, odds ratios, and adjusted p values found a BMI ≥ 31 kg/m2 to have the highest association with postoperative complication (p = 0.012). Obesity is associated with increased postoperative complications in ALIF, including ileus, wound complications, and UTI. ALIF is a safe and effective procedure. However, patients with a BMI ≥ 31 kg/m2 should be counseled on their increased risks and warrant careful preoperative medical optimization and close monitoring in the postoperative setting.


Breaking symmetry: the marine environment, prey size, and the evolution of asymmetry in cetacean skulls.
Skulls of odontocetes (toothed whales, including dolphins and porpoises) are typified by directional asymmetry, particularly in elements associated with the airway. Generally, it is assumed this asymmetry is related to biosonar production. However, skull asymmetry may actually be a by-product of selection pressure for an asymmetrically positioned larynx. The odontocete larynx traverses the pharynx and is held permanently in place by a ring of muscle. This allows prey swallowing while remaining underwater without risking water entering the lungs and causing injury or death. However, protrusion of the larynx through the pharynx causes a restriction around which prey must pass to reach the stomach. The larynx and associated hyoid apparatus has, therefore, been shifted to the left to provide a larger right piriform sinus (lateral pharyngeal food channel) for swallowing larger prey items. This asymmetry is reflected in the skull, particularly the dorsal openings of the nares. It is hypothesized that there is a relationship between prey size and skull asymmetry. This relationship was examined in 13 species of odontocete cetaceans from the northeast Atlantic, including four narrow-gaped genera (Mesoplodon, Ziphius, Hyperoodon, and Kogia) and eight wide-gaped genera (Phocoena, Delphinus, Stenella, Lagenorhynchus, Tursiops, Grampus, Globicephala, and Orcinus). Skulls were examined from 183 specimens to assess asymmetry of the anterior choanae. Stomach contents were examined from 294 specimens to assess prey size. Results show there is a significant positive relationship between maximum relative prey size consumed and average asymmetry relative to skull size in odontocete species (wide-gape species: R2 = 0.642, P = 0.006; narrow-gape species: R2 = 0.909, P = 0.031). This finding provides support for the hypothesis that the directional asymmetry found in odontocete skulls is related to an aquatic adaptation enabling swallowing large, whole prey while maintaining respiratory tract protection.