Evidence-based care in a population with chronic kidney disease and acute coronary syndrome. Findings from the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE).
Acute coronary syndrome (ACS) guidelines recommend that patients with chronic kidney disease (CKD) be offered the same therapies as other high-risk ACS patients with normal renal function. Our objective was to describe the gaps in evidence-based care offered to patients with ACS and concomitant CKD. Patients presenting to 41 Australian hospitals with suspected ACS were stratified by presence of CKD (glomerular filtration rate <60 mL/min). Receipt of evidence-based care including, coronary angiography (CA), evidence-based discharge medications (EBMs), and cardiac rehabilitation (CR) referral, were compared between patients with and without CKD. Hospital and clinical factors that predicted receipt of care were determined using multilevel multivariable stepwise logistic regression models. Of the 4,778 patients admitted with suspected ACS, 1,227 had CKD. On univariate analyses, patients with CKD were less likely to undergo CA (59.1% vs 85.0%, P < .0001) or receive EBM (69.4% vs 78.7%, P < .0001), or were offered CR (49.5% vs 68.0%, P < .0001). After adjusting for patient characteristics and clustering by hospital, CKD remained an independent predictor of not undergoing CA only (odds ratio 0.48, 95% CI 0.37-0.61). Within the CKD cohort, presenting to a hospital with a catheterization laboratory was the strongest predictor of undergoing CA (odds ratio 3.07, 95% CI 1.91-4.93). The presence of CKD independently predicts failure to undergo CA but not failure to receive EBM or CR, which is predicted by comorbidities. Among the CKD population, performance of CA is largely determined by admission to a catheterization capable hospital. Targeting these patients through standardization of care across institutions offers opportunities to improve outcomes in this high-risk population.


Interprofessional Health Care Delivery: Perceptions of oral health care integration in a Federally Qualified Health Center.
Purpose: The purpose of this qualitative ethnographic case study was to explore the perceptions of a team of interprofessional healthcare providers regarding how oral health care was integrated into health care provided within a Federally Qualified Health Center (FQHC) in Brighton, Colorado.Methods: Data were gathered through one-on-one, semi-structured personal interviews, which were recorded and professionally transcribed for evaluation. Purposive sampling included physicians, physician assistants, dentists, and dental hygienists. Descriptive analysis was used to describe the sample demographics. An inductive and deductive approach was utilized to assess the qualitative data and subsequently develop themes. Validity was established using triangulation, member checks, and peer review of data and themes by co-investigators.Results: Eight participants (n=8) were interviewed. Subjects were between the ages of 31 and 58 and had been practicing between 5 and 30 years with an average of 13.6 years and had been employed by the FQHC an average of 6.8 years. Thematic analysis revealed seven themes: interprofessional collaboration supports patient care, immediate consultations lead to improved outcomes for all, shared expertise to optimize care delivery, oral health is health, increased communication through collocation, role clarity does not impede team functioning, and mission driven to provide excellent care. These themes support the domains of patient centered care, communication, and the role clarity of the Interprofessional Care Competency Framework and Team Assessment Toolkit (ICCFTAT).Conclusion: Findings from this study can aid FQHC's in the implementation of integrated oral health care delivery systems. Further research is needed to understand how interprofessional health care collaboration (IPHC) affects the team dynamic in FQHC settings.


Direct action and modulating effect of (+)- and (-)-nicotine on ion channels expressed in trigeminal sensory neurons.
Nicotine sensory perception is generally thought to be mediated by nicotinic acetylcholine (nACh) receptors. However, recent data strongly support the idea that other receptors (e.g., transient receptor potential A1 channel, TRPA1) and other pathways contribute to the detection mechanisms underlying the olfactory and trigeminal cell response to nicotine flavor. This is in accordance with the reported ability of humans to discriminate between (+)- and (-)- nicotine enantiomers. To get a more detailed understanding of the molecular and cellular basis underlying the sensory perception of nicotine, we studied the activity of (+)- and (-)-nicotine on cultured murine trigeminal sensory neurons and on a range of heterologously expressed receptors. The human TRPA1 channel is activated by (-)-nicotine. In this work, we show that (+)-nicotine is also an activator of this channel. Pharmacological experiments using nicotinic acetylcholine receptors and transient receptor potential blockers revealed that trigeminal neurons express one or more unidentified receptors that are sensitive to (+)- and/or (-)-nicotine. Results also indicate that the presence of extracellular calcium ions is required to elicit trigeminal neuron responses to (+)- and (-)-nicotine. Results also show that both (+)-nicotine and (-)-nicotine can block 5-hydroxytryptamine type 3 (5-HT3) receptor-mediated responses in recombinant expression systems and in cultured trigeminal neurons expressing 5-HT3 receptors. Our investigations broaden the spectra of receptors that are targets for nicotine enantiomers and give new insights into the physiological role of nicotine.


Guanylyl cyclases A and B are asymmetric dimers that are allosterically activated by ATP binding to the catalytic domain.
It is not known how natriuretic peptides and adenosine triphosphate (ATP) activate guanylyl cyclase A (GC-A) and GC-B, which generate the second messenger cyclic guanosine monophosphate. We determined that natriuretic peptides increased the maximum rate of these enzymes >10-fold in a positive cooperative manner in the absence of ATP. In the absence of natriuretic peptides, ATP shifted substrate-velocity profiles from cooperative to linear but did not increase the affinity of GCs for the substrate guanosine triphosphate (GTP) since the Michaelis constant was unchanged. However, in the presence of natriuretic peptides, ATP competed with GTP for binding to an allosteric site, which enhanced the activation of GCs by decreasing the Michaelis constant. Thus, natriuretic peptide binding was required for communication of the allosteric activation signal to the catalytic site. The ability of ATP to activate GCs decreased and enzyme potency (a measure of sensitivity to stimulation) increased with increasing GTP concentrations. Point mutations in the purine-binding site of the catalytic domain abolished GC activity but not allosteric activation. Coexpression of inactive mutants produced half the activity expected for symmetric catalytic dimers. 2'-Deoxy-ATP and 2'-deoxy-GTP were poor allosteric activators, but 2'-deoxy-GTP was an effective substrate, consistent with distinct binding requirements for the allosteric and catalytic sites. We conclude that membrane GC domains are asymmetric homodimers with distinct and reciprocally regulated catalytic and allosteric sites that bind to GTP and ATP, respectively. These data define a new membrane GC activation model and provide evidence of a previously unidentified GC drug interaction site.


Enhanced surface imprinting of lysozyme over a new kind of magnetic chitosan submicrospheres.
Surface protein imprinting over nano- or micron-sized substrates is an effective approach for improving the biomacromolecule mass transfer and rebinding capacity. For achieving high recognition performance, it is necessary to introduce certain functional groups onto the surface of the support materials which can interact with the template protein. Herein, we report a surface protein imprinting approach using a new kind of core-shell magnetic chitosan submicrospheres as the supports. The surface of these magnetic chitosan particles is tethered with uncross-linked chitosan chains, hence bearing plenty of amino and hydroxyl groups, where a large amount of functional ligands can be readily coupled for capturing of the protein template. With lysozyme as a model print protein, the magnetic supports were functionalized with maleic acid and then coated with imprinted polymer layers. The resulting imprinted microspheres show significantly selective rebinding for lysozyme. In particular, they exhibit a specific rebinding capacity about three times higher than achieved with our previous lysozyme-imprinted particles synthesized in similar way but with maleic acid modified silica nanoparticles as the supports. This can be attributed to the much higher template binding capacity to the modified magnetic chitosan submicrospheres. Also, the resultant imprinted particles can be easily collected by a magnet. Therefore, such kind of chitosan submicrospheres may be a versatile carrier for constructing high-capacity and magnetically recyclable surface protein-imprinted particles.


Simultaneous Discovery of Positive and Negative Interactions Among Rhizosphere Bacteria Using Microwell Recovery Arrays.
Understanding microbe-microbe interactions is critical to predict microbiome function and to construct communities for desired outcomes. Investigation of these interactions poses a significant challenge due to the lack of suitable experimental tools available. Here we present the microwell recovery array (MRA), a new technology platform that screens interactions across a microbiome to uncover higher-order strain combinations that inhibit or promote the function of a focal species. One experimental trial generates 104 microbial communities that contain the focal species and a distinct random sample of uncharacterized cells from plant rhizosphere. Cells are sequentially recovered from individual wells that display highest or lowest levels of focal species growth using a high-resolution photopolymer extraction system. Interacting species are then identified and putative interactions are validated. Using this approach, we screen the poplar rhizosphere for strains affecting the growth of Pantoea sp. YR343, a plant growth promoting bacteria isolated from Populus deltoides rhizosphere. In one screen, we montiored 3,600 microwells within the array to uncover multiple antagonistic Stenotrophomonas strains and a set of Enterobacter strains that promoted YR343 growth. The later demonstrates the unique ability of the platform to discover multi-membered consortia that generate emergent outcomes, thereby expanding the range of phenotypes that can be characterized from microbiomes. This knowledge will aid in the development of consortia for Populus production, while the platform offers a new approach for screening and discovery of microbial interactions, applicable to any microbiome.


Metabolites of lorazepam: Relevance of past findings to present day use of LC-MS/MS in analytical toxicology.
The advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the sensitivity it confers, permits the analysis of both phase I and II drug metabolites that in the past would have been difficult to target using other techniques. These metabolites may have relevance to current analytical toxicology employing LC-MS/MS, and lorazepam was chosen as a model drug for investigation, as only the parent compound has been targeted for screening purposes. Following lorazepam administration (2 mg, p.o.) to 6 volunteers, metabolites were identified in urine by electrospray ionization LC-MS/MS, aided by the use of deuterated analogues generated by microsomal incubation for use as internal chromatographic and mass spectrometric markers. Metabolites present were lorazepam glucuronide, a quinazolinone, a quinazoline carboxylic acid, and two hydroxylorazepam isomers, one of which is novel, having the hydroxyl group located on the fused chlorobenzene ring. The quinazolinone, and particularly the quinazoline carboxylic acid metabolite, provided longer detection windows than lorazepam in urine extracts not subjected to enzymatic hydrolysis, a finding that is highly relevant to toxicology laboratories that omit hydrolysis in order to rapidly reduce the time spent on gas chromatography-mass spectrometry (GC-MS) analysis. With hydrolysis, the longest windows of detection were achieved by monitoring lorazepam, supporting the targeting of the aglycone with free drug for those incorporating hydrolysis in their analytical toxicology procedures.


Antagonistic pleiotropy and fitness trade-offs reveal specialist and generalist traits in strains of canine distemper virus.
Theoretically, homogeneous environments favor the evolution of specialists whereas heterogeneous environments favor generalists. Canine distemper is a multi-host carnivore disease caused by canine distemper virus (CDV). The described cell receptor of CDV is SLAM (CD150). Attachment of CDV hemagglutinin protein (CDV-H) to this receptor facilitates fusion and virus entry in cooperation with the fusion protein (CDV-F). We investigated whether CDV strains co-evolved in the large, homogeneous domestic dog population exhibited specialist traits, and strains adapted to the heterogeneous environment of smaller populations of different carnivores exhibited generalist traits. Comparison of amino acid sequences of the SLAM binding region revealed higher similarity between sequences from Canidae species than to sequences from other carnivore families. Using an in vitro assay, we quantified syncytia formation mediated by CDV-H proteins from dog and non-dog CDV strains in cells expressing dog, lion or cat SLAM. CDV-H proteins from dog strains produced significantly higher values with cells expressing dog SLAM than with cells expressing lion or cat SLAM. CDV-H proteins from strains of non-dog species produced similar values in all three cell types, but lower values in cells expressing dog SLAM than the values obtained for CDV-H proteins from dog strains. By experimentally changing one amino acid (Y549H) in the CDV-H protein of one dog strain we decreased expression of specialist traits and increased expression of generalist traits, thereby confirming its functional importance. A virus titer assay demonstrated that dog strains produced higher titers in cells expressing dog SLAM than cells expressing SLAM of non-dog hosts, which suggested possible fitness benefits of specialization post-cell entry. We provide in vitro evidence for the expression of specialist and generalist traits by CDV strains, and fitness trade-offs across carnivore host environments caused by antagonistic pleiotropy. These findings extend knowledge on CDV molecular epidemiology of particular relevance to wild carnivores.


Mono-(2-ethylhexyl) phthalate induces oxidative stress and inhibits growth of mouse ovarian antral follicles.
Mono-(2-ethylhexyl) phthalate (MEHP) is the active metabolite of the most commonly used plasticizer, di-(2-ethylhexyl) phthalate, and is considered to be a reproductive toxicant. However, little is known about the effects of MEHP on ovarian antral follicles. Thus, the present study tested the hypothesis that MEHP inhibits follicle growth via oxidative stress pathways. The data indicate that MEHP increases reactive oxygen species (ROS) levels and inhibits follicle growth in antral follicles, whereas N-acetylcysteine (NAC; an antioxidant) restores ROS levels to control levels and rescues follicles from MEHP-induced inhibition of follicle growth. To further analyze the mechanism by which MEHP induces oxidative stress and inhibits follicle growth, the expression and activities of various key antioxidant enzymes (copper/zinc superoxide dismutase [SOD1], glutathione peroxidase [GPX], and catalase [CAT]) and the expression of key cell-cycle regulators (Ccnd2, Ccne1, and Cdk4) and apoptotic regulators (Bcl-2 and Bax) were compared in control and MEHP-treated follicles. The data indicate that MEHP inhibits the expression and activities of SOD1 and GPX; does not inhibit Cat expression; inhibits the expression of Ccnd2, Ccne1, Cdk4, and Bcl-2; but increases the expression of Bax compared to controls. Furthermore, NAC blocks these toxic effects of MEHP. Collectively, these data suggest that MEHP induces oxidative stress by disrupting the activities of antioxidant enzymes. This may lead to decreased expression of cell-cycle regulators and antiapoptotic regulators and increased expression of proapoptotic factors, which then may lead to inhibition of follicle growth.


Using content analysis to link texts on assessment and intervention to the International Classification of Functioning, Disability and Health - version for Children and Youth (ICF-CY).
To explore how content analysis can be used together with linking rules to link texts on assessment and intervention to the International Classification of Functioning, Disability and Health - version for children and youth (ICF-CY). Individual habilitation plans containing texts on assessment and intervention for children with disabilities and their families were linked to the ICF-CY using content ana-lysis. Texts were first divided into meaning units in order to extract meaningful concepts. Meaningful concepts that were difficult to link to ICF-CY codes were grouped, and coding schemes with critical attributes were developed. Meaningful concepts that could not be linked to the ICF-CY were assigned to the categories "not-definable" and "not-covered", using coding schemes with mutually exclusive categories. The size of the meaning units selected resulted in different numbers and contents of meaningful concepts. Coding schemes with critical attributes of ICF-CY codes facilitated the linking of meaningful concepts to the most appropriate ICF-CY codes. Coding schemes with mutually exclusive categories facilitated the classification of meaningful concepts that could or could not be linked to the ICF-CY. Content analysis techniques can be applied together with linking rules in order to link texts on assessment and intervention to the ICF-CY.


Bees under stress: sublethal doses of a neonicotinoid pesticide and pathogens interact to elevate honey bee mortality across the life cycle.
Microbial pathogens are thought to have a profound impact on insect populations. Honey bees are suffering from elevated colony losses in the northern hemisphere possibly because of a variety of emergent microbial pathogens, with which pesticides may interact to exacerbate their impacts. To reveal such potential interactions, we administered at sublethal and field realistic doses one neonicotinoid pesticide (thiacloprid) and two common microbial pathogens, the invasive microsporidian Nosema ceranae and black queen cell virus (BQCV), individually to larval and adult honey bees in the laboratory. Through fully crossed experiments in which treatments were administered singly or in combination, we found an additive interaction between BQCV and thiacloprid on host larval survival likely because the pesticide significantly elevated viral loads. In adult bees, two synergistic interactions increased individual mortality: between N. ceranae and BQCV, and between N. ceranae and thiacloprid. The combination of two pathogens had a more profound effect on elevating adult mortality than N. ceranae plus thiacloprid. Common microbial pathogens appear to be major threats to honey bees, while sublethal doses of pesticide may enhance their deleterious effects on honey bee larvae and adults. It remains an open question as to whether these interactions can affect colony survival.


Decoding the locational information in the orb web vibrations of Araneus diadematus and Zygiella x-notata.
A spider's web is a multifunctional structure that captures prey and provides an information platform that transmits vibrational information. Many physical factors interact to influence web vibration and information content, from vibration source properties and input location, to web physical properties and geometry. The aim of the study was to test whether orb web vibration contains information about the location of the source of vibration. We used finite-element analysis model webs to control and vary major physical factors, investigating webs where spiders use a direct or remote monitoring strategy. When monitoring with eight sensors (legs) at the web centre, a comparison of longitudinal and transverse wave amplitude between the sensors gave sufficient information to determine source direction and distance, respectively. These localization cues were robust to changes in source amplitude, input angle and location, with increased accuracy at lower source amplitudes. When remotely monitoring the web using a single thread connected to the web's hub (a signal thread), we found that locational information was not available when the angle of the source input was unknown. Furthermore, a free sector and a stiff hub were physical mechanisms to aid information transfer, which provides insights for bioinspired fibre networks for sensing technologies.


Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis.
Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed. To synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH. MEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016. Randomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH. Two investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool. The primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs. This study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy. Pioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study.


Is it lawful to use Medicaid to pay for circumcision?
Since 1965, tens of millions of boys have been circumcised under the Medicaid program, most at birth, at a cost to the United States Federal Government, the States and taxpayers of billions of dollars. Although 18 States have ended coverage since 1982, the United States Government and 32 States continue to pay for non-therapeutic circumcision, even though no medical association in the world recommends it. Many cite American medical association policy that the procedure has potential medical benefits as well as disadvantages, and that the circumcision decision should be left to parents. This article shows that Medicaid coverage of circumcision is not a policy issue because it is prohibited by federal and State law. As American medical associations concede, non-therapeutic circumcision is unnecessary, elective, cosmetic surgery on healthy boys, usually performed for cultural, personal or religious reasons. The fundamental principle of Medicaid law is that Medicaid only covers necessary medical treatments after the diagnosis of a current medical condition. Physicians and hospitals face severe penalties for charging Medicaid for circumcisions. Medicaid officials and the Federal and State Governments are also required to end coverage. It is unlawful to circumcise and to allow the circumcision of healthy boys at the expense of the government and taxpayers.


Clinical value of prostate segmentation and volume determination on MRI in benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is a nonmalignant pathological enlargement of the prostate, which occurs primarily in the transitional zone. BPH is highly prevalent and is a major cause of lower urinary tract symptoms in aging males, although there is no direct relationship between prostate volume and symptom severity. The progression of BPH can be quantified by measuring the volumes of the whole prostate and its zones, based on image segmentation on magnetic resonance imaging. Prostate volume determination via segmentation is a useful measure for patients undergoing therapy for BPH. However, prostate segmentation is not widely used due to the excessive time required for even experts to manually map the margins of the prostate. Here, we review and compare new methods of prostate volume segmentation using both manual and automated methods, including the ellipsoid formula, manual planimetry, and semiautomated and fully automated segmentation approaches. We highlight the utility of prostate segmentation in the clinical context of assessing BPH.


Evaluation of articles in metabolism research on the basis of their citations.
The number of research papers and journals each year is increasing and millions of dollars are spent. Despite this there is evidence to suggest that many publications do not impact clinical practice. We used citation analysis to measure the influence of metabolism publications from 2003-2013. Those papers with lower citation rates are likely to be of the least value and high rates of such publications may be a marker of research waste. We analysed 67 journals with 81,954 articles related to metabolism indexed on the Scopus station database from 2003-2013. We identified those articles with less than 5 citations within 5 years from publication date as poorly cited. Journals were ranked by the percentage of articles that were poorly cited or uncited. Over the 10-year period, the number of total articles increased by 127%. We found that 24% of articles were poorly cited within 5 years of publication. Journals in the bottom 25% and top 25% of rankings by citation rates accounted for a similar proportion of poorly cited articles. Most of the open access journals were ranked in the top 25% for citation rates. Our analysis contradicts concerns over increasing amounts of publications with little impact. The proportion of poorly cited articles are low, with little change in the trend over 10 years. The top and bottom ranked journals produced similar proportions of poorly cited articles. These findings suggest the necessity of pursuing further research to study waste in metabolism research.


Toll-like receptor cascade and gene polymorphism in host-pathogen interaction in Lyme disease.
Lyme disease (LD) risk occurs in North America and Europe where the tick vectors of the causal agent Borrelia burgdorferi sensu lato are found. It is associated with local and systemic manifestations, and has persistent posttreatment health complications in some individuals. The innate immune system likely plays a critical role in both host defense against B. burgdorferi and disease severity. Recognition of B. burgdorferi, activation of the innate immune system, production of proinflammatory cytokines, and modulation of the host adaptive responses are all initiated by Toll-like receptors (TLRs). A number of Borrelia outer-surface proteins (eg, OspA and OspB) are recognized by TLRs. Specifically, TLR1 and TLR2 were identified as the receptors most relevant to LD. Several functional single-nucleotide polymorphisms have been identified in TLR genes, and are associated with varying cytokines types and synthesis levels, altered pathogen recognition, and disruption of the downstream signaling cascade. These single-nucleotide polymorphism-related functional alterations are postulated to be linked to disease development and posttreatment persistent illness. Elucidating the role of TLRs in LD may facilitate a better understanding of disease pathogenesis and can provide an insight into novel therapeutic targets during active disease or postinfection and posttreatment stages.


Challenges and Opportunities for the Veterinary Pathologist in Biomedical Research.
Animal models have critical roles in biomedical research in promoting understanding of human disease and facilitating development of new therapies and diagnostic techniques to improve human and animal health. In the study of myriad human conditions, each model requires in-depth characterization of its assets and limitations in order for it to be used to greatest advantage. Veterinary pathology expertise is critical in understanding the relevance and translational validity of animal models to conditions under study, assessing morbidity and mortality, and validating outcomes as relevant or not to the study interventions. Clear communication with investigators and education of research personnel on the use and interpretation of pathology endpoints in animal models are critical to the success of any research program. The veterinary pathologist is underutilized in biomedical research due to many factors including misconceptions about high fiscal costs, lack of perceived value, limited recognition of their expertise, and the generally low number of veterinary pathologists currently employed in biomedical research. As members of the multidisciplinary research team, veterinary pathologists have an important role to educate scientists, ensure accurate interpretation of pathology data, maximize rigor, and ensure reproducibility to provide the most reliable data for animal models in biomedical research.


T cell growth factor receptors. Quantitation, specificity, and biological relevance.
To examine directly the hypothesis that T cell growth factor (TCGF) interacts with target cells in a fashion similar to polypeptide hormones, the binding of radiolabeled TCGF to various cell populations was investigated. The results indicate that TCGF interacts with activated T cells via a receptor through which it initiates the T cell proliferative response. Internally radiolabeled TCGF, prepared from a human T leukemia cell line and purified by gel filtration and isoelectric focusing, retained biological activity and was uniform with respect to size and charge. Binding of radiolabeled TCGF to TCGF-dependent cytolytic T cells occurred rapidly (within 15 rain at 37 degrees C) and was both saturable and largely reversible. In addition, at 37 degrees C, a receptor- and lysosome-dependent degradation of TCGF occurred. Radiolabeled TCGF binding was specific for activated, TCGF-responsive T cells. Whereas unstimulated lymphocytes of human or murine origin and lipopolysaccharide-activated B cell blasts expressed few if any detectable binding sites, lectin- or alloantigen-activated cells had easily detectable binding sites. Moreover, compared with lectin- or alloantigen-activated T cells, long-term TCGF-dependent cytolytic and helper T cell lines and TCGF-dependent neo-plastic T cell lines bound TCGF with a similar affinity (dissociation constant of 5-25 pM) and expressed a similar number of receptor sites per cell (5,000-15,000). In contrast, a number of TCGF-independent cell lines of T cell, B cell, or myeloid origin did not bind detectable quantities of radiolabeled TCGF. Binding of radiolabeled TCGF to TCGF-responsive cells was specific, in that among several growth factors and polypeptide hormones tested, only TCGF competed for binding. Finally, the relative magnitude of T cell proliferation induced by a given concentration of TCGF closely paralleled the fraction of occupied receptor sites. As the extent of T cell clonal expansion depends on TCGF and on the TCGF receptor, the dissection of the molecular events surrounding the interaction of TCGF and its receptor that these studies permit, should provide new insight into the hormonelike regulation of the immune response by this lymphokine.


The G protein-coupled estrogen receptor (GPER) is expressed in two different subcellular localizations reflecting distinct tumor properties in breast cancer.
The G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen but also by tamoxifen. The aim of our study was to analyze the frequency of GPER in a large collective of primary invasive breast carcinomas, with special emphasis on the subcellular expression and to evaluate the association with clinicopathological parameters and patient overall survival. The tissue microarrays from formalin-fixed, paraffin embedded samples of primary invasive breast carcinomas (n = 981) were analyzed for GPER expression using immunohistochemistry. Expression data were compared to the clinicopathological parameters and overall survival. GPER localization was also analyzed in two immortalized breast cancer cell lines T47D and MCF7 by confocal immunofluorescence microscopy. A predominantly cytoplasmic GPER expression was found in 189 carcinomas (19.3%), whereas a predominantly nuclear expression was observed in 529 cases (53.9%). A simultaneous comparable positive expression of both patterns was found in 32 of 981 cases (3.2%), and negative staining was detected in 295 cases (30%). Confocal microscopy confirmed the occurrence of cytoplasmic and nuclear GPER expression in T47D and MCF7. Cytoplasmic GPER expression was significantly associated with non-ductal histologic subtypes, low tumor stage, better histologic differentiation, as well as Luminal A and B subtypes. In contrast, nuclear GPER expression was significantly associated with poorly differentiated carcinomas and the triple-negative subtype. In univariate analysis, cytoplasmic GPER expression was associated with better overall survival (p = 0.012). Our data suggest that predominantly cytoplasmic and/or nuclear GPER expression are two distinct immunohistochemical patterns in breast carcinomas and may reflect different biological features, reason why these patterns should be clearly distinguished in histological evaluations. Prospective studies will be needed to assess whether the expression status of GPER in breast carcinomas should be routinely observed by clinicians, for instance, before implementing endocrine breast cancer treatment.


[Micronutrients in enteral nutrition formulas. Is it possible to innovate?]
The term "micronutrients" include vitamins and trace elements. Their recommended intakes in enteral formulas has been adhered to RDI/RDA and, in addition, their content is regulated in the European Union. However, deficiencies in micronutrients has been reported in specific patient groups under enteral nutrition (EN) in the last years. Even so, the research in micronutrients in EN is scarce. The aim of this review was to assess the literature to establish possible improvements in micronutrients in EN formulas for adult patients. In general, NE formulas meet the European reference values and, theoretically, they are completely acceptable for long term EN in most patients. However, formulas with different contents may be required in specific clinical situations or diseases. The main micronutrients in which specific needs have been detected was vitamins C, D, and E and the trace elements zinc, copper, selenium, and possibly boron and silicon. The diseases or clinical conditions more predisposed to require especial doses of micronutrients were critically ill patients, burns, neurological patients, elderly frail patients, patients with pressure ulcers, patients with Crohn disease, and patients with gastrectomy or with alimentation jejunostomy. In addition, cooking current formulas should be avoided due to the loss of micronutrient bioavailability in the process. In conclusion, it seems that there is still possibility for the development of more specific formulas with micronutrients more adapted for these groups of patients.


Does the removal of anonymity reduce sperm donors in Australia?
The National Health and Medical Research Council's guidelines implemented in 2005 removed a sperm donor's ability to remain anonymous in every Australian State except Victoria, which had removed anonymity completely by 1998. To assess the impact of these changes on sperm donor numbers in Australia, Assisted Reproductive Technology clinics were surveyed to obtain sperm donation figures between 2000 and 2012, with additional data collected from State-based oversight groups. There was an increase in total sperm donor numbers over the study period, including the year anonymity was removed as well as the non-anonymous period. Variations in total donor numbers and numbers of new recruits observed during the period could not be attributed to any specific change in policy or practice. As total sperm donor numbers have been increasing, the removal of a donor's ability to remain anonymous has not been detrimental to the availability of sperm donors in Australia.


Hepatotoxicity caused by methotrexate therapy in children with inflammatory bowel disease: a systematic review and meta-analysis.
Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%-18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%-9.5%), whereas 4.5% (95% CI 2.8%-7.2%) of patients required discontinuation. Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.


Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs.
Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27 +/- 4 microU/ml to a maximum of 84 +/- 22 microU/ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132 +/- 25 pg/ml to 251 +/- 39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCl acidosis. Evaluation of the arteriovenous potassium difference across the hindleg during ketoacid infusion demonstrates that peripheral uptake of potassium is unlikely to be responsible for the observed hypokalemia. Although the tissue responsible for the different kalemic responses could not be defined with certainty, the data are compatible with an hepatic role in response to alterations in the portal vein insulin and/or glucagon levels in both acid infusion studies. We propose that cellular uptake of potassium is enhanced by hyperinsulinemia in ketoacid infusion, and release of potassium results from increased glucagon levels in HCl acidosis. Whether the changes in plasma potassium that other types od organic acid acidosis produce are accounted for by a similar hormonal mechanism remains to be determined.


Multiline two-dimensional guided-mode resonant filters.
A novel multiline filter using a two-dimensional guided-mode resonant (GMR) filter is proposed. The filter concept utilizes the multiple planes of diffraction produced by the two-dimensional grating. Multiple resonances are obtained by matching the guided modes in the different planes of diffraction to different wavelengths. It is shown that the location and the separation between resonances can be specifically controlled by modifying the periodicity of the grating and the other physical dimensions of the structure. This is in contrast to the one-dimensional GMR filters where the location of the resonances is material dependent. Two-line reflection filter designs with spectral linewidths less than 1 nm and a controllable spectral separation of up to 23% of the short resonance wavelength are presented using rectangular-grid grating GMR structures. Three-line filters are designed in hexagonal-grid grating GMR structures with two independently controllable resonance locations.


Perceptions and experiences of the implementation, management, use and optimisation of electronic prescribing systems in hospital settings: protocol for a systematic review of qualitative studies.
There is increasing evidence that electronic prescribing (ePrescribing) or computerised provider/physician order entry (CPOE) systems can improve the quality and safety of healthcare services. However, it has also become clear that their implementation is not straightforward and may create unintended or undesired consequences once in use. In this context, qualitative approaches have been particularly useful and their interpretative synthesis could make an important and timely contribution to the field. This review will aim to identify, appraise and synthesise qualitative studies on ePrescribing/CPOE in hospital settings, with or without clinical decision support. Data sources will include the following bibliographic databases: MEDLINE, MEDLINE In Process, EMBASE, PsycINFO, Social Policy and Practice via Ovid, CINAHL via EBSCO, The Cochrane Library (CDSR, DARE and CENTRAL databases), Nursing and Allied Health Sources, Applied Social Sciences Index and Abstracts via ProQuest and SCOPUS. In addition, other sources will be searched for ongoing studies (ClinicalTrials.gov) and grey literature: Healthcare Management Information Consortium, Conference Proceedings Citation Index (Web of Science) and Sociological abstracts. Studies will be independently screened for eligibility by 2 reviewers. Qualitative studies, either standalone or in the context of mixed-methods designs, reporting the perspectives of any actors involved in the implementation, management and use of ePrescribing/CPOE systems in hospital-based care settings will be included. Data extraction will be conducted by 2 reviewers using a piloted form. Quality appraisal will be based on criteria from the Critical Appraisal Skills Programme checklist and Standards for Reporting Qualitative Research. Studies will not be excluded based on quality assessment. A postsynthesis sensitivity analysis will be undertaken. Data analysis will follow the thematic synthesis method. The study does not require ethical approval as primary data will not be collected. The results of the study will be published in a peer-reviewed journal and presented at relevant conferences. CRD42016035552.


Extracytoplasmic proteins of Mycobacterium tuberculosis - mature secreted proteins often start with aspartic acid and proline.
A surrogate expression system, based on fusions to the phoA bacterial reporter gene, was used to identify Mycobacterium tuberculosis genes that encode exported proteins and the promoter regions required for their expression in the heterologous host Mycobacterium smegmatis. To assess these results in the context of the complete M. tuberculosis genome sequence, the corresponding genes were identified and computational algorithms were employed to identify signal peptide (SP), transmembrane domain and membrane lipoprotein attachment motifs. This information was used to predict the subset of M. tuberculosis genes that encode exported proteins. Of the 34 genes identified by the phoA method, 22 were classified to encode potential soluble secreted proteins. Among these, 14 genes may encode novel secreted proteins. Six of the remaining 12 genes were predicted to encode membrane lipoproteins and an additional six to encode integral membrane proteins. Published observations of proteins proven to be secreted into M. tuberculosis culture filtrates were reviewed to further characterize the mycobacterial SP motif. It was concluded that mycobacterial SPs are comparable in size to Gram-positive SPs, but certain features are different. In particular, arginine was the predominant N-terminally positively charged amino acid in contrast to lysine in the Gram-positives. The hydrophobic transmembrane segment of the SP was dominated by alanine, in contrast to leucine. At the C-terminal end of the SPs, the (-3, -1) rule (AXA motif) holds, with alanine as the dominant amino acid in both positions, being most dominant in the (-1) position. A high proportion of mature sequences start with aspartic acid in the (+1) position and proline in the (+2) position - the DP motif. The authors propose that the DP sequence serves as a sorting signal, following translocation and cleavage by signal peptidase I. Alternatively, the DP motif may be part of the recognition site for the signal peptidase.


Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome.
Studies of copy-number variation and linkage disequilibrium (LD) have typically excluded complex regions of the genome that are rich in duplications and prone to rearrangement. In an attempt to assess the heritability and LD of copy-number polymorphisms (CNPs) in duplication-rich regions of the genome, we profiled copy-number variation in 130 putative "rearrangement hotspot regions" among 269 individuals of European, Yoruba, Chinese, and Japanese ancestry analyzed by the International HapMap Consortium. Eighty-four hotspot regions, corresponding to 257 bacterial artificial chromosome (BAC) probes, showed evidence of copy-number differences. Despite a predisposing genetic architecture, no polymorphism was ever observed in the remaining 46 "rearrangement hotspots," and we suggest these represent excellent candidate sites for pathogenic rearrangements. We used a combination of BAC-based and high-density customized oligonucleotide arrays to resolve the molecular basis of structural rearrangements. For common variants (frequency >10%), we observed a distinct bias against copy-number losses, suggesting that deletions are subject to purifying selection. Heritability estimates did not differ significantly from 1.0 among the majority (30 of 34) of loci analyzed, consistent with normal Mendelian inheritance. Some of the CNPs in duplication-rich regions showed strong LD with nearby single-nucleotide polymorphisms (SNPs) and were observed to segregate on ancestral SNP haplotypes. However, LD with the best available SNP markers was weaker than has been reported for deletion polymorphisms in less complex regions of the genome. These observations may be accounted for by a low density of SNP data in duplicated regions, challenges in mapping and typing the CNPs, and the possibility that CNPs in these regions have rearranged on multiple haplotype backgrounds. Our results underscore the need for complete maps of genetic variation in duplication-rich regions of the genome.


What lies beneath? Population dynamics conceal pace-of-life and sex ratio variation, with implications for resilience to environmental change.
Life-history and pace-of-life syndrome theory predict that populations are comprised of individuals exhibiting different reproductive schedules and associated behavioural and physiological traits, optimized to prevailing social and environmental factors. Changing weather and social conditions provide in situ cues altering this life-history optimality; nevertheless, few studies have considered how tactical, sex-specific plasticity over an individual's lifespan varies in wild populations and influences population resilience. We examined the drivers of individual life-history schedules using 31 years of trapping data and 28 years of pedigree for the European badger (Meles meles L.), a long-lived, iteroparous, polygynandrous mammal that exhibits heterochrony in the timing of endocrinological puberty in male cubs. Our top model for the effects of environmental (social and weather) conditions during a badger's first year on pace-of-life explained <10% of variance in the ratio of fertility to age at first reproduction (F/α) and lifetime reproductive success. Conversely, sex ratio (SR) and sex-specific density explained 52.8% (males) and 91.0% (females) of variance in adult F/α ratios relative to the long-term population median F/α. Weather primarily affected the sexes at different life-history stages, with energy constraints limiting the onset of male reproduction but playing a large role in female strategic energy allocation, particularly in relation to ongoing mean temperature increases. Furthermore, the effects of social factors on age of first reproduction and year-to-year reproductive success covaried differently with sex, likely due to sex-specific responses to potential mate availability. For females, low same-sex densities favoured early primiparity; for males, instead, up to 10% of yearlings successfully mated at high same-sex densities. We observed substantial SR dynamism relating to differential mortality of life-history strategists within the population, and propose that shifting ratios of 'fast' and 'slow' life-history strategists contribute substantially to population dynamics and resilience to changing conditions.


Overall and Gender-specific Associations between Dimensions of Adverse Childhood Experiences and Mental Health Outcomes among Homeless Adults: Associations Générales et Sexospécifiques Entre les Dimensions des Expériences Défavorables de L'enfance et les Résultats de Santé Mentale Chez les Adultes Sans Abri.
The associations between adverse childhood experiences (ACEs) and psychopathology have been well-established in the general population. Research on ACEs in the homeless population has been limited. This study examined whether ACE exposure is associated with specific mental health outcomes among a national sample of homeless adults with mental illness and whether this association varies according to ACE dimension and gender. This cross-sectional study utilized data from a national sample of 2,235 homeless adults with mental illness in Canada to evaluate their sociodemographic characteristics, exposure to ACEs, and mental health outcomes. Exploratory and confirmatory factor analyses were conducted to identify and confirm ACE dimensions (maltreatment, sexual abuse, neglect, divorce, and household dysfunction) from individual ACE items. Multivariable logistic regression was used to examine the associations between total ACE score and ACE dimensions with mental illness diagnoses and psychopathology severity. The mean total ACE score among all study participants was 4.44 (standard deviation [SD]: 2.99). Total ACE score was positively associated with several mental illness diagnoses and psychopathology severity. Unique associations were found between specific ACE dimensions and poor mental health outcomes. The prevalence of almost all ACEs was significantly higher among women. Yet, associations between several ACE dimensions and poor mental health outcomes existed uniquely among men. There are unique and gender-specific associations between specific ACE dimensions and mental health outcomes among homeless adults. Better understanding of the mechanisms underlying these associations is needed to inform screening, prevention, and treatment efforts, particularly given the very high prevalence of ACEs among this vulnerable and marginalized population.


Evidencing the mask effect of graphene oxide: a comparative study on primary human and murine phagocytic cells.
Graphene oxide (GO) is attracting an ever-growing interest in different fields and applications. Not much is known about the possible impact of GO sheet lateral dimensions on their effects in vitro, especially on human primary cells. In an attempt to address this issue, we present a study to evaluate, how highly soluble 2-dimensional GO constituted of large or small flakes affects human monocyte derived macrophages (hMDM). For this purpose, the lateral size of GO was tuned using sonication and three samples were obtained. The non sonicated one presented large flakes (~1.32 μm) while sonication for 2 and 26 hours generated small (~0.27 μm) and very small (~0.13 μm) sheets of GO, respectively. Cell studies were then conducted to evaluate the cytotoxicity, the oxidative stress induction, the activation potential and the pro-inflammatory effects of these different types of GO at increasing concentrations. In comparison, the same experiments were run on murine intraperitoneal macrophages (mIPM). The interaction between GO and cells was further examined by TEM and Raman spectroscopy. Our data revealed that the GO sheet size had a significant impact on different cellular parameters (i.e. cellular viability, ROS generation, and cellular activation). Indeed, the more the lateral dimensions of GO were reduced, the higher were the cellular internalization and the effects on cellular functionality. Our data also revealed a particular interaction of GO flakes with the cellular membrane. In fact, a GO mask due to the parallel arrangement of the graphene sheets on the cellular surface was observed. Considering the mask effect, we have hypothesized that this particular contact between GO sheets and the cell membrane could either promote their internalization or isolate cells from their environment, thus possibly accounting for the following impact on cellular parameters.


UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport.
We investigate the role of axonal transport in regulating neuronal mitochondrial density. We show that the density of mitochondria in the touch receptor neuron (TRN) of adult Caenorhabditis elegans is constant. Mitochondrial density and transport are controlled both by the Kinesin heavy chain and the Dynein-Dynactin complex. However, unlike in other models, the presence of mitochondria in C. elegans TRNs depends on a Kinesin light chain as well. Mutants in the three C. elegans miro genes do not alter mitochondrial density in the TRNs. Mutants in the Kinesin-1 associated proteins, UNC-16/JIP3 and UNC-76/FEZ1, show increased mitochondrial density and also have elevated levels of both the Kinesin Heavy and Light Chains in neurons. Genetic analyses suggest that, the increased mitochondrial density at the distal end of the neuronal process in unc-16 and unc-76 depends partly on Dynein. We observe a net anterograde bias in the ratio of anterograde to retrograde mitochondrial flux in the neuronal processes of unc-16 and unc-76, likely due to both increased Kinesin-1 and decreased Dynein in the neuronal processes. Our study shows that UNC-16 and UNC-76 indirectly limit mitochondrial density in the neuronal process by maintaining a balance in anterograde and retrograde mitochondrial axonal transport.


Effects of chlorophyll availability on phycobilisomes in Synechocystis sp. PCC 6803.
Inactivation of the chlL gene in Synechocystis sp. PCC 6803 resulted in negligible chlorophyll content when the mutant was grown in darkness. Upon phycocyanin excitation at 580 nm, the 77K fluorescence spectrum of dark-grown cells showed three peaks at 648 nm, 665 nm, and 685 nm, this last being the largest. This reflects the functional presence of major components of phycobilisomes, including phycocyanin, allophycocyanin, and the terminal emitter, and efficient energy transfer between these components. As expected, no fluorescence emission peaks corresponding to chlorophyll in the photosystems were observed. Intact phycobilisomes could be isolated from the dark-grown chlL-deletion mutant. However, the phycobilisomes had a lower efficiency of energy transfer than did those isolated from the light-grown mutant, probably because of a decreased phycobilisome stability in the absence of chlorophyll. Exposing the dark-grown chlL-deletion mutant to light triggered the biosynthesis of chlorophyll. For the first 6 h in the light, upon phycocyanin excitation at 580 nm, the 77K fluorescence emission spectrum of greening cells was identical to that of dark-grown cells that lacked significant amounts of chlorophyll. With increased chlorophyll synthesis, gradual energy transfer from phycobilisomes to the two photosystems can be demonstrated.


CracidMex1: a comprehensive database of global occurrences of cracids (Aves, Galliformes) with distribution in Mexico.
Cracids are among the most vulnerable groups of Neotropical birds. Almost half of the species of this family are included in a conservation risk category. Twelve taxa occur in Mexico, six of which are considered at risk at national level and two are globally endangered. Therefore, it is imperative that high quality, comprehensive, and high-resolution spatial data on the occurrence of these taxa are made available as a valuable tool in the process of defining appropriate management strategies for conservation at a local and global level. We constructed the CracidMex1 database by collating global records of all cracid taxa that occur in Mexico from available electronic databases, museum specimens, publications, "grey literature", and unpublished records. We generated a database with 23,896 clean, validated, and standardized geographic records. Database quality control was an iterative process that commenced with the consolidation and elimination of duplicate records, followed by the geo-referencing of records when necessary, and their taxonomic and geographic validation using GIS tools and expert knowledge. We followed the geo-referencing protocol proposed by the Mexican National Commission for the Use and Conservation of Biodiversity. We could not estimate the geographic coordinates of 981 records due to inconsistencies or lack of sufficient information in the description of the locality. Given that current records for most of the taxa have some degree of distributional bias, with redundancies at different spatial scales, the CracidMex1 database has allowed us to detect areas where more sampling effort is required to have a better representation of the global spatial occurrence of these cracids. We also found that particular attention needs to be given to taxa identification in those areas where congeners or conspecifics co-occur in order to avoid taxonomic uncertainty. The construction of the CracidMex1 database represents the first comprehensive research effort to compile current, available global geographic records for a group of cracids. The database can now be improved by continuous revision and addition of new records. The CracidMex1 database will provide high quality input data that could be used to generate species distribution models, to assess temporal changes in species distributions, to identify priority areas for research and conservation, and in the definition of management strategies for this bird group. This compilation exercise could be replicated for other cracid groups or regions to attain a better knowledge of the global occurrences of the species in this vulnerable bird family.


Low-level and high-level processes in apparent motion.
When a group of dots within a random-dot array is discontinuously displaced, it appears as a moving region perceptually segregated from its stationary surround. The spastial, temporal and other constraints governing this effect are markedly different from those classically found for the apparent motion of isolated stimulus elements. The random-dot display appears to tap a low-level motion-detecting process, distinct from the more interpretive process elicited by the classical displays. The distinct contributions of these processes can be identified in 'multi-stable' displays which yield alternative percepts of apparent motion depending on which one or both of the processes is activated. Such experiments illustrate the interaction of relatively stimulus-constrained and relatively autonomous processes invisual perception.


The relationship between start performance and race outcome in elite 500-m short-track speed skating.
Initial short-track speed-skating 14-m start performance has substantial influence on 500-m race outcome at the international level, yet the relationship has not been systematically quantified. The purpose of this investigation was to examine the relationship between rank position entering first corner (RPEFC) and race outcome and to understand how this relationship changes with competition round and absolute race intensity. Data were compiled from 2011-2014 World Cup seasons and 2010 and 2014 Olympic Winter Games. Association between RPEFC and race outcome was determined through Kendall tau-rank correlations. A visual comparison was made of how the relationship changes with relative competition level (race tau correlations were sorted by competition round) and with race intensity (race tau correlations were sorted by within-event winning time). A very large relationship between RPEFC and race outcome was observed (correlations for cohort, τ = .60; men, τ = .53; women, τ = .67). When examined by competition round (quarter- to A-finals), no substantial change in relationship was observed (men, τ = .57-.46; women, τ = .73-.53). However, when the start-performance relationship was considered by within-event winning time, the relationship strength increased with decreasing time (men, τ = .61 to .46; women, τ = .76 to .57; fastest to 7th- and 8th-fastest combined, respectively). These results establish and quantify RPEFC as an important aspect of elite short-track 500-m race outcome. RPEFC as an indicator of race outcome becomes increasingly important with absolute race intensity, suggesting that RPEFC capability is a discriminating factor for competitors of similar top speed and speed endurance.


Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic "scotomas".
The spatial memory functions of the monkey's prefrontal cortex were examined with oculomotor delayed-response (ODR) paradigms that required the animal to remember the spatial location of peripheral visual cues, while maintaining fixation on a central visual target during the presentation of each cue and during a subsequent 1.5-8 sec delay period. Four rhesus monkeys received unilateral or serial prefrontal lesions in and around the principal sulcus after they reached criterion performance on the ODR tasks. Unilateral lesions disrupted the performance of memory-guided eye movements to spatial cues in the visual field contralateral to the hemisphere in which the lesion was placed. Memory-guided eye movements to ipsilateral cues were mildly affected by unilateral lesions, and these lesions had little or no effect on performance in visually guided control tasks. With addition of a second lesion in the opposite hemisphere, the deficit was extended to include the opposite hemifield. The impairment was characterized by eye movements of inappropriate direction, and, excepting the one lesion that extended into the frontal eye field region of the arcuate sulcus, saccadic reaction times and velocities were the same before and after the lesions. The effect of the lesions was delay dependent: performance was rarely altered at the shortest (1.5 sec) delay but became progressively worse as the delay period was lengthened. The present results strengthen the evidence that the delayed-response deficits of monkeys with prefrontal lesions are caused by failure to maintain a transient memory "trace" in working memory, and indicate for the first time that working memory mechanisms are lateralized: memories for visuo-spatial coordinates in each hemifield are processed primarily in the contralateral prefrontal cortex. These findings provide evidence for the concept of mnemonic hemianopias and mnemonic scotomas, that is, memory deficits for particular hemifields or visual field locations, unaccompanied by simple sensory or motor deficits.


Bradykinin generation by dialysis membranes: possible role in anaphylactic reaction.
Several recent reports have described a high incidence of anaphylactic reactions in patients being dialyzed with high-flux membranes while simultaneously using angiotensin-converting enzyme inhibitors. Many of these reports implicate polyacrylonitrile (PAN) as the membrane commonly involved in these reactions. To elucidate potential mechanisms of these anaphylactic reactions, whether dialysis membranes can activate the Hageman factor-dependent (contact) pathways as assessed by the in vitro generation of activated Hageman factor (Hfa), as well as the formation of kallikrein and subsequent bradykinin generation was examined. Both cuprophane (CUP) and PAN membranes were able to activate Hageman factor and convert prekallikrein to kallikrein as measured by an ELISA against kallikrein-C1-inactivator complexes. Subsequently, the active kallikrein was able to cleave bradykinin from its endogenous substrate, high-molecular-weight kininogen. However, it was found that the PAN membrane consistently led to an earlier and significantly higher formation of Hfa and kallikrein when compared with CUP. Importantly, there was also a pronounced but transient generation of bradykinin by the PAN membrane, in contrast to slower bradykinin formation by CUP, with both normal and uremic blood. It was proposed that the early and vigorous bradykinin generation induced by the contact of blood with PAN could explain, in part, the pathogenesis of the reported anaphylactoid reactions.


A Hierarchy of Functional States in Working Memory.
Extensive research has examined how information is maintained in working memory (WM), but it remains unknown how WM is used to guide behavior. We addressed this question by combining human electrophysiology (50 subjects, male and female) with pattern analyses, cognitive modeling, and a task requiring the prolonged maintenance of two WM items and priority shifts between them. This enabled us to discern neural states coding for memories that were selected to guide the next decision from states coding for concurrently held memories that were maintained for later use, and to examine how these states contribute to WM-based decisions. Selected memories were encoded in a functionally active state. This state was reflected in spontaneous brain activity during the delay period, closely tracked moment-to-moment fluctuations in the quality of evidence integration, and also predicted when memories would interfere with each other. In contrast, concurrently held memories were encoded in a functionally latent state. This state was reflected only in stimulus-evoked brain activity, tracked memory precision at longer timescales, but did not engage with ongoing decision dynamics. Intriguingly, the two functional states were highly flexible, as priority could be dynamically shifted back and forth between memories without degrading their precision. These results delineate a hierarchy of functional states, whereby latent memories supporting general maintenance are transformed into active decision circuits to guide flexible behavior.SIGNIFICANCE STATEMENT Working memory enables maintenance of information that is no longer available in the environment. Abundant neuroscientific work has examined where in the brain working memories are stored, but it remains unknown how they are represented and used to guide behavior. Our study shows that working memories are represented in qualitatively different formats, depending on behavioral priorities. Memories that are selected for guiding behavior are encoded in an active state that transforms sensory input into decision variables, whereas other concurrently held memories are encoded in a latent state that supports precise maintenance without affecting ongoing cognition. These results dissociate mechanisms supporting memory storage and usage, and open the door to reveal not only where memories are stored but also how.


The cytoskeleton of trypanosomatid parasites.
Species of the trypanosomatid parasite genera Trypanosoma and Leishmania exhibit a particular range of cell shapes that are defined by their internal cytoskeletons. The cytoskeleton is characterized by a subpellicular corset of microtubules that are cross-linked to each other and to the plasma membrane. Trypanosomatid cells possess an extremely precise organization of microtubules and filaments, with some of their organelles, such as the mitochondria, kinetoplasts, basal bodies, and flagella, present as single copies in each cell. The duplication of these structures and changes in their position during life cycle differentiations provide markers and insight into events involved in determining cell form and division. We have a rapidly increasing catalog of these structures, their molecular cytology, and their ontogeny. The current sophistication of available molecular genetic techniques for use in these organisms has allowed a new functional analysis of the cytoskeleton, including functions that are intrinsic to the proliferation and pathogenicity of these parasites.


Potential applications of next generation DNA sequencing of 16S rRNA gene amplicons in microbial water quality monitoring.
The applicability of next generation DNA sequencing (NGS) methods for water quality assessment has so far not been broadly investigated. This study set out to evaluate the potential of an NGS-based approach in a complex catchment with importance for drinking water abstraction. In this multi-compartment investigation, total bacterial communities in water, faeces, soil, and sediment samples were investigated by 454 pyrosequencing of bacterial 16S rRNA gene amplicons to assess the capabilities of this NGS method for (i) the development and evaluation of environmental molecular diagnostics, (ii) direct screening of the bulk bacterial communities, and (iii) the detection of faecal pollution in water. Results indicate that NGS methods can highlight potential target populations for diagnostics and will prove useful for the evaluation of existing and the development of novel DNA-based detection methods in the field of water microbiology. The used approach allowed unveiling of dominant bacterial populations but failed to detect populations with low abundances such as faecal indicators in surface waters. In combination with metadata, NGS data will also allow the identification of drivers of bacterial community composition during water treatment and distribution, highlighting the power of this approach for monitoring of bacterial regrowth and contamination in technical systems.


Effect of synthetic disaccharide-protein conjugate as an immunogen in Salmonella infection in mice.
The synthetic disaccharide 3-O-alpha-tyvelopyranosyl-alpha-D-mannopyranoside, identical to the O antigen 9 determinant in Salmonella, covalently linked to bovine serum albumin and suspended in Freund complete adjuvant, was used as an immunogen in mice. Antibodies in high titer were formed against the O9 determinant as estimated by a bactericidal assay, whereas only low titers of hemagglutinating antibodies were found. A sensitive in vivo assay demonstrated that in immunized mice, after challenge with two strains of equal virulence but with different O antigens (O9, 12 and O4, 5, 12, respectively), the growth of the strain with the O9 determinant was suppressed in comparison to that with the O4 determinant.


The legislative and litigation history of special education.
Between the mid 1960s and 1975, state legislatures, the federal courts, and the U.S. Congress spelled out strong educational rights for children with disabilities. Forty-five state legislatures passed laws mandating, encouraging, and/or funding special education programs. Federal courts, interpreting the equal protection and due process guarantees of the Fourteenth Amendment to the U.S. Constitution, ruled that schools could not discriminate on the basis of disability and that parents had due process rights related to their children's schooling. Congress, in legislation now retitled the Individuals with Disabilities Education Act (IDEA), laid out detailed procedural protections regarding eligibility for special educational services, parental rights, individualized education programs (IEPs), the requirement that children be served in the least restrictive environment, and the need to provide related (noneducational) services. Decisions on instructional matters such as curricula and the elements of the IEP remain the province of local and state authorities. Advocates for students with disabilities have continually sought separate (categorical) funding for special education services. Current movements toward block grants rather than categorical programs and toward greater inclusion of special education students in general education classrooms raise concerns in some quarters about whether students with disabilities will continue to have full access to the special services they need. While the cost of special services may be an unexpressed criterion in many decisions made by school districts, nowhere does the IDEA explicitly allow cost to be considered. Where a service is necessary for an individual child, cost considerations would not allow a school district to escape its obligations to the child. However, in instances where more than one appropriate configuration of services is available to meet a child's needs, the school district may be allowed to consider the cost of different alternatives.


A call for parental monitoring to improve condom use among secondary school students in Dar es Salaam, Tanzania.
The number of people newly infected with human immunodeficiency virus (HIV) has been decreasing in sub-Saharan Africa, but prevalence of the infection remains unacceptably high among young people. Despite the alarming pervasiveness of the virus, young people in this region continue to engage in risky sexual behaviors including unprotected sexual intercourse. In developed countries, parents can play important roles in protecting young people from such behaviors, but evidence regarding the impact of parental involvement is still limited in sub-Saharan Africa. Therefore, we conducted this study to examine the magnitude of risky sexual behaviors and the association of parental monitoring and parental communication with condom use at last sexual intercourse among secondary school students in Dar es Salaam, Tanzania. We conducted this cross-sectional study among 2,217 male and female students aged 15 to 24 years from 12 secondary schools in Dar es Salaam. From October to November 2011, we collected data using a self-administered questionnaire. Multiple logistic regression analyses were conducted to examine the association of parental monitoring and parental communication with condom use at last sexual intercourse, adjusting for potential confounders. A total of 665 (30.3%) secondary school students reported being sexually active within the year prior to data collection. Among them, 41.7% had multiple sexual partners, 10.5% had concurrent sexual partners, and 41.1% did not use a condom at last sexual intercourse. A higher level of parental monitoring was associated with increased likelihood of condom use at last sexual intercourse among male students (AOR: 1.56, 95% CI: 1.05-2.32; p = 0.03) but not among female students (AOR: 1.54, 95% CI: 0.71-3.37; p = 0.28). The association between parental communication and condom use at last sexual intercourse among both male and female students was not statistically significant. A high level of parental monitoring is associated with more consistent condom use among male students in Dar es Salaam, Tanzania -- many of whom have engaged in high-risk sexual behaviors such as multiple sexual partnerships, concurrent sexual partnerships, and unprotected sexual intercourse in the past one year. Interventions should thus be strengthened to reduce multiple sexual partnerships, concurrent sexual partnerships, and to improve parental monitoring among such students toward increasing condom use.


Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells.
Recruitment of effector T cells to inflamed peripheral tissues is regulated by chemokines and their receptors, but the factors regulating recruitment to tumors remain largely undefined. Ionizing radiation (IR) therapy is a common treatment modality for breast and other cancers. Used as a cytocidal agent for proliferating cancer cells, IR in combination with immunotherapy has been shown to promote immune-mediated tumor destruction in preclinical studies. In this study we demonstrate that IR markedly enhanced the secretion by mouse and human breast cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and plays an important role in their recruitment to sites of inflammation. Using a poorly immunogenic mouse model of breast cancer, we found that irradiation increased the migration of CD8(+)CXCR6(+) activated T cells to tumors in vitro and in vivo. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4. These results provide the first evidence that IR can induce the secretion by cancer cells of proinflammatory chemotactic factors that recruit antitumor effector T cells. The ability of IR to convert tumors into "inflamed" peripheral tissues could be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy.


Synthesis, structures and thermal decomposition of ammine MxB12H12 complexes (M = Li, Na, Ca).
A series of ammine metal-dodecahydro-closo-dodecaboranes, MxB12H12·nNH3 (M = Li, Na, Ca) were synthesized and their structural and thermal properties studied with in situ time-resolved synchrotron radiation powder X-ray diffraction, thermal analysis, Fourier transformed infrared spectroscopy, and temperature-programmed photographic analysis. The synthesized compounds, Li2B12H12·7NH3, Na2B12H12·4NH3 and CaB12H12·6NH3, contain high amounts of NH3, 43.3, 26.6 and 35.9 wt% NH3, respectively, which can be released and absorbed reversibly at moderate conditions without decomposition, thereby making the closo-boranes favorable 'host' materials for ammonia or indirect hydrogen storage in the solid state. In this work, fifteen new ammine metal dodecahydro-closo-dodecaborane compounds are observed by powder X-ray diffraction, of which six are structurally characterized, Li2B12H12·4NH3, Li2B12H12·2NH3, Na2B12H12·4NH3, Na2B12H12·2NH3, CaB12H12·4NH3 and CaB12H12·3NH3. Li2B12H12·4NH3 and Na2B12H12·4NH3 are isostructural and monoclinic (P21/n) whereas Na2B12H12·2NH3 and CaB12H12·3NH3 are both trigonal with space groups P3[combining macron]m1 and R3[combining macron]c, respectively. Generally, coordination between the metal and the icosahedral closo-borane anion is diverse and includes point sharing, edge sharing, or face sharing, while coordination of ammonia always occurs via the lone pair on nitrogen to the metal. Furthermore, a liquid intermediate is observed during heating of Li2B12H12·7NH3. This work provides deeper insight into the structural, physical, and chemical properties related to thermal decomposition and possible ammonia and hydrogen storage.


Intrinsic and extrinsic effects on image memorability.
Previous studies have identified that images carry the attribute of memorability, a predictive value of whether a novel image will be later remembered or forgotten. Here we investigate the interplay between intrinsic and extrinsic factors that affect image memorability. First, we find that intrinsic differences in memorability exist at a finer-grained scale than previously documented. Second, we test two extrinsic factors: image context and observer behavior. Building on prior findings that images that are distinct with respect to their context are better remembered, we propose an information-theoretic model of image distinctiveness. Our model can automatically predict how changes in context change the memorability of natural images. In addition to context, we study a second extrinsic factor: where an observer looks while memorizing an image. It turns out that eye movements provide additional information that can predict whether or not an image will be remembered, on a trial-by-trial basis. Together, by considering both intrinsic and extrinsic effects on memorability, we arrive at a more complete and fine-grained model of image memorability than previously available.


Optical isomer analysis of 3,4-methylene-dioxyamphetamine analogues and their stereoselective disposition in rats.
Identification of the optical activity and simultaneous analysis of racemates (+/-) of three hallucinogens, 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA), and the urinary excretion of their optical isomers in rats was performed by high-performance liquid chromatographic analysis. Analysis of optical enantiomers of three N-alkyl MDA derivatives was performed within 50 min using two different detectors, polarimetry (OR) and ultraviolet spectroscopy (UV). The OR detector proved suitable for identification of the optically active forms, whereas the UV detector was suitable for simultaneous analysis of the enantiomers in urine. After the administration of each of the three N-alkylated derivatives, rat urine specimens were collected over four intervals, 0-4, 4-12, 12-20, and 20-24 h. After the administration of 30 mg/kg of racemic MDA and MDMA, somewhat less of the S(+)-forms of unchanged MDA and MDMA than of the R(-)-forms in each urine specimen were detected, which gave R/S ratios greater than 1.00 (p < 0.01). Conversely, after the administration of 30 mg/kg of racemic MDEA, more of the S(+)-form than the R(-)-form was found in the urine, thus giving R/S ratios less than 1.00 (p < 0.01). The percentage of the dose excreted up to 24 h was approximately 29.4% of the administered dose for MDA [S(+) 13.40% and R(-) 15.98%], 5.8% for MDMA [S(+) 1.96% and R(-) 3.79%], and 7.3% for MDEA [S(+) 3.89% and R(-) 3.43%]. Urinary excretion of optical isomers of N-dealkylated MDA from MDMA and MDEA origin were the opposite of those of the unchanged forms, and their R/S ratios up to 24 h were 0.48 to 0.72 (p < 0.01) and 1.31 to 1.50 (p < 0.01), respectively. The urinary excretion rates up to 24 h were approximately 4.3% for N-dealkylated MDA from MDMA origin [S(+) 2.72% and R(-) 1.63%] and 0.8% for N-dealkylated MDA from MDEA origin [S(+) 0.36% and R(-) 0.47%]. The total percent of unchanged forms and N-dealkylated MDA was approximately 10.1% for MDMA [S(+) 4.68% and R(-) 5.42%] and 8.2% for MDEA [S(+) 4.25% and R(-) 3.91%]. The total R/S ratio of MDMA was found to be 1.95 (p < 0.01), whereas that of MDEA was 0.88 (p < 0.01). The total R/S ratio of MDA was 1.20 (p < 0.01 ), which was comparable with that of MDMA. These three R/S ratios did not conform to the theoretical values for three N-alkyl derivatives used and neither did the R/S ratios of urine specimens collected at the four interval. These results suggested the stereoselective disposition of three N-alkyl MDA analogues in rat. The method would be suitable for the forensic chemistry and toxicology analysis of specimens obtained from hallucinogen abusers.


Effects of base excision repair gene polymorphisms on pancreatic cancer survival.
To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p = 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population.


Contextual organismality: Beyond pattern to process in the emergence of organisms.
Biologists have taken the concept of organism largely for granted. However, advances in the study of chimerism, symbiosis, bacterial-eukaryote associations, and microbial behavior have prompted a redefinition of organisms as biological entities exhibiting low conflict and high cooperation among their parts. This expanded view identifies organisms in evolutionary time. However, the ecological processes, mechanisms, and traits that drive the formation of organisms remain poorly understood. Recognizing that organismality can be context dependent, we advocate elucidating the ecological contexts under which entities do or do not act as organisms. Here we develop a "contextual organismality" framework and provide examples of entities, such as honey bee colonies, tumors, and bacterial swarms, that can act as organisms under specific life history, resource, or other ecological circumstances. We suggest that context dependence may be a stepping stone to the development of increased organismal unification, as the most integrated biological entities generally show little context dependence. Recognizing that organismality is contextual can identify common patterns and testable hypotheses across different entities. The contextual organismality framework can illuminate timeless as well as pressing issues in biology, including topics as disparate as cancer emergence, genomic conflict, evolution of symbiosis, and the role of the microbiota in impacting host phenotype.


Harmful effects of silver nanoparticles on a complex detrital model system.
The rapid proliferation of silver nanoparticles (AgNP) in industry and the environment requires realistic toxicity assessments based on approaches that consider the biological complexity of ecosystems. Here we assessed the acute toxicity of carbonate-coated AgNP and, for comparison, AgNO3 (Ag(+)) by using a model system consisting of decomposing plant litter and the associated fungal and bacterial decomposers as central players in the functioning of stream ecosystems. Little variation in size and surface charge during the experiment indicated that the AgNP used were essentially stable. AgNP disrupted bacterial growth (≤83% reduction in protein biosynthesis, EC50 = 0.3 μM), clearly affected fungal growth (≤61% reduction in ergosterol synthesis, EC50 = 47 μM) with both endpoints more sensitive to AgNP than to Ag(+). Fungal reproduction, in contrast, was stimulated by AgNP, but not Ag(+), at concentrations up to 25 μM. Both AgNP and Ag(+ )also stimulated extracellular alkaline phosphatase but reduced leucine aminopeptidase, whereas β-glucosidase was stimulated by AgNP and reduced by Ag(+). Importantly, the provision of cysteine, a chelating ligand that complexes free Ag(+), failed to alleviate AgNP toxicity to microbial growth, clearly demonstrating particle-mediated toxicity independent of the presence of ionic silver. This contrasts with the observed inhibition of leucine aminopeptidase by Ag(+), which accounted for 2-6% of the total silver in treatments receiving AgNP. These results show that although outcomes of AgNP and Ag(+ )exposure assessed by different functional endpoints vary widely, AgNP strongly interferes with bacterial growth and a range of other microbial processes, resulting in severe consequences for natural microbial communities and ecosystem functioning.


Signal pathways regulating hyaluronan secretion into static and cycled synovial joints of rabbits.
Joint lubrication, synovial fluid conservation and many pathophysiological processes depend on hyaluronan (HA). Intra-articular HA injection and exercise, which stimulates articular HA production, ameliorate osteoarthritis. We therefore investigated the pathways regulating movement-stimulated articular HA secretion rate ( ) in vivo. Endogenous HA was removed from the knee joint cavity of anaesthetised rabbits by washout. Joints were then cycled passively or remained static for 5 h, with/without intra-articular agonist/inhibitor, after which newly secreted HA was harvested for analysis. Movement almost doubled . Similar or larger increases were elicited in static joints by the intra-articular Ca(2+) ionophore ionomycin, prostaglandin E(2), cAMP-raising agents, serine/threonine phosphatase inhibitor and activation of protein kinase C (PKC). PKC-stimulated secretion was inhibited by the PKC inhibitor bisindolylmaleimide I and inhibitors of the downstream kinases MEK-ERK (U0126, PD98059). These agents inhibited movement-stimulated secretion of HA (MSHA) only when the parallel p38 kinase path was simultaneously inhibited by SB203580 (ineffective alone). The phospholipase C inhibitor U73122 almost fully blocked MSHA (P = 0.001, n = 10), without affecting static . The ENaC channel blocker amiloride inhibited MSHA, whereas other inhibitors of stretch-activated channels (Gd(3+), ruthenium red, SKF96365) did not. It is proposed that MSHA may be mediated by PLC activation, leading to activation of parallel PKC-MEK-ERK and p38 kinase pathways.


Protective effect of paeoniflorin on Aβ25-35-induced SH-SY5Y cell injury by preventing mitochondrial dysfunction.
Alzheimer's disease (AD) is a major neurodegenerative brain disorder affecting about 14 million people worldwide. Aβ-induced cell injury is a crucial cause of neuronal loss in AD, thus the suppression of which might be useful for the treatment of this disease. In this study, we aimed to evaluate the effect of paeoniflorin (PF), a monoterpene glycoside isolated from aqueous extract of Radix Paeoniae Alba, on Aβ25-35-induced cytotoxicity in SH-SY5Y cells. The results showed PF could attenuate or restore the viability loss, apoptotic increase, and ROS production induced by Aβ25-35 in SH-SY5Y cells. In addition, PF strikingly inhibited Aβ25-35-induced mitochondrial dysfunction, which includes decreased mitochondrial membrane potential, increased Bax/Bcl-2 ratio, cytochrome c release and activity of caspase-3 and caspase-9. Therefore, our study provided the first experimental evidence that PF could modulate ROS production and apoptotic mitochondrial pathway in model of neuron injury in vitro and which might provide new insights into its application toward Alzheimer's disease therapy.


Mitigation of informational masking in individuals with single-sided deafness by integrated bone conduction hearing aids.
To confirm an increased susceptibility to informational masking among individuals with single-sided deafness (SSD). To demonstrate a reduction in informational masking when SSD is treated with an integrated bone conduction hearing aid (IBC). To identify the acoustic cues that contribute to IBC-aided masking release. To determine the effects of device experience on the IBC advantage. Informational masking was evaluated with the coordinate-response measure. Participants performed the task by reporting color and number coordinates that changed randomly within target sentences. The target sentences were presented in free field accompanied by zero to three distracting sentences. Target and distracting sentences were spoken by different talkers and originated from different source locations, creating two sources of information for auditory streaming. Susceptibility to informational masking was inferred from the error rates of unaided SSD patients relative to normal controls. These baseline measures were derived by testing inexperienced IBC users without the device on the day of their initial fitting. The benefits of IBC-aided listening were assessed by measuring the aided performance of users who had at least 3 months' device experience. The acoustic basis of the listening advantage was isolated by correlating response errors with the voice pitch and location of distracting sentences. The effects of learning on cue effectiveness were evaluated by comparing the error rates of experienced and inexperienced users. Unaided SSD participants (inexperienced users) performed as well as normal controls when tested without distracting sentences but produced significantly higher error rates when tested with distracting sentences. Most errors involved responding with coordinates that were contained in distracting sentences. This increased susceptibility to informational masking was significantly reduced when experienced IBC users were tested with the device. The listening advantage was most strongly correlated with the availability of voice pitch cues, although performance was also influenced by the location of distracting sentences. Directional asymmetries appear to be dictated by location-dependent cues that are derived from the distinctive transmission characteristics of IBC stimulation. Experienced users made better use of these cues than inexperienced users. These results suggest that informational masking is a significant source of communication impairment among individuals with SSD. Despite the lateralization of auditory function, unaided SSD subjects experience informational masking when distractors occur in either the deaf or normal spatial hemifield. Restoration of aural sensitivity in the deaf hemifield with an IBC enhances speech intelligibility under complex listening conditions, presumably by providing additional sound-segregation cues that are derived from voice pitch and spatial location. The optimal use of these cues is not immediate, but a significant listening advantage is observed after 3 months of unstructured use.