A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals.
To assess the effectiveness of different strategies for increasing the uptake of prophylaxis for venous thromboembolism (VTE) in hospitalized patients through a systematic review of the literature. Literature databases and the Internet were searched from 1996 to May 2003. Studies of strategies to improve VTE prophylaxis practice were included. Studies where no policy or guideline was implemented or where the focus of the study was not VTE prevention were excluded. Thirty studies were included. The quality of the available evidence was average with the majority of studies being uncontrolled before and after design and thus limited by the historical nature of much of the available data. Adherence to guidelines and the provision of adequate prophylaxis were poor in studies which relied on passive dissemination of guidelines. In general, the use of multiple strategies was more effective than a single strategy used in isolation. The most effective strategies incorporated a system for reminding clinicians to assess patients for VTE risk, either electronic decision-support systems or paper-based reminders, and used audit and feedback to facilitate the iterative refinement of the intervention. There were no studies adequately powered to demonstrate a reduction in rates of VTE. Insufficient evidence was available to make useful comparisons of strategies in terms of costs and resource utilization. Passive dissemination of guidelines is unlikely to improve VTE prophylaxis practice. A number of active strategies used together, which incorporate some method for reminding clinicians to assess patients for DVT risk and assisting the selection of appropriate prophylaxis, are likely to result in the achievement of optimal outcomes.


Rabies virus vector transgene expression level and cytotoxicity improvement induced by deletion of glycoprotein gene.
The glycoprotein (G) of rabies virus (RV) is required for binding to neuronal receptors and for viral entry. G-deleted RV vector is a powerful tool for investigating the organization and function of the neural circuits. It gives the investigator the ability to genetically target initial infection to particular neurons and to control trans-synaptic propagation. In this study we have quantitatively evaluated the effect of G gene deletion on the cytotoxicity and transgene expression level of the RV vector. We compared the characteristics of the propagation-competent RV vector (rHEP5.0-CVSG-mRFP) and the G-deleted RV vector (rHEP5.0-ΔG-mRFP), both of which are based on the attenuated HEP-Flury strain and express monomeric red fluorescent protein (mRFP) as a transgene. rHEP5.0-ΔG-mRFP showed lower cytotoxicity than rHEP5.0-CVSG-mRFP, and within 16 days of infection we found no change in the basic electrophysiological properties of neurons infected with the rHEP5.0-ΔG-mRFP. The mRFP expression level of rHEP5.0-ΔG-mRFP was much higher than that of rHEP5.0-CVSG-mRFP, and 3 days after infection the retrogradely infected neurons were clearly visualized by the expressed fluorescent protein without any staining. This may be due to the low cytotoxicity and/or the presumed change in the polymerase gene (L) expression level of the G-deleted RV vector. Although the mechanisms remains to be clarified, the results of this study indicate that deletion of the G gene greatly improves the usability of the RV vector for studying the organization and function of the neural circuits by decreasing the cytotoxicity and increasing the transgene expression level.


The Etiology of Juvenile Idiopathic Arthritis.
Over the years, the commonly used term to describe juvenile idiopathic arthritis (JIA) has changed. By definition, JIA includes all types of arthritis with no apparent cause, lasting more than 6 weeks, in patients aged less than 16 years at onset. JIA pathogenesis is still poorly understood: the interaction between environmental factors and multiple genes has been proposed as the most relevant working mechanism to the development of JIA. The concept that various microbes that colonize or infect not only the mucosal surfaces, like the oral cavity, but also the airways and gut might trigger autoimmune processes, resulting in chronic arthritides, and JIA was first drafted at the outset of last century. JIA development might be initiated and sustained by the exposure to environmental factors, including infectious agents which affect people at a young age, depending on the underlying genetic predisposition to synovial inflammation. Many data from patients with JIA suggest a scenario in which different external antigens incite multiple antigen-specific pathways, cytotoxic T cell responses, activation of classical complement cascade, and production of proinflammatory cytokines. In this review, emphasis is paid not only to the potential role of parvovirus B19 and Epstein-Barr virus in primis but also to the general involvement of different bacteria as Salmonella spp., Shigella spp., Campylobacter spp., Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bartonella henselae, and Streptococcus pyogenes for the development of immune-mediated arthritides during childhood. No unequivocal evidence favoring or refuting these associations has been clearly proved, and today, the strict definition of JIA etiology remains unknown. The infection can represent a random event in a susceptible individual, or it can be a necessary factor in JIA development, always in combination with a peculiar genetic background. Further studies are needed in order to address the unsolved questions concerning this issue.


Covariates of amikacin disposition in a large pediatric oncology cohort.
Amikacin pharmacokinetics (PK) in children display large variability due to maturational and disease-related covariates. The objective was to explore amikacin PK in a large pediatric oncology cohort, taking into account within-patient changes. Clinical data and amikacin therapeutic drug monitoring (TDM) observations were collected retrospectively from children with an oncology diagnosis receiving amikacin during febrile neutropenia. Individual amikacin PK parameters were calculated using a 1-compartment model with instantaneous input and first-order output. This approach was selected based on a pragmatic study design using TDM from routine clinical care, with availability of 2 TDM samples per treatment episode. To explore covariates of clearance (Cl) and volume of distribution (Vd), linear mixed models were used, modelling a random effect for patient to account for clustering due to repeated measurements. Based on 188 amikacin treatment episodes in 114 patients, median (interquartile range) amikacin Cl was 1.37 (1.05; 2.46) L/h and Vd 7.98 (5.66; 12.73) L. Height and creatinemia were significant covariates for Cl (marginal R2 71.1%), while weight, height, and creatinemia determined Vd (marginal R2 59.5%). We described extensive variability of amikacin PK in a large cohort of pediatric oncology patients, including within-patient changes across treatment episodes. Maturational covariates and creatinemia determined amikacin Cl and Vd, while primary non-maturational covariates were not significant. Our observations, based on combined clinical and PK data in children with oncology diagnoses, can be useful to feed dosing software programs to improve drug exposure in special populations.


A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.


Evaluating the allergic risk of genetically modified soybean.
Genetically modified (GM) soybean (carrying the EPSPS transgene) is the most common GM food in Korea. In order to assess whether genetic modification increases the allergenic risk of soybeans, the allergenicity and IgE-reactive components of wild-type and GM soybean extracts were compared in allergic adults who had been sensitized to soybeans. We enrolled 1,716 adult allergy patients and 40 healthy, non-atopic controls. Skin prick tests and IgE enzyme linked immunosorbent assays (ELISAs) were performed using wild-type and GM soybean extracts, along with other common inhaled allergens. The specificities of serum IgE antibodies from allergic patients and the identities of the IgE-reactive components of the soybean extracts were compared using ELISA inhibition testing, 2-dimensional gel electrophoresis, and IgE immunoblotting. To evaluate the effects of digestive enzymes and heat treatment, the soybean extracts were heated or pre- incubated with or without simulated gastric and intestinal fluids. The IgE sensitization rates to wild-type and GM soybeans were identical (3.8% of allergic adults), and circulating IgE antibodies specific for the two extracts were comparable. The results of the ELISA inhibition test, SDS-PAGE, and IgE immunoblotting showed a similar composition of IgE-binding components within the wild-type and GM extracts, which was confirmed using two-dimensional gel electrophoresis, IgE immunoblotting, and amino acid sequencing. None of the subjects had a positive response to purified EPSPS protein in the skin prick test, ELISA, or IgE immunoblot analysis. These findings suggest that the IgE sensitization rate to GM soybean extracts is identical to that of wild-type soybean extracts in adult allergy patients. In addition, based on both in vivo and in vitro methods, the allergenicity of wild type and GM soybean extracts was identical.


A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.
A novel polymorphism in the extracellular domain 2 (EC2) of FcgammaRIIIA affects ligand binding by natural killer (NK) cells and monocytes from genotyped homozygous normal donors independently of receptor expression. The nonconservative T to G substitution at nucleotide 559 predicts a change of phenylalanine (F) to valine (V) at amino acid position 176. Compared with F/F homozygotes, FcgammaRIIIa expressed on NK cells and monocytes in V/V homozygotes bound more IgG1 and IgG3 despite identical levels of receptor expression. In response to a standard aggregated human IgG stimulus, FcgammaRIIIa engagement on NK cells from V/V (high-binding) homozygotes led to a larger rise in [Ca2+]i, a greater level of NK cell activation, and a more rapid induction of activation-induced cell death (by apoptosis). Investigation of an independently phenotyped normal cohort revealed that all donors with a low binding phenotype are F/F homozygotes, while all phenotypic high binding donors have at least one V allele. Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype. Thus, the FcgammaRIIIa polymorphism at residue 176 appears to impact directly on human biology, an effect which may extend beyond autoimmune disease characterized by immune complexes to host defense mechanisms.


Effects of inhibitors of Cl conductance on Cl self-exchange in rabbit cortical collecting tubule.
Electroneutral vs. conductive pathways of Cl transport were examined by measuring transepithelial conductance (GT) and the lumen-to-bath 36Cl rate coefficient (KCl). Experimental conditions minimized both Cl-HCO3 exchange [HCO3/CO2-free, N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid (HEPES)-buffered solutions] and the electrical driving force for paracellular Cl diffusion (amiloride in the perfusate, transepithelial voltage near zero). Two agents known to inhibit Cl conductances in other epithelia, anthracene-9-carboxylate (9AC, 1 mM) and diphenylamine carboxylate (DPC, 0.1-0.5 mM) reversibly reduced GT and KCl when added to the bath. Both reduced KCl to values consistent with paracellular diffusion. Bath DPC had no effect on GT in the presence of 4 mM lumen Ba2+, suggesting that the DPC-sensitive conductance is in series with an apical K conductance, i.e., resides on the basolateral membrane. Lumen DPC also reduced GT and KCl, but was less potent than bath DPC. Because the lumen DPC effect on GT was also blocked by lumen Ba2+, lumen DPC probably inhibits a basolateral Cl conductance. K removal and ouabain (0.5 mM) had no effect on KCl, suggesting that Cl tracer movement is not predominantly through the principal cell. We assume that these agents are inhibiting Cl conductive pathways and propose a model in which transcellular Cl movement through the intercalated cell occurs via an apical electroneutral entry step in series with a basolateral conductive pathway.


County-level exposures to greenness and associations with COVID-19 incidence and mortality in the United States.
COVID-19 is an infectious disease that has killed more than 246,000 people in the US. During a time of social distancing measures and increasing social isolation, green spaces may be a crucial factor to maintain a physically and socially active lifestyle while not increasing risk of infection. We evaluated whether greenness is related to COVID-19 incidence and mortality in the United States. We downloaded data on COVID-19 cases and deaths for each US county up through June 7, 2020, from Johns Hopkins University, Center for Systems Science and Engineering Coronavirus Resource Center. We used April-May 2020 Normalized Difference Vegetation Index (NDVI) data, to represent the greenness exposure during the initial COVID-19 outbreak in the US. We fitted negative binomial mixed models to evaluate associations of NDVI with COVID-19 incidence and mortality, adjusting for potential confounders such as county-level demographics, epidemic stage, and other environmental factors. We evaluated whether the associations were modified by population density, proportion of Black residents, median home value, and issuance of stay-at-home order. An increase of 0.1 in NDVI was associated with a 6% (95% Confidence Interval: 3%, 10%) decrease in COVID-19 incidence rate after adjustment for potential confounders. Associations with COVID-19 incidence were stronger in counties with high population density and in counties with stay-at-home orders. Greenness was not associated with COVID-19 mortality in all counties; however, it was protective in counties with higher population density. Discussion: Exposures to NDVI had beneficial impacts on county-level incidence of COVID-19 in the US and may have reduced county-level COVID-19 mortality rates, especially in densely populated counties.


Towards a Biopsychosocial Psychiatry.
Objective: Constructing a meaningful biopsychosocial model for the mental health field has been extremely elusive. Identifying the linkages between the biological, psychological and social domains has been especially daunting. There has been important progress in clarifying general correlations of certain social factors related to the mental health of individuals and in developing training programs to recognize these social factors. However, efforts have usually focused on broad correlations and there have been serious deficiencies in developing methods for understanding and dealing with the specific processes happening at the psychological and social interface. For this reason, it would be important to be able to do such things as for example have a means to clarify the processes that connect the individual's mental health and its specific interactions with his or her social class. In this report we suggest two approaches that can contribute to solving this problem. Methods: We will describe approaches from the fields of anthropology and microhistory that link the specific experiences of the individual and the nature of the social context in which he or she finds him/herself. Results: Careful application of certain anthropological and history study methods that "take seriously" the specific interactions between the environmental situation and the individual can provide approaches to improved understanding of the relevant variables and the causal links between "psycho" and "social" in the biopsychosocial model. Conclusions: Teaching and applying these principles in treatment and research can contribute to a more effective model of biopsychosocial interactions in the mental health field.


The expression of atrial natriuretic peptide receptor in the mouse inner ear labyrinth.
To compare the relative expression levels of NPR-A mRNA in the stria vascularis (StV), nonstrial tissue of the cochlear lateral wall (NSt) and vestibula in the mouse inner ear to determine the potential contribution of ANP signaling in different parts to inner ear fluid homeostasis. Atrial natriuretic peptide (ANP) is a cardiac hormone known to be involved in the regulation of body fluid homeostasis. It is assumed that ANP might also participate in the regulation of inner ear fluid dynamics. ANP selectively binds with atrial natriuretic peptide receptor (NPR-A) to exert its physiological function. We have previously shown the presence of NPR-A transcripts in the mouse stria vascularis as well as in the nonstrial tissue of the cochlear lateral wall and vestibular organ by polymerase-chain reaction. Total RNA of samples of stria vascularis, nonstrial tissue of the cochlear lateral wall and vestibular organ tissue from ears of 10 adult mice was isolated, amplified by the real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using consensus primers flanking a region of 127 bp at the target sequences. The brain of mice known to contain NPR-A was used as a positive control. The one-way analysis of variance, ANOVA and Student-Newman-Keuls method were performed to analyze the data. NPR-A mRNA expression was found in tissue samples of all the three areas. The mRNA expression level of NPR-A in the StV was higher than that in the NSt and vestibula (p<0.05). The difference of NPR-A mRNA expression level in the NSt and vestibula was not statistically significant (p>0.05). Our results suggest that the StV may be the most important place for ANP to regulate endolymph fluid balance via NPR-A.


Haematotoxicology: scientific basis and regulatory aspects.
Haematopoietic tissues are the targets of numerous xenobiotics. The purpose of in vitro haematotoxicology is the prediction of adverse haematological effects from toxicants on human haematopoietic targets under controlled experimental conditions in the laboratory. Building on its foundations in experimental haematology and the wealth of haematotoxicological data found in experimental oncology, this field of alternative toxicology has developed rapidly during the past decade. Preclinical and clinical drug development for anti-cancer drugs differs from that for other pharmaceuticals, because of the life-threatening nature of the disease. Treatment with anti-cancer drugs at clinically efficacious doses usually induces serious side-effects. The design of preclinical toxicology studies for anti-cancer drugs is intended to identify a safe clinical starting dose, characterise toxicities that could be encountered in human clinical trials, and determine whether these toxicities are reversible, manageable, and predictable. Although the myeloid colony-forming unit (CFU-GM) progenitor is most frequently evaluated, other defined progenitors and stem cells, as well as cell types found in the marrow stroma, can now be evaluated in vitro. Genetic damage to haematopoietic cells can occur in the absence of any overt haematological signs. The development of tissue-specific screening systems that are able to give information about the toxic effects of chemicals, drugs and environmental hazards on target genes is needed, in order to make preliminary decisions or to set priorities for selection among large groups of chemicals and possible drugs.


The role of driver education in the licensing process in Quebec.
In many jurisdictions, driver education (DE) graduates, compared to non-graduates, are granted a time-discount that allows them to drive unsupervised several months earlier, despite little evidence of a safety benefit and consistent evidence of increased crash risk. Confounding factors may be threatening the validity of DE evaluations. A theoretical framework called the "licensing process" (LP) is proposed to identify and explore potential confounding factors in DE evaluations. Prospective study data on a cohort of 1804 novice drivers 16 to 19 years of age of both sexes are analyzed in relation to the LP framework. These data derive from two sources that were linked together: an extensive questionnaire on learning methods, risk-taking, and lifestyles, and government records on exam performance, violations, and crashes. Violation and crash records are not associated with DE attendance. DE attendance is associated with younger ages, greater financial support from family, and fewer hours of supervised driving practice with a learner's permit. For both sexes, more hours of supervised driving practice with a learner's permit is associated with increased crash risk. Most participants, particularly males under 19 years of age, attended DE partly or entirely to save time or money; these motivations are associated with higher violation and crash rates. DE evaluations need to identify and control for potential confounding factors. Research is needed to understand the associations between increased crash risk and potential confounding factors like motivation to attend DE and hours of supervised driving practice.


International survey of older adults finds shortcomings in access, coordination, and patient-centered care.
Industrialized nations face the common challenge of caring for aging populations, with rising rates of chronic disease and disability. Our 2014 computer-assisted telephone survey of the health and care experiences among 15,617 adults age sixty-five or older in Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States has found that US older adults were sicker than their counterparts abroad. Out-of-pocket expenses posed greater problems in the United States than elsewhere. Accessing primary care and avoiding the emergency department tended to be more difficult in the United States, Canada, and Sweden than in other surveyed countries. One-fifth or more of older adults reported receiving uncoordinated care in all countries except France. US respondents were among the most likely to have discussed health-promoting behaviors with a clinician, to have a chronic care plan tailored to their daily life, and to have engaged in end-of-life care planning. Finally, in half of the countries, one-fifth or more of chronically ill adults were caregivers themselves.


Minor head injury: guidelines for the use of CT--a multicenter validation study.
To prospectively and externally validate published national and international guidelines for the indications of computed tomography (CT) in patients with a minor head injury. The study protocol was institutional review board approved. All patients implicitly consented to use of their deidentified data for research purposes. Between February 2002 and August 2004, data were collected in consecutive adult patients with blunt minor head injury (Glasgow Coma Scale score of 13-14 or 15) and a risk factor for neurocranial traumatic complications at presentation at four Dutch university hospitals. Primary outcome was any neurocranial traumatic CT finding. Secondary outcomes were clinically relevant traumatic CT findings and neurosurgical intervention. Sensitivity and specificity of each guideline for all outcomes and the number of patients needed to scan to detect one outcome (ie, the number of patients needed to undergo CT to find one patient with a neurocranial traumatic CT finding, a clinically relevant traumatic CT finding, or a CT finding that required neurosurgical intervention) were estimated. Data were available for 3181 patients. Only the European Federation of Neurological Societies guidelines reached a sensitivity of 100% for all outcomes. Specificity was 0.0%-0.5%. The Dutch guidelines had the lowest sensitivity (76.5%) for neurosurgical interventions. The best specificities for traumatic CT findings and neurosurgical interventions were reached with the criteria proposed by the United Kingdom National Institute for Clinical Excellence (NICE) (46.1% and 43.6%, respectively), albeit at relatively low sensitivities (82.1% and 94.1%, respectively). The number of patients needed to scan ranged from six to 13 for traumatic CT findings and from 79 to 193 for neurosurgical interventions. All validated guidelines demonstrated a trade-off between sensitivity and specificity. The lowest number of patients needed to scan for either of the outcomes was reached with the NICE criteria. radiology.rsnajnls.org/cgi/content/full/2452061509/DC1 (c) RSNA, 2007.


Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori-Infected CAPZA1-Overexpressing Cells.
CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori-infected gastric mucosa. CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.


Shotgun proteomics, in-silico evaluation and immunoblotting assays for allergenicity assessment of lesser mealworm, black soldier fly and their protein hydrolysates.
Since 2018, insects have belonged the category of Novel Foods and the presence of allergens represents one of the main hazards connected to their consumption, also due to the potential cross-reactivity with Arthropoda pan-allergens. In the present work, the allergenicity assessment of black soldier fly and lesser mealworm was performed with a shotgun bottom-up proteomic approach combined with in-silico assessment, followed by IgG- and IgE-immunoblotting experiments. The peptides identified, filtered for their abundance and robustness, belonged mainly to muscle proteins, which represented the most abundant protein group. The relevant potential allergens were in-silico identified by sequence similarity to known allergens, and among them tropomyosin resulted the most abundant insect allergen. IgG-immunoblotting analysis with anti-Tropomyosin I antibodies and IgE-immunoblotting assay with serum from patient allergic to crustacean tropomyosin were performed in order to assess the immunoreactivity in both insects. The immunoassays were carried out also on protein hydrolysates extracted by treating insects with Protease from Bacillus licheniformis (1%, 60 °C, pH 7.5). While IgG-immunoblotting demonstrated the loss of immunoreactivity for both hydrolysates, IgE-immunoblotting showed a partial immunoreactivity preservation, also after hydrolysis, in the case of black soldier fly hydrolysate, and a total loss of immunoreactivity for lesser mealworm hydrolysate.


Formation of the definitive endoderm in mouse is a Smad2-dependent process.
TGFbeta growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific cell surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast. Here we have generated chimeric embryos using lacZ-marked Smad2-deficient ES cells. Smad2 mutant cells extensively colonize ectodermal and mesodermal populations without disturbing normal development, but are not recruited into the definitive endoderm lineage during gastrulation. These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate. In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected. These results strongly suggest that other Smad(s) act downstream of Nodal signals in mesodermal populations. We found Smad2 and Smad3 transcripts both broadly expressed in derivatives of the epiblast. However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population.


Endoskeletal mineralization in chimaera and a comparative guide to tessellated cartilage in chondrichthyan fishes (sharks, rays and chimaera).
An accepted uniting character of modern cartilaginous fishes (sharks, rays, chimaera) is the presence of a mineralized, skeletal crust, tiled by numerous minute plates called tesserae. Tesserae have, however, never been demonstrated in modern chimaera and it is debated whether the skeleton mineralizes at all. We show for the first time that tessellated cartilage was not lost in chimaera, as has been previously postulated, and is in many ways similar to that of sharks and rays. Tesserae in Chimaera monstrosa are less regular in shape and size in comparison to the general scheme of polygonal tesserae in sharks and rays, yet share several features with them. For example, Chimaera tesserae, like those of elasmobranchs, possess both intertesseral joints (unmineralized regions, where fibrous tissue links adjacent tesserae) and recurring patterns of local mineral density variation (e.g. Liesegang lines, hypermineralized 'spokes'), reflecting periodic accretion of mineral at tesseral edges as tesserae grow. Chimaera monstrosa's tesserae, however, appear to lack the internal cell networks that characterize tesserae in elasmobranchs, indicating fundamental differences among chondrichthyan groups in how calcification is controlled. By compiling and comparing recent ultrastructure data on tesserae, we also provide a synthesized, up-to-date and comparative glossary on tessellated cartilage, as well as a perspective on the current state of research into the topic, offering benchmark context for future research into modern and extinct vertebrate skeletal tissues.


Exertional gastro-oesophageal reflux: a mechanism for symptoms in patients with angina pectoris and normal coronary angiograms.
During 24 hour oesophageal pH monitoring 52 patients who had angina pectoris and normal coronary angiograms underwent exercise testing, as far as their symptoms allowed, on a treadmill to determine whether gastro-oesophageal reflux occurred during exertion. In 11 patients the 24 hour oesophageal pH score was abnormally high; 10 of these showed exertional gastro-oesophageal reflux, and in nine this was associated with their usual chest pain. A further 13 patients had a normal 24 hour pH score but had exertional reflux coincident with chest pain during exercise testing. The mean lower oesophageal sphincter pressure in both of these groups of patients was appreciably lower than that in 28 patients who had a normal 24 hour pH score and no exertional reflux. These findings suggest that exertional gastro-oesophageal reflux accounts for the symptoms of a large proportion of patients who have angina pectoris and normal coronary angiograms and that oesophageal pH monitoring during exercise testing on a treadmill enables this group of patients to be identified.


Use of intracytoplasmic sperm injection (ICSI) in normospermic men may result in lower clinical pregnancy and live birth rates.
While intracytoplasmic sperm injection (ICSI) was developed for overcoming male infertility, it is increasingly being used for non-male factor indications, without consensus regarding the safety and efficacy of this approach. To determine whether ICSI offers any benefit compared to standard in vitro fertilisation (IVF), in the setting of normal semen parameters. Retrospective analysis of reproductive outcomes in 3363 stimulated cycles (IVF = 1661; ICSI = 1702), in patients treated between 2009-2015, was performed. Selected couples had no male factor infertility. Couples with abnormal semen parameters (based on WHO 2010 guidelines), presence of anti-sperm antibodies and low oocyte yield of ≤4 oocytes, were excluded. The outcomes analysed included: (1) fertilisation rate (FR); (2) clinical pregnancy rate (CPR); and (3) live birth rate (LBR), by method of fertilisation used (IVF vs ICSI) and controlling for significant confounders. FR, CPR and LBR were significantly higher in the IVF group compared with ICSI (67.1% vs 62.3%, 23.06% vs 16.8%, 17.22% vs 13.2%, respectively). Pregnancy rate with ICSI was approximately 30% lower than with IVF, even when controlling for significant factors such as day of embryo transfer and number of embryos transferred. This translates to one less pregnancy in every 15 cycles where ICSI was used without clear indication. Our data suggest that ICSI may be detrimental to clinical outcomes and contributes to the wider understanding of use of ICSI in normospermic men.


Caulicolous Botryosphaeriales from Thailand.
Members of Botryosphaeriales are commonly encountered as endophytes or pathogens of various plant hosts. The Botryosphaeriaceae represents the predominant family within this order, containing numerous species associated with canker and dieback disease on a wide range of woody hosts. During the course of routine surveys from various plant hosts in Thailand, numerous isolates of Botryosphaeriaceae, including Aplosporellaceae were collected. Isolates were subsequently identified based on a combination of morphological characteristics and phylogenetic analysis of a combined dataset of the ITS and EF1-α gene regions. The resulting phylogenetic tree revealed 11 well-supported clades, correlating with different members of Botryosphaeriales. Other than confirming the presence of taxa such as Lasiodiplodia theobromae, L. pseudotheobromae and Neofusicoccum parvum, new records for Thailand include Pseudofusicoccum adansoniae and P. ardesiacum. Furthermore, four novel species are described, namely Diplodia neojuniperi from Juniperus chinensis, Lasiodiplodia thailandica from Mangifera indica, Pseudofusicoccum artocarpi and Aplosporella artocarpi from Artocarpus heterophyllus, while a sexual morph is also newly reported for L. gonubiensis. Further research is presently underway to determine the pathogenicity and relative importance of these species on different woody hosts in Thailand.


UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN.
A syndrome of profound hypotonia, intellectual disability, intrauterine growth retardation with subsequent failure to thrive, dyskinesia and epilepsy was diagnosed in Bedouin Israeli families. Mild dysmorphism was evident: plagiocephaly, broad forehead with prominent nose, smooth philtrum and congenital esotropia. We set out to decipher the molecular basis of this syndrome. Genome-wide linkage analysis and fine mapping were done. Whole exome sequencing data were filtered for candidate variants within locus. Validation and segregation of the mutation was assayed via Sanger sequencing. UNC80 expression pattern was analysed through reverse transcription PCR. Homozygosity mapping followed by fine mapping identified a 7.5 Mb disease-associated locus (logarithm of odds score 3.5) on chromosome 2. Whole exome and Sanger sequencing identified a single homozygous nonsense mutation within this locus, segregating within the families as expected for recessive heredity and not found in a homozygous state in 150 Bedouin controls: c.151C>T, p.(R51*) in UNC80. The syndrome described is caused by a mutation in UNC80, truncating most of the 3258 amino acids highly conserved encoded protein, that has no known motifs. UNC80 bridges between UNC79 and the cation channel NALCN, enabling NALCN's role in basal Na(+) leak conductance in neurons, essential for neuronal function. The phenotype caused by the UNC80 mutation resembles that previously described for homozygous NALCN mutations.


Extensive traumatic anterior skull base fractures with cerebrospinal fluid leak: classification and repair techniques using combined vascularized tissue flaps.
This article introduces a classification scheme for extensive traumatic anterior skull base fracture to help stratify surgical treatment options. The authors describe their multilayer repair technique for cerebrospinal fluid (CSF) leak resulting from extensive anterior skull base fracture using a combination of laterally pediculated temporalis fascial-pericranial, nasoseptal-pericranial, and anterior pericranial flaps. Retrospective chart review identified patients treated surgically between January 2004 and May 2014 for anterior skull base fractures with CSF fistulas. All patients were treated with bifrontal craniotomy and received pedicled tissue flaps. Cases were classified according to the extent of fracture: Class I (frontal bone/sinus involvement only); Class II (extent of involvement to ethmoid cribriform plate); and Class III (extent of involvement to sphenoid bone/sinus). Surgical repair techniques were tailored to the types of fractures. Patients were assessed for CSF leak at follow-up. The Fisher exact test was applied to investigate whether the repair techniques were associated with persistent postoperative CSF leak. Forty-three patients were identified in this series. Thirty-seven (86%) were male. The patients' mean age was 33 years (range 11-79 years). The mean overall length of follow-up was 14 months (range 5-45 months). Six fractures were classified as Class I, 8 as Class II, and 29 as Class III. The anterior pericranial flap alone was used in 33 patients (77%). Multiple flaps were used in 10 patients (3 salvage) (28%)--1 with Class II and 9 with Class III fractures. Five (17%) of the 30 patients with Class II or III fractures who received only a single anterior pericranial flap had persistent CSF leak (p < 0.31). No CSF leak was found in patients who received multiple flaps. Although postoperative CSF leak occurred only in high-grade fractures with single anterior flap repair, this finding was not significant. Extensive anterior skull base fractures often require aggressive treatment to provide the greatest long-term functional and cosmetic benefits. Several vascularized tissue flaps can be used, either alone or in combination. Vascularized flaps are an ideal substrate for cranial base repair. Dual and triple flap techniques that combine the use of various anterior, lateral, and nasoseptal flaps allow for a comprehensive arsenal in multilayered skull base repair and salvage therapy for extensive and severe fractures.


Improved Baculovirus Vectors for Transduction and Gene Expression in Human Pancreatic Islet Cells.
Pancreatic islet transplantation is a promising treatment for type 1 diabetes mellitus offering improved glycaemic control by restoring insulin production. Improved human pancreatic islet isolation has led to higher islet transplantation success. However, as many as 50% of islets are lost after transplantation due to immune responses and cellular injury, gene therapy presents a novel strategy to protect pancreatic islets for improved survival post-transplantation. To date, most of the vectors used in clinical trials and gene therapy studies have been derived from mammalian viruses such as adeno-associated or retrovirus. However, baculovirus BacMam vectors provide an attractive and safe alternative. Here, a novel BacMam was constructed containing a frameshift mutation within fp25, which results in virus stocks with higher infectious titres. This improved in vitro transduction when compared to control BacMams. Additionally, incorporating a truncated vesicular stomatitis virus G protein increased transduction efficacy and production of EGFP and BCL2 in human kidney (HK-2) and pancreatic islet β cells (EndoC βH3). Lastly, we have shown that our optimized BacMam vector can deliver and express egfp in intact pancreatic islet cells from human cadaveric donors. These results confirm that BacMam vectors are a viable choice for providing delivery of transgenes to pancreatic islet cells.


Perceived job insecurity as a risk factor for incident coronary heart disease: systematic review and meta-analysis.
To determine the association between self reported job insecurity and incident coronary heart disease. A meta-analysis combining individual level data from a collaborative consortium and published studies identified by a systematic review. We obtained individual level data from 13 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. Four published prospective cohort studies were identified by searches of Medline (to August 2012) and Embase databases (to October 2012), supplemented by manual searches. Prospective cohort studies that reported risk estimates for clinically verified incident coronary heart disease by the level of self reported job insecurity. Two independent reviewers extracted published data. Summary estimates of association were obtained using random effects models. The literature search yielded four cohort studies. Together with 13 cohort studies with individual participant data, the meta-analysis comprised up to 174,438 participants with a mean follow-up of 9.7 years and 1892 incident cases of coronary heart disease. Age adjusted relative risk of high versus low job insecurity was 1.32 (95% confidence interval 1.09 to 1.59). The relative risk of job insecurity adjusted for sociodemographic and risk factors was 1.19 (1.00 to 1.42). There was no evidence of significant differences in this association by sex, age (<50 v ≥ 50 years), national unemployment rate, welfare regime, or job insecurity measure. The modest association between perceived job insecurity and incident coronary heart disease is partly attributable to poorer socioeconomic circumstances and less favourable risk factor profiles among people with job insecurity.


Airways inflammation in subjects with chronic bronchitis who have never smoked.
Smoking is the single most common cause of chronic bronchitis but the disease can also occur in non-smokers. Alterations in the lung responsible for the disease, such as oxidant/antioxidant and protease/antiprotease imbalance, have been investigated in smokers. The aim of our study was to evaluate local cellular and soluble factors (albumin, immunoglobulins, proteases, alpha 1-antitrypsin, and transferrin) that may be involved in the development of chronic bronchitis in subjects who have never smoked. Sixteen clinically stable patients with chronic bronchitis who had never been smokers were studied and 17 healthy non-smokers served as controls. All subjects underwent bronchoalveolar lavage (BAL). Total and differential cell counts and concentrations of the main proteins (albumin, immunoglobulins, complement fractions, alpha 1-antitrypsin, and transferrin) were measured. Elastase-like activity was assessed in cells and supernatants. To estimate the oxidant burden the release of superoxide anion (O2-) from native cell populations was evaluated. Recovery of BAL fluid was reduced in older individuals in both the chronic bronchitis and control groups. There was no difference in total cell count, but neutrophil percentage count was higher in those with chronic bronchitis (median (range) 3.5 (1.6-14.2)) than in controls (1.3 (0.5-3.7)). These differences were most pronounced in the first recovery, representative of the bronchial lavage. There was no difference in bronchial epithelial cells. Total proteins and albumin levels were comparable and IgG, IgA, IgM, C3, C4, transferrin and alpha 1-antitrypsin values standardised to albumin did not show any significant differences. No differences in elastase-like levels in supernatants were detected. In cell lysates elastase-like activity x 10(7) cells (macrophages+neutrophils) was increased in patients with chronic bronchitis (0.25 (0.06-4.3) compared with controls 0.08 (0.03-0.9) micrograms PPEeq). The release of O2- both at baseline and after opsonised zymosan phagocytosis did not show any differences. Correlation analysis between FEV1 and BAL fluid data showed a negative correlation only with neutrophils/ml. Clinically stable non-smokers with chronic bronchitis show no alterations of local immune components, oxidant burden, and free elastase-like activity in BAL fluids, while the content of elastase-like activity in phagocytic cells is increased. As in smokers, bronchial neutrophilia is the most significant cellular modification which correlates with the degree of airflow obstruction.


Riding the crimson tide: mobile terrestrial consumers track phenological variation in spawning of an anadromous fish.
When resources are spatially and temporally variable, consumers can increase their foraging success by moving to track ephemeral feeding opportunities as these shift across the landscape; the best examples derive from herbivore-plant systems, where grazers migrate to capitalize on the seasonal waves of vegetation growth. We evaluated whether analogous processes occur in watersheds supporting spawning sockeye salmon (Oncorhynchus nerka), asking whether seasonal activities of predators and scavengers shift spatial distributions to capitalize on asynchronous spawning among populations of salmon. Both glaucous-winged gulls and coastal brown bears showed distinct shifts in their spatial distributions over the course of the summer, reflecting the shifting distribution of spawning sockeye salmon, which was associated with variation in water temperature among spawning sites. By tracking the spatial and temporal variation in the phenology of their principal prey, consumers substantially extended their foraging opportunity on a superabundant, yet locally ephemeral, resource. Ecosystem-based fishery management efforts that seek to balance trade-offs between fisheries and ecosystem processes supported by salmon should, therefore, assess the importance of life-history variation, particularly in phenological traits, for maintaining important ecosystem functions, such as providing marine-derived resources for terrestrial predators and scavengers.


Impacts of the antidepressant fluoxetine on the anti-predator behaviours of wild guppies (Poecilia reticulata).
Chemical pollution from pharmaceuticals is increasingly recognised as a major threat to aquatic communities. One compound of great concern is fluoxetine, which is one of the most widely prescribed psychoactive drugs in the world and frequently detected in the environment. The aim of this study was to investigate the effects of 28-d fluoxetine exposure at two environmentally relevant levels (measured concentrations: 4ng/L and 16ng/L) on anti-predator behaviour in wild guppies (Poecilia reticulata). This was achieved by subjecting fluoxetine-exposed and unexposed guppies to a simulated bird strike and recording their subsequent behavioural responses. We found that exposure to fluoxetine affected the anti-predator behaviour of guppies, with exposed fish remaining stationary for longer (i.e. 'freezing' behaviour) after the simulated strike and also spending more time under plant cover. By contrast, control fish were significantly more active and explored the tank more, as indicated by the distance covered per minute over the period fish spent swimming. Furthermore, behavioural shifts were sex-dependent, with evidence of a non-monotonic dose-response among the fluoxetine-exposed fish. This is one of the first studies to show that exposure to environmentally relevant concentrations of fluoxetine can alter the anti-predator behaviour of adult fish. In addition to the obvious repercussions for survival, impaired anti-predator behaviour can have direct impacts on fitness and influence the overall population dynamics of species.


Evaluating competition for forage plants between honey bees and wild bees in Denmark.
A recurrent concern in nature conservation is the potential competition for forage plants between wild bees and managed honey bees. Specifically, that the highly sophisticated system of recruitment and large perennial colonies of honey bees quickly exhaust forage resources leading to the local extirpation of wild bees. However, different species of bees show different preferences for forage plants. We here summarize known forage plants for honey bees and wild bee species at national scale in Denmark. Our focus is on floral resources shared by honey bees and wild bees, with an emphasis on both threatened wild bee species and foraging specialist species. Across all 292 known bee species from Denmark, a total of 410 plant genera were recorded as forage plants. These included 294 plant genera visited by honey bees and 292 plant genera visited by different species of wild bees. Honey bees and wild bees share 176 plant genera in Denmark. Comparing the pairwise niche overlap for individual bee species, no significant relationship was found between their overlap and forage specialization or conservation status. Network analysis of the bee-plant interactions placed honey bees aside from most other bee species, specifically the module containing the honey bee had fewer links to any other modules, while the remaining modules were more highly inter-connected. Despite the lack of predictive relationship from the pairwise niche overlap, data for individual species could be summarized. Consequently, we have identified a set of operational parameters that, based on a high foraging overlap (>70%) and unfavorable conservation status (Vulnerable+Endangered+Critically Endangered), can guide both conservation actions and land management decisions in proximity to known or suspected populations of these species.


An alternative approach to the identification of respiratory central chemoreceptors in the brainstem.
Central chemoreceptors (CCRs) play a crucial role in autonomic respiration. Although a variety of brainstem neurons are CO(2) sensitive, it remains to know which of them are the CCRs. In this article, we discuss a potential alternative approach that may allow an access to the CCRs. This approach is based on identification of specific molecules that are CO(2) or pH sensitive, exist in brainstem neurons, and regulate cellular excitability. Their molecular identity may provide another measure in addition to the electrophysiologic criteria to indicate the CCRs. The inward rectifier K(+) channels (Kir) seem to be some of the CO(2) sensing molecules, as they regulate membrane potential and cell excitability and are pH sensitive. Among homomeric Kirs, we have found that even the most sensitive Kir1.1 and Kir2.3 have pK approximately 6.8, suggesting that they may not be capable of detecting hypocapnia. We have studied their biophysical properties, and identified a number of amino acid residues and molecular motifs critical for the CO(2) sensing. By comparing all Kirs using the motifs, we found the same amino acid sequence in Kir5.1, and demonstrated the pH sensitivity in heteromeric Kir4.1 and Kir5.1 channels to be pK approximately 7.4. In current clamp, we show evidence that the Kir4.1-Kir5.1 can detect P(CO(2)) changes in either hypercapnic or hypocapnic direction. Our in-situ hybridization studies have indicated that they are coexpressed in brainstem cardio-respiratory nuclei. Thus, it is likely that the heteromeric Kir4.1-Kir5.1 contributes to the CO(2)/pH sensitivity in these neurons. We believe that this line of research intended to identify CO(2) sensing molecules is an important addition to current studies on the CCRs.


Clonal Expansion of Human Immunodeficiency Virus-Infected Cells and Human Immunodeficiency Virus Persistence During Antiretroviral Therapy.
The latent HIV-1 reservoir in blood decays very slowly, even during prolonged suppression of viral replication by antiretroviral therapy (ART). Mechanisms for reservoir persistence include replenishment through low-level viral replication, longevity and homeostatic proliferation of memory T cells, and most recently appreciated, clonal expansion of HIV-infected cells. Clonally expanded cells make up a large and increasing fraction of the residual infected cell population on ART, and insertion of HIV proviruses into certain host cellular genes has been associated with this proliferation. That the vast majority of proviruses are defective clouds our assessment of the degree to which clonally expanded cells harbor infectious viruses, and thus the extent to which they contribute to reservoirs relevant to curing infection. This review summarizes past studies that have defined our current understanding and the gaps in our knowledge of the mechanisms by which proviral integration and clonal expansion sustain the HIV reservoir.


Glomerulonephritis in bacterial endocarditis.
For a modern assessment of the clinical and morphologic features of glomerulonephritis accompanying bacterial endocarditis, postmortem and renal biopsy files were reviewed for the years 1965 to 1979, a period of changing epidemiology, etiology, and therapeutic regimens in infective endocarditis. The incidence of glomerulonephritis in 107 patients examined at postmortem was 22.4%; focal glomerulonephritis was present in 8.4%, diffuse glomerulonephritis in 14%. Glomerulonephritis occurred as frequently in acute as in subacute bacterial endocarditis. Staphylococcus aureus, which has replaced Streptococcus viridans as the predominant etiology of fatal bacterial endocarditis, was frequently associated with glomerulonephritis, especially in parenteral drug abusers. Renal functional impairment due to focal glomerulonephritis did not necessitate dialysis or contribute to the death of any patient. Presentation with advanced renal insufficiency due to diffuse glomerulonephritis was associated with both failure of antibiotic therapy to eradicate infection and failure to recover renal function. In patients with diffuse glomerulonephritis and less severe impairment of renal function, antibiotic therapy was successful in achieving bacteriologic cure, and complete recovery of renal function occurred in the majority. Features of persistent glomerular disease were frequent in patients with diffuse glomerulonephritis long after bacteriologic cure of endocarditis.


Default mode network connectivity change corresponds to ketamine's delayed glutamatergic effects.
Ketamine exerts rapid antidepressant effects peaking 24 h after a single infusion, which have been suggested to be reflected by both reduced functional connectivity (FC) within default mode network (DMN) and altered glutamatergic levels in the perigenual anterior cingulate cortex (pgACC) at 24 h. Understanding the interrelation and time point specificity of ketamine-induced changes of brain circuitry and metabolism is thus key to future therapeutic developments. We investigated the correlation of late glutamatergic changes with FC changes seeded from the posterior cingulate cortex (PCC) and tested the prediction of the latter by acute fractional amplitude of low-frequency fluctuations (fALFF). In a double-blind, randomized, placebo-controlled study of 61 healthy subjects, we compared effects of subanesthetic ketamine infusion (0.5 mg/kg over 40 min) on resting-state fMRI and MR-Spectroscopy at 7 T 1 h and 24 h post-infusion. FC decrease between PCC and dorsomedial prefrontal cortex (dmPFC) was found at 24 h post-infusion (but not 1 h) and this FC decrease correlated with glutamatergic changes at 24 h in pgACC. Acute increase in fALFF was found in ventral PCC at 1 h which was not observed at 24 h and inversely correlated with the reduced dPCC FC towards the dmPFC at 24 h. The correlation of metabolic and functional markers of delayed ketamine effects and their temporal specificity suggest a potential mechanistic relationship between glutamatergic modulation and reconfiguration of brain regions belonging to the DMN.


When are do-gooders treated badly? Legitimate power, role expectations, and reactions to moral objection in organizations.
Organization members who engage in "moral objection" by taking a principled stand against ethically questionable activities help to prevent such activities from persisting. Unfortunately, research suggests that they also may be perceived as less warm (i.e., pleasant, nice) than members who comply with ethically questionable procedures. In this article, we draw on role theory to explore how legitimate power influences observers' responses to moral objection. We argue that individuals expect those high in legitimate power to engage in moral objection, but expect those low in legitimate power to comply with ethically questionable practices. We further propose that these contrasting role expectations influence the extent to which moral objectors are perceived as warm and subjected to social sanctions (i.e., insults, pressure, unfriendly behavior). We test our predictions with 3 experiments. Study 1, which draws on participants' prior workplace experiences, supports the first section of our mediated moderation model in which the negative association between an actor's moral objection (vs. compliance) and observers' warmth perceptions is weaker when the actor is high rather than low in legitimate power and this effect is mediated by observers' met role expectations. Study 2, an online experiment featuring a biased hiring task, reveals that the warmth perceptions fostered by the Behavior × Legitimate Power interaction influence observers' social sanctioning intentions. Finally, Study 3, a laboratory experiment which exposes participants to unethical behavior in a virtual team task, replicates Study 2's findings and extends the results to actual as well as intended social sanctions. (PsycINFO Database Record


A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus.
Neurogenesis continues through the adult life of mice in the subgranular zone of the dentate gyrus in the hippocampus, but its function remains unclear. Measuring cellular proliferation in the hippocampus of 719 outbred heterogeneous stock mice revealed a highly significant correlation with the proportions of CD8+ versus CD4+ T lymphocyte subsets. This correlation reflected shared genetic loci, with the exception of the H-2Ea locus that had a dominant influence on T cell subsets but no impact on neurogenesis. Analysis of knockouts and repopulation of TCRα-deficient mice by subsets of T cells confirmed the influence of T cells on adult neurogenesis, indicating that CD4+ T cells or subpopulations thereof mediate the effect. Our results reveal an organismal impact, broader than hitherto suspected, of the natural genetic variation that controls T cell development and homeostasis.


Implications of a molecular phylogenetic study of the Malagasy genus Cedrelopsis and its relatives (Ptaeroxylaceae).
Ptaeroxylaceae is an Afro-Malagasy family containing three genera, Bottegoa, Cedrelopsis, and Ptaeroxylon. Although the family is morphologically well delimited, it is currently considered part of the subfamily Spathelioideae in a broadly circumscribed orange family (Rutaceae). The Malagasy Cedrelopsis has traditionally been associated with different families of the order Sapindales and its phylogenetic placement in Rutaceae sensu lato has yet to be tested with molecular data. The present molecular phylogenetic study reaffirms the monophyly of Ptaeroxylaceae and its placement in Spathelioideae. Therefore, molecules and morphology support close affinities between Bottegoa, Cedrelopsis, and Ptaeroxylon and also their current generic circumscriptions. We report a case of an evolutionary change from one-seeded to two-seeded carpels within the Harrisonia-Cneorum-Ptaeroxylaceae clade of Spathelioideae. Finally, the sister-group relationship between the African Bottegoa and the Afro-Malagasy Ptaeroxylon-Cedrelopsis clade suggests an African origin of Cedrelopsis.


Bordetella pertussis adenylate cyclase toxin translocation across a tethered lipid bilayer.
Numerous bacterial toxins can cross biological membranes to reach the cytosol of mammalian cells, where they exert their cytotoxic effects. Our model toxin, the adenylate cyclase (CyaA) from Bordetella pertussis, is able to invade eukaryotic cells by translocating its catalytic domain directly across the plasma membrane of target cells. To characterize its original translocation process, we designed an in vitro assay based on a biomimetic membrane model in which a tethered lipid bilayer (tBLM) is assembled on an amine-gold surface derivatized with calmodulin (CaM). The assembled bilayer forms a continuous and protein-impermeable boundary completely separating the underlying calmodulin (trans side) from the medium above (cis side). The binding of CyaA to the tBLM is monitored by surface plasmon resonance (SPR) spectroscopy. CyaA binding to the immobilized CaM, revealed by enzymatic activity, serves as a highly sensitive reporter of toxin translocation across the bilayer. Translocation of the CyaA catalytic domain was found to be strictly dependent on the presence of calcium and also on the application of a negative potential, as shown earlier in eukaryotic cells. Thus, CyaA is able to deliver its catalytic domain across a biological membrane without the need for any eukaryotic components besides CaM. This suggests that the calcium-dependent CyaA translocation may be driven in part by the electrical field across the membrane. This study's in vitro demonstration of toxin translocation across a tBLM provides an opportunity to explore the molecular mechanisms of protein translocation across biological membranes in precisely defined experimental conditions.


Long-term ventilation in children: ten years later.
Home mechanical ventilation (HMV) represents a treatment option for patients with chronic respiratory failure and has changed prognosis and survival of many disorders in children. The aim of this study was to characterize a group of children on long-term mechanical ventilation (LTMV) for a period longer than 10 years. A retrospective analysis was carried out including patients on LTMV for more than 10 years (LTMV-10) in a tertiary pediatric hospital. PASW Statistics 18(®). Thirty-one children (61% female) belong to the LTMV-10 group. Median age at the beginning of ventilatory support was 3 years (birth to 13 years). Main indications for assisted ventilation were neuromuscular disease (n=12, 39%), metabolic disease (n=7, 23%) and central hypoventilation (n=6, 19%). Volume ventilation was used in 2 children, and positive pressure ventilation in the others, mainly bilevel positive airway pressure (n=25, 81%). Invasive ventilation via tracheostomy was used since the beginning in four cases, and subsequently in two other children. The mean time of ventilatory support was 146 months and the maximum was 219 months. Respiratory morbidity was the most frequent cause of hospitalization and the annual rate of such episodes was 0.17 per child. Global mortality rate was 19%. HMV programs provide necessary and safe assistance for children with severe chronic respiratory failure. As shown in our series, it is possible to be kept on this respiratory support modality for long periods with good compliance and a small number of hospitalizations.


A review of current surgical practice in the operative treatment of proximal humeral fractures: Does the PROFHER trial demonstrate a need for change?
The PROximal Fracture of the Humerus: Evaluation by Randomisation (PROFHER) trial has recently demonstrated that surgery is non-superior to non-operative treatment in the management of displaced proximal humeral fractures. The objective of this study was to assess current surgical practice in the context of the PROFHER trial in terms of patient demographics, injury characteristics and the nature of the surgical treatment. A total of ten consecutive patients undergoing surgery for the treatment of a proximal humeral fracture from each of 11 United Kingdom hospitals were retrospectively identified over a 15 month period between January 2014 and March 2015. Data gathered for the 110 patients included patient demographics, injury characteristics, mode of surgical fixation, the grade of operating surgeon and the cost of the surgical implants. A majority of the patients were female (66%, 73 of 110). The mean patient age was 62 years (range 18 to 89). A majority of patients met the inclusion criteria for the PROFHER trial (75%, 83 of 110). Plate fixation was the most common mode of surgery (68%, 75 patients), followed by intramedullary fixation (12%, 13 patients), reverse shoulder arthroplasty (10%, 11 patients) and hemiarthroplasty (7%, eight patients). The consultant was either the primary operating surgeon or supervising the operating surgeon in a large majority of cases (91%, 100 patients). Implant costs for plate fixation were significantly less than both hemiarthroplasty (p < 0.05) and reverse shoulder arthroplasty (p < 0.0001). Implant costs for intramedullary fixation were significantly less than plate fixation (p < 0.01), hemiarthroplasty (p < 0.0001) and reverse shoulder arthroplasty (p < 0.0001). Our study has shown that the majority of a representative sample of patients currently undergoing surgical treatment for a proximal humeral fracture in these United Kingdom centres met the inclusion criteria for the PROFHER trial and that a proportion of these patients may, therefore, have been effectively managed non-operatively.Cite this article: Mr B. J. F. Dean. A review of current surgical practice in the operative treatment of proximal humeral fractures: Does the PROFHER trial demonstrate a need for change? Bone Joint Res 2016;5:178-184. DOI: 10.1302/2046-3758.55.2000596.


Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease.
Cardiovascular disease is the leading cause of death and the leading source of healthcare expenditure in the US and most other industrialised countries. Cholesterol lowering by pharmacological means prevents atherosclerotic plaque progression and has been shown to reduce both fatal and nonfatal coronary events in patients with or without coronary artery disease (CAD). Because of their excellent efficacy and safety profiles, the introduction of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known an 'statins') in 1987 raised hopes for demonstrating the survival benefit of cholesterol reduction. In the past decade, several large-scale placebo-controlled trials with statin therapy have revisited the relationship between cholesterol reduction, cardiovascular disease and mortality. The West of Scotland Coronary Prevention Study (WOSCOPS) [pravastatin] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [lovastatin] have shown significant cardiovascular disease reduction in primary prevention trials of patients with elevated and normal cholesterol levels, respectively. The Scandinavian Simvastatin Survival Study (4S), the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study and the Cholesterol and Recurrent Events (CARE) trial [pravastatin] have shown significant cardiovascular disease reduction in patients with a previous history of CAD with high, moderate and normal cholesterol levels, respectively. Three of these studies (4S, WOSCOPS and LIPID) have shown significant reduction in all-cause mortality, while all the statin secondary prevention trials (4S, CARE and LIPID) have demonstrated significant reduction in cerebrovascular disease/ Earlier cholesterol reduction cost-effectiveness studies with nonstatin treatments (bile acid resins, fibrates, niacin and diet) suggested that only patients at extremely high risk could be treated with lipid therapy in a cost-effective manner. More recently, rigorous outcomes evidence demonstrates that statins, particularly for simvastatin for secondary prevention and lovastatin for primary prevention, have a broadly favourable cost-effectiveness profile. Based on US medical price levels and the available clinical trial data on statins, it would be cost effective [e.g. cost less than $US50,000/year of life saved] to intervene with statin therapy in any patient with an annual CAD risk exceeding 1%. This includes all patients with pre-existing CAD or diabetes mellitus, and many more primary prevention patients than are currently contemplated by the US National Cholesterol Education Panel treatment guidelines. Achieving such a goal will require enormous changes in patient education, clinical perspective, healthcare practice and healthcare finances. But any proven opportunity for saving the lives of 25% of those dying from cardiovascular disease each year deserves to be considered with the utmost seriousness and urgency.


Re-revision Knee Arthroplasty in a Tertiary Center: Infection and Multiple Previous Surgeries Were Associated With Poor Early Clinical and Functional Outcomes.
The incidence of re-revision knee arthroplasty (re-revision KA) is increasing and associated with high complication and failure rates. The aim of this study was to investigate re-revision rates, complications, and patient-reported outcomes following re-revision KA and factors associated with poor outcome. This was a retrospective cohort study of 206 patients (250 knees) undergoing re-revision KA at a major revision center from 2015 to 2018. The mean follow-up was 26 months (range, 0 to 61) and mean age at re-revision KA was 69 years (range, 31 to 91 years). The main indications for surgery were prosthetic joint infection (PJI) (n = 171/250, 68.4%) and aseptic loosening (n = 25/250, 10.0%). We compared re-revision rates, joint function, and complications for aseptic and infective indications. Logistic regressions were performed to identify risk factors for further reoperation. The estimated re-revision rates at 2 years were 28.7% (95% confidence interval [CI]: 22.7-35.9) and at 4 years were 42.0% (95% CI: 32.8-52.6). Mean Oxford Knee Score was 26 points (range, 1 to 48). Mean EuroQoL-5D-5L utility was 0.539 (range, -0.511 to 1.000). Multivariable analyses demonstrated that PJI (Odds Ratio [OR] 2.39, 95% CI 1.06-5.40, P = .036), greater number of previous surgeries (OR 1.18, 95% CI 1.04-1.33, P = .008), and higher Elixhauser score (OR 1.06, 95% CI 1.01-1.13, P = .045) were independently associated to further surgery. Re-revision KA carried a high risk of early failure. Multiple revised joints and patients with more comorbidities had worse function. Patients undergoing re-revision KA for PJI should be counseled to expect higher failure rates and complications than patients who have aseptic indications.


Plastic sexual ornaments: Assessing temperature effects on color metrics in a color-changing reptile.
Conspicuous coloration is an important subject in social communication and animal behavior, and it can provide valuable insight into the role of visual signals in social selection. However, animal coloration can be plastic and affected by abiotic factors such as temperature, making its quantification problematic. In such cases, careful consideration is required so that metric choices are consistent across environments and least sensitive to abiotic factors. A detailed assessment of plastic trait in response to environmental conditions could help identify more robust methods for quantifying color. Temperature affects sexual ornamentation of eastern fence lizards, Sceloporus undulatus, with ventral coloration shifting from green to blue hues as temperatures rise, making the calculation of saturation (color purity) difficult under conditions where temperatures vary. We aimed to characterize how abiotic factors influence phenotypic expression and to identify a metric for quantifying animal color that is either independent from temperature (ideally) or best conserves individual's ranks. We compared the rates of change in saturation across two temperature treatments using seven metrics: three that are based on fixed spectral ranges (with two of them designed by us specifically for this system) and three that track the expressed hue (with one of them designed by us to circumvent spurious results in unornamented individuals). We also applied a lizard visual sensitivity model to understand how temperature-induced color changes may be perceived by conspecifics. We show that the rate of change in saturation between two temperatures is inconsistent across individuals, increasing at a higher rate in individuals with higher baseline saturation at lower temperatures. In addition, the relative color rank of individuals in a population varies with the temperature standardized by the investigator, but more so for some metrics than others. While we were unable to completely eliminate the effect of temperature, current tools for quantifying color allowed us to use spectral data to estimate saturation in a variety of ways and to largely preserve saturation ranks of individuals across temperatures while avoiding erroneous color scores. We describe our approaches and suggest best-practices for quantifying and interpreting color, particularly in cases where color changes in response to environmental factors.


Structural Considerations on the Use of Endo-Xylanases for the Production of prebiotic Xylooligosaccharides from Biomass.
Xylooligosaccharides (XOS) have gained increased interest as prebiotics during the last years. XOS and arabinoxylooligosaccharides (AXOS) can be produced from major fractions of biomass including agricultural by-products and other low cost raw materials. Endo-xylanases are key enzymes for the production of (A)XOS from xylan. As the xylan structure is broadly diverse due to different substitutions, diverse endo-xylanases have evolved for its degradation. In this review structural and functional aspects are discussed, focusing on the potential applications of endo-xylanases in the production of differently substituted (A)XOS as emerging prebiotics, as well as their implication in the processing of the raw materials. Endo-xylanases are found in at least eight different glycoside hydrolase families (GH), and can either have a retaining or an inverting catalytic mechanism. To date, it is mainly retaining endo-xylanases that are used in applications to produce (A)XOS. Enzymes from these GH-families (mainly GH10 and GH11, and the more recently investigated GH30) are taken as prototypes to discuss substrate preferences and main products obtained. Finally, the need of new and accessory enzymes (new specificities from new families or sources) to increase the yield of different types of (A)XOS is discussed, along with in vitro tests of produced oligosaccharides and production of enzymes in GRAS organisms to facilitate use in functional food manufacturing.


Bird fancier's lung: a series of 86 patients.
Bird fancier's lung (BFL) is one of the most common types of hypersensitivity pneumonitis. Nevertheless, the criteria for diagnosing this condition are not standardized. The current study is an in-depth investigation into the clinical characteristics of BFL in the largest series examined for this purpose by a single group, to our knowledge, taking into account the acute, subacute, or chronic clinical presentation. From 1977 to 2003, BFL was diagnosed in 86 patients using a homogeneous protocol. Data from the clinical history and physical examination were analyzed, as well as the results from the following complementary examinations: laboratory analyses, specific serum IgG antibodies determination, chest X-ray, chest computed tomography (CT), pulmonary function testing, immediate hypersensitivity skin testing, delayed cutaneous hypersensitivity testing, bronchofibroscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy, bronchial challenge testing, and surgical lung biopsy. In addition, clinical and epidemiologic characteristics were determined in a control group of 60 pigeon breeders who did not meet the diagnostic criteria of BFL. Eighty-six patients (21 men and 65 women) with a mean age of 47 years were studied. Seven (8%) patients were younger than 15 years of age at the time of the diagnosis. In 3 cases, the disease was caused by exposure to feather-filled bedding. Nearly 1 in 5 patients was diagnosed in the chronic phase of the disease. The mean diagnostic delay was 1.6 years overall, and 3.2 years in patients diagnosed in the chronic phase of the disease. Among the 17% of patients with chronic disease, the mean interval from initiation of exposure to diagnosis was 16 years, a higher value than in the acute or subacute presentation forms. Dyspnea and cough were the most common clinical symptoms (98% and 82%, respectively), and nearly 25% had grade III or IV dyspnea at diagnosis. Only 18% of patients experienced chest tightness, a symptom classically considered to be frequent in this condition. Erythrocyte sedimentation rate was elevated (>30 mm/h) in 44% of patients. Urinary calcium was elevated in 20% of patients. Angiotensin-converting enzyme was not elevated in any of the patients in which it was measured. Lactate dehydrogenase increases were found in 51% of patients. Specific IgG antibodies to avian antigens were documented in 92% of BFL patients, but also in 87% of pigeon breeder controls. The most frequent radiologic finding was an interstitial pattern in 79% of patients. Common chest CT features were ground glass areas (68%) and a mosaic pattern (61%); areas of emphysema were found in 7/41 (17%) patients, 5 of whom had never smoked. Two patients had a CT pattern of pulmonary fibrosis indistinguishable from idiopathic pulmonary fibrosis. Immediate hypersensitivity skin testing with bird sera and pigeon bloom was positive in 78% and 100% of BFL patients, respectively, and in 64% and 88% of control pigeon breeders, respectively. Almost one-third of the patients (29%) presented an anergic response on delayed cutaneous hypersensitivity testing. Restrictive ventilatory impairment was the most frequent functional pattern (77%), although 9% and 4% showed a pure obstructive and mixed pattern, respectively. The carbon monoxide diffusing capacity was decreased (<80% of the predicted value) in 85% of cases. Forty-one percent of patients had PaO2 <60 mm Hg at diagnosis when blood gas analysis was performed. Lymphocytosis (>20% lymphocytes) was documented in 83% of patients who underwent BAL, with a similar frequency in the 3 presentation forms: 70% acute, 89% subacute, and 85% chronic. In addition, inversion of the CD4/CD8 ratio (<1) was observed in 62% of the patients, but 38% of cases showed a CD4 predominance. The characteristic triad of histopathologic findings in hypersensitivity pneumonitis was found in only 9% of patients undergoing transbronchial biopsy, but at least 1 of these findings was seen in 69%. Surgical lung biopsy was undertaken in 14/86 (16%) patients; the complete triad was observed in 50% and at least 1 finding in 100%. In 54/86 (63%) patients, the diagnosis was confirmed by bronchial challenge testing, a test with a sensitivity of 92% and specificity of 100%. BFL is a potentially severe disease that can progress to respiratory failure secondary to pulmonary fibrosis or chronic obstructive pulmonary disease, as a form of chronic occupational respiratory disease. Respiratory symptoms in exposed patients, including children and adults who have only 1 pet bird at home, should raise the suspicion of BFL. Diagnosis in the chronic phase is frequent, and the delay to diagnosis was greatest in these cases. Elevated urinary calcium, lactate dehydrogenase, and erythrocyte sedimentation rate in a bird fancier may constitute a combined marker for suspected BFL. Chest CT frequently discloses emphysema and a pattern of idiopathic pulmonary fibrosis in some patients. An anergic response on delayed cutaneous hypersensitivity testing is not infrequent. The presentation with respiratory failure and the predominance of CD4 T lymphocytes in some patients' BAL are both remarkable. Lymphocytosis on BAL also persists in the chronic phase of the disease. Bronchial challenge testing has a high diagnostic yield, and surgical lung biopsy is not needed to reach the final diagnosis in the vast majority of cases.


Protein-losing enteropathy after the Fontan operation: clinical analysis of nine cases.
Protein-losing enteropathy (PLE) is a serious complication of a Fontan operation and has a very high mortality rate. The purpose of this study was to investigate the incidence, clinical manifestations, diagnostic approaches, laboratory findings, therapeutic modalities and outcome of patients with PLE at our institution. The diagnosis of PLE was based on clinical manifestations and laboratory studies. We reviewed medical records of patients who received a Fontan operation at our hospital form July 1985 to October 2005. A total 101 patients underwent various modifications of the Fontan procedure during this period. Nine of the 75 patients (12%) who survived 30 days after surgery developed PLE, including 4 boys and 5 girls. The median time interval between the Fontan operation and onset of PLE was 3.7 years (range 1.2 to 9.7 years). Laboratory examination showed low serum albumin levels and increased fecal alpha-1-antitrypsin excretion. Lymphangiectasia was found on intestinal biopsy. Six patients had cardiac catheterization after development of PLE which demonstrated an elevated mean right atrium pressure (22.5 +/- 6.4 mmHg, range 16 to 33 mmHg) and mean pulmonary artery pressure (22.3 +/- 6.4 mmHg, range 16 to 33 mmHg). Treatment included diet modification, albumin infusion, diuretics, inotropes, corticosteroids, heparin, and surgery. Four patients received medical treatment only. Two of these patients died due to sepsis and heart failure and 2 survived with partial relief of PLE. The remaining five received surgery for PLE after medical treatment failure. Three of them died after the operation and the two survivors were free of PLE, but one died of ventricular tachycardia 8 years later. The overall mortality rate was 67% (6/9). The current treatment for PLE is associated with a very high mortality rate. Further investigation is needed to determine the exact mechanism of the disease and to develop new therapeutic approaches.


Comparison of short-term results of intraarticular platelet-rich plasma (PRP) and hyaluronic acid treatments in early-stage gonarthrosis patients.
The present study aimed to compare short-term clinical outcomes between intraarticular platelet-rich plasma (PRP) and hyaluronic acid (HA) treatments in early-stage gonarthrosis patients. Data of gonarthrosis patients, who were stage 1 or stage 2 according to Kellgren-Lawrence classification and underwent intraarticular PRP or HA treatment, were obtained retrospectively. The patients received treatment for three times at one-week intervals (intraarticular PRP or HA). They were evaluated using the Knee Society's Knee Scoring System (KSS) and the visual analog scale (VAS) scoring system before treatment and at the second and sixth months of treatment. The study included 132 patients (mean age, 55.06±8.41 years). Sixty-three patients (86 knees) were in the HA group and 69 patients (89 knees) were in the PRP group. Changes in KSS and VAS scores over time and the differences between the treatment groups in terms of changes in KSS and VAS scores over time were significant. In conclusion, PRP appears to be an appropriate option for intraarticular treatment in patients with early-stage knee osteoarthritis.


Poxvirus uracil-DNA glycosylase-An unusual member of the family I uracil-DNA glycosylases.
Uracil-DNA glycosylases are ubiquitous enzymes, which play a key role repairing damages in DNA and in maintaining genomic integrity by catalyzing the first step in the base excision repair pathway. Within the superfamily of uracil-DNA glycosylases family I enzymes or UNGs are specific for recognizing and removing uracil from DNA. These enzymes feature conserved structural folds, active site residues and use common motifs for DNA binding, uracil recognition and catalysis. Within this family the enzymes of poxviruses are unique and most remarkable in terms of amino acid sequences, characteristic motifs and more importantly for their novel non-enzymatic function in DNA replication. UNG of vaccinia virus, also known as D4, is the most extensively characterized UNG of the poxvirus family. D4 forms an unusual heterodimeric processivity factor by attaching to a poxvirus-specific protein A20, which also binds to the DNA polymerase E9 and recruits other proteins necessary for replication. D4 is thus integrated in the DNA polymerase complex, and its DNA-binding and DNA scanning abilities couple DNA processivity and DNA base excision repair at the replication fork. The adaptations necessary for taking on the new function are reflected in the amino acid sequence and the three-dimensional structure of D4. An overview of the current state of the knowledge on the structure-function relationship of D4 is provided here.


Glycoprotein gene truncation in avian metapneumovirus subtype C isolates from the United States.
The length of the published glycoprotein (G) gene sequences of avian metapneumovirus subtype-C (aMPV-C) isolated from domestic turkeys and wild birds in the United States (1996-2003) remains controversial. To explore the G gene size variation in aMPV-C by the year of isolation and cell culture passage levels, we examined 21 turkey isolates of aMPV-C at different cell culture passages. The early domestic turkey isolates of aMPV-C (aMPV/CO/1996, aMPV/MN/1a-b, and 2a-b/97) had a G gene of 1,798 nucleotides (nt) that coded for a predicted protein of 585 amino acids (aa) and showed >97% nt similarity with that of aMPV-C isolated from Canada geese. This large G gene got truncated upon serial passages in Vero cell cultures by deletion of 1,015 nt near the end of the open reading frame. The recent domestic turkey isolates of aMPV-C lacked the large G gene but instead had a small G gene of 783 nt, irrespective of cell culture passage levels. In some cultures, both large and small genes were detected, indicating the existence of a mixed population of the virus. Apparently, serial passage of aMPV-C in cell cultures and natural passage in turkeys in the field led to truncation of the G gene, which may be a mechanism of virus evolution for survival in a new host or environment.


A Guide to Teaching Data Science.
Demand for data science education is surging and traditional courses offered by statistics departments are not meeting the needs of those seeking training. This has led to a number of opinion pieces advocating for an update to the Statistics curriculum. The unifying recommendation is that computing should play a more prominent role. We strongly agree with this recommendation, but advocate the main priority is to bring applications to the forefront as proposed by Nolan and Speed (1999). We also argue that the individuals tasked with developing data science courses should not only have statistical training, but also have experience analyzing data with the main objective of solving real-world problems. Here, we share a set of general principles and offer a detailed guide derived from our successful experience developing and teaching a graduate-level, introductory data science course centered entirely on case studies. We argue for the importance of statistical thinking, as defined by Wild and Pfannkuch (1999) and describe how our approach teaches students three key skills needed to succeed in data science, which we refer to as creating, connecting, and computing. This guide can also be used for statisticians wanting to gain more practical knowledge about data science before embarking on teaching an introductory course.


Sirt1 exerts anti-inflammatory effects and promotes steroidogenesis in Leydig cells.
To investigate the anti-inflammatory effects of Sirt1 and its roles in steroidogenesis in Leydig cells. In vitro cell culture study. Reproductive medical center. C57BL/6 male mice. TM3 Leydig cells were treated with proinflammatory cytokines including tumor necrosis factor-α, interleukin-6, or interleukin-1β. Sirt1 mRNA and protein levels were measured by real-time polymerase chain reaction and Western blotting in TM3 Leydig cells treated with proinflammatory cytokines. The cell viability was determined using MTT and BrdU incorporation assays. The effect of Sirt1 on the coactivation of steroidogenic factor 1 (SF-1) was characterized by coimmunoprecipitation and luciferase reporter assays. Sirt1 mRNA and protein levels were significantly down-regulated by proinflammatory cytokines treatment in TM3 Leydig cells. Sirt1 agonist or overexpression could efficiently protect cytotoxicity induced by proinflammatory cytokines. Sirt1 promoted steroidogenesis through its coactivation of SF-1. Sirt1 plays protective roles and promotes steroidogenesis in Leydig cells through its anti-inflammatory actions and coactivation of SF-1.


Ductal adenocarcinoma of the prostate with endometrioid features in a 69-year-old man.
We describe a case of ductal adenocarcinoma of the prostate with endometrioid characteristics presenting as painless hematuria and intraurethral tumor. A 69-year-old man had intermittent painless hematuria for 2 months. The serum prostate-specific antigen concentration was elevated (22.0 ng/mL). An enlarged prostate with a necrotic tumor was noted in the right lobe of the prostate on computerized tomography and magnetic resonance imaging studies. A polypoid and worm-like tumor was found within the prostatic urethra near the verumontanum. The tumor had a distinctly papillary configuration with a focal glandular structure on microscopy. Radical prostatectomy was performed and histology of the tumor specimen revealed it to be composed of a closely packed glandular structure lined by single layers of high columnar cells with focal stratification. Frequent papillary projections of glandular epithelium and intraglandular bridging were noted, with a histopathologic appearance similar to endometrioid carcinoma of the uterus. Androgen deprivation therapy was started immediately following surgery. No evidence of recurrence or metastasis was found at follow-up 27 months postoperatively. Distinct features of ductal adenocarcinoma of the prostate include intraurethral papillary tumor close to the verumontanum, urethral obstruction, and easy bleeding of the tumor. Its more aggressive behavior than classical microacinar adenocarcinoma of the prostate makes early recognition of this type of prostatic malignancy important.


Familial influences on substance use by adolescents and young adults.
This study uses data from the Ontario Health Survey to examine within-family influences (sibship number, age and sex composition; family structure and parental substance use) on the use of tobacco, alcohol and marijuana in households (N = 4,643) among offspring aged 12 to 24 years. Using a modification of the kappa statistic, concordance among siblings is modest generally and undifferentiated across substance type. Concordance is stronger among sibships that are either all male or older (19-24 years) and is particularly strong for siblings < or = two years apart in age. The dominant influence of substance use behaviour appears to be from older siblings to younger siblings and not from parents to offspring. Sibling concordance for substance use suggests that the treatment and prevention of substance use (and abuse) among adolescents and young adults might be enhanced by including a family focus, especially where there are two or more siblings at home.


Features and treatment options of Chinese hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. More than 53% of the total HCC patients in the world come from China. The absolute number of new Chinese HCC cases still keeps increasing and it remains a most dominant cancer burden in the next several decades. Compared to the HCC occurred in Europe and North America, Chinese HCC patients have their own special features in etiology, demographic features (risk factors, age of onset, gender distribution time trend of incidence), biological behavior, clinical manifestation, treatment strategy and prognosis. The success or failure of a series of clinical trials related with systemic therapy for advanced HCC can be partly attributed to those features of Chinese HCC. Thus it is suggested that new trials should be performed respectively for Chinese HCC patients from the Western population, like the success of sorafenib SHARP and ORIENTAL studies. The protocal design, organization and practice of trials in HCC of China should be made individually to avoid or reduce the possible heterogeneity of HCC populations and facilitate the personalized therapy of HCC. The present review discussed the features and treatment options of HCC in China that maybe help to understand the clinical course for Chinese patients with HCC. More importantly, the future strategies for clinical trials of Chinese HCC were emphasized.


A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women.
To examine functional interleukin-6 (IL-6) -174 G-->C allelic variants in relation to bone turnover and bone mineral density (BMD) in postmenopausal women. Four hundred thirty-four healthy women living in the community (mean +/- SD age 71.7 +/- 5.7 years) were genotyped for the IL-6 -174 G-->C polymorphism. Serum levels of C-telopeptide of type I collagen (CTx), a marker of bone resorption, and osteocalcin (OC), a marker of bone formation, were determined. BMD at the hip and forearm was measured by dual-energy x-ray absorptiometry. CTx levels differed significantly (P = 0.006) among IL-6 genotypes (mean +/- SEM 0.275 +/- 0.02 ng/ml, 0.325 +/- 0.01 ng/ml, and 0.356 +/- 0.02 ng/ml in women with the CC genotype [n = 68], the GC genotype [n = 204], and the GG genotype [n = 162], respectively). Compared with the GG group, age-adjusted odds ratios for high bone resorption were 0.65 (95% confidence interval [95% CI] 0.41-1.0, P = 0.06) and 0.37 (95% CI 0.18-0.73, P = 0.0047) in GC and CC subjects, respectively. In contrast, OC levels did not differ by genotype. BMD at the hip and forearm was 1.5-5% higher in CC subjects compared with GG subjects (P not significant). When the cohort was divided according to the median age (70.5 years), BMD was significantly decreased in older compared with younger postmenopausal women with the GG and GC genotypes (-9.6% on average; P < 0.01), but not in those with the CC genotype (-5.1% on average; P not significant). Compared with the GC and GG IL-6 -174 G-->C genotypes, the CC genotype is associated with lower bone resorption and lesser decrease in bone mass in older postmenopausal women. These results suggest that IL-6 -174 G-->C alleles may be significant determinants of the risk for osteoporosis in elderly subjects.