The causes and circumstances of drinking water incidents impact consumer behaviour: Comparison of a routine versus a natural disaster incident.
When public health is endangered, the general public can only protect themselves if timely messages are received and understood. Previous research has shown that the cause of threats to public health can affect risk perception and behaviours. This study compares compliance to public health advice and consumer behaviour during two "Boil Water" notices issued in the UK due to a routine incident versus a natural disaster incident. A postal questionnaire was sent to 1000 randomly selected households issued a routine "Boil Water" notice. Findings were then compared to a previous study that explored drinking water behaviour during a "Boil Water" notice issued after serious floods. Consumers affected by the routine incident showed a significant preference for official water company information, whereas consumers affected by the natural disaster preferred local information sources. Confusion over which notice was in place was found for both incidents. Non-compliance was significantly higher for the natural disaster (48.3%) than the routine incident (35.4%). For the routine incident, compliance with advice on drinking as well as preparing/cooking food and brushing teeth was positively associated with receiving advice from the local radio, while the opposite was true for those receiving advice from the water company/leaflet through the post; we suggest this may largely be due to confusion over needing boiled tap water for brushing teeth. No associations were found for demographic factors. We conclude that information dissemination plans should be tailored to the circumstances under which the advice is issued. Water companies should seek to educate the general public about water notices and which actions are safe and unsafe during which notice, as well as construct and disseminate clearer advice on brushing teeth and preparing/cooking food.


TBC1D14 regulates autophagosome formation via Rab11- and ULK1-positive recycling endosomes.
Autophagy is a bulk degradation process characterized by the formation of double membrane vesicles called autophagosomes. The exact molecular mechanism of autophagosome formation and the origin of the autophagosomal membrane remain unclear. We screened 38 human Tre-2/Bub2/Cdc16 domain-containing Rab guanosine triphosphatase-activating proteins (GAPs) and identified 11 negative regulators of starvation-induced autophagy. One of these putative RabGAPs, TBC1D14, colocalizes and interacts with the autophagy kinase ULK1. Overexpressed TBC1D14 tubulates ULK1-positive recycling endosomes (REs), impairing their function and inhibiting autophagosome formation. TBC1D14 binds activated Rab11 but is not a GAP for Rab11, and loss of Rab11 prevents TBC1D14-induced tubulation of REs. Furthermore, Rab11 is required for autophagosome formation. ULK1 and Atg9 are found on Rab11- and transferrin (Tfn) receptor (TfnR)-positive recycling endosomes. Amino acid starvation causes TBC1D14 to relocalize from REs to the Golgi complex, whereas TfnR and Tfn localize to forming autophagosomes, which are ULK1 and LC3 positive. Thus, TBC1D14- and Rab11-dependent vesicular transport from REs contributes to and regulates starvation-induced autophagy.


Retrospective Analysis of Bacterial Cultures Sampled in German Chicken-Fattening Farms During the Years 2011-2012 Revealed Additional VIM-1 Carbapenemase-Producing Escherichia coli and a Serologically Rough Salmonella enterica Serovar Infantis.
Carbapenems are last-resort antibiotics used in human medicine. The increased detection of carbapenem-resistant Enterobacteriaceae (CRE) is therefore worrying. In 2011 we reported the first livestock-associated VIM-1-producing Salmonella (S.) enterica serovar Infantis (R3) isolate from dust, sampled in a German chicken fattening farm. Due to this observation we retrospectively investigated more than 536 stored bacterial cultures, isolated from 45 chicken fattening farms during the years 2011 and 2012. After a non-selective overnight incubation, the bacteria were transferred to selective media. Escherichia (E.) coli and Salmonella growing on these media were further investigated, including antibiotic susceptibility testing, carbapenemase gene screening and whole genome sequencing (WGS). In total, four CRE were found in three out of 45 investigated farms: Besides R3, one additional Salmonella (G-336-1a) as well as two E. coli isolates (G-336-2, G-268-2). All but G-268-2 harbored the blaVIM-1 gene. Salmonella isolates R3 and G-336-1 were closely related although derived from two different farms. All three blaVIM-1-encoding isolates possessed identical plasmids and the blaVIM-1- containing transposon showed mobility at least in vitro. In isolate G-268-2, the AmpC beta-lactamase gene blaCMY-2 but no known carbapenemase gene was identified. However, a transfer of the phenotypic resistance was possible. Furthermore, G-268-2 contained the mcr-1 gene, combining phenotypical carbapenem- as well as colistin resistance in one isolate. Carbapenem-resistant Enterobacteriaceae have been found in three out of 45 investigated chicken flocks. This finding is alarming and emphasizes the importance of intervention strategies to contain the environmental spread of resistant bacteria in animals and humans.


Colloidal trains.
Single and double paramagnetic colloidal particles are placed above a magnetic square pattern and are driven with an external magnetic field processing around a high symmetry direction of the pattern. The external magnetic field and that of the pattern confine the colloids into lanes parallel to a lattice vector of the pattern. The precession of the external field causes traveling minima of the magnetic potential along the direction of the lanes. At sufficiently high frequencies of modulation, only the doublets respond to the external field and move in direction of the traveling minima along the lanes, while the single colloids cannot follow and remain static. We show how the doublets can induce a coordinated motion of the single colloids building colloidal trains made of a chain of several single colloids transported by doublets.


Epithelial Organization: The Gut and Beyond.
Epithelial cells are essential to the survival and homeostasis of complex organisms. These cells cover the surfaces of all mucosae, the skin, and other compartmentalized structures essential to physiological function. In addition to maintenance of barriers that separate internal and external compartments, epithelia display a variety of organ-specific differentiated functions. Function is reflected in overall epithelial structure and organization, shape of individual cells, and proteins expressed by these cells. More than one epithelial cell type is often present within a single organ and, in many cases, individual cells differentiate to change their functional behaviors as part of normal development or in response to extracellular stimuli. This article discusses the diversity of epithelial structure and function in general terms and explores representative tissues in greater depth to highlight organ specific functions and their contributions to physiology and disease. © 2017 American Physiological Society. Compr Physiol 7:1497-1518, 2017.


Validation of the "Step-by-Step" Approach in the Management of Young Febrile Infants.
A sequential approach to young febrile infants on the basis of clinical and laboratory parameters, including procalcitonin, was recently described as an accurate tool in identifying patients at risk for invasive bacterial infection (IBI). Our aim was to prospectively validate the Step-by-Step approach and compare it with the Rochester criteria and the Lab-score. Prospective study including infants ≤90 days with fever without source presenting in 11 European pediatric emergency departments between September 2012 and August 2014. The accuracy of the Step-by-Step approach, the Rochester criteria, and the Lab-score in identifying patients at low risk of IBI (isolation of a bacterial pathogen in a blood or cerebrospinal fluid culture) was compared. Eighty-seven of 2185 infants (4.0%) were diagnosed with an IBI. The prevalence of IBI was significantly higher in infants classified as high risk or intermediate risk according to the Step by Step than in low risk patients. Sensitivity and negative predictive value for ruling out an IBI were 92.0% and 99.3% for the Step by Step, 81.6% and 98.3% for the Rochester criteria, and 59.8% and 98.1% for the Lab-score. Seven infants with an IBI were misclassified by the Step by Step, 16 by Rochester criteria, and 35 by the Lab-score. We validated the Step by Step as a valuable tool for the management of infants with fever without source in the emergency department and confirmed its superior accuracy in identifying patients at low risk of IBI, compared with the Rochester criteria and the Lab-score.


Brood parasitism increases provisioning rate, and reduces offspring recruitment and adult return rates, in a cowbird host.
Interspecific brood parasitism in birds presents a special problem for the host because the parasitic offspring exploit their foster parents, causing them to invest more energy in their current reproductive effort. Nestling brown-headed cowbirds (Molothrus ater) are a burden to relatively small hosts and may reduce fledgling quality and adult survival. We documented food-provisioning rates of one small host, the prothonotary warbler (Protonotaria citrea), at broods that were similar in age (containing nestlings 8-9 days old), but that varied in composition (number of warbler and cowbird nestlings) and mass, and measured the effect of brood parasitism on offspring recruitment and adult returns in the host. The rate of food provisioning increased with brood mass, and males and females contributed equally to feeding nestlings. Controlling for brood mass, the provisioning rate was higher for nests with cowbirds than those without. Recruitment of warbler fledglings from unparasitized nests was 1.6 and 3.7 times higher than that of fledglings from nests containing one or two cowbirds, respectively. Returns of double-brooded adult male and female warblers decreased with an increase in the number of cowbirds raised, but the decrease was more pronounced in males. Reduced returns of warbler adults and recruitment of warbler fledglings with increased cowbird parasitism was likely a result of reduced survival. Cowbird parasitism increased the warblers' investment in current reproductive effort, while exerting additional costs to current reproduction and residual reproductive value. Our study provides the strongest evidence to date for negative effects of cowbird parasitism on recruitment of host fledglings and survival of host adults.


Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits.
Ribonucleotide reductase (RR) plays a key role in the synthesis of DNA and is the only enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, providing a balanced supply of precursors for DNA synthesis and repair. There are three known human RR subunits, hRRM1, hRRM2, and p53R2, which is encoded by a p53 target gene. It is not clear whether p53 and RR can directly interact at the protein level to regulate DNA repair. It is also not known where deoxyribonucleotides are synthesized in the cell. In coimmunoprecipitation experiments, we found that hRRM2 and p53R2, but not hRRM1, bound to p53 in KB cells, which express wild-type p53. Moreover, in response to UV irradiation, both p53R2 and hRRM2 were released from p53 and shifted to bind hRRM1. Confocal microscopy confirmed the colocalization of p53 with p53R2 and hRRM2 and the translocation of hRRM1, p53R2 and hRRM2 from the cytoplasm to the nucleus after UV treatment. An in vivo RR activity assay showed that the kinetic profile of increased RR activity was consistent with the accumulation of RR subunits in the nucleus. The ability of p53R2 and hRRM2 to shift from binding p53 to hRRM1 in response to UV irradiation was deficient in the presence of mutant p53. Moreover, in cells overexpressing hRRM2, binding of p53R2 to p53 decreased, whereas binding to hRRM1 increased. Our results suggest that wild-type p53 directly interacts with both p53R2 and hRRM2. In response to UV irradiation, p53R2 and hRRM2 dissociate from p53 and p53R2, and hRRM2 and hRRM1 transfer to the nucleus and form an active RR complex to provide dNDPs for DNA repair. Therefore, the direct interaction of p53 with p53R2 and hRRM2 and the nuclear accumulation of RR subunits after UV exposure might play a pivotal role in DNA repair.


Biochemical characterization of the neutrophil-specific antigen NB1.
Neutrophil-specific alloantibodies and the antigens they recognize are important in clinical medicine, but little is known about the structure of these antigens. Alloimmunization to the antigen NB1 is a clinically important cause of neonatal neutropenia and febrile transfusion reactions. To study the immunochemistry of the NB1 antigen, we prepared neutrophil plasma membranes and granules by nitrogen cavitation and differential centrifugation and then analyzed them by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting with alloantibodies to several neutrophil-specific antigens. Two different antisera to the neutrophil-specific antigen NB1 identified an approximately 55-Kd protein by immunoblotting on neutrophil membranes from four NB1-positive donors but not on neutrophil membranes from five NB1-negative donors. Four anti-NB1 antisera immunoprecipitated a 58- to 64-Kd protein from extracts of NB1-positive neutrophils surface-labeled with 125I using lactoperoxidase, but not from similarly treated NB1-negative neutrophils. Normal human serum did not immunoprecipitate or immunoblot any proteins from these same neutrophil preparations. The NB1 antigen was detected by immunoblotting in secondary granules but was not found in primary granules. The electrophoretic mobility of the antigen was decreased slightly by reduction, suggesting that intrachain disulfide bonds were present. After reduction, the antigen could no longer be recognized by anti-NB1 antisera, but treatment of the antigen with periodate had no effect on the ability of anti-NB1 antisera to recognize the antigen, suggesting that it is not a carbohydrate. The data suggest that the neutrophil-specific antigen NB1 is present on a 58- to 64-Kd surface glycoprotein that is also present in secondary granules, and that the NB1 epitope is not a carbohydrate but probably resides in the tertiary structure of the protein backbone.


Pertussis.
Pertussis, a disease that has been well described since the Middle Ages, has a worldwide distribution and can infect all ages. It is caused by the gram-negative, pleomorphic bacillus Bordetella pertussis, which is transmitted from human to human via aerosolized droplets at close range. Descriptions such as the one-hundred day cough in Chinese and whooping cough in English, describe the severity of this disease seen in both the developed and the developing world.


Landscape factors influencing the spatial distribution and abundance of mosquito vector Culex quinquefasciatus (Diptera: Culicidae) in a mixed residential-agricultural community in Hawai'i.
Mosquito-borne avian diseases, principally avian malaria (Plasmodium relictum Grassi and Feletti) and avian pox (Avipoxvirus sp.) have been implicated as the key limiting factor associated with recent declines of endemic avifauna in the Hawaiian Island archipelago. We present data on the relative abundance, infection status, and spatial distribution of the primary mosquito vector Culex quinquefasciatus Say (Diptera: Culicidae) across a mixed, residential-agricultural community adjacent to Hawai'i Volcanoes National Park on Hawai'i Island. We modeled the effect of agriculture and forest fragmentation in determining relative abundance of adult Cx. quinquefasciatus in Volcano Village, and we implement our statistical model in a geographic information system to generate a probability of mosquito capture prediction surface for the study area. Our model was based on biweekly captures of adult mosquitoes from 20 locations within Volcano Village from October 2001 to April 2003. We used mixed effects logistic regression to model the probability of capturing a mosquito, and we developed a set of 17 competing models a priori to specifically evaluate the effect of agriculture and fragmentation (i.e., residential landscapes) at two spatial scales. In total, 2,126 mosquitoes were captured in CO2-baited traps with an average probability of 0.27 (SE = 0.10) of capturing one or more mosquitoes per trap night. Twelve percent of mosquitoes captured were infected with P. relictum. Our data indicate that agricultural lands and forest fragmentation significantly increase the probability of mosquito capture. The prediction surface identified areas along the Hawai'i Volcanoes National Park boundary that may have high relative abundance of the vector. Our data document the potential of avian malaria transmission in residential-agricultural landscapes and support the need for vector management that extends beyond reserve boundaries and considers a reserve's spatial position in a highly heterogeneous landscape.


Survival following stereotactic radiosurgery for newly diagnosed and recurrent glioblastoma multiforme: a multicenter experience.
Despite decades of clinical trials investigating new treatment modalities for glioblastoma multiforme (GBM), there have been no significant treatment advances since the 1980s. Reported median survival times for patients with GBM treated with current modalities generally range from 9 to 19 months. The purpose of the current study is to retrospectively review the ability of CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) radiosurgery to provide local tumor control of newly diagnosed or recurrent GBM. Twenty patients (43.5%) underwent CyberKnife treatment at the time of the initial diagnosis and/or during the first 3 months of their initial clinical management. Twenty-six patients (56.5%) were treated at the time of tumor recurrence or progression. CyberKnife was performed in addition to the traditional therapy. The median survival from diagnosis for the patients treated with CyberKnife as an initial clinical therapy was 11.5 months (range, 2-33) compared to 21 months (range, 8-96) for the patients treated at the time of tumor recurrence/progression. This difference was statistically significant (Kaplan-Meier analysis, P = 0.0004). The median survival from the CyberKnife treatment was 9.5 months (range, 0.25-31 months) and 7 months (range, 1-34 months) for patients in the newly diagnosed and recurrent GBM groups (Kaplan-Meier analysis, P = 0.79), respectively. Cox proportional hazards survival regression analysis demonstrated that survival time did not correlate significantly with treatment parameters (Dmax, Dmin, number of fractions) or target volume. Survival time and recursive partitioning analysis class were not correlated (P = 0.07). Patients with more extensive surgical interventions survived longer (P = 0.008), especially those who underwent total tumor resection vs. biopsy (P = 0.004). There is no apparent survival advantage in using CyberKnife in initial management of glioblastoma patients, and it should be reserved for patients whose tumors recur or progress after conventional therapy.


Analysis of the mRNA targetome of microRNAs expressed by Marek's disease virus.
Marek's disease virus 1 (MDV-1), an oncogenic α-herpesvirus that induces T-cell lymphomas in chickens, serves as model system to study transformation by lymphotropic herpesviruses. Like the oncogenic human γ-herpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), MDV-1 encodes several viral microRNAs (miRNAs). One MDV-1 miRNA, miR-M4, shares the same "seed" targeting sequence with both a KSHV miRNA, miR-K11, and cellular miR-155. Importantly, miR-M4 plays a critical role in T-cell transformation by MDV-1, while miR-K11 and cellular miR-155 are thought to play key roles in B-cell transformation by KSHV and EBV, respectively. Here, we present an analysis of the mRNAs targeted by viral miRNAs expressed in the chicken T-cell line MSB1, which is naturally coinfected with MDV-1 and the related nonpathogenic virus MDV-2. Our analysis identified >1,000 endogenous mRNAs targeted by miRNAs encoded by each virus, many of which are targeted by both MDV-1 and MDV-2 miRNAs. We present a functional analysis of an MDV-1 gene, RLORF8, targeted by four MDV-1 miRNAs and a cellular gene, encoding interleukin-18 (IL-18) and targeted by both MDV-1 and MDV-2 miRNAs, and show that ectopic expression of either protein in a form resistant to miRNA inhibition results in inhibition of cell proliferation. Finally, we present a restricted list of 9 genes targeted by not only MDV-1 miR-M4 but also KSHV miR-K11 and human miR-155. Given the critical role played by miR-155 seed family members in lymphomagenesis in humans and chickens, these mRNA targets may contain genes whose inhibition plays a conserved role in herpesvirus transformation. Herpesviruses cause lymphomas in both humans and chickens, and in both cases, evidence indicates that virally encoded miRNAs, or virally subverted cellular miRNAs, belonging to the miR-155 seed family, play a critical role in this process. However, because each miRNA regulates numerous cellular mRNAs species, it has been difficult to elucidate which miRNA targets are important. Given the evolutionary distance between chickens and humans and the observation that miR-155 is nevertheless highly conserved in both species, we reasoned that the identification of shared miR-155 targets might shed light on this process. Here, we present an analysis of the mRNAs targeted by miRNAs encoded by the oncogenic avian herpesvirus MDV-1 in transformed chicken T cells, including a short list of mRNAs that are also targeted by miR-155 seed family miRNAs in EBV- or KSHV-transformed human B cells, and present an initial functional analysis of some of these miRNA targets.


Multimodal coding of three-dimensional rotation and translation in area MSTd: comparison of visual and vestibular selectivity.
Recent studies have shown that most neurons in the dorsal medial superior temporal area (MSTd) signal the direction of self-translation (i.e., heading) in response to both optic flow and inertial motion. Much less is currently known about the response properties of MSTd neurons during self-rotation. We have characterized the three-dimensional tuning of MSTd neurons while monkeys passively fixated a central, head-fixed target. Rotational stimuli were either presented using a motion platform or simulated visually using optic flow. Nearly all MSTd cells were significantly tuned for the direction of rotation in the absence of optic flow, with more neurons preferring roll than pitch or yaw rotations. The preferred rotation axis in response to optic flow was generally the opposite of that during physical rotation. This result differs sharply from our findings for translational motion, where approximately half of MSTd neurons have congruent visual and vestibular preferences. By testing a subset of neurons with combined visual and vestibular stimulation, we also show that the contributions of visual and vestibular cues to MSTd responses depend on the relative reliabilities of the two stimulus modalities. Previous studies of MSTd responses to motion in darkness have assumed a vestibular origin for the activity observed. We have directly verified this assumption by recording from MSTd neurons after bilateral labyrinthectomy. Selectivity for physical rotation and translation stimuli was eliminated after labyrinthectomy, whereas selectivity to optic flow was unaffected. Overall, the lack of MSTd neurons with congruent rotation tuning for visual and vestibular stimuli suggests that MSTd does not integrate these signals to produce a robust perception of self-rotation. Vestibular rotation signals in MSTd may instead be used to compensate for the confounding effects of rotatory head movements on optic flow.


Cholesterol and metal ions in Alzheimer's disease.
Cholesterol and metal ions have been suggested to be associated with the onset and progression of Alzheimer's disease (AD). Moreover, recent findings have demonstrated a potential interconnection between these two factors. For example, (a) cholesterol has been shown to be misregulated in AD-afflicted brains, and the aberrant activity of proteins (particularly, apolipoprotein E (ApoE) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)) has been linked to cholesterol-related AD exacerbation; (b) dyshomeostasis of metal ions associated with misfolded proteins (i.e., amyloid-β (Aβ) aggregates) found in the brains of AD patients is shown to promote oxidative stress leading to the malfunction of multiple proteins, including cytochrome c oxidase (CcO), and Cu/Zn superoxide dismutase (SOD1); (c) metal ion misregulation has also been observed to disrupt the activity of proteins (e.g., HMGR, low-density lipoproteins (LDL)), required for cholesterol production and regulation. Herein, we briefly discuss the potential involvement of cholesterol and metal ions in AD neuropathogenesis in both individual and interrelated manners.


Nuclear localization of the transcriptional regulator MIER1α requires interaction with HDAC1/2 in breast cancer cells.
MIER1α is a transcriptional regulator that functions in gene repression through its ability to interact with various chromatin modifiers and transcription factors. We have also shown that MIER1α interacts with ERα and inhibits estrogen-stimulated growth. While MIER1α is localized in the nucleus of MCF7 cells, previous studies have shown that it does not contain a nuclear localization signal. In this report, we investigate the mechanism involved in transporting MIER1α into the nucleus. We explored the possibility that MIER1α is transported into the nucleus through a 'piggyback' mechanism. One obvious choice is via interaction with ERα, however we demonstrate that nuclear targeting of MIER1α does not require ERα. Knockdown of ERα reduced protein expression to 22% of control, but did not alter the percentage of cells with nuclear MIER1α (98% nuclear with scrambled shRNA vs. 95% with ERα shRNA). Further evidence was obtained using two stable transfectants derived from the ER-negative MDA231 cell line: MC2 (ERα+) and VC5 (ERα-). Confocal analysis showed no difference in MIER1α localization (86% nuclear in MC2 vs. 89% in VC5). These data demonstrate that ERα is not involved in nuclear localization of MIER1α. To identify the critical MIER1α sequence, we performed a deletion analysis and determined that the ELM2 domain was necessary and sufficient for nuclear localization. This domain binds HDAC1 & 2, therefore we investigated their role. Confocal analysis of an MIER1α containing an ELM2 point mutation previously shown to abolish HDAC binding revealed that this mutation results in almost complete loss of nuclear targeting: 10% nuclear vs. 97% with WT-MIER1α. Moreover, double knockdown of HDAC1 and 2 caused a reduction in percent nuclear from 86% to 44%. The results of this study demonstrate that nuclear targeting of MIER1α requires an intact ELM2 domain and is dependent on interaction with HDAC1/2.


Effect of extracellular ATP on the Na+ current in rat ventricular myocytes.
Extracellular ATP concentration can rise because of its release by nerve terminals and by damaged cells during ischemia. After the activation of P2-purinergic receptors, ATP induces a positive inotropic effect and increases the L-type Ca2+ current via activation of a Gs protein but without cAMP production. In addition, ATP shifts the voltage characteristics of Ca2+ current toward hyperpolarized potentials. If ATP produced similar effects on the Na+ current (INa), this compound should also affect cardiac excitability and conduction. Using the whole-cell patch-clamp to record INa in rat ventricular cells, we show that extracellular application of ATP induced hyperpolarizing shifts in the current-voltage relation and the availability of INa. The ED50 for the shifts in both conductance and availability was obtained with 0.7 mumol/L ATP. Maximal shifts in conductance and availability were respectively 9.7 +/- 0.6 and 10.6 +/- 0.7 mV. The leftward shift of the availability curve is responsible for the decrease of INa amplitude at less polarized holding potentials. These effects were not cholera toxin sensitive and thus cannot be attributed to activation of the Gs protein. At 100 mumol/L, ATP gamma S and alpha,beta-methylene ATP could induce shift, whereas UTP and beta,gamma-methylene ATP as well as ADP and adenosine were without effect. Thus, depending on the resting membrane potential, ATP should either enhance excitability or favor slow conduction and weaken cardiac electrical homogeneity and consequently favor arrhythmia.


Relationship of internet addiction severity with depression, anxiety, and alexithymia, temperament and character in university students.
The aim of the study was to investigate the relationship of Internet addiction (IA) severity with alexithymia, temperament, and character dimensions of personality in university students while controlling for the effect of depression and anxiety. A total of 319 university students from two conservative universities in Ankara volunteered for the study. Students were investigated using the Toronto Alexithymia Scale-20, the Temperament and Character Inventory, the Internet Addiction Scale, the Beck Anxiety Inventory, and the Beck Depression Inventory. Of the university students enrolled in the study, 12.2 percent (n=39) were categorized into the moderate/high IA group (IA 7.2 percent, high risk 5.0 percent), 25.7 percent (n=82) were categorized into the mild IA group, and 62.1 percent (n=198) were categorized into the group without IA. Results revealed that the rate of moderate/high IA group membership was higher in men (20.0 percent) than women (9.4 percent). Alexithymia, depression, anxiety, and novelty seeking (NS) scores were higher; whereas self-directedness (SD) and cooperativeness (C) scores were lower in the moderate/high IA group. The severity of IA was positively correlated with alexithymia, whereas it was negatively correlated with SD. The "difficulty in identifying feelings" and "difficulty in describing feelings" factors of alexithymia, the low C and high NS dimensions of personality were associated with the severity of IA. The direction of this relationship between alexithymia and IA, and the factors that may mediate this relationship are unclear. Nevertheless, university students exhibiting high alexithymia and NS scores, along with low character scores (SD and C) should be closely monitored for IA.


Cobalt Chalcogenides/Cobalt Phosphides/Cobaltates with Hierarchical Nanostructures for Anode Materials of Lithium-Ion Batteries: Improving the Lithiation Environment.
Lithium-ion batteries (LIBs) are widely used in electric vehicles and portable electronic devices due to their high energy density, long cycle life, environmental friendliness, and negligible memory effect, though they also suffer from low power density, safety issues, and an aging effect. Cobalt chalcogenides/phosphides as promising anode materials have attracted intensive interests due to their high theoretical capacity based on the conversion mechanism. Cobaltates (XCo2 O4 , X = the other metal) have attracted attention because the X element can partially replace the high cost and toxic cobalt element. The serious volume variation during the cycling process has an impact, however, on the lithiation environment of above materials. Hierarchical construction can provide more active sites and shorten the diffusion pathways of Li ions as well as accommodating the volume expansion during lithiation processes. Herein, the research progress on the synthesis methods, structural characteristics, and electrochemical performances of cobalt chalcogenides/cobalt phosphides/cobaltates with hierarchical nanostructures for LIBs is presented. The concluding remarks highlight the research challenges and possible development directions of cobalt chalcogenides/cobalt phosphides/cobaltates with tailored hierarchical nanostructures for LIBs.


Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-κB pathways in monocytes/macrophages.
Most solid tumor tissues possess a significant population of macrophages, which are known to be closely linked with tumor progression and metastasis. Clusterin has been reported to be overexpressed in various tumors and to have a tumor-promoting role. As clusterin induction and macrophage infiltration occur concurrently at the tumor site, it raises a possibility that clusterin may regulate the function of macrophages via facilitating ECM remodeling. Here, we demonstrate for the first time the expression of MMP-9 by clusterin in human primary monocytes as well as human and murine macrophage cell lines, THP-1, and Raw264.7. MMP-9 expression was accompanied by increased enzymatic activity, as revealed by gelatin zymography. The MMP-9 activity promoted by clusterin was found to be dependent on the activation of ERK1/2 and PI3K/Akt but not p38 or JNK pathways. Inhibition of PI3K activity did not affect the activation of ERK1/2 and vice versa, indicating that the two pathways were independently operated to stimulate MMP-9 activity. Moreover, clusterin facilitated nuclear translocation of NF-κB p65 along with IκB-α degradation and phosphorylation, which was critical for MMP-9 expression. As NF-κB is a central regulator of inflammation, clusterin may provide a molecular link between inflammation and cancer via up-regulating NF-κB and MMP-9. Collectively, these data highlight a novel role of clusterin as a stimulator for MMP-9 expression in macrophages, which may contribute to the tissue reorganization by serving as a modulator for ECM degradation.


Bats limit insects in a neotropical agroforestry system.
Exclosure experiments have demonstrated the effects of bird predation on arthropods. In a Mexican coffee plantation, we excluded foliage-gleaning bird and bat predators from coffee plants. Effects of bats and birds were additive. In the dry season, birds reduced arthropods in coffee plants by 30%; birds and bats together reduced arthropods by 46%. In the wet season, bats reduced arthropods by 84%, whereas birds reduced them by only 58%. We conclude that previous "bird" exclosure experiments may have systematically underestimated the effects of bats.


Nomenclature for factors of the HLA system.
A Nomenclature Committee composed of geneticists and immunologists, including specialists in tissue typing, has met after each of the Histocompatibility Workshops beginning with the Third Workshop in 1967. The Committee, in part under the auspices of the World Health Organization and the International Union of Immunological Societies (WHO/IUIS), met after the Sixth Workshop in Aarhus in July 1975. The expanding knowledge of the genetics of the major histocompatibility system of man has necessitated a revision of the terminology for the HLA region following the principles established in previous reports. This has been done with as few changes as possible.


Association Between Sleep Characteristics and Incident Dementia Accounting for Baseline Cognitive Status: A Prospective Population-Based Study.
Although research has shown that sleep disorders are prevalent among people with dementia, the temporal relationship is unclear. We investigated whether atypical sleep characteristics were associated with incident dementia while accounting for baseline cognitive functioning. Screening Across the Lifespan Twin (SALT) study participants were 11,247 individuals from the Swedish Twin Registry who were at least 65 years at baseline (1998-2002). Sleep and baseline cognitive functioning were assessed via the SALT telephone screening interview. Data on dementia diagnoses came from national health registers. Cox regression was performed to estimate hazard ratios for dementia. After 17 years of follow-up, 1,850 dementia cases were identified. Short (≤6 hours) and extended (>9 hours) time in bed (TIB) compared to the middle reference group (hazard ratio = 1.40, 95% confidence interval = 1.06-1.85; hazard ratio = 1.11, 95% confidence interval = 1.00-1.24, respectively) and rising at 8:00 AM or later compared to earlier rising (hazard ratio = 1.12, 95% confidence interval = 1.01-1.24) were associated with higher dementia incidence. Bedtime, sleep quality, restorative sleep, and heavy snoring were not significant predictors. Findings stratified by baseline cognitive status indicated that the association between short TIB and dementia remained in those cognitively intact at the start. Short and extended TIB and delayed rising among older adults predicted increased dementia incidence in the following 17 years. The pattern of findings suggests that extended TIB and late rising represent prodromal features whereas short TIB appeared to be a risk factor for dementia.


Controlling the spatial arrangement of organic magnetic anions adsorbed on epitaxial graphene on Ru(0001).
Achieving control over the self-organization of functional molecules on graphene is critical for the development of graphene technology in organic electronic and spintronic. Here, by using a scanning tunneling microscope (STM), we show that the electron acceptor molecule 7,7',8,8'-tetracyano-p-quinodimethane (TCNQ) and its fluorinated derivative 2,3,5,6-tetrafluoro-7,7',8,8'-tetracyano-p-quinodimethane (F4-TCNQ), co-deposited on the surface of epitaxial graphene on Ru(0001), transform spontaneously into their corresponding magnetic anions and self-organize in two remarkably different structures. TCNQ forms densely packed linear magnetic arrays, while F4-TCNQ molecules remain as isolated non interacting magnets. With the help of density functional theory (DFT) calculations, we trace back the origin of this behavior in the competition between the intermolecular repulsion experienced by the individual charged anions, which tends to separate the molecules, and the delocalization of the electrons transferred from the surface to the molecules, which promotes the formation of molecular oligomers. Our results demonstrate that it is possible to control the spatial arrangement of organic magnetic anions co-adsorbed on a surface by means of chemical substitution, paving the way for the design of two-dimensional fully organic magnetic structures on graphene and on other surfaces.


Autonomic Hyperactivity.
Autonomic hyperactivity is a relatively common consequence of severe acute brain injury and can also be seen with spinal cord and peripheral nerve disorders. This article reviews basic pathophysiologic concepts regarding autonomic hyperactivity, its various forms of clinical presentation, and practical management considerations. Paroxysmal sympathetic hyperactivity is most common after traumatic brain injury but can also occur after other forms of severe acute diffuse or multifocal brain injury. Formal criteria for the diagnosis and severity grading of paroxysmal sympathetic hyperactivity have now been proposed. A growing body of literature is beginning to elucidate the mechanisms underlying this disorder, but treatment remains based on observational data. Our mechanistic understanding of other distinct forms of autonomic hyperactivity, such as autonomic dysreflexia after traumatic spinal cord injury and dysautonomia after Guillain-Barré syndrome, remains rudimentary, yet clinical experience shows that their appropriate management can minimize the risk of serious complications. Syndromes of autonomic hyperactivity can result from injury at all levels of the neuraxis. Much more research is needed to refine our understanding of these disorders and guide optimal management decisions.


Amplification of insulin secretion by lipid messengers.
D-glucose induces a rise in pancreatic islet beta-cell cytosolic [Ca2+] by processes requiring both glucose metabolism and Ca2+ entry from the extracellular space, and this Ca2+ signal is thought to be critical to the induction of insulin secretion. Insulin secretagogues also induce phospholipid hydrolysis and accumulation of phospholipid-derived mediators in islets, including the lipid messengers DAG, nonesterified arachidonic acid, and arachidonate 12-LO products. This study offers the following viewpoints on potential roles of these lipid messengers in insulin secretion as working hypotheses: 1) the Ca2+ signal provided to the beta-cell by D-glucose induces insulin secretion only in the context of amplifying background signals provided by the beta-cell content of messengers including DAG; 2) muscarinic receptor agonists amplify glucose-induced insulin secretion in part by altering the beta-cell content of DAG; 3) the Ca2+ signal provided by metabolism of D-glucose is amplified by the level of nonesterified arachidonic acid in beta-cell membranes, which acts to facilitate Ca2+ entry; 4) metabolism of glucose induces accumulation of nonesterified arachidonate in beta-cells via activation of a recently identified ASCI-PLA2 enzyme, which may be a component of the beta-cell fuel sensor apparatus; and 5) arachidonate 12-LO metabolites are potential candidates as adjunctive modulators of beta-cell K(+)-channel activity.


Acute right ventricular resynchronization improves haemodynamics in children after surgical repair of tetralogy of Fallot.
Right bundle branch block is associated with right ventricular (RV) electromechanical dyssynchrony, which may contribute to acute haemodynamic impairment after repair of tetralogy of Fallot (ToF). We sought to evaluate the effects of RV resynchronization on haemodynamics and tissue oxygenation during the first 24 h after surgery. Arterial pressures, cardiac output, and tissue oxygenation were measured in 28 consecutive patients (median age 10.1 months) during baseline sinus rhythm with right bundle branch block and after RV resynchronization by atrial-triggered RV free wall pacing in complete fusion with spontaneous activation. Studied variables were compared in a crossover design in four 5-min intervals (baseline rhythm and stimulation, 2x each). Resynchronization reduced the QRS complex duration from median 110 to 70 ms (P < 0.001), increased significantly median arterial systolic, mean and pulse pressure, cardiac index, left ventricular maximum +dP/dT and decreased central venous pressure (P < 0.001 for all). Both cerebral and renal oxygenation improved (P < 0.001). Eleven of the 28 patients showed a clinically highly significant resynchronization effect defined as an increase in arterial pulse pressure of ≥ 10%. The q-RV interval (expressed as % of QRS duration) at the RV pacing site during baseline rhythm was the only predictor of resynchronization effect. RV resynchronization carried short-term improvement of haemodynamics in children early after surgery for ToF and might be a useful non-pharmacologic adjunct to the management of haemodynamically compromised patients. Resynchronization effect was maximized when pacing from area of the latest RV activation.


Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma.
Despite the availability of several evidence-based therapies and non-pharmacological strategies to improve control of symptoms and prevent exacerbations of asthma, patients with asthma continue to be at risk for mortality and morbidity.Previous trials have demonstrated the potentially beneficial effects of the long-acting muscarinic antagonist (LAMA) tiotropium on lung function in patients with asthma; however, a definitive conclusion on the benefit of LAMA in asthma is lacking, as is information on where in the current step-wise management strategy they would be most beneficial. To assess the efficacy and safety of a LAMA added to any dose of an inhaled corticosteroid (ICS) compared with the same dose of ICS alone for adults whose asthma is not well controlled. We searched the Cochrane Airways Group Specialised Register (CAGR) from inception to April 2015, and we imposed no restriction on language of publication. We also searched clinicaltrials.gov, the World Health Organization (WHO) trials portal and drug company registries to identify unpublished studies. We searched for parallel and cross-over randomised controlled trials in which adults whose asthma was not well controlled by ICS alone were randomly assigned to receive LAMA add-on or placebo (both combined with ICS) for at least 12 weeks. Two review authors independently screened the searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data and risk of bias ratings. Pre-specified primary outcomes included exacerbations requiring oral corticosteroids, quality of life and all-cause serious adverse events. We identified five studies that met the inclusion criteria. All studies applied a double-blind, double-dummy design, and the population of all studies totalled 2563 adult participants. Study duration ranged from 12 weeks to 52 weeks, and risk of bias across domains in all studies was low. Trials included more women than men (33% to 47% male), and mean age of participants ranged from 41 to 48 years. Participants generally had a long history of asthma, and mean baseline predicted forced expiratory volume in one second (FEV1) was between 72% and 75% in three studies reporting pre-bronchodilator values.The rate of exacerbations requiring oral corticosteroids (OCS) was lower in patients prescribed an LAMA add-on than in those receiving the same dose of ICS alone (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.46 to 0.93; 2277 participants; four studies; I(2) = 0%; high-quality evidence), meaning that 27 fewer people per 1000 would have an exacerbation over 21 weeks requiring OCS with LAMA compared with ICS alone (95% CI 42 fewer to 6 fewer).All-cause serious adverse events (SAEs) and exacerbations requiring hospital admission were rare and the effects too imprecise to permit firm conclusions, but effects suggested that LAMA add-on may be associated with fewer of both compared with ICS alone (SAEs: OR 0.60, 95% CI 0.23 to 1.57; 2532 participants; four studies; low-quality evidence; exacerbations requiring hospital admission: OR 0.42, 95% CI 0.12 to 1.47; 2562 participants; five studies; moderate-quality evidence). Additional therapy with a LAMA showed no clear benefit in terms of quality of life compared with ICS given alone; high-quality evidence showed only a small mean improvement in quality of life as measured on the Asthma Quality of Life Questionnaire (AQLQ), which was not statistically significant. The same was true for asthma control as measured on the Asthma Control Questionnaire (ACQ), which was based on moderate-quality evidence. LAMA combined with ICS showed consistent benefit in a range of lung function measures compared with the same dose of ICS alone, and LAMA was not associated with significantly higher rates of adverse events than were reported with placebo. For adults taking ICS for asthma without a long-acting beta₂-agonist (LABA), LAMA given as add-on treatment reduces the likelihood of exacerbations requiring treatment with OCS and improves lung function. The benefits of LAMA combined with ICS for hospital admissions, all-cause serious adverse events, quality of life and asthma control remain unknown.Results of this review, along with findings of related reviews conducted to assess the use of LAMA in other clinical scenarios involving asthma, can help to define the role of LAMA in the management of asthma. Trials of longer duration (up to 52 weeks) would provide a better opportunity to observe rare events such as serious adverse events and exacerbations requiring hospital admission.


Vector coupled-mode analysis of coupling between two identical optical fiber cores.
The vector coupled-mode analysis considering the exact HE(11) modes is applied to two single-mode coupled optical fiber cores, including the strongly guiding fibers. The accuracy of the conventional coupled-mode theory and the recently formulated new theory as applied to the two-core system is examined. Array modes of different polarization states are considered. It is shown that the full-wave coupled-mode calculations behave well in predicting the array-mode propagation constants beyond the weakly guiding regime and that the simpler conventional theory can provide satisfactory results when applied in the vectorial form.


Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation.
The plasma membrane of cells is composed of lateral heterogeneities, patches and microdomains. These membrane microdomains or lipid rafts are enriched in glycosphingolipids and cholesterol and have been implicated in cellular processes such as membrane sorting and signal transduction. In this study we investigated the importance of lipid raft formation in the innate immune recognition of bacteria using biochemical and fluorescence imaging techniques. We found that receptor molecules that are implicated in lipopolysaccharide (LPS)-cellular activation, such as CD14, heat shock protein (hsp) 70, 90, Chemokine receptor 4 (CXCR4), growth differentiation factor 5 (GDF5) and Toll-like receptor 4 (TLR4), are present in microdomains following LPS stimulation. Lipid raft integrity is essential for LPS-cellular activation, since raft-disrupting drugs, such as nystatin or MCD, inhibit LPS-induced TNF-alpha secretion. Our results suggest that the entire bacterial recognition system is based around the ligation of CD14 by bacterial components and the recruitment of multiple signalling molecules, such as hsp70, hsp90, CXCR4, GDF5 and TLR4, at the site of CD14-LPS ligation, within the lipid rafts.


Neighbourhood socioeconomic disadvantage and behavioural problems from late childhood into early adolescence.
This study investigates whether neighbourhood socioeconomic disadvantage may contribute to child behavioural and emotional problems, beyond the effects of parental socioeconomic status. It also examines the influence of neighbourhood disadvantage on changes in the frequency of behavioural problems from late childhood into early adolescence. The study was conducted in a large community sample in Rotterdam, the Netherlands. An index of neighbourhood socioeconomic disadvantage was calculated for each of the city's 74 neighbourhoods. Multilevel regression analysis estimated effects of neighbourhood disadvantage and individual variables (parental socioeconomic status, child's gender, and age) on behavioural problems reported by children (Youth Self-Report) and parents (Child Behavior Checklist) and on changes in these scores over a two year follow up. A cohort of all children born in 1978 and living in Rotterdam. Of those eligible, 73% (n=2587) participated in the first measurement (T1), at 10-12 years; 71% of the T1 respondents participated again two years later (T2), at 12-14 years. Neighbourhood disadvantage was associated with higher Total, Internalising, and Externalising Problems, as assessed with both the Child Behavior Checklist and the Youth Self-Report, even after controlling for parental socioeconomic status. Neighbourhood disadvantage also seemed to contribute to increases in Total Problems over the follow up. Living in a disadvantaged neighbourhood is associated with greater behavioural problems and may lead to an exacerbation of problems as children move from childhood into adolescence. Public health interventions to improve child mental health must take the neighbourhood environment into account.


Tetra-kis(μ-3-chloro-benzoato-κ(2) O:O')bis-[(N,N-di-ethyl-nicotinamide-κN (1))copper(II)].
In the title centrosymmetric binuclear Cu(II) complex, [Cu2(C7H4ClO2)4(C10H14N2O)2], the two Cu(II) cations [Cu⋯Cu = 2.6314 (4) Å] are bridged by four 3-chloro-benzoate (CB) anions. The four carboxyl-ate O atoms around each Cu(II) cation form a distorted square-planar arrangement, the distorted square-pyramidal coordination geometry being completed by the pyridine N atom of the N,N-di-ethyl-nicotinamide (DENA) mol-ecule. The dihedral angle between the benzene ring and the carboxyl-ate group is 4.49 (11)° in one of the independent CB ligands and 12.00 (10)° in the other. The benzene rings of the independent CB ligands are oriented at a dihedral angle of 84.13 (6)°. In the crystal, weak C-H⋯O hydrogen bonds link the binuclear complex mol-ecules into supra-molecular chains running along [101].


INCOG recommendations for management of cognition following traumatic brain injury, part II: attention and information processing speed.
Traumatic brain injury, due to its diffuse nature and high frequency of injury to frontotemporal and midbrain reticular activating systems, may cause disruption in many aspects of attention: arousal, selective attention, speed of information processing, and strategic control of attention, including sustained attention, shifting and dividing of attention, and working memory. An international team of researchers and clinicians (known as INCOG) convened to develop recommendations for the management of attentional problems. The experts selected recommendations from published guidelines and then reviewed literature to ensure that recommendations were current. Decision algorithms incorporating the recommendations based on inclusion and exclusion criteria of published trials were developed. The team then prioritized recommendations for implementation and developed audit criteria to evaluate adherence to these best practices. The recommendations and discussion highlight that metacognitive strategy training focused on functional everyday activities is appropriate. Appropriate use of dual task training, environmental modifications, and cognitive behavioral therapy is also discussed. There is insufficient evidence to support mindfulness meditation and practice on de-contextualized computer-based tasks for attention. Administration of the medication methylphenidate should be considered to improve information-processing speed. The INCOG recommendations for rehabilitation of attention provide up-to-date guidance for clinicians treating people with traumatic brain injury.


Analysis of lung tumor risks in rats exposed to radon.
Using data on 3117 rats exposed by inhalation to radon, radon progeny and uranium ore dust, the hazard function (or age-specific risk) for lung tumor incidence was modeled as a function of exposure, exposure rate and other factors. The overall estimate of lifetime risk was 237 cases per 10(6) rats per WLM (237 per 10(6) WLM), reasonably comparable to estimates obtained from data for humans. The data below 1000 WLM (20-640 WLM) were consistent with linearity with positive excess risks at all levels; however, evidence of statistically significant excess risk was limited to exposures of 80 WLM or greater. Evidence for an inverse exposure-rate effect was limited primarily to cumulative exposures exceeding 1000 WLM (1280-10,240 WLM) and to comparison of results at 100 and 1000 WL. Even at these levels, the possibility that the effect might be explained by time since last exposure or by heterogeneity across experiments could not be entirely excluded. The inverse exposure-rate effect was strongest for epidermoid and adenosquamous tumors, and the only indication of such an effect at exposures below 1000 WLM was modest evidence (P=0.024) in analyses limited to these tumors. When all lung tumors, or all malignant lung tumors, were included, there was no evidence of such an effect below 1000 WLM. These data support the viewpoint that the inverse exposure-rate effect is primarily a high-dose phenomenon.


Adherence to oral cancer therapies: nursing interventions.
This article reviews nursing interventions to increase adherence to oral cancer therapies, such as patient and care-partner education, side-effect and medication management, and safety issues. Data sources included peer-reviewed nursing and medical literature, healthcare Web sites, and published monographs. Oncology nurses are uniquely positioned to promote patient adherence to oral cancer therapies by ensuring that patients understand the goals of treatment, promoting safe prescriptive practices, proactively managing treatment side effects, and identifying and resolving underlying barriers to adherence. When adherence is optimized, clinical outcomes are greatly improved. Primary responsibility for adherence to an oral cancer therapy regimen remains with the patient. Oncology nurses, as part of a healthcare team, can have a significant influence on patient adherence by providing thorough and timely patient and family education and by monitoring and managing side effects of treatment. Monitoring adherence to oral cancer therapies is not a recent phenomenon nor limited to oral cancer treatments but presents an increasing challenge as additional oral therapies enter the marketplace. Oncology nurses should develop and enhance strategies and materials for patient education on oral cancer therapies, improve side-effect management, assist with patient access to medications, and develop practice guidelines to ensure adherence and promote safety.


Return to Sport After Pediatric Anterior Cruciate Ligament Reconstruction and Its Effect on Subsequent Anterior Cruciate Ligament Injury.
Anterior cruciate ligament (ACL) graft failure and contralateral ACL tears are more frequent in children and adolescents than adults. The reasons for higher subsequent injury rates in this population are incompletely understood. We analyzed a continuous cohort of patients who were <18 years of age. Subjects underwent isolated, primary ACL reconstruction with autograft between 2006 and January 1, 2014, and had a minimum 2-year follow-up. Return-to-sport characteristics were described, and multivariable Cox regression modeling was used to identify predictors of a second ACL injury. Candidate variables included patient factors (age, sex, physeal status, tibial slope, notch width index), surgical characteristics (graft type, surgical technique), measures of recovery (time to return to sport, duration of physical therapy), and patients' preoperative and postoperative sports involvement (primary and secondary sports, number of sports). A total of 112 subjects met inclusion criteria; of these patients, 85 (76%) had complete follow-up data and were analyzed. The mean age (and standard deviation) was 13.9 ± 2.1 years (range, 6 to 17 years); 77% had open physes. The mean follow-up was 48.3 ± 15.3 months. Seventy-seven patients (91%) returned to sports, and 84% returned to the same sport. The mean Marx activity score at the time of the latest follow-up was 13.7 ± 3.5 points. Patients were involved in fewer sports after ACL reconstruction, 1.48 ± 0.92 compared with 1.83 ± 1.01 sports before reconstruction (p = 0.002). Sixteen patients (19%) sustained an ACL graft rupture, 11 patients (13%) sustained a contralateral ACL tear, and 1 of these patients (1%) sustained both. The overall prevalence of a second ACL injury was 32%. Time to return to sport was the only significant predictor of a second ACL injury, with a slower return being protective (hazard ratio per month, 0.87 [95% confidence interval, 0.73 to 0.99]; p = 0.04). Pediatric athletes return to sports at a high rate (91%) after ACL reconstruction. Unfortunately, the prevalence of a second ACL injury is high at 32%. Within this population, an earlier return to sport is predictive of a second ACL injury. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.
There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).


Dural Puncture Epidural Technique Improves Labor Analgesia Quality With Fewer Side Effects Compared With Epidural and Combined Spinal Epidural Techniques: A Randomized Clinical Trial.
The dural puncture epidural (DPE) technique is a modification of the combined spinal epidural (CSE) technique, where a dural perforation is created from a spinal needle but intrathecal medication administration is withheld. The DPE technique has been shown to improve caudal spread of analgesia compared with epidural (EPL) technique without the side effects observed with the CSE technique. We hypothesized that the onset of labor analgesia would follow this order: CSE > DPE > EPL techniques. A total of 120 parturients in early labor were randomly assigned to EPL, DPE, or CSE groups. Initial dosing for EPL and DPE consisted of epidural 20 mL of 0.125% bupivacaine plus fentanyl 2 μg/mL over 5 minutes, and for CSE, intrathecal 0.25% bupivacaine 1.7 mg and fentanyl 17 μg. Upon block completion, a blinded coinvestigator assessed the outcomes. Two blinded obstetricians retrospectively interpreted uterine contractions and fetal heart rate tracings 1 hour before and after the neuraxial technique. The primary outcome was time to numeric pain rating scale (NPRS) ≤ 1 analyzed by using Kaplan-Meier curves and Cox proportional hazard model. Secondary outcomes included block quality, maternal adverse effects, uterine contraction patterns, and fetal outcomes analyzed by using the χ test with Yates continuity correction. There was no significant difference in the time to NPRS ≤ 1 between DPE and EPL (hazard ratio 1.4; 95% confidence interval [CI] 0.83-2.4, P = .21). DPE achieved NPRS ≤ 1 significantly slower than CSE (hazard ratio 0.36; 95% CI 0.22-0.59, P = .0001). The median times (interquartile range) to NPRS ≤ 1 were 2 (0.5-6) minutes for CSE, 11 (4-120) minutes for DPE, and 18 (10-120) minutes for EPL. Compared with EPL, DPE had significantly greater incidence of bilateral S2 blockade at 10 minutes (risk ratio [RR] 2.13; 95% CI 1.39-3.28; P < .001), 20 minutes (RR 1.60; 95% CI 1.26-2.03; P < .001), and 30 minutes (RR 1.18; 95% CI 1.01-1.30; P < .034), a lower incidence of asymmetric block after 30 minutes (RR 0.19; 95% CI 0.07-0.51; P < .001) and physician top-up intervention (RR 0.45; 95% CI 0.23-0.86; P = .011). Compared with CSE, DPE had a significantly lower incidence of pruritus (RR 0.15; 95% CI 0.06-0.38; P < .001), hypotension (RR 0.38; 95% CI 0.15-0.98; P = .032), combined uterine tachysystole and hypertonus (RR 0.22; 95% CI 0.08-0.60; P < .001), and physician top-up intervention (RR 0.45; 95% CI 0.23-0.86; p = .011). Analgesia onset was most rapid with CSE with no difference between DPE and EPL techniques. The DPE technique has improved block quality over the EPL technique with fewer maternal and fetal side effects than the CSE technique for parturients requesting early labor analgesia.


Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype.
Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.


Prenatally diagnosed portocaval shunt and postnatal outcome: a case report.
Congenital absence of the portal vein (CAPV) is a rare anomaly in the form of a portocaval shunt, whereby the intestinal and splenic venous drainage bypasses the liver and drains directly into the systemic circulation. We report a case of CAPV diagnosed prenatally after the recognition of a dilated umbilical vein draining directly into a large inferior vena cava (IVC). The IVC then drained into the right atrium of a dilated, hyperdynamic heart. The ductus venosus could not be identified. Repeated postnatal scans showed a gradual disappearance of venous lakes in the region of the porta hepatis and a clear drainage of the splenic vein to the left renal vein and the superior mesenteric vein to the IVC. From birth up to twelve months follow-up there was no evidence of liver dysfunction, encephalopathy or liver lesions.


Matrix-Targeting Immunotherapy Controls Tumor Growth and Spread by Switching Macrophage Phenotype.
The interplay between cancer cells and immune cells is a key determinant of tumor survival. Here, we uncovered how tumors exploit the immunomodulatory properties of the extracellular matrix to create a microenvironment that enables their escape from immune surveillance. Using orthotopic grafting of mammary tumor cells in immunocompetent mice and autochthonous models of breast cancer, we discovered how tenascin-C, a matrix molecule absent from most healthy adult tissues but expressed at high levels and associated with poor patient prognosis in many solid cancers, controls the immune status of the tumor microenvironment. We found that, although host-derived tenascin-C promoted immunity via recruitment of proinflammatory, antitumoral macrophages, tumor-derived tenascin-C subverted host defense by polarizing tumor-associated macrophages toward a pathogenic, immune-suppressive phenotype. Therapeutic monoclonal antibodies that blocked tenascin-C activation of Toll-like receptor 4 reversed this phenotypic switch in vitro and reduced tumor growth and lung metastasis in vivo, providing enhanced benefit in combination with anti-PD-L1 over either treatment alone. Combined tenascin-C:macrophage gene-expression signatures delineated a significant survival benefit in people with breast cancer. These data revealed a new approach to targeting tumor-specific macrophage polarization that may be effective in controlling the growth and spread of breast tumors.


Marginal hepatectomy in the rat: from anatomy to surgery.
Based on the 3-dimensional visualization of vascular supply and drainage, a vessel-oriented resection technique was optimized. The new surgical technique was used to determine the maximal reduction in liver mass enabling a 50% 1-week survival rate. Determination of the minimal liver mass is necessary in clinical as well as in experimental liver surgery. In rats, survival seems to depend on the surgical technique applied. Extended hepatectomy with removal of 90% of the liver mass was long regarded as a lethal model. Introduction of a vessel-oriented approach enabled long-term survival in this model. The lobar and vascular anatomy of rat livers was visualized by plastination of the whole organ, respectively, by corrosion casts of the portal vein, hepatic artery and liver veins. The three-dimensional models were used to extract the underlying anatomic structure. In 90% partial hepatectomy, the liver parenchyma was clamped close to the base of the respective liver lobes (left lateral, median and right, liver lobe). Piercing sutures were placed through the liver parenchyma, so that the stem of portal vein and the accompanying hepatic artery but also the hepatic vein were included. A 1-week survival rate of 100% was achieved after 90% hepatectomy. Extending the procedure to 95% resection by additional removal of the upper caudate lobe led to a 1-week survival rate of 66%; 97% partial hepatectomy, accomplished by additional resection of the lower caudate lobe only leaving the paracaval parts of the liver behind, resulted in 100% lethality within 4 days. Using a anatomically based, vessel-oriented, parenchyma-preserving surgical technique in 95% liver resections led to long-term survival. This represents the maximal reduction of liver mass compatible with survival.


Potential hominin affinities of Graecopithecus from the Late Miocene of Europe.
The split of our own clade from the Panini is undocumented in the fossil record. To fill this gap we investigated the dentognathic morphology of Graecopithecus freybergi from Pyrgos Vassilissis (Greece) and cf. Graecopithecus sp. from Azmaka (Bulgaria), using new μCT and 3D reconstructions of the two known specimens. Pyrgos Vassilissis and Azmaka are currently dated to the early Messinian at 7.175 Ma and 7.24 Ma. Mainly based on its external preservation and the previously vague dating, Graecopithecus is often referred to as nomen dubium. The examination of its previously unknown dental root and pulp canal morphology confirms the taxonomic distinction from the significantly older northern Greek hominine Ouranopithecus. Furthermore, it shows features that point to a possible phylogenetic affinity with hominins. G. freybergi uniquely shares p4 partial root fusion and a possible canine root reduction with this tribe and therefore, provides intriguing evidence of what could be the oldest known hominin.


Sacrospinous hysteropexy with a low weight transvaginal polypropylene mesh for treatment of complete uterovaginal eversion.
Pelvic Organ Prolapse (POP) is a common condition in elderly resulting from the weakening of the organ suspension elements of multifactorial origin. It compromises significantly the quality of life and can affect more than 50% of multiparous women. Stage IV prolapse or complete uterovaginal eversion corresponds to 10% of the cases and the only form of curative treatment is the surgical correction. The aim of this video is to demonstrate our technique of sacrospinous hysteropexy with a low weight transvaginal polypropylene mesh for treatment of this challenge condition, focusing on technical details in order to prevent mesh related complications. Major, but rare complications, include: infection, prolapse recurrence, abscess formation, bladder perforation and urinary fistula. These situations are related mostly to low volume centers. A 70 years old female with a stage IV POP had obstructive lower urinary tract symptoms. Only after reducing prolapse, it was possible to urinate, but without stress urinary incontinence. No topic estrogen was prescribed before the surgery and she also didn´t take any kind of hormone replacement therapy. Transvaginal ultrasound and the Pap smear screening were done with normal results. Cystoscopy wasn´t employed at anytime of this procedure. Hydrodissection of vaginal wall was followed by longitudinal incision from the level of bladder neck to the cervix. Notice that the ideal dissection should maintain the vaginal thickness, and address the plane of the connective tissue between the bladder and the vagina. Bladder base is then released from the anterior aspect of the cervix in order to create a site to pericervical ring repair and to fix the apex of the Calistar Soft® with polypropylene 3.0 stitches. A blunt dissection extended downwards through the lateral aspect of the levator ani fascia till the identification of the ischial spine and sacrospinous ligaments bilaterally. Two polypropilene 2.0 threads mounted on a specially designed tissue anchor system (TAS) are then fixed into each sacrospinous ligament 1.5 to 2 cm away from the ischial spine and repaired for further prosthesis anchoring. Then, a longitudinal incision is done at the posterior vaginal wall and the recto-vaginal fascia detachment from the posterior aspect of the pericervical ring is identified and corrected with interrupted polypropylene 2.0 stitches to the cervix and to the pericervical aspect of elongated uterosacrus ligaments bilaterally. The Calistar Soft A (anterior) and P (posterior)® prosthesis were fixed at the anterior and posterior aspects of the cervix, respectively, with interrupted polypropylene 3.0 stitches and meshes' arms are fixed to the sacrospinous ligament using the previously implanted TAS. Then, the distal Calistar Soft A® arms were bilaterally fixed into the internal obturator muscles using its fish spine-like multipoint fix device in order to prevent mesh folding. Finally, perineal body repair was done and vaginal wall was closed with individual absorbable interrupted polyglactin 2.0 sutures and a 16 Fr Foley catheter as well as a vaginal pack embedded on neomicin-bacitracin cream were kept overnight. A high satisfaction rate has been computed with synthetic mesh to POP surgery correction. Approximately 10% of cases of mesh exposure may occur, most of them oligosymptomatic and easy handed by excision or with topic estrogen preparations. After 1 year follow-up, our patient is still satisfied without any complain and no relapse. We described a successful treatment of stage IV POP in an old female patient. This technique can be used for advanced end stage POP patients, especially those with some contraindication to sacropromontopexy, but who want to keep vaginal length and uterus. Anatomical knowledge, obedience to technical care, and intensive training are the keys for minimizing the risk of complications. Although we had success with this technique, more studies with proper randomization are necessary to compare success and complications of sacrospinous hysteropexy with a low weight transvaginal polypropylene mesh to sacropromontopexy.


Fetal growth and subsequent mental health problems in children aged 4 to 13 years.
To test the hypothesis that children with suboptimal fetal growth have significantly poorer mental health outcomes than those with optimal growth, a population random sample survey of children aged 4 to 16 years in Western Australia in 1993 was conducted. The Child Behavior Checklist (Achenbach 1991a) and the Teacher Report Form (Achenbach 1991b) were used to define mental health morbidity. Survey data for 1775 children aged 4 to 13 years were available for linkage with original birth information. The percentage of expected birthweight (PEBW) was used as the measure of fetal growth. Children below the 2nd centile of PEBW who had achieved only 57% to 72% of their expected birthweight given their gestation at delivery were at significant risk of a mental health morbidity (OR 2.9, 95% CI 1.18, 7.12). In addition, they were more likely to be rated as academically impaired (OR 6.0, 95% CI 2.25, 16.06) and to have poor general health (OR 5.1, 95% CI 1.69, 15.52).


Relationship between Proximal Urethrovaginal Space Thickness and Detrusor Overactivity in Women with Stress Urinary Incontinence.
Detrusor overactivity (DO) cannot be predicted by clinical symptoms. Although it is possible that DO could be related to anatomical structures, scanty data exist about the relations between DO and anatomical structures. The aim of this study was to investigate anatomical differences in DO by measuring the thickness of the urethrovaginal space (UVS) and the urethral length (UL) in women with stress urinary incontinence (SUI). Prospective data were collected from 72 women with SUI who underwent the midurethral sling operation. The subjects were divided into 2 groups according to the presence of DO by preoperative urodynamic study (UDS). UVS thickness was measured by trans-vaginal ultrasound. UL was measured by using a urethral catheter and a ruler. UVS thickness, UL, Q-tip, and urodynamic parameters, such as maximal urethral closure pressure (MUCP) and Valsalva leak point pressure, were compared between the two groups. Of 72 women, 23 patients had DO (31.9%). The proximal UVS was significantly thinner (p<0.001) and the MUCP was significantly lower (p=0.008) in women with DO. According to the receiver operating characteristic (ROC) curve based DO prediction, the best cutoff value for UVS thickness was 0.84 cm (area under the ROC curve 0.763). In this study, the proximal UVS was significantly thinner and the MUCP was significantly lower in patients with DO. A proximal UVS thickness of less than 0.84 cm was shown to be a predictive parameter for the development of DO on preoperative UDS. A large-scale prospective study is needed to validate these results.


Validation of serum protein profiles by a dual antibody array approach.
In recent years, affinity-based technologies have become important tools for serum profiling to uncover protein expression patterns linked to disease state or therapeutic effects. In this study, we describe a path towards the production of an antibody microarray to allow protein profiling of biotinylated human serum samples with reproducible sensitivity in the picomolar range. With the availability of growing numbers of affinity reagents, protein profiles are to be validated in efficient manners and we describe a cross-platform strategy based on data concordance with a suspension bead array to interrogate the identical set of antibodies with the same cohort of serum samples. Comparative analysis enabled to screen for high-performing antibodies, which were displaying consistent results across the two platforms and targeting known serum components. Moreover, data processing methods such as sample referencing and normalization were evaluated for their effects on inter-platform agreement. Our work suggests that mutual validation of protein expression profiles using alternative microarray platforms holds great potential in becoming an important and valuable component in affinity-based high-throughput proteomic screenings as it allows to narrow down the number of discovered targets prior to orthogonal, uniplexed validation approaches.


Transcending the brain: is there a cost to hacking the nervous system?
Great advancements have recently been made to understand the brain and the potential that we can extract out of it. Much of this has been centred on modifying electrical activity of the nervous system for improved physical and cognitive performance in those with clinical impairment. However, there is a risk of going beyond purely physiological performance improvements and striving for human enhancement beyond traditional human limits. Simple ethical guidelines and legal doctrine must be examined to keep ahead of technological advancement in light of the impending mergence between biology and machine. By understanding the role of modern ethics, this review aims to appreciate the fine boundary between what is considered ethically justified for current neurotechnology.


Characterization of time-resolved fluorescence response measurements for distributed optical-fiber sensing.
A distributed optical-fiber sensing system based on pulsed excitation and time-gated photon counting has been used to locate a fluorescent region along the fiber. The complex Alq3 and the infrared dye IR-125 were examined with 405 and 780 nm excitation, respectively. A model to characterize the response of the distributed fluorescence sensor to a Gaussian input pulse was developed and tested. Analysis of the Alq3 fluorescent response confirmed the validity of the model and enabled the fluorescence lifetime to be determined. The intrinsic lifetime obtained (18.2±0.9 ns) is in good agreement with published data. The decay rate was found to be proportional to concentration, which is indicative of collisional deactivation. The model allows the spatial resolution of a distributed sensing system to be improved for fluorophores with lifetimes that are longer than the resolution of the sensing system.


H2 evolution by a cobalt selenolate electrocatalyst and related mechanistic studies.
[Co(bds)2][nBu4N] (where bds = 1,2-benzenediselenolate) was identified as an electrocatalyst for the hydrogen evolution reaction. Mechanistic studies indicated that a black precipitate, which formed upon treating [Co(bds)2]- with acid, as well as the one-electron reduced species, [Co(bds)2]2-, were viable catalytic intermediates. We propose two kinetically-competent pathways for H2 evolution: EC and CE (E = electrochemical, C = chemical step).


Identifying target cells for a tick-borne virus that causes fatal hemorrhagic fever.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease in China, South Korea, and Japan caused by the tick-borne SFTS virus (SFTSV). Severe and fatal SFTS presents as a hemorrhagic fever characterized by high viral load, uncontrolled inflammatory response, dysregulated adaptive immunity, coagulation abnormalities, hemorrhage, and multiorgan failure with up to 33% case fatality rates (CFRs). Despite its public health significance in Asia, vaccines and specific therapeutics against SFTS are still unavailable. A better understanding of the pathogenesis of SFTS is crucial to improving medical countermeasures against this devastating disease. In this issue of the JCI, Suzuki and colleagues analyzed histopathological samples from 22 individuals who succumbed to SFTS, and identified antibody-producing B cell-lineage plasmablasts and macrophages as principal target cells for SFTSV infection in fatal SFTS. Their results suggest that SFTSV-infected post-germinal center B cells, plasmablasts, and macrophages affect systemic immunopathology and dysregulation, which likely leads to fatal outcomes.


Artificial intelligence for clinical decision support in neurology.
Artificial intelligence is one of the most exciting methodological shifts in our era. It holds the potential to transform healthcare as we know it, to a system where humans and machines work together to provide better treatment for our patients. It is now clear that cutting edge artificial intelligence models in conjunction with high-quality clinical data will lead to improved prognostic and diagnostic models in neurological disease, facilitating expert-level clinical decision tools across healthcare settings. Despite the clinical promise of artificial intelligence, machine and deep-learning algorithms are not a one-size-fits-all solution for all types of clinical data and questions. In this article, we provide an overview of the core concepts of artificial intelligence, particularly contemporary deep-learning methods, to give clinician and neuroscience researchers an appreciation of how artificial intelligence can be harnessed to support clinical decisions. We clarify and emphasize the data quality and the human expertise needed to build robust clinical artificial intelligence models in neurology. As artificial intelligence is a rapidly evolving field, we take the opportunity to iterate important ethical principles to guide the field of medicine is it moves into an artificial intelligence enhanced future.


Donor hematopoietic progenitor cells in nonmyeloablated rat recipients of allogeneic bone marrow and liver grafts.
Although the persistence of multilineage microchimerism in recipients of long-surviving organ transplants implies engraftment of migratory pluripotent donor stem cells, the ultimate localization in the recipient of these cells has not been determined in any species. Progenitor cells were demonstrated in the bone marrow and nonparenchymal liver cells of naive rats and in Brown Norway (BN) recipients of Lewis (LEW) allografts by semiquantitative colony-forming unit in culture (CFU-C) assays. The LEW allografts of bone marrow cells (BMC) (2.5x10(8)), orthotopic livers, or heterotopic hearts (abdominal site) were transplanted under a 2-week course of daily tacrolimus, with additional single doses on days 20 and 27. Donor CFU-C colonies were distinguished from recipient colonies in the allografts and recipient bone marrow with a donor-specific MHC class II monoclonal antibody. The proportions of donor and recipient colonies were estimated from a standard curve created by LEW and BN bone marrow mixtures of known concentrations. After the BMC infusions, 5-10% of the CFU-C in the bone marrow of BN recipients were of the LEW phenotype at 14, 30, and 60 days after transplantation. At 100 days, however, donor CFU-C could no longer be found at this site. The pattern of LEW CFU-C in the bone marrow of BN liver recipients up to 60 days was similar to that in recipients of 2.5x10(8) BMC, although the donor colonies were only 1/20 to 1/200 as numerous. This was expected, because the progenitor cells in the passenger leukocytes of a single liver are equivalent to those in 1-5x10(6) BMC. Using a liquid CFU-C assay, donor progenitor cells were demonstrated among the nonparenchymal cells of liver allografts up to 100 days. In contrast, after heart transplantation, donor CFU-C could not be identified in the recipient bone marrow, even at 14 days. effective immunosuppression, allogeneic hematopoietic progenitors compete effectively with host cells for initial engraftment in the bone marrow of noncytoablated recipients, but disappear from this location between 60 and 100 days after transplantation, coincident with the shift of donor leukocyte chimerism from the lymphoid to the nonlymphoid compartment that we previously have observed in this model. It is possible that the syngeneic parenchymal environment of the liver allografts constitutes a privileged site for persistent progenitor donor cells.


Direct-acting Oral Anticoagulants: An Overview.
In today's practice, an increasing number of patients are prescribed anticoagulant therapy. Short-term anticoagulation as a primary or secondary prophylaxis of thrombosis is standard of care in many clinical indications. In addition, there has been a significant increase in the number of patients receiving long-term full therapeutic anticoagulation, particularly among patients with atrial fibrillation and those with venous thrombosis having a high risk of recurrence. Therefore, clinicians and patients warmly accepted the timely introduction of non-Vitamin K antagonists to clinical practice. Anticoagulants such as anti-Xa and antithrombin have been found to be effective and safe as compared with the standard of care using low-molecular-weight heparin and warfarin. Importantly, the new anticoagulants exhibit rapid onset of action and do not require regular monitoring, making them convenient and user-friendly. Another interesting and consistent observation is that the new anticoagulants have a lower incidence of intracranial bleeding as compared with warfarin therapy. However, before prescribing these drugs, clinicians should check and periodically monitor the renal function of their patients, particularly when new drugs known to affect renal function are introduced. Clinicians should also be aware that these new anticoagulants cannot be considered as a replacement for warfarin in all indications. For example, warfarin remains the drug of choice in patients with prosthetic valves and in those suffering from the antiphospholipid syndrome. Finally, clinicians should be aware and adhere to the appropriate indications for the use of these new anticoagulants and use them at their approved dosage.


Psychomotor skills acquisition of novice learners: a case for contextual learning.
Deficiencies in procedural competency compromise patient safety and the quality of care provided. Educators in prelicensure nursing programs are challenged to design effective instruction to develop psychomotor skills abilities among novice learners. Highly contextualized learning and frequent opportunities for performance rehearsal promote knowledge retention and procedural competence. The author discusses data from an evaluation study that explored students' perceptions of the effectiveness of skills instruction and suggests strategies for curricular integration and effective instruction.


A case of tuberculosis pericarditis with an interesting echocardiographic image.
Tuberculosis-associated pericardial disorders are an excessively rare manifestation of extrapulmonary tuberculosis. The patients may present with constrictive pericarditis or pericardial fluid accumulation leading to cardiac tamponade. This paper reports a case of tuberculosis-associated pericardial effusion with dense fibrinous material not causing tamponade in a foreigner presenting with nonspecific symptoms. It also provides a discussion about the diagnostic and therapeutic methods as well as interesting echocardiographic images of the patient.


Up-regulation of 14-3-3zeta in lung cancer and its implication as prognostic and therapeutic target.
A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3zeta as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3zeta is believed to function in cell signaling, cycle control, and apoptotic death. Following our initial finding, here, we analyzed its expression in lung tumor tissues obtained from 205 patients with various histologic and stage non-small cell lung cancers (NSCLC) using immunohistochemistry and then explored the effects of specific suppression of the gene in vitro and in a xenograft model using small interfering RNA. The increased 14-3-3zeta expression was positively correlated with a more advanced pathologic stage and grade of NSCLCs (P = 0.001 and P = 0.006, respectively) and was associated with overall and cancer-specific survival rates of the patients (P = 0.022 and P = 0.018, respectively). Down-regulation of 14-3-3zeta in lung cancer cells led to a dose-dependent increased sensitivity to cisplatin-induced cell death, which was associated with the inhibition of cell proliferation and increased G2-M arrest and apoptosis. The result was further confirmed in the animal model, which showed that the A549 lung cancer cells with reduced 14-3-3zeta grew significantly slower than the wild-type A549 cells after cisplatin treatment (P = 0.008). Our results suggest that 14-3-3zeta is a potential target for developing a prognostic biomarker and therapeutics that can enhance the antitumor activity of cisplatin for NSCLC.


A fourth Denisovan individual.
The presence of Neandertals in Europe and Western Eurasia before the arrival of anatomically modern humans is well supported by archaeological and paleontological data. In contrast, fossil evidence for Denisovans, a sister group of Neandertals recently identified on the basis of DNA sequences, is limited to three specimens, all of which originate from Denisova Cave in the Altai Mountains (Siberia, Russia). We report the retrieval of DNA from a deciduous lower second molar (Denisova 2), discovered in a deep stratigraphic layer in Denisova Cave, and show that this tooth comes from a female Denisovan individual. On the basis of the number of "missing substitutions" in the mitochondrial DNA determined from the specimen, we find that Denisova 2 is substantially older than two of the other Denisovans, reinforcing the view that Denisovans were likely to have been present in the vicinity of Denisova Cave over an extended time period. We show that the level of nuclear DNA sequence diversity found among Denisovans is within the lower range of that of present-day human populations.


Pinch1 is required for normal development of cranial and cardiac neural crest-derived structures.
Pinch1, an adaptor protein composed of 5 LIM domains, has been suggested to play an important role in multiple cellular processes. We found that Pinch1 is highly expressed in neural crest cells and their derivatives. To examine the requirement for Pinch1 in neural crest development, we generated neural crest conditional Pinch1 knockout mice using the Wnt1-Cre/loxP system. Neural crest conditional Pinch1 mutant embryos die perinatally from severe cardiovascular defects with an unusual aneurysmal common arterial trunk. Pinch1 mutants also exhibit multiple deficiencies in cranial neural crest-derived structures. Fate mapping demonstrated that initial migration of neural crest cells to the pharyngeal arch region occurs normally in the mutant embryos. However, in the cardiac outflow tract of mutants, neural crest cells exhibited hyperplasia and failed to differentiate into smooth muscle. Markedly increased apoptosis is observed in outflow tract cushions of mutants between embryonic days 11.5 and 13.5, likely contributing to the observed defects in cushion/valve remodeling and ventricular septation. Expression of transforming growth factor-beta(2), which plays a crucial role in outflow tract development, was decreased or absent in the outflow tract of the mutants. The decrease in transforming growth factor-beta(2) expression preceded neural crest cell death. Together, our results demonstrate that Pinch1 plays an essential role in neural crest development, perhaps in part through transforming growth factor-beta signaling.


Inactivation of cytochrome P4502B1 by the monoamine oxidase inhibitors R-(-)-deprenyl and clorgyline.
The monoamine oxidase inhibitors R-(-)-deprenyl (deprenyl) and clorgyline inactivated the 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity of purified cytochrome P4502B1 (P4502B1) in a reconstituted system containing P4502B1, NADPH-cytochrome P450 oxidoreductase, and L-alpha-phosphatidylcholine dilauroyl as the lipid. The inactivation was time- and concentration-dependent. The inactivation required NADPH, demonstrated saturation kinetics, and no lag time for inactivation was observed. The inactivation was not affected by the presence of an excess exogenous nucleophile, such as glutathione. Deprenyl exhibited a KI (concentration of inactivator required for half-maximal inactivation) of 1.05 microM, and clorgyline had a KI of 1.5 microM. The maximum rate of inactivation of the enzyme at saturating levels of inactivator (kinactivation) was 0.23 min-1 for deprenyl and 0.28 min-1 for clorgyline. The partition ratio for deprenyl and clorgyline was between 2 and 3. Studies on the isozyme specificity of these compounds in microsomes from rats pretreated with specific inducers demonstrate that the inactivation was relatively specific for the major phenobarbital-inducible isozyme, P4502B1, because significant inactivation of P4501A1 and P4502E1 was not observed. When the purified P4502B1 in the reconstituted system was incubated with either inactivator in the presence of NADPH, there was approximately a 60-70% loss in spectrally detectable P450 over 5 min at a 1:21 ratio of P450 to inactivator. However, at this ratio of enzyme to inactivator, there was > 90% loss of the O-deethylase activity. This loss in enzyme activity was irreversible, and the protein did not regain activity after dialysis or extensive washing to remove excess inactivator.


Application of the chicken embryo in testing for embryotoxicity: thiurams.
A test protocol was developed for the testing of chemicals for toxicity on the chicken embryo. The protocol called for a continuous monitoring of the developing embryo for those that died before maceration. The eggs were injected on day 3, and the test was continued up to day 14 of incubation. The following parameters of embryotoxicity were used: early deaths (spanning the first 2 d after injection), late deaths with malformed embryos, late deaths with nonmalformed embryos, and malformed survivors. The order of embryotoxic potency, in descending order, among the thiurams was tetramethylthiuramdisulfide, tetramethylthiurammonosulfide, tetraethylthiuramdisulfide. It was found that late deaths were seen in 70% of the cases with malformations. The most common types of malformations were eye defects and open coeloms. Dead embryos frequently had multiple malformations. In lethal cases, embryonic development terminated at stages 25/26 and 29 on the Hamburger-Hamilton scale.