Niche-specific requirement for hyphal wall protein 1 in virulence of Candida albicans.
Specialized Candida albicans cell surface proteins called adhesins mediate binding of the fungus to host cells. The mammalian transglutaminase (TG) substrate and adhesin, Hyphal wall protein 1 (Hwp1), is expressed on the hyphal form of C. albicans where it mediates fungal adhesion to epithelial cells. Hwp1 is also required for biofilm formation and mating thus the protein functions in both fungal-host and self-interactions. Hwp1 is required for full virulence of C. albicans in murine models of disseminated candidiasis and of esophageal candidiasis. Previous studies correlated TG activity on the surface of oral epithelial cells, produced by epithelial TG (TG1), with tight binding of C. albicans via Hwp1 to the host cell surfaces. However, the contribution of other Tgs, specifically tissue TG (TG2), to disseminated candidiasis mediated by Hwp1 was not known. A newly created hwp1 null strain in the wild type SC5314 background was as virulent as the parental strain in C57BL/6 mice, and virulence was retained in C57BL/6 mice deleted for Tgm2 (TG2). Further, the hwp1 null strains displayed modestly reduced virulence in BALB/c mice as did strain DD27-U1, an independently created hwp1Δ/Δ in CAI4 corrected for its ura3Δ defect at the URA3 locus. Hwp1 was still needed to produce wild type biofilms, and persist on murine tongues in an oral model of oropharyngeal candidiasis consistent with previous studies by us and others. Finally, lack of Hwp1 affected the translocation of C. albicans from the mouse intestine into the bloodstream of mice. Together, Hwp1 appears to have a minor role in disseminated candidiasis, independent of tissue TG, but a key function in host- and self-association to the surface of oral mucosa.


The number of subordinates moderates intrasexual competition among males in cooperatively breeding meerkats.
For dominant individuals in cooperatively breeding species, the presence of subordinates is associated with both benefits (i.e. increased reproductive output and other group-living benefits) and costs (i.e. intrasexual competition on reproduction). The biological market theory predicts that dominant individuals are tolerant to same-sex group members when there are only a few subordinates, so as to maximize their own reproductive success. We investigated factors affecting aggression by dominant males and submission by subordinate males for a cooperatively breeding mammal, meerkats, Suricata suricatta. In this species, reproductive conflict occurs between the dominant male and the non-offspring males. As predicted, the number of subordinates in a group was positively associated with the aggression frequency by the dominant male and with the submission frequency by the subordinate males. Relative to the aggression frequency against male offspring, the frequency of aggression against non-offspring males was comparable in small groups, but was higher in large groups. These results indicate that reproductive conflict is present between the dominant male and the non-offspring males but is moderated in groups with small numbers of subordinates. This study provides an empirical data agreeing with the biological market theory in the context of intrasexual competition in cooperatively breeding species.


Precise Temporal Profiling of Signaling Complexes in Primary Cells Using SWATH Mass Spectrometry.
Spatiotemporal organization of protein interactions in cell signaling is a fundamental process that drives cellular functions. Given differential protein expression across tissues and developmental stages, the architecture and dynamics of signaling interaction proteomes is, likely, highly context dependent. However, current interaction information has been almost exclusively obtained from transformed cells. In this study, we applied an advanced and robust workflow combining mouse genetics and affinity purification (AP)-SWATH mass spectrometry to profile the dynamics of 53 high-confidence protein interactions in primary T cells, using the scaffold protein GRB2 as a model. The workflow also provided a sufficient level of robustness to pinpoint differential interaction dynamics between two similar, but functionally distinct, primary T cell populations. Altogether, we demonstrated that precise and reproducible quantitative measurements of protein interaction dynamics can be achieved in primary cells isolated from mammalian tissues, allowing resolution of the tissue-specific context of cell-signaling events.


Pharmacokinetics of Amikacin in Critical Care Patients on Extracorporeal Device.
In this study, we evaluate the effect of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (Levitronix) on the pharmacokinetic of amikacin in critically ill patients. Twelve patients with ECMO and three with Levitronix devices who started treatment with amikacin were included. Amikacin pre (Cmax) and post (Cmin) dose serum concentrations were measured during the first 72-96 hours of treatment initiation. Pharmacokinetic parameters were performed by Bayesian adjustment. The median initial dose was 1,000 mg (range: 600-1,400 mg). Mean plasma concentrations were Cmax 58.6 mg/L (17.0 mg/L); Cmin 9.58 mg/L (7.8 mg/L). Patients with an ECMO device had a higher volume of distribution (0.346 [0.033] vs. 0.288 [0.110] L/kg) and a lower plasma clearance (1.58 [0.21] vs. 3.73 [1.03] L/h) than the control group. This phenomenon was also observed in those patients with simultaneous use of ECMO and hemodilafiltration. For patients with Levitronix system, no significant alterations in the volume of distribution were observed, although a lower plasma clearance was noticed. Placement of ECMO devices alters the pharmacokinetic parameters of amikacin in the critically ill patients and should be considered when selecting the initial dose.


Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice.
Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have focused historically on antibiotic development and vaccine-enhanced adaptive immunity. However, we have reported recently that the lungs' innate defenses can be induced therapeutically by inhalation of a bacterial lysate that protects mice against otherwise lethal pneumonia. In this study, we tested in mice the hypothesis that TLRs are required for this antimicrobial phenomenon and found that resistance could not be induced in the absence of the TLR signaling adaptor protein MyD88. We then attempted to recapitulate the protection afforded by the bacterial lysate by stimulating the lung epithelium with aerosolized synthetic TLR ligands. Although most single or combination treatments yielded no protection, simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent gram-positive and gram-negative pathogens. Protection was associated with rapid pathogen killing in the lungs, and pathogen killing could be induced from lung epithelial cells in isolation. Taken together, these data demonstrate the requirement for TLRs in inducible resistance against pneumonia, reveal a remarkable, unanticipated synergistic interaction of TLR2/6 and TLR9, reinforce the emerging evidence supporting the antimicrobial capacity of the lung epithelium, and may provide the basis for a novel clinical therapeutic that can protect patients against pneumonia during periods of peak vulnerability.


Connexin 40 regulates lung endothelial permeability in acute lung injury via the ROCK1-MYPT1- MLC20 pathway.
Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung microvascular endothelium. Yet, the role of Cx40 in the regulation of lung vascular permeability and its underlying mechanisms are unclear. Here, we tested the hypothesis that Cx40 participates in regulation of lung endothelial permeability via a mechanism involving a Rho-associated protein kinase (ROCK) dependent regulation of myosin light chain (MLC). In murine models of intratracheal acid- or LPS-induced lung injury, genetic deficiency of Cx40 attenuated key features of ALI including vascular barrier failure. In human pulmonary microvascular endothelial cells (PMVECs), thrombin-induced loss of transendothelial electrical resistance was attenuated by a Cx40-inhibiting mimetic peptide (40GAP27), Cx40-specific shRNA, or ROCK inhibitor Y27632. In isolated perfused mouse lungs, platelet-activating factor-induced lung weight gain was abrogated by gap junction blocker carbenoxolone, 40GAP27, Y27632, or genetic deficiency of Cx40. Phosphorylation of MLC20 increased drastically in both LPS-treated PMVECs and HCl-treated mouse lungs. Expression of ROCK1 was increased in both LPS-treated PMVECs and HCl-treated mouse lungs, and paralleled by phosphorylation of MLC20. Coimmunoprecipitation experiments revealed protein-protein interaction between ROCK1 and Cx40. LPS-induced upregulation of ROCK1 and phosphorylation of MLC20 were blocked by knockdown of Cx40. LPS caused phosphorylation of myosin phosphatase targeting subunit 1, which could be abrogated by Y27632 or Cx40-shRNA. Our findings reveal a role of Cx40 in regulation of ROCK1 and MLC20 that contributes critically to lung vascular barrier failure in ALI.


Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats.
Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.


[The role of tumoral stroma in prognosis of course of luminal mammary gland cancer type A].
Peculiarities of tumoral stroma, the indices of overall survival (OS) and disease free survival (DFS) were studied up in patients, suffering luminal mammarial gland cancer MGC type A. If the stroma have had occupied more than 50% of the tumor square, the OS and DFS indices were the highest. The link was established between the OS and DFS indices, the stromal square and expression of the MGC cells toward the estrogen and progesterone receptors. The pronounced stromal reaction was connected with the OS index improvement even in a less pronounced expression to estrogen and progesterone.


HIV/AIDS awareness and risk behaviour among pregnant women in Semey, Kazakhstan, 2007.
Central Asia has one of the most rapidly increasing HIV prevalence in the world. The aim of this study was to evaluate current knowledge, risk behaviour and attitudes to voluntary counselling and testing concerning HIV/AIDS among pregnant women in Semey, Kazakhstan. We collected 226 questionnaires in a consecutive sample from a population on 520 pregnant women. The results were related to ethnicity, age and education level. Ninety-six percent had heard about HIV. Positive findings were that 89% and 86% of the women were aware of the two main routes of transmission: sexual intercourses without a condom and sharing needles while injecting drugs. The women had first heard about HIV/AIDS through the media with, 52%, and at school with 40%. Only 46% and 68% of the women pointed out breastfeeding and mother-to-child transmission during pregnancy or delivery as routes of transmission. Eighty-three percent were prepared not to breastfeed their baby if they were found to be HIV positive. Slightly more, 86%, accepted the need to take medicine, but fewer women, 68%, were positive to Caesarean section. Negative findings were that only 28% answered that there are ways to protect oneself against sexually transmitted HIV/AIDS and specified that this was condom use. The pregnant women in Semey have poor knowledge about specific mother-to-child HIV transmission and do not know about the means of reducing mother-to-child HIV infection. The information in the public health program needs to be improved. However, most of the women in Semey were positive to prevention strategies for mother-to-child transmission after hearing about it.


Bone characteristics in condylar hyperplasia of the temporomandibular joint: a microcomputed tomography, histology, and Raman microspectrometry study.
Unilateral condylar hyperplasia (UCH) of the temporomandibular joint is a progressive deformation of the mandibular condyle of unknown origin. UCH is characterized by excessive growth of the condylar head and neck, leading to an increase in size and volume. The aim of this study was to investigate the characteristics of the bone in patients with UCH using microcomputed tomography (micro-CT), histology, and Raman microspectroscopy. The mandibular condyles of six patients with UCH were analysed using micro-CT, histology, and Raman microspectrometry and imaging, and the results were compared with those obtained for a normal control subject. Three-dimensional micro-CT models revealed focal abnormalities of the bone microarchitecture, with foci of osteosclerosis. Histological sections showed that these foci included islands of calcified cartilage matrix with live chondrocytes. Raman analysis revealed that the cartilage matrix was more heavily calcified than the bone matrix and that the cartilage could be identified by the phenylalanine (PHE) band of its matrix, as well as by its glycosaminoglycan (GAG) content. The persistence of foci of live and active chondrocytes within the bone matrix is intriguing and appears to be pathognomonic of UCH. These new findings on UCH could help to determine its pathophysiology and thus prevent this disease, which can lead to major facial deformity.


General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs.
Cytochrome P450 (CYP) 3A4 is the most prevalent metabolising enzyme in the human liver and is also a target for various drug interactions of significant clinical concern. Even though there are numerous reports regarding drug interactions involving CYP3A4, it is far from easy to estimate all potential interactions, since too many drugs are metabolised by CYP3A4. For this reason, a comprehensive framework for the prediction of CYP3A4-mediated drug interactions would be of considerable clinical importance. The objective of this study was to provide a robust and practical method for the prediction of drug interactions mediated by CYP3A4 using minimal in vivo information from drug-interaction studies, which are often carried out early in the course of drug development. The analysis was based on 113 drug-interaction studies reported in 78 published articles over the period 1983-2006. The articles were used if they contained sufficient information about drug interactions. Information on drug names, doses and the magnitude of the increase in the area under the concentration-time curve (AUC) were collected. The ratio of the contribution of CYP3A4 to oral clearance (CR(CYP)(3A4)) was calculated for 14 substrates (midazolam, alprazolam, buspirone, cerivastatin, atorvastatin, ciclosporin, felodipine, lovastatin, nifedipine, nisoldipine, simvastatin, triazolam, zolpidem and telithromycin) based on AUC increases observed in interaction studies with itraconazole or ketoconazole. Similarly, the time-averaged apparent inhibition ratio of CYP3A4 (IR(CYP)(3A4)) was calculated for 18 inhibitors (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, saquinavir, nefazodone, erythromycin, diltiazem, fluconazole, verapamil, cimetidine, ranitidine, roxithromycin, fluvoxamine, azithromycin, gatifloxacin and fluoxetine) primarily based on AUC increases observed in drug-interaction studies with midazolam. The increases in the AUC of a substrate associated with coadministration of an inhibitor were estimated using the equation 1/(1 - CR(CYP)(3A4) x IR(CYP)(3A4)), based on pharmacokinetic considerations. The proposed method enabled predictions of the AUC increase by interactions with any combination of these substrates and inhibitors (total 251 matches). In order to validate the reliability of the method, the AUC increases in 60 additional studies were analysed. The method successfully predicted AUC increases within 67-150% of the observed increase for 50 studies (83%) and within 50-200% for 57 studies (95%). Midazolam is the most reliable standard substrate for evaluation of the in vivo inhibition of CYP3A4. The present analysis suggests that simvastatin, lovastatin and buspirone can be used as alternatives. To evaluate the in vivo contribution of CYP3A4, ketoconazole or itraconazole is the selective inhibitor of choice. This method is applicable to (i) prioritize clinical trials for investigating drug interactions during the course of drug development and (ii) predict the clinical significance of unknown drug interactions. If a drug-interaction study is carefully designed using appropriate standard drugs, significant interactions involving CYP3A4 will not be missed. In addition, the extent of CYP3A4-mediated interactions between many other drugs can be predicted using the current method.


Living conditions, HIV and gender affirmation care pathways of transgender people living with HIV in France: a nationwide, comprehensive, cross-sectional, community-based research protocol (ANRS Trans&HIV).
Transgender identity is poorly accepted in France, and data on living conditions and the daily difficulties transgender people encounter are scarce. This lack of data reinforces their invisibility in social life, contributes to their stigmatisation and probably increases the burden of HIV infection, especially for HIV-positive transgender people (TRHIV). The main objective of the community-based research study ANRS Trans&HIV is to identify personal and social situations of vulnerability in TRHIV, the obstacles they encounter in terms of access to and retention in medical care, and their gender affirmation and HIV care needs. ANRS Trans&HIV is a national, comprehensive, cross-sectional survey of all TRHIV currently being followed in HIV care units in France. TRHIV women are exclusively included in the quantitative component, and TRHIV men in the qualitative component. Data are collected by community-based interviewers and will be analysed to explore patient care pathways and living conditions in the TRHIV population with regard to gender affirmation and HIV. Data collection began in October 2020 and should be completed in December 2021. The statistical analyses techniques used will be adapted to each of the study's objectives and to the type of data collected (cross-sectional (questionnaires) and retrospective (biographical trajectory)). The study's results will provide a greater understanding of TRHIV health needs in order to suggest possible national recommendations for comprehensive HIV and gender affirmation medical care. ANRS Trans&HIV was approved by Inserm's Ethical Evaluation Committee (no 20-694 on 12 May 2020) and is registered with the National Commission on Informatics and Liberty under number 2518030720. Potential participants are informed about the study through an information note provided by their attending HIV physician. All results published in peer-reviewed journals will be disseminated to the HIV transgender community, institutional stakeholders and healthcare providers. NCT04849767.


Endogenous adenosine is an autacoid feedback inhibitor of chloride transport in the shark rectal gland.
The present studies define the physiologic role of endogenous adenosine in the perfused shark rectal gland, a model epithelia for hormone-stimulated chloride transport. Chloride ion secretion, and venous adenosine and inosine concentrations increased in parallel in response to hormone stimulation. From a basal rate of 157 +/- 26 mu eq/h per g, chloride secretion increased to 836 +/- 96 and 2170 +/- 358 with 1 and 10 microM forskolin, venous adenosine increased from 5.0 +/- 1 to 126 +/- 29 and 896 +/- 181 nM, and inosine increased from 30 +/- 9 to 349 +/- 77 and 1719 +/- 454 nM (all P less than 0.01). Nitrobenzylthioinosine (NBTI), a nucleoside transport inhibitor, completely blocked the release of adenosine and inosine. Inhibition of chloride transport with bumetanide, an inhibitor of the Na+/K+/2Cl- cotransporter, or ouabain, an inhibitor of Na+/K+ ATPase activity, reduced venous adenosine and inosine to basal values. When the interaction of endogenous adenosine with extracellular receptors was prevented by adenosine deaminase, NBTI, or 8-phenyltheophylline, the chloride transport response to secretagogues increased by 1.7-2.3-fold. These studies demonstrate that endogenous adenosine is released in response to hormone-stimulated cellular work and acts at A1 adenosine receptors as a feedback inhibitor of chloride transport.


Determination of dosimetric quantities in pediatric abdominal computed tomography scans.
Aiming at contributing to the knowledge on doses in computed tomography (CT), this study has the objective of determining dosimetric quantities associated with pediatric abdominal CT scans, comparing the data with diagnostic reference levels (DRL). The study was developed with a Toshiba Asteion single-slice CT scanner and a GE BrightSpeed multi-slice CT unit in two hospitals. Measurements were performed with a pencil-type ionization chamber and a 16 cm-diameter polymethylmethacrylate trunk phantom. No significant difference was observed in the values for weighted air kerma index (CW), but the differences were relevant in values for volumetric air kerma index (CVOL), air kerma-length product (PKL,CT) and effective dose. Only the CW values were lower than the DRL, suggesting that dose optimization might not be necessary. However, PKL,CT and effective dose values stressed that there still is room for reducing pediatric radiation doses. The present study emphasizes the importance of determining all dosimetric quantities associated with CT scans.


Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity.
Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)β sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.


Neurophenotypes of COVID-19: Risk factors and recovery outcomes.
Coronavirus disease 2019 (COVID-19) infection is associated with risk of persistent neurocognitive and neuropsychiatric complications. It is unclear whether the neuropsychological manifestations of COVID-19 present as a uniform syndrome or as distinct neurophenotypes with differing risk factors and recovery outcomes. We examined post-acute neuropsychological profiles following SARS-CoV-2 infection in 205 patients recruited from inpatient and outpatient populations, using an unsupervised machine learning cluster analysis, with objective and subjective measures as input features. This resulted in three distinct post-COVID clusters. In the largest cluster (69%), cognitive functions were within normal limits, although mild subjective attention and memory complaints were reported. Vaccination was associated with membership in this "normal cognition" phenotype. Cognitive impairment was present in the remaining 31% of the sample but clustered into two differentially impaired groups. In 16% of participants, memory deficits, slowed processing speed, and fatigue were predominant. Risk factors for membership in the "memory-speed impaired" neurophenotype included anosmia and more severe COVID-19 infection. In the remaining 15% of participants, executive dysfunction was predominant. Risk factors for membership in this milder "dysexecutive" neurophenotype included disease-nonspecific factors such as neighborhood deprivation and obesity. Recovery outcomes at 6-month follow-up differed across neurophenotypes, with the normal cognition group showing improvement in verbal memory and psychomotor speed, the dysexecutive group showing improvement in cognitive flexibility, and the memory-speed impaired group showing no objective improvement and relatively worse functional outcomes compared to the other two clusters. These results indicate that there are multiple post-acute neurophenotypes of COVID-19, with different etiological pathways and recovery outcomes. This information may inform phenotype-specific approaches to treatment.


The relationship between extracellular volume fraction in symptomatic adults with tetralogy of Fallot and adverse cardiac events.
To investigate the relationship between the extracellular volume fraction (ECV) measured using cardiac magnetic resonance (CMR) T1 mapping and cardiac events in symptomatic adults with tetralogy of Fallot (TOF). A total of 60 consecutive symptomatic adults (35.4±13.8 years old) with repaired TOF who were in New York Heart Association functional class 2-4 were prospectively enrolled. Native T1 values and ECV of the free walls of the right ventricle (RV), the left ventricle, and the ventricular septum were obtained by CMR T1 mapping using a 3.0T scanner and the saturation recovery method. Correlations between T1 mapping measurements, conventional parameters, and predictors of adverse cardiac events were analyzed. The patients with episodes of only atrial arrhythmia were excluded. Significant correlations were observed between RV functional parameters, RV-ECV, and septum-ECV. Follow-up period was 747.1±315 days and 13 patients had cardiac events: Acute heart failure and/or sustained ventricular tachycardia occurred in 8 patients and 5 patients underwent cardiac surgery. Cox-hazard analysis revealed that septum-ECV and RV-ECV were predictors of adverse events (hazard ratio of septum-ECV and RV-ECV: 1.41 and 1.19, 95% CI: 1.05-1.89, 1.004-1.41 with p-values of 0.02, and 0.045, respectively). Adults with septum-ECV >29.0% and RV ejection fraction (EF) <45.0% were more likely to experience cardiac events (log rank test: p<0.043). RV-ECV and septum-ECV correlate with RV functional parameters. Biventricular ECVs can be predictors of adverse cardiac events in adults with TOF. In particular, the combination of septum-ECV and RVEF was a useful predictor, compared to the use of a single CMR parameter.


Abscisic acid signal transduction in guard cells is mediated by phospholipase D activity.
In guard cells, the plant hormone abscisic acid (ABA) inhibits stomatal opening and induces stomatal closure through the coordinated regulation of ion transport. Despite this central role of ABA in regulating stomatal function, the signal transduction events leading to altered ion fluxes remain incompletely understood. We report that the activity of the enzyme phospholipase D (PLD) transiently increased in guard cell protoplasts at 2.5 and 25 min after ABA application. Treatment of guard cell protoplasts with phosphatidic acid (PtdOH), one of the products of PLD activity, led to an inhibition of the activity of the inward K+ channel. PtdOH also induced stomatal closure and inhibited stomatal opening when added to epidermal peels. Application of 1-butanol (1-buOH), a selective inhibitor of PtdOH production by PLD, inhibited the increase in PtdOH production elicited by ABA. 1-BuOH treatment also partially prevented ABA-induced stomatal closure and ABA-induced inhibition of stomatal opening. This inhibitory effect of buOH was enhanced by simultaneous application of nicotinamide, an inhibitor of cADP ribose action. These results suggest that in the guard cell, ABA activates the enzyme PLD, which leads to the production of PtdOH. This PtdOH is then involved in triggering subsequent ABA responses of the cell via a pathway operating in parallel to cADP ribose-mediated events.


Characterization of olfactory sensory neurons in the white clover seed weevil, Apion fulvipes (Coleoptera: Apionidae).
Seed-eating Apion weevils (Coleoptera: Apionidae) cause large economic losses in white and red clover seed production across Europe. Monitoring and control of clover weevils would be facilitated by semiochemical-based methods. Until now, however, nothing was known about physiological or behavioral responses to semiochemicals in this insect group. Here we analyzed the antenna of the white clover (Trifolium repens L.) specialist Apion fulvipes Geoffroy with scanning electron microscopy, and used single sensillum recordings with a set of 28 host compounds to characterize 18 classes of olfactory sensory neurons (OSNs). Nine of the OSN classes responded strongly to synthetic compounds with high abundance in clover leaves, flowers, or buds. Eight classes responded only weakly to the synthetic stimuli, whereas one collective class responded exclusively to volatiles released from a crushed clover leaf. The OSNs showed a remarkable degree of specificity, responding to only one or a few chemically related compounds. In addition, we recorded a marked difference in the temporal dynamics of responses between different neurons, compounds, and doses. The identified physiologically active compounds will be screened for behavioral activity, with the ultimate goal to develop an odor-based control strategy for this pest.


Nonsuicidal self-injury in college students: the role of perfectionism and rumination.
A paucity of research exists examining personality and cognitive characteristics that may contribute to nonsuicidal self-injury (NSSI). The purpose of the current study was to clarify the contribution of perfectionism and rumination, along with depression and anxiety, to NSSI within a sample of 170 college students. Group comparisons revealed that participants with a history of NSSI endorsed significantly more rumination and depressive and anxious symptoms then non-NSSI controls. Results regarding perfectionism were mixed, with NSSI participants differing from controls on select aspects of perfectionism. Results suggest higher levels of depression and anxiety and a ruminative cognitive style may increase vulnerability for NSSI; however, further research is needed to clarify the contribution of perfectionism.


Synchrony analysis of spontaneous MEG activity in Alzheimer's disease patients.
The aim of this study was to analyze the magnetoencephalography (MEG) background activity in Alzheimer's disease (AD) patients using cross-approximate entropy (Cross-ApEn). Cross-ApEn is a nonlinear measure of asynchrony between time series. Five minutes of recording were acquired with a 148-channel whole-head magnetometer in 12 AD patients and 12 age-matched control subjects. We found significantly higher synchrony between MEG signals from AD patients compared with control subjects. Additionally, we evaluated the ability of Cross-ApEn to discriminate these two groups using receiver operating characteristic (ROC) curves with a leave-one-out cross-validation procedure. We obtained an accuracy of 70.83% (66.67% sensitivity, 75% specificity) and a value of area under the ROC curve of 0.83. These results provide evidence of disconnection problems in AD. Our findings show the usefulness of Cross-ApEn to detect the brain dysfunction in AD.


The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor.
The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. Our work suggests that one of these, Disrupted In Renal Carcinoma 3 (DIRC3), may be a clinically important MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that activates expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in cancer associated processes and is needed for DIRC3 control of anchorage-independent growth. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets that can act not only as downstream mediators of MITF-SOX10 function but as feedback regulators of MITF-SOX10 activity.


A Dermatologist's Approach to Genitourinary Syndrome of Menopause.
Genitourinary syndrome of menopause (GSM) is a debilitating condition caused by hypoestrogenism that presents with vaginal dryness and dyspareunia as well as other genital, sexual, and urinary symptoms. Previously known as atrophic vaginitis, the term GSM is now used. To help familiarise dermatologists with diagnosing and managing GSM. In total, 218 articles were identified and reviewed by 2 independent authors using PubMed. Articles included were from December 2005 to December 2015. Sixty-seven articles met our inclusion criteria. GSM is a clinical diagnosis, requiring the presence of symptoms that should be bothersome and not accounted for by another condition. A pH test may help with diagnosis as vaginal pH will be increased from acidic to neutral. The Papanicolaou test is not recommended because of poor clinical correlation. First-line treatment is low-dose local vaginal estrogen therapy, which has proven efficacy and safety. Serum estrogen levels are not significantly affected with the exception of creams containing high-dose conjugated equine estrogens. Other options have yet to be approved for use in Canada but show promise. GSM is a debilitating and common condition that suffers from barriers to diagnosis and treatment. Current treatments are well tolerated, rewarding, and effective with rapid onset.


Automated Determination of the H3 K27-Altered Status in Spinal Cord Diffuse Midline Glioma by Radiomics Based on T2-Weighted MR Images.
Conventional MR imaging is not sufficient to discern the H3 K27-altered status of spinal cord diffuse midline glioma. This study aimed to develop a radiomics-based model based on preoperative T2WI to determine the H3 K27-altered status of spinal cord diffuse midline glioma. Ninety-seven patients with confirmed spinal cord diffuse midline gliomas were retrospectively recruited and randomly assigned to the training (n = 67) and test (n = 30) sets. One hundred seven radiomics features were initially extracted from automatically-segmented tumors on T2WI, then 11 features selected by the Pearson correlation coefficient and the Kruskal-Wallis test were used to train and test a logistic regression model for predicting the H3 K27-altered status. Sensitivity analysis was performed using additional random splits of the training and test sets, as well as applying other classifiers for comparison. The performance of the model was evaluated through its accuracy, sensitivity, specificity, and area under the curve. Finally, a prospective set including 28 patients with spinal cord diffuse midline gliomas was used to validate the logistic regression model independently. The logistic regression model accurately predicted the H3 K27-altered status with accuracies of 0.833 and 0.786, sensitivities of 0.813 and 0.750, specificities of 0.857 and 0.833, and areas under the curve of 0.839 and 0.818 in the test and prospective sets, respectively. Sensitivity analysis confirmed the robustness of the model, with predictive accuracies of 0.767-0.833. Radiomics signatures based on preoperative T2WI could accurately predict the H3 K27-altered status of spinal cord diffuse midline glioma, providing potential benefits for clinical management.


The reliability of lung ultrasound in assessment of idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is the severest form of idiopathic interstitial pneumonia, with a median survival time estimated at 2-5 years from the time of diagnosis. It occurs mainly in elderly adults, suggesting a strong link between the fibrosis process and aging. Although chest high-resolution computed tomography (HRCT) is currently the method of choice in IPF assessment, diagnostic imaging with typical usual interstitial pneumonia (UIP) provides definitive results in only 55%, requiring an invasive surgical procedure such as lung biopsy or cryobiopsy for the final diagnostic analysis. Lung ultrasound (LUS) as a noninvasive, non-radiating examination is very sensitive to detect subtle changes in the subpleural space. The evidence of diffuse, multiple B-lines defined as vertical, hyperechoic artifacts is the hallmark of interstitial syndrome. A thick, irregular, fragmented pleura line is associated with subpleural fibrotic scars. The total numbers of B-lines are correlated with the extension of pulmonary fibrosis on HRCT, being an LUS marker of severity. The average distance between two adjacent B-lines is an indicator of a particular pattern on HRCT. It is used to appreciate a pure reticular fibrotic pattern as in IPF compared with a predominant ground glass pattern seen in fibrotic nonspecific interstitial pattern. The distribution of the LUS artifacts has a diagnostic value. An upper predominance of multiple B-lines associated with the thickening of pleura line is an LUS feature of an inconsistent UIP pattern, excluding the IPF diagnosis. LUS is a repeatable, totally radiation-free procedure, well tolerated by patients, very sensitive in detecting early changes of fibrotic lung, and therefore a useful imaging technique in monitoring disease progression in the natural course or after initiation of treatment.


Measuring multimorbidity beyond counting diseases: systematic review of community and population studies and guide to index choice.
To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage. Systematic review. Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications. Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level. Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use. 35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones. PROSPERO CRD42017074211.


Visual, musculoskeletal and balance symptoms in individuals with visual impairment.
Visual impairment is globally among the most prevalent disabilities. Research concerning the health consequences of visual deficits is challenged by confounding effects of age, because visual impairment becomes more prevalent with age. This study investigates the influence of visual deficits on visual, musculoskeletal and balance symptoms in adults with and without visual impairment, while controlling for age effects. Thirty-nine patients with visual impairment, aged 18-72 years, were compared to 37 age-matched controls with normal vision, allocated to two age groups: < 45 and ≥ 45 years. Self-reported symptoms were measured using the Visual, Musculoskeletal and Balance Symptoms Questionnaire and compared with demographic and optometric variables. In total, patients with visual impairment reported more symptoms than age-matched normally sighted controls. Younger adults in the control group were almost free from symptoms, whereas younger adults with visual impairment reported levels of symptoms equal to older adults with visual impairment. Multiple logistic regression modelling identified use of eyeglasses, magnifying aids and presence of anisometropia to be the most influential risk factors for reporting visual, musculoskeletal and balance symptoms, with accentuated influence on balance symptoms. People with visual impairments and people with age-related normal visual deficits are both predisposed to report visual, musculoskeletal and balance symptoms relative to people without visual defects or need for eye-wear correction. Age-related variations in symptoms were observed in the control groups but not in the visual impairment groups, with younger visual impairment patients reporting as many symptoms as older visual impairment patients. These findings indicate a need for a wider interdisciplinary perspective on eye care concerning people with visual impairment and people with need for habitual daily use of eye wear correction.


DNAzyme Nanomachine with Fluorogenic Substrate Delivery Function: Advancing Sensitivity in Nucleic Acid Detection.
We have developed a hook-equipped DNA nanomachine (HDNM) for the rapid detection of specific nucleic acid sequences without a preamplification step. HDNM efficiently unwinds RNA structures and improves the detection sensitivity. Compared to the hookless system, HDNM offers an 80-fold and 13-fold enhancement in DNA and RNA detection, respectively, reducing incubation time from 3 to 1 h.


Genomic characterization of SARS-CoV-2 and its association with clinical outcomes: a 1-year longitudinal study of the pandemic in Colombia.
This study aimed to explore associations between the molecular characterization of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and disease severity in ambulatory and hospitalized patients in two main Colombian epicentres during the first year of the coronavirus disease 2019 pandemic. In total, 1000 patients with SARS-CoV-2 infection were included in this study. Clinical data were collected from 997 patients, and 678 whole-genome sequences were obtained by massively parallel sequencing. Bivariate, multi-variate, and classification and regression tree analyses were run between clinical and genomic variables. Age >88 years, and infection with lineages B.1.1, B.1.1.388, B.1.523 or B.1.621 for patients aged 71-88 years were associated with death [odds ratio (OR) 6.048036, 95% confidence interval (CI) 1.346567-32.92521; P=0.01718674]. The need for hospitalization was associated with higher age and comorbidities. The hospitalization rate increased significantly for patients aged 38-51 years infected with lineages A, B, B.1.1.388, B.1.1.434, B.1.153, B.1.36.10, B.1.411, B.1.471, B.1.558 or B.1.621 (OR 8.368427, 95% CI 2.573145-39.10672, P=0.00012). Associations between clades and clinical outcomes diverged from previously reported data. Infection with lineage B.1.621 increased the hospitalization and mortality rates. These findings, plus the rapidly increasing prevalence in Colombia and other countries, suggest that lineage B.1.621 should be considered as a 'variant of interest'. If associated disease severity is confirmed, possible designation as a 'variant of concern' should be considered.


Filter-free exhaustive odds ratio-based genome-wide interaction approach pinpoints evidence for interaction in the HLA region in psoriasis.
Deciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the heritability of traits and diseases. Epistasis, one potentially important cause of this missing heritability, is difficult to explore at the genome-wide level. Here, we develop and assess a tool based on interactive odds ratios (IOR), Fast Odds Ratio-based sCan for Epistasis (FORCE), as a novel approach for exhaustive genome-wide epistasis search. IOR is the ratio between the multiplicative term of the odds ratio (OR) of having each variant over the OR of having both of them. By definition, an IOR that significantly deviates from 1 suggests the occurrence of an interaction (epistasis). As the IOR is fast to calculate, we used the IOR to rank and select pairs of interacting polymorphisms for P value estimation, which is more time consuming. FORCE displayed power and accuracy similar to existing parametric and non-parametric methods, and is fast enough to complete a filter-free genome-wide epistasis search in a few days on a standard computer. Analysis of psoriasis data uncovered novel epistatic interactions in the HLA region, corroborating the known major and complex role of the HLA region in psoriasis susceptibility. Our systematic study revealed the ability of FORCE to uncover novel interactions, highlighted the importance of exhaustiveness, as well as its specificity for certain types of interactions that were not detected by existing approaches. We therefore believe that FORCE is a valuable new tool for decoding the genetic basis of complex diseases.


Hypothesis testing in distributed source models for EEG and MEG data.
Hypothesis testing in distributed source models for the electro- or magnetoencephalogram is generally performed for each voxel separately. Derived from the analysis of functional magnetic resonance imaging data, such a statistical parametric map (SPM) ignores the spatial smoothing in hypothesis testing with distributed source models. For example, when intending to test a single voxel, actually an entire region of voxels is tested simultaneously. Because there are more parameters than observations, typically constraints are employed to arrive at a solution which spatially smooths the solution. If ignored, it can be concluded from the hypothesis test that there is activity at some location where there is none. In addition, an SPM on distributed source models gives the illusion of very high resolution. As an alternative, a multivariate approach is suggested in which a region of interest is tested that is spatially smooth. In simulations with MEG and EEG it is shown that clear hypothesis testing in distributed source models is possible, provided that there is high correspondence between what is intended to be tested and what is actually tested. The approach is also illustrated by an application to data from an experiment measuring visual evoked fields when presenting checkerboard patterns.


Expatriates: special considerations in pretravel preparation.
Expatriates comprise a diverse set of travelers who face unique medical, psychiatric, and non-health-related risks as a result of increased exposure to host country environment and associated lifestyle. Expatriates have an increased risk of developing malaria, gastrointestinal disorders, latent tuberculosis, vaccine-preventable infections, and psychological disorders, when compared with other travelers, yet the majority of existing pretravel guidelines have been designed to suit the needs of nonexpatriates. Although greater interest in expatriate health issues has led to improved characterization of illness in this population, expatriate-specific risk mitigation strategies-including modifications to chemoprophylaxis recommendations, limiting tuberculosis exposure, and prevention of occupational or sexual blood-borne virus transmission-are poorly described. Occupations and destinations affect travel-related disease risk and should inform the pretravel consultation.


Implications for Social Impact of Dialogic Teaching and Learning.
The science of dialogic teaching and learning has especially flourished over the last four decades across age-groups, cultures, and contexts. A wide array of studies has examined the uniqueness of dialogue as a powerful tool to lead effective instructional practices, transform the socio-cultural context and people's mindsets, among many others. However, despite the efforts to extend the benefits of this approach, certain difficulties exist which have hindered the consolidation of dialogic pedagogies in the classroom. This review discusses the implications for social impact of the scientific developments on dialogic teaching and learning. Particularly, an overview of the state of the art on dialogic education is presented. Social improvements in academic attainment and social cohesion are some of the fundamental issues discussed. Those are especially relevant to address crucial needs in education and solve some of the most pressing social problems. A communicative mix-methods approach emerges as one of the critical aspects of this field of research in educational psychology to achieve social impact. Some limitations, such as teachers sustaining different forms of monologic discourse, and challenges for a broader impact are discussed in this review.


Use of Ondansetron for Vomiting After Head Trauma: Does It Mask Clinically Significant Traumatic Brain Injury?
We describe ondansetron use in children with head injury evaluated in pediatric emergency departments and its association with return visits and late diagnoses of intracranial injuries requiring intervention. Children ages 6 months to 18 years discharged without neuroimaging from 35 pediatric emergency departments with a diagnosis of head injury from 2009 to 2013 were identified retrospectively from the Pediatric Health Information System. We evaluated the rates of ondansetron use during the study period and of the association of ondansetron treatment with the diagnosis of intracranial injury, skull fracture, and return visits within 72 hours requiring admission or operative intervention. We identified 218,904 encounters during the study period. Of these, 5894 patients (2.8%) were given ondansetron. There was significant variation in the use of ondansetron during the index visit between hospitals (0.1%-5.7%), and ondansetron use significantly increased over the study period. Return visits within 72 hours were more likely for patients treated with ondansetron during the index visit (3.7% vs 1.9%; adjusted odds ratio, 1.99; 95% confidence interval, 1.7-2.4). These patients were more likely to be admitted than those not treated initially with ondansetron (7% vs 4%; adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.55). There were no significant differences in rates of skull fractures, intracranial injury, intensive care unit admission, or operative intervention between groups. Ondansetron use during an initial emergency department visit for head trauma in children not requiring neuroimaging is associated with a higher likelihood of return within 72 hours and subsequent admission. There were no differences in rates of missed skull fractures, intracranial injury, intensive care admission, or operative intervention for groups who were and were not treated with ondansetron; however, this study was underpowered to detect significant differences in these categories. Future investigations with greater numbers would be required to confidently assess these critical differences.


The role of oxidants and free radicals in reperfusion injury.
While timely reperfusion of acute ischemic myocardium is essential for myocardial salvage, reperfusion results in a unique form of myocardial damage. Functional alterations occur, including depressed contractile function and decreased coronary flow as well as altered vascular reactivity. Both myocardial stunning and infarction are seen. Over the last two decades, it has become increasingly clear that oxidant and oxygen radical formation is greatly increased in the post-ischemic heart and serves as a critical central mechanism of post-ischemic injury. This oxidant formation is generated through a series of interacting pathways in cardiac myocytes and endothelial cells and triggers subsequent leukocyte chemotaxis and inflammation. Nitric oxide (NO) production and NO levels are also greatly increased in ischemic and post-ischemic myocardium, and this occurs through NO synthase (NOS)-dependent NO formation and NOS-independent nitrite reduction. Recently, it has been shown that the pathways of oxygen radical and NO generation interact and can modulate each other. Under conditions of oxidant stress, NOS can switch from NO to oxygen radical generation. Under ischemic conditions, xanthine oxidase can reduce nitrite to generate NO. NO and peroxynitrite can inhibit pathways of oxygen radical generation, and, in turn, oxidants can inhibit NO synthesis from NOS. Ischemic preconditioning markedly decreases NO and oxidant generation, and this appears to be an important mechanism contributing to preconditioning-induced myocardial protection.


Migraine and sleep: new connections.
"Attack" is often a word associated with migraine, and for good reason. If you suffer from migraine headaches or know someone who does, you are well aware of its crippling nature. This story focuses on new research that has uncovered an important link between migraine and sleep patterns. A better understanding of the relationships among the body's circadian rhythms, the brain's hypothalamus, and a mutated gene holds enormous promise of improved care for the more than 36 million Americans who experience migraine (three times more common in women) and the number of people suffering from familial advanced sleep phase syndrome (FASP).


Emerging trends of herbal care in dentistry.
Herbs are staging a comeback and herbal 'renaissance' is happening all over the globe. The herbal products, today, symbolize safety, in contrast to the synthetics that are regarded as unsafe to humans and the environment. A herb, botanically speaking, is any plant that lacks the woody tissue which is characteristic of shrubs or trees. More specifically, herbs are plants which are used medicinally or for their flavour or scent. Herbs with medicinal properties are a useful and an effective source of treatment for various disease processes. Herbal extracts have been successfully used in dentistry as tooth cleaning and antimicrobial plaque agents. The use of herbal medicines continues to expand rapidly across the world. Many people take herbal medicines or herbal products now for their health care in different national healthcare settings. Herbal extracts have been used in dentistry for reducing inflammation, as antimicrobial plaque agents, for preventing release of histamine and as antiseptics, antioxidants, antimicrobials, antifungals, antibacterials, antivirals and analgesics. They also aid in healing and are effective in controlling microbial plaque in gingivitis and periodontitis, thereby improving immunity.


Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis.
People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers. We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship. These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.


Factors affecting beef cattle producer perspectives on feed efficiency.
To establish the basis for implementation of a producer education program, a social assessment of the willingness and barriers to adoption of a measure of feed efficiency in beef cattle [residual feed intake (RFI)] was conducted. A 35-question mailed survey was sent to 1,888 producers acquired from the stratified random sample of the Idaho Cattle Association member list (n = 488), Red Angus Association of America member list (n = 2,208), and Red Angus Association of America bull buyer list (n = 5,325). The adjusted response rate for the survey was 49.9%. Of the survey respondents, 58.7% were commercial cow/calf producers and 41.3% were seedstock producers or operated a combination seedstock/commercial operation. Commercial operations had an average of 223 ± 17 cows and 13 ± 3 bulls, whereas seedstock herds (including combination herds) had slightly fewer cows (206 ± 24) and more bulls (23 ± 6). Both commercial and seedstock operators indicated that calving ease/birth weight was the most important trait used to evaluate genetic merit of breeding bulls. Only 3.8 and 4.8% of commercial and seedstock producers indicated that feed efficiency was the most important characteristic used for bull selection. Binary logistic regression models were used to predict willingness of seedstock producers to begin collecting data for the calculation of RFI on their bulls, or to predict willingness of commercial producers to begin selecting bulls based on RFI data. In response, 49.1% of commercial producers and 43.6% of seedstock producers indicated they were willing to adopt RFI as a measure of feed efficiency. These data indicate that feed efficiency was one of the traits that producers consider important; those who perceive feed efficiency as important tended to be actively involved in data collection on their herds, underpinning the notion that objective assessment was valued and used by some. Additional data collection in a future social assessment will continue to elaborate the proportion of producers who perceive feed efficiency as an increasingly important decision and management tool for beef production.


Assessing the Validity of Standing Long Jump to Predict Muscle Power in Children With and Without Motor Delays.
To determine the validity of standing long jump (SLJ) for predicting muscle power in children with and without developmental coordination disorder (DCD). A total of 589 children were recruited as part of the Coordination and Activity Tracking in CHildren study (251 girls and 338 boys; mean age 59.2 mo). Children were classified as typically developing (>16th percentile), at risk for DCD (sixth to 16th percentile), or probable DCD (<sixth percentile) based on Movement Assessment Battery for Children-Second Edition scores. SLJ was measured from the back of the heel. Peak power and mean power over 10 seconds and 30 seconds were measured using the Wingate test. SLJ was moderately correlated with peak and mean powers in all groups (R = .51-.55). Regression analysis showed that when combined with weight and age, SLJ performance could predict peak power and mean power over 10 seconds and 30 seconds in typically developing children (adjusted R2 = .68, .61, and .58, P < .001, respectively) and in children with risk for DCD (adjusted R2 = .74, .65, and .60, respectively) and probable DCD (adjusted R2 = .68, .61, and .59, respectively). SLJ, in combination with weight and age, may be used to measure muscle power in typically developing children, and in children with risk for DCD and probable DCD. This measure can be used as an inexpensive estimate of musculoskeletal fitness in children regardless of motor abilities.


A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.
With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.


Independent regulation of the divergent Escherichia coli nrfA and acsP1 promoters by a nucleoprotein assembly at a shared regulatory region.
Expression from the Escherichia coli nrfA promoter (pnrfA) is activated by both the FNR protein (an anaerobically triggered transcription activator) and the NarL or NarP proteins (transcription activators triggered by nitrite and nitrate). Under anaerobic conditions, FNR binds to a site centred at position -41.5 at pnrfA and activates transcription. Further activation, induced by the presence of nitrite, results from the binding of NarL and NarP to a site centred at position -74.5. A second promoter (pacsP1), which directs transcription into the adjacent gene encoding acetyl coenzyme A synthetase (acs), is overlapping and divergent to pnrfA. Despite extensive overlap of regulatory elements, pnrfA and pacsP1 are regulated independently. We demonstrate that at least two nucleoid-associated factors bind to the nrfA-acs intergenic region. The Fis protein binds to a site centred at position -15 (in relation to pnrfA transcription), whereas the IHF protein binds to a site centred at position -54. Both Fis and IHF repress in vivo expression from pacsP1, but have smaller repressive effects on expression from pnrfA. Gel retardation assays were used to investigate the pairwise binding of FNR, NarL, Fis and IHF proteins to the nrfA-acs intergenic region. The binding of NarL and IHF is mutually exclusive, whereas all other combinations can bind simultaneously. Experiments in which deletions and point mutations were introduced into the upstream region of pnrfA demonstrated that an additional factor must bind upstream to inhibit FNR-dependent transcription. We conclude that the nrfA-acs intergenic region is folded into an ordered nucleoprotein structure that permits the two divergent promoters to be regulated independently in response to different physiological signals.


Androgen and Src signaling regulate centrosome activity.
Microtubules nucleated from gamma-tubulin ring complexes located at the centrosome regulate the localization of organelles, promote vesicular transport and direct cell migration. Although several signaling mechanisms have been identified that regulate microtubule dynamics during interphase, signaling pathways that promote microtubule nucleation remain elusive. We assayed microtubule regrowth following nocodazole washout in human fibroblasts and CHO-K1 cells adhered to fibronectin in either normal serum-free medium or the serum-free, growth-promoting medium, CCM1, which contains IGF1 and androgen, as well as other nutrients. The results indicate that integrin-mediated adhesion is not sufficient to promote rapid microtubule regrowth in either cell type. The addition of androgen, but not IGF1, for 5 minutes was sufficient to promote rapid regrowth and this occurred by a mechanism requiring the androgen receptor. Since Src is a component of the cytoplasmic androgen-receptor-signaling complex, we examined its role using Src siRNA, the Src kinase inhibitor SU6656, and the expression of a constitutively active Src mutant. The data show that Src signaling is both required and sufficient to promote rapid microtubule regrowth in cells adhered to fibronectin. Measurement of the density of microtubules close to the centrosome and the rates of GFP-EB1-labeled microtubules emanating from the centrosome indicated that Src signaling promotes microtubule nucleation. Furthermore, recovery of GFP-gamma-tubulin at the centrosome following photobleaching and measurements of endogenous gamma-tubulin levels at the centrosome showed that androgen and Src signaling regulate the levels of centrosomal gamma-tubulin. Thus, we propose that androgen and Src signaling regulate microtubule nucleation during interphase by promoting the centrosomal localization of gamma-tubulin.


Down Regulation of CLDND1 Induces Apoptosis in Breast Cancer Cells.
Identification of targets for apoptosis induction is important to provide novel therapeutic approaches in breast cancer. Our earlier studies showed that down regulation of protein kinase C δ (PKCδ) induces death in breast cancer cells. In this study we set out to identify previously unrecognized apoptosis regulators in breast cancer cells. To identify candidates, global expression analysis with microarray was performed after down regulation of PKCδ in the basal-like breast cancer cell lines MDA-MB-231, MDA-MB-468 and BT-549. Genes that were down regulated in all cell lines were further studied for survival-supporting effects. The claudin-like CLDND1 was singled out since several independent siRNAs targeting CLDND1 induced cell death in several cell lines. The cell death induced by CLDND1 knockdown was caspase-dependent, suggesting induction of apoptosis. Nuclear fragmentation, cleavage of caspase-3 and PARP and release of cytochrome C from the mitochondria upon CLDND1 depletion demonstrated involvement of the intrinsic apoptotic pathway. Inhibition of MEK1/2 and JNK further potentiated the cell death induction by CLDND1 knockdown. However, CLDND1 down regulation augmented ERK1/2 phosphorylation, which thereby may protect against the apoptosis inducing effects of CLDND1 down regulation. A concomitant inhibition of MEK1/2 suppresses the ERK1/2 phosphorylation and markedly potentiates the cell death following CLDND1 siRNA treatment. There is today little information on the function of CLDND1. These data provide novel information on CLDND1 and highlight it as a novel survival factor in basal-like breast cancer cell lines.


A Note on Observation Processes in Epidemic Models.
Many disease models focus on characterizing the underlying transmission mechanism but make simple, possibly naive assumptions about how infections are reported. In this note, we use a simple deterministic Susceptible-Infected-Removed (SIR) model to compare two common assumptions about disease incidence reports: Individuals can report their infection as soon as they become infected or as soon as they recover. We show that incorrect assumptions about the underlying observation processes can bias estimates of the basic reproduction number and lead to overly narrow confidence intervals.


1-year trajectories of patients undergoing primary total hip arthroplasty: Patient reported outcomes and resource needs according to education level.
Objectives were first to evaluate by education level one-year trajectories of pain, function and general health, as well as hospital resource and medication needs in patients undergoing primary total hip arthroplasty (THA); and second, to evaluate whether outcome differences are related to existing baseline differences in health and disease severity. We included all primary THAs from a public hospital-based prospective arthroplasty registry, performed in a high-income country 2010 to 2017. Education was classified in three levels: ≤8years of schooling (low), 9-12years (medium), and ≥13years (high). Pain and function prior to and one-year after surgery were assessed with the Western Ontario McMaster Universities score (WOMAC) and general health with the 12-item short-form health survey (SF-12). Overall 963 patients were included, 340 (35.3%) with low, 306 (31.8%) with medium, and 317 (32.9%) with high education. With increasing educational level preoperative scores for pain, function and SF-12 mental health component increased. One year after surgery improvement was observed in all education categories for WOMAC pain and function, SF-12 mental and physical component. However, absolute postoperative scores remained lower in all four domains for the low education group. After adjustment for baseline characteristics differences were much attenuated and no longer significant. There was also greater resource need in low educated patients. The inferior absolute results one year after surgery in less educated patients were largely due to older age, worse preoperative health and greater symptom severity calling for greater attention to timely and equal management, for more targeted perioperative care and increased support for the lower education group.


T follicular regulatory cells.
Pathogen exposure elicits production of high-affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh-mediated B-cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh-mediated B-cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr-cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody-mediated diseases.


TLR induces reorganization of the IgM-BCR complex regulating murine B-1 cell responses to infections.
In mice, neonatally-developing, self-reactive B-1 cells generate steady levels of natural antibodies throughout life. B-1 cells can, however, also rapidly respond to infections with increased local antibody production. The mechanisms regulating these two seemingly very distinct functions are poorly understood, but have been linked to expression of CD5, an inhibitor of BCR-signaling. Here we demonstrate that TLR-mediated activation of CD5+ B-1 cells induced the rapid reorganization of the IgM-BCR complex, leading to the eventual loss of CD5 expression, and a concomitant increase in BCR-downstream signaling, both in vitro and in vivo after infections of mice with influenza virus and Salmonella typhimurium. Both, initial CD5 expression and TLR-mediated stimulation, were required for the differentiation of B-1 cells to IgM-producing plasmablasts after infections. Thus, TLR-mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization.


Car and truck tire wear particles in complex environmental samples - A quantitative comparison with "traditional" microplastic polymer mass loads.
Tire wear particles (TWP) are assumed to be the most dominant source of environmental microplastics (MP). Besides rubber components around 60% of tires are additives such as filling material and various chemicals added for vulcanization. The inevitably released TWP in daily traffic are therefore considered a threat to the ecosystem. Nevertheless, published studies on MP mass loads often exclude elastomers. Data concerning composition and concentrations of TWP compared to prominent "traditional" MP polymers, such as polyethylene, polypropylene, poly(ethylene terephthalate) and poly(vinyl chloride), are missing. Identification and quantification of TWP was implemented in an existing pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) method for MP determination. An approach to differentiate between car and truck tire wear and to quantify their respective mass loads is presented. Complex environmental samples such as road dust, fresh water and marine sediments, blue mussels, and marine salts were partly retrospectively analyzed using Py-GC/MS. The results showed ratios of car to truck tire wear up to 16 to 1 and underline the dominance of car compared to truck tire wear mass loads in all analyzed samples. Even though some retrospective data sets might be affected by suboptimal density separation conditions (NaBr, ρ = 1.5 g/cm3), TWP concentrations in road dust clearly exceeded those of "traditional" MP (Ø 5 g TWP vs 0.3 g MP per kg road dust (dry weight). Samples included in this study, which were archived further away from TWP sources such as roads, reflected decreasing TWP concentrations (Ø 24 μg TWP vs. 107 μg MP per kg sediment (dry weight); Ø 126 μg TWP vs. 378 μg MP per kg marine salt) or were no longer present (blue mussels), while "traditional" polymers were still ubiquitously distributed.


Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09.
PURPOSE To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. PATIENTS AND METHODS Men with T1b-T2b prostate cancer and prostate-specific antigen </= 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes. Results A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade >/= 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade >/= 3 GI toxicity. CONCLUSION This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade >/= 3 late urinary or rectal morbidity.


The Biological Basis of Mathematical Beauty.
Our past studies have led us to divide sensory experiences, including aesthetic ones derived from sensory sources, into two broad categories: biological and artifactual. The aesthetic experience of biological beauty is dictated by inherited brain concepts, which are resistant to change even in spite of extensive experience. The experience of artifactual beauty on the other hand is determined by post-natally acquired concepts, which are modifiable throughout life by exposure to different experiences (Zeki, 2009; Zeki and Chén, 2016). Hence, in terms of aesthetic rating, biological beauty (in which we include the experience of beautiful faces or human bodies) is characterized by less variability between individuals belonging to different ethnic origins and cultural backgrounds or the same individual at different times. Artifactual beauty (in which we include the aesthetic experience of human artifacts, such as buildings and cars) is characterized by greater variability between individuals belonging to different ethnic and cultural groupings and by the same individual at different times. In this paper, we present results to show that the experience of mathematical beauty (Zeki et al., 2014), even though it constitutes an extreme example of beauty that is dependent upon (mathematical) culture and learning, is consistent with one of the characteristics of the biological categories, namely a lesser variability in terms of the aesthetic ratings given to mathematical formulae experienced as beautiful.


Coordinated expression of dopamine transporter and vesicular monoamine transporter in the primate striatum during development.
Several addictive or neurotoxic drugs are dependent on the dopamine transporter (DAT) and/or vesicular monoamine transporter (VMAT2) to exert their detrimental effects on dopamine neurons. For example, methamphetamine and MPTP are substrates for both DAT and VMAT2, with the ratio of DAT to VMAT2 in striatum being a determinant of the degree of toxicity inflicted by these drugs on dopamine neurons. Thus, the susceptibility of dopamine neurons to agents whose pharmacology involves DAT and VMAT2 may vary during development if the ontogeny of DAT and VMAT2 differs, and this is relevant as exposure of dopamine neurons to toxic agents during development is hypothesized to underlie some neurological or psychiatric disorders. However, the relative expression of DAT and VMAT2 has not been studied in either primate or nonprimate fetal brain, and this was addressed in the present study by measuring the binding of specific radioligands of DAT and VMAT2 to striatal membranes from nonhuman primates at mid-gestation, late-gestation, and the postnatal and adult periods. Dopamine concentration was also determined in striatal tissue from the same brains. These data indicate that in striatum of primates, unlike rodents, there is a sharp increase in DAT and VMAT2 expression after mid-gestation, with adult levels being attained at the time of birth. In addition, this study demonstrated that there is a coordinated expression of DAT and VMAT2 from the time of mid-gestation to adulthood.


Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583.
Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans.


Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors.
The present study extends our previous work on social behavior impairment in young males with fragile X syndrome (FraX). Specifically, we evaluated whether the autistic phenomenon in FraX is expressed as a range of behavioral impairments as in idiopathic autism (Aut). We also examined whether there are behaviors, identified as items of the Autism Diagnostic Interview-Revised (ADI-R), that in FraX predispose to or differentiate subjects with autism spectrum disorder (ASD) diagnosis. Finally, regression models were utilized to test the relative contribution of reduced communication and socialization skills to ADI-R scores and diagnoses. A cohort of 56 boys (3-8 years) with FraX was examined in terms of scores on measures of cognition (IQ was a co-variate in most analyses.), autistic behavior, problem/aberrant behavior, adaptive behavior, and language development. We found that, indeed, in terms of problem behavior and adaptive skills, there is a range of severity from FraX + Aut to FraX + PDD (Pervasive Developmental Disorder) to FraX + none. ADI-R items representing "Play" types of interaction appear to be "susceptibility" factors since they were abnormal across the FraX cohort. Integrated regression models demonstrated that items reflecting complex social interaction differentiated the FraX + ASD (Aut + PDD) subgroup from the rest of the FraX cohort, while abnormalities in basic verbal and non-verbal communication distinguished the most severely affected boys with FraX + Aut from the milder FraX + PDD cohort. Models incorporating language, adaptive communication, and adaptive socialization skills revealed that socialization was not only the main influence on scores but also a predictor of ASD diagnosis. Altogether, our findings demonstrate that the diagnosis of ASD in FraX reflects, to a large extent, an impairment in social interaction that is expressed with variable severity in young males with FraX.


The Role of TARC in the Pathogenesis of Allergic Asthma.
TARC (thymus and activation-regulated chemokine), as a selective chemoattractant of Th2 cells, is a reasonable candidate as a key regulator of Th2-mediated inflammation in allergic asthma. Studies have determined that TARC is up-regulated in the airways of human subjects with asthma and that CCR4- and CCR8-bearing T cells are also present in the airways of asthmatic subjects after allergen challenge. Mouse models of allergic airway inflammation have shown that neutralization of TARC can not only inhibit T-cell and eosinophil infiltration into the lung but can also inhibit bronchial hyperresponsiveness. The exact mechanism by which TARC can participate in allergic inflammation and what triggers the expression of TARC following allergen exposure is still unknown. Studies suggest that it could be involved not only in allergic asthma, but in the pathogenesis of allergic Th2-mediated diseases in general. (c) 2002 Prous Science. All rights reserved.


Metabolic Alterations in Shrimp Stomach During Acute Hepatopancreatic Necrosis Disease and Effects of Taurocholate on Vibrio parahaemolyticus.
Acute hepatopancreatic necrosis disease (AHPND), a recently emerged bacterial shrimp disease, has increased shrimp mortality and caused huge economic losses in many Asian countries. However, molecular factors underlying pathogenesis of this disease remain largely unknown. Our objective was to characterize metabolic alterations in shrimp stomach during AHPND and determine effects of taurocholate on AHPND-causing Vibrio parahaemolyticus. Based on metabolomics, pathways for lipid metabolism and for primary bile acid (BA) synthesis were majorly affected following AHPND infection. Bile acid metabolites, namely taurocholate, were downregulated in the metabolomics database. This prompted us to study effects of taurocholate on biofilm formation, PirAB vp toxin release and biofilm detachment capabilities in AHPND-causing V. parahaemolyticus. Treatment of this bacterium with high concentration of taurocholate, a primary bile acid, induced biofilm formation, PirAB vp toxin release and facilitated the dispersion of bacterial cells. Taken together, our findings suggest that AHPND infection can affect the lipid metabolites in shrimp stomach, and further suggest that the primary bile acid taurocholate is important for the virulence of AHPND-causing V. parahaemolyticus.


Sclerosing adenosis of the prostate.
A 76-year-old man with frequency, dysuria, and urinary incontinence underwent a transurethral resection of the prostate. On microscopic examination, three prostatic chips had a proliferation of irregular crowded acini, small nests, and single cells within a cellular stroma, which created an infiltrative pattern that was though by some observers to represent carcinoma. The acini were lined by columnar, and focally, by basal (myoepithelial) cells; the latter were more clearly demonstrated with immunoperoxidase stains for cytokeratin and S100 protein. In our opinion, the lesion represents a rare variant of benign prostatic hyperplasia analogous to sclerosing adenosis of the breast.


Assessment of the impact of the removal of cerebrospinal fluid on cerebral tissue volumes by advanced volumetric 3D-MRI in posthaemorrhagic hydrocephalus in a premature infant.
Current clinical practice in the premature infant with posthaemorrhagic ventricular dilatation (PHVD) includes drainage of cerebrospinal fluid (CSF). This case study used advanced volumetric three dimensional magnetic resonance imaging to document the impact of CSF removal on the volume of regional brain tissues in a premature infant with PHVD. The removal of a large volume of CSF was associated with an identical reduction in CSF volume, but more dramatically with a significant increase in the regional volumes of cortical grey matter and myelinated white matter. The alterations in cerebral cortical grey matter and myelinated white matter volumes may provide insight into the established association of PHVD with deficits in cognitive and motor functions.


Severe gastritis in guinea-pigs infected with Helicobacter pylori.
An appropriate animal model is essential to study Helicobacter pylori infection. The aim of this study was to investigate if H. pylori can colonise the guinea-pig stomach and whether the infection causes gastritis and a serological response similar to that observed in man. Guinea-pigs were infected either with fresh H. pylori isolates from human gastric biopsies or with a guinea-pig passaged strain. When the animals were killed, 3 and 7 weeks after inoculation, samples were taken for culture, histopathology and serology. H. pylori was cultured from 22 of 29 challenged animals. All culture-positive animals exhibited a specific immune response against H. pylori antigens in Western blotting and gastritis in histopathological examination. Antibody titres in enzyme immunoassay were elevated among animals challenged with H. pylori. The inflammatory response was graded as severe in most animals and consisted of both polymorphonuclear leucocytes and lymphocytes. Erosion of the gastric epithelium was found in infected animals. These results suggest that the guinea-pig is suitable for studying H. pylori-associated diseases. Moreover, guinea-pigs are probably more similar to man than any other small laboratory animal as regards gastric anatomy and physiology.


Ionocovalency and applications 1. Ionocovalency model and orbital hybrid scales.
Ionocovalency (IC), a quantitative dual nature of the atom, is defined and correlated with quantum-mechanical potential to describe quantitatively the dual properties of the bond. Orbiotal hybrid IC model scale, IC, and IC electronegativity scale, X(IC), are proposed, wherein the ionicity and the covalent radius are determined by spectroscopy. Being composed of the ionic function I and the covalent function C, the model describes quantitatively the dual properties of bond strengths, charge density and ionic potential. Based on the atomic electron configuration and the various quantum-mechanical built-up dual parameters, the model formed a Dual Method of the multiple-functional prediction, which has much more versatile and exceptional applications than traditional electronegativity scales and molecular properties. Hydrogen has unconventional values of IC and X(IC), lower than that of boron. The IC model can agree fairly well with the data of bond properties and satisfactorily explain chemical observations of elements throughout the Periodic Table.


The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice.
Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3′ untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.


Intravenous ondansetron as antiemetic prophylaxis for postoperative nausea and vomiting after shoulder arthroscopy.
Nausea and vomiting are common chief postoperative complaints. The clinical literature indicates that postoperative nausea and vomiting (PONV) is common after orthopedic surgery. This study examines the clinical therapeutic efficacy of Ondansetron injected intravenously before the end of shoulder arthroscopy as antiemetic prophylaxis to help reduce the incidence of PONV. Participants were identified through retrospective chart review and patients undergoing shoulder arthroscopy performed by the same orthopedic surgeon at the same hospital from 2005 to 2009 were analyzed. Subjects were classified into two groups based on whether Ondansetron was given. Differences in the incidence of PONV among the two groups were compared. Basic patient information, anesthesia records, and surgical records were obtained, as well as records on PONV, postoperative pain intensity, and postoperative analgesic injections within 24 hours after surgery. The study involved 90 patients. The Group A contained 34 patients who did not receive Ondansetron, and the Group B contained 56 patients who were given Ondansetron. Analytical results for the postoperative 24 hour period showed a significant difference in the incidence of vomiting between the two groups, with a lower incidence (p < 0.05) for the. Group B. However there was no significant difference in the incidence of nausea between the two groups in the same postoperative 24 hour period, although there was a trend of a lower incidence in the Group B (p = 0.17). The overall incidence of PONV during the 24-hour period was lower in the Group B (14%) than the Group A (32%), and the Group B demonstrated lower pain intensity and lower analgesic injection needs. Routine intravenous injection of Ondansetron 30 minutes before completion of shoulder arthroscopy can reduce the incidence of vomiting and overall PONV in patients. Additionally, the patients using Ondansetron demonstrated lower pain intensity and lower analgesic injection needs than the control group.


Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature.
Sickle cell anemia-associated nephropathy is a growing matter of concern because renal failure affects most aging sickle cell anemia patients. Glomerular damage is a common feature revealed by a microalbuminuria or a macroalbuminuria. Although glomerular hyperfiltration has been described for decades in this population, its prevalence in young adults is unknown. To address this issue, as well as the clinical and biologic correlates of hyperfiltration, a single-center, cross-sectional study of 280 homozygous SS disease patients was performed. The prevalence of hyperfiltration assessed by Modification of Diet in Renal Disease estimated GFR was 51%. Among patients with hyperfiltration, 49% had hyperfiltration alone, whereas 36% and 15% had an associated microalbuminuria or macroalbuminuria, respectively. Estimated GFR sensitivity and specificity for hyperfiltration were 94% and 63%, respectively, in a selected subgroup of 48 patients (measured GFR was assessed by urinary (51)Cr EDTA clearance). In patients with no albuminuria, hyperfiltration status was significantly associated with a young age (years), the absence of alpha thalassemia, a lower hemoglobin level (g/dl), and a lower fetal hemoglobin. The role of chronic hemolysis was further strengthened by multivariate analysis showing a correlation between estimated GFR and a low plasma fetal hemoglobin level, a young age, and a high reticulocyte count (r(2) = 0.54). Together, the data suggest that the pathophysiology of hyperfiltration would rather be attributable to the hemolysis-associated vasculopathy rather than a viscosity-vaso-occlusive process.


Effect of bleeding on hematopoiesis following irradiation and marrow transplantation.
In previous studies, bleeding after irradiation did not affect the rate of regeneration of endogenous spleen colony-forming cells, but induced an early (4-6 days after irradiation) appearance of erythrocytic colonies which differentiated and disappeared by days 7-8. This "abortive" wave was associated with a similarly abortive wave of splenic 59Fe uptake. The present experiments were done to determine whether or not an abortive wave of erythropoiesis could be induced in the transplanted, exogenous stem cell system. Lethally irradiated mice were given normal bone marrow cells and one-half of the group were bled of about one-third their blood volume within 4 hr of irradiation. Groups were killed on days 3-10 after irradiation. Seventeen to twenty hours prior to killing, 59Fe was injected. Hematocrits, spleen weights, colony numbers, and per cent 59Fe uptake were determined. Hematocrits of bled mice averaged about 70% of those of cell-injected controls. Spleen weights, colony counts, and per cent 59Fe uptake per spleen began to increase about 1 day earlier in bled mice (days 4-5 as compared to days 5-6), and rates of increase were the same as those of controls. However, no abortive wave of erythropoiesis was detected. A large cell dose resulted in earlier increases in all parameters than a small dose. Thus, bleeding after injection of cells produced results similar to those obtained by increasing the cell dose. The inability of bleeding to induce an early abortive wave of erythropoiesis in transplanted as compared to endogenous colony-forming systems may reflect differences in the cell cycling characteristics of these systems.