Fine-scale foraging behaviour of a medium-ranging marine predator.
1. Movement patterns of predators should allow them to detect and respond to prey patches at different spatial scales, particularly through the adoption of area-restricted search (ARS) behaviour. Here we use fine-scale movement and activity data combined with first-passage time (FPT) analysis to examine the foraging strategy of northern gannets Morus bassanus in the western North Sea, and to test the following hypotheses: (i) birds adopt a hierarchical foraging strategy characterized by nested ARS behaviour; (ii) the locations and characteristics of ARS zones are strongly influenced by physical oceanography; (iii) the initiation of ARS behaviour is triggered by the detection and pursuit of prey; (iv) ARS behaviour is strongly linked to increased foraging effort, particularly within nested ARS areas. 2. Birds on 13 of 15 foraging trips adopted ARS behaviour at a scale of 9.1 +/- 1.9 km, and birds on 10 of these 13 trips adopted a second, nested ARS scale of 1.5 +/- 0.8 km, supporting hypothesis 1 above. ARS zones were located 117 +/- 55 km from the colony and over half were within 5 km of a tidal mixing front ~50 km offshore, supporting hypothesis 2 above. 3. The initiation of ARS behaviour was usually followed after only a short time interval (typically ~5 min) by the commencement of diving. Gannets do not dive until after they have located prey, and so this pattern strongly suggests that ARS behaviour was triggered by prey detection, supporting hypothesis 3 above. However, ~33% of dives in mixed coastal water and 16% of dives in stratified water were not associated with any detectable ARS behaviour. Hence, while ARS behaviour resulted from the detection and pursuit of prey, encounters with prey species did not inevitably induce ARS behaviour. 4. Following the initiation of ARS behaviour, dive rates were almost four times higher within ARS zones than elsewhere and almost three times higher in zones with nested ARS behaviour than in those without, supporting hypothesis 4 above and suggesting that the foraging success of birds was linked to their ability to match the hierarchical distribution of prey.


Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension.
Hypoxia is a common cause of persistent pulmonary hypertension in the newborn (PPHN), a condition associated with endothelial dysfunction and abnormal pulmonary vascular remodeling. The GTPase RhoA has been implicated in the pathogenesis of PPHN, but its contribution to endothelial remodeling and function is not known. We studied pulmonary artery endothelial cells (PAECs) taken from piglets with chronic hypoxia-induced pulmonary hypertension and from healthy animals and analyzed the roles of Rho GTPases in the regulation of the endothelial phenotype and function under basal normoxic conditions, acute hypoxia, and reoxygenation. The activities of RhoA, Rac1, and Cdc42 were correlated with changes in the endothelial cytoskeleton, adherens junctions, permeability, ROS production, VEGF levels, and activities of transcription factors hypoxia-inducible factor (HIF)-1alpha and NF-kappaB. Adenoviral gene transfer was used to express dominant-negative GTPases, kinase-dead p21-activated kinase (PAK)-1, and constitutively activated Rac1 in cells. PAECs from pulmonary hypertensive piglets had a stable abnormal phenotype with a sustained reduction in Rac1 activity and an increase in RhoA activity, which correlated with an increase in actin stress fiber formation, increased permeability, and a decrease in VEGF and ROS production. Cells from pulmonary hypertensive animals were still able to respond to acute hypoxia. They also showed high activities of HIF-1alpha and NF-kappaB, likely to result from changes in the activities of Rho GTPases. Activation of Rac1 and its effector PAK-1 as well as inhibition of RhoA restored the abnormal phenotype and permeability of hypertensive PAECs to normal.


The Cooperative Research Centre for Living with Autism (Autism CRC) Conceptual Model to Promote Mental Health for Adolescents with ASD.
Despite an increased risk of mental health problems in adolescents with autism spectrum disorder (ASD), there is limited research on effective prevention approaches for this population. Funded by the Cooperative Research Centre for Living with Autism, a theoretically and empirically supported school-based preventative model has been developed to alter the negative trajectory and promote wellbeing and positive mental health in adolescents with ASD. This conceptual paper provides the rationale, theoretical, empirical and methodological framework of a multilayered intervention targeting the school, parents and adolescents on the spectrum. Two important interrelated protective factors have been identified in community adolescent samples, namely the sense of belonging (connectedness) to school and the capacity for self and affect regulation in the face of stress (i.e. resilience). We describe how a confluence of theories from social psychology, developmental psychology and family systems theory, along with empirical evidence (including emerging neurobiological evidence), supports the interrelationships between these protective factors and many indices of wellbeing. However, the characteristics of ASD (including social and communication difficulties, and frequently difficulties with changes and transitions, and diminished optimism and self-esteem) impair access to these vital protective factors. The paper describes how evidence-based interventions at the school level for promoting inclusive schools (using the Index for Inclusion) and interventions for adolescents and parents to promote resilience and belonging [using the Resourceful Adolescent Program (RAP)] are adapted and integrated for adolescents with ASD. This multisite proof-of-concept study will confirm whether this multilevel school-based intervention is promising, feasible and sustainable.


IL-3 augments adhesiveness for endothelium and CD11b expression in human basophils but not neutrophils.
A number of natural and recombinant human cytokines have been tested for their ability to activate basophil and neutrophil adhesiveness for human umbilical vein endothelial cells in vitro. Coincubation of basophils and endothelial cell monolayers for 10 min with biologically relevant concentrations of rIL-1, natural IL-2, rIL-4, rIL-5, rIL-6, rIL-8, rGM-CSF, and rIFN-gamma had no effect on basophil adhesiveness. In contrast, rIL-3 induced basophil adhesiveness for endothelial cells (optimal at 1 ng/ml: 144 +/- 18% of control adherence (mean +/- SEM); control basophil binding, 13 +/- 3%, n = 9, p less than or equal to 0.05). This increase in adhesiveness was similar in magnitude to that induced by an optimal concentration of a known potent inducer of basophil adhesiveness (1 microM FMLP, 164 +/- 15% of control adherence, n = 9). Under these experimental conditions, the effects of rIL-3 occurred at concentrations of 0.1 to 30 ng/ml, were partially dependent on calcium, and were not accompanied by histamine release. Fixation experiments demonstrated that the effect of rIL-3 was directed against the basophil rather than the endothelial cell. Neither rIL-3 nor the other cytokines tested had any effect on the adherence of 51Cr-labeled neutrophils, even when tested simultaneously on cells from the same donors. Under experimental conditions that permitted histamine release, no correlation was seen between the ability of rIL-3 (0.3 to 300 ng/ml) to induce histamine release or enhance adhesiveness (n = 8). mAb blocking experiments demonstrated a role for both CD11 and CD18 adherence glycoproteins in basophil adherence induced by rIL-3, and indirect immunofluorescence and flow cytometric analysis revealed that rIL-3 treatment led to rapid and sustained increases in cell surface expression of CD11b antigens on basophils but not neutrophils (e.g., after 10 min: 217 +/- 29 vs 91 +/- 11% of control mean fluorescence intensity, p less than 0.05). However, no correlation was seen between the magnitude of changes in CD11b expression and changes in adhesion when tested simultaneously. These results suggest that local production of IL-3 during allergic reactions in vivo may selectively promote basophil activation, adhesion to endothelium, and recruitment to extravascular sites of inflammation.


[Mortality in Colombia traffic accidents. Comparative study with other countries].
Traffic accidents (TA) are a global problem with mortality of 1.25 million each year. The objective of this study was to compare adjusted mortality rates (AMR) by AT of Colombia, with Spain and the United States (US). The selection is justified because Colombia is a country with less development in road safety, Spain a nation that has adhered to European guidelines and US for having little adherence to international guidelines. A descriptive cross-sectional study was carried out for five-year periods, by calculating the AMRs by the direct method of standardization according to sex and age groups, as well as the adjustment of the motorization index. The mean values, the 95% confidence interval for each country and the relative change between the periods studied were calculated. The AMR of periods P1 and P2 in all countries decreased significantly (p <0.005). In periods P2 and P3 also decreased significantly in Spain, by 52.0% (p = 0.010), and in the US, by 23.6% p = 0.001), while in Colombia the difference of 4.0% it was not significant (p = 0.724). Spain stood out for the reduction in mortality (P1-P3), by 69.0%. Colombia presented a less favorable evolution of mortality due to AT than Spain and the US. Men aged 15 to 44, motorcyclists and cyclists were the most committed. The TAs are a public health problem that Colombia has raised and must adapt to its reality those successful measures in other countries.


Expression of matrix metalloproteinases and their tissue inhibitor messenger ribonucleic acids in macaque periovulatory granulosa cells: time course and steroid regulation.
Progesterone appears essential for ovulation and luteinization of the primate follicle, but specific gene targets of progesterone action remain elusive. Limited evidence supports a role for progesterone in the induction of collagenolytic activity in the periovulatory follicle of primate and nonprimate species. This study was designed to elucidate the pattern of expression and progesterone regulation of mRNAs for the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in macaque granulosa cells during controlled ovarian stimulation cycles before (0 h) and after (up to 36 h) administration of an ovulatory hCG bolus. Levels of mRNAs for interstitial collagenase, gelatinase A, matrilysin, TIMP-1 and TIMP-2 increased (p < 0.05) within 12 h of hCG, while gelatinase B mRNA increased later, by 36 h after hCG. Administration of a 3beta-hydroxysteroid dehydrogenase inhibitor (Trilostane [TRL]) during hCG treatment decreased (p < 0.05) mRNA levels for interstitial collagenase, gelatinase B, matrilysin, TIMP-1, and TIMP-2. Progestin (R5020) replacement during hCG+TRL treatment returned interstitial collagenase and TIMP-1 mRNAs to control levels. These data suggest that one action of progesterone, and possibly other steroids, in the cascade of events leading to ovulation and luteinization of the primate follicle is to regulate the expression of specific ovarian proteases and protease inhibitors.


Platelet Recruitment during Multiple Donor Platelet Apheresis Differs between Cell Separators.
SUMMARY: BACKGROUND: Recruitment of platelets (PLT) during donor PLT apheresis may facilitate the harvest of multiple units within a single donation. METHODS: We compared two PLT apheresis procedures (Amicus and Trima Accel) in a prospective, randomized, paired cross-over study in 60 donors. The 120 donations were compared for depletion of circulating PLT in the donors, PLT yields and PLT recruitment. A recruitment was defined as ratio of total PLT yield and donor PLT depletion > 1. RESULTS: Despite comparable differences of pre- and post-apheresis PLT counts (87 × 10(9)/l in Trima Accel vs. 92 × 10(9)/l in Amicus, p = 0.383), PLT yields were higher with Trima Accel (7.48 × 10(11) vs. 6.06 × 10(11), p < 0.001), corresponding to a higher PLT recruitment (1.90 vs. 1.42, p < 0.001). We observed a different increase of WBC counts after aphereses, which was more pronounced with Trima Accel than with Amicus (1.30 × 10(9)/l vs. 0.46 × 10(9)/l, p < 0.001). CONCLUSION: Both procedures induced PLT recruitment. This was higher in Trima Accel, contributing to a higher yield in spite of a comparable depletion of circulating PLT in the donors. This recruitment facilitates the harvest of multiple units within a single donation and seems to be influenced by the procedure utilized. The different increases of circulating donor white blood cells after donation need further investigation.


Synthesis of murine mammary tumor viral proteins in vitro.
The coding potential of murine mammary tumor viral genomic RNA was investigated by in vitro translation of various size classes of RNAs isolated from the virions. The major products of translation of full-size 35S polyadenylylated virion RNA were gag-related polyproteins of 75,000, 105,000, and 180,000 daltons (P75, P105, and P180, respectively). Studies on the kinetics of translation of these three proteins established that they were synthesized independently and that the smaller proteins were not post-translational cleavage products of the larger proteins. Tryptic peptide mapping showed that almost all of the P75 sequences were contained within P105 and almost all of the P105 sequences were contained within P180. The syntheses of all three proteins were inhibited by m7GTP, indicating that they were translated from capped mRNA's. Although a 24S polyadenylylated RNA had been identified as the intracellular mRNA for env precursor polyprotein, no such protein could be translated from the 24S polyadenylylated RNA isolated from the virions. However, translation of a 14S size class of polyadenylylated virion yielded four prominent proteins of about 36,000, 23,000, 21,000, and 20,000 daltons. These proteins were unrelated to murine mammary tumor viral structural proteins, as suggested from tryptic peptide mapping and immunoprecipitation data. They might be the products of an as-yet-unidentified gene located near the 3' terminus of the murine mammary tumor viral genomic RNA.


Cell-extrinsic hematopoietic impact of Ezh2 inactivation in fetal liver endothelial cells.
Despite the well-established cell-intrinsic role of epigenetic factors in normal and malignant hematopoiesis, their cell-extrinsic role remains largely unexplored. Herein we investigated the hematopoietic impact of inactivating Ezh2, a key component of polycomb repressive complex 2 (PRC2), in the fetal liver (FL) vascular niche. Hematopoietic specific (Vav-iCre) Ezh2 inactivation enhanced FL hematopoietic stem cell (HSC) expansion with normal FL erythropoiesis. In contrast, endothelium (Tie2-Cre) targeted Ezh2 inactivation resulted in embryonic lethality with severe anemia at embryonic day 13.5 despite normal emergence of functional HSCs. Ezh2-deficient FL endothelium overexpressed Mmp9, which cell-extrinsically depleted the membrane-bound form of Kit ligand (mKitL), an essential hematopoietic cytokine, in FL. Furthermore, Mmp9 inhibition in vitro restored mKitL expression along with the erythropoiesis supporting capacity of FL endothelial cells. These data establish that Ezh2 is intrinsically dispensable for FL HSCs and provides proof of principle that modulation of epigenetic regulators in niche components can exert a marked cell-extrinsic impact.


Concurrent and predictive validation of robotic simulator Tube 3 module.
We previously described a new procedure specific module (Tube 3) to allow the practice of vesicourethral anastomosis after robot-assisted radical prostatectomy. Herein, we report a predetermined proficiency level of Tube 3 and preliminary validation to explore whether this new module can lead to performance improvement in the da Vinci system. Eight urology residents and three urology fellows performed the Tube 3 module 1 hour daily for 7 days. The learning curve was depicted through a scatterplot and the stable point was identified through the cumulative sum chart. Concurrent and predictive validations were performed with the da Vinci system. The mean time to complete the task and end product rating score between Tube 3 training group and no Tube 3 training group were compared. Concerning the learning curve, about 41 repetitions comprising about 5 hours were needed to achieve this stable point when the mean time to complete Tube of 384 seconds was set as a target. With regarding to the concurrent and predictive validation, there significant differences were evident in the mean time to complete 16 needle passages and the vesicourethral anastomosis and the end product rating score. The virtual reality (VR) simulator can yield sufficient improvement in technical performance in Tube 3 within 5 hours. The acquired proficiency can be transferable to the vesicourethral anastomosis using the da Vinci system.


Decision Making Impairment: A Shared Vulnerability in Obesity, Gambling Disorder and Substance Use Disorders?
Addictions are associated with decision making impairments. The present study explores decision making in Substance use disorder (SUD), Gambling disorder (GD) and Obesity (OB) when assessed by Iowa Gambling Task (IGT) and compares them with healthy controls (HC). For the aims of this study, 591 participants (194 HC, 178 GD, 113 OB, 106 SUD) were assessed according to DSM criteria, completed a sociodemographic interview and conducted the IGT. SUD, GD and OB present impaired decision making when compared to the HC in the overall task and task learning, however no differences are found for the overall performance in the IGT among the clinical groups. Results also reveal some specific learning across the task patterns within the clinical groups: OB maintains negative scores until the third set where learning starts but with a less extend to HC, SUD presents an early learning followed by a progressive although slow improvement and GD presents more random choices with no learning. Decision making impairments are present in the studied clinical samples and they display individual differences in the task learning. Results can help understanding the underlying mechanisms of OB and addiction behaviors as well as improve current clinical treatments.


Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.
Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions.


Evidence for degradation of gastrointestinal mucin by Candida albicans secretory aspartyl proteinase.
A zone of extracellular digestion of the mucin layer around Candida albicans blastoconidia was observed by transmission electron microscopy in the jejunum of mice inoculated intragastrically (G. T. Cole, K. R. Seshan, L. M. Pope, and R. J. Yancey, J. Med. Vet. Mycol. 26:173-185, 1988). This observation prompted the hypothesis that a putative mucinolytic enzyme(s) may contribute to the virulence of C. albicans by facilitating penetration of the mucus barrier and subsequent adherence to and invasion of epithelial cells. Mucinolytic activity was observed as zones of clearing around colonies of C. albicans LAM-1 grown on agarose containing yeast nitrogen base, glucose, and hog gastric mucin. In addition, concentrated culture filtrate obtained after growth for 24 h in yeast nitrogen base, supplemented with glucose and mucin as the sole nitrogen source, contained proteolytic activity against biotin-labelled mucin which was inhibited by pepstatin A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the culture filtrate revealed two components of 42 and 45 kDa, with pIs of 4.1 and 5.3, respectively. A zymogram showed that mucin was degraded only by the 42-kDa component, which was also recognized by immunoblotting with an anti-secretory aspartyl proteinase (anti-Sap) 2p monoclonal antibody. The N-terminal sequence of the first 20 amino acids matched that reported for Sap2p. These results demonstrate that Sap2p is responsible for proteolysis of mucin by C. albicans in vitro and may be involved as a virulence factor in the breakdown of mucus and penetration of the mucin barrier by C. albicans.


An improved hydrogen bond potential: impact on medium resolution protein structures.
A new semi-empirical force field has been developed to describe hydrogen-bonding interactions with a directional component. The hydrogen bond potential supports two alternative target angles, motivated by the observation that carbonyl hydrogen bond acceptor angles have a bimodal distribution. It has been implemented as a module for a macromolecular refinement package to be combined with other force field terms in the stereochemically restrained refinement of macromolecules. The parameters for the hydrogen bond potential were optimized to best fit crystallographic data from a number of protein structures. Refinement of medium-resolution structures with this additional restraint leads to improved structure, reducing both the free R-factor and over-fitting. However, the improvement is seen only when stringent hydrogen bond selection criteria are used. These findings highlight common misconceptions about hydrogen bonding in proteins, and provide explanations for why the explicit hydrogen bonding terms of some popular force field sets are often best switched off.


The influence of atrial fibrillation on the mortality of incident ESRD patients undergoing maintenance hemodialysis.
Atrial fibrillation (AF) is highly prevalent, occurring in 1%-2% of the adult population, increasing the risk of stroke, and resulting in considerable healthcare costs. While stroke is a major complication of AF, end-stage renal disease (ESRD) patients also have a high risk of stroke, suggesting that AF is a possible risk factor for mortality of ESRD patients. However, whether the existence of AF at the initiation of hemodialysis predicts higher mortality risk of incident ESRD patients remains to be defined. This retrospective cohort study was performed at Wanfang Hospital from January 2004 to May 2018. The end points were mortality of patients or the end of the study. Incident ESRD patients who were on maintenance hemodialysis for more than 3 months were eligible for inclusion. Cox proportional regression and Kaplan-Meier survival curves were used to determine the association between predictors and mortality. The association between AF and echocardiographic parameters, causes of death were also investigated. Of the 393 incident ESRD patients at initiation of hemodialysis, 57 (14.5%) had AF and the median age was 71 years. Patients with AF were significantly older; showed significantly higher C-reactive protein levels, more heart failure, chronic obstructive pulmonary disease and mortality. Multivariate Cox regression showed that AF had a hazard ratio of 4.1 (95% confidence interval: 2.4-7.0) for mortality. Age-specific analysis showed that AF was significantly associated with mortality in all age groups. Echocardiography measurements including ejection fraction and left ventricular hypertrophy (LVH) were similar in AF and non-AF patients. Cause-specific analysis showed that AF significantly associated with overall cardiovascular death and death due to acute myocardial infarction/coronary artery disease and sepsis. AF at the initiation of hemodialysis predicts higher mortality risk of incident ESRD patients regardless of age. The systolic function and degree of LVH were similar in AF and non-AF patients. The association between AF and sepsis-related death suggested the role of systemic inflammation on the pathogenesis of AF.


PROLONG-9FP clinical development program--phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP).
Hemophilia B is a severe bleeding disorder that is characterized by a deficiency or dysfunction of coagulation factor IX (FIX). Replacement therapy using recombinant or plasma-derived FIX is available, but the relatively short half-life of FIX (approximately 18 hours) necessitates administration every 2-3 days to prevent bleeding episodes. A recombinant fusion protein linking coagulation factor IX with albumin, known as rIX-FP, was developed to extend the half-life of recombinant FIX and allow for less frequent dosing. In a phase I, multicenter, dose-escalation trial (PROLONG-9FP), the safety and pharmacokinetics of rIX-FP were assessed in patients with hemophilia B. At a dose of 25-75 IU/kg, rIX-FP was well tolerated: no serious adverse events were reported and there was no evidence of hypersensitivity or immunogenic reactions. Pharmacokinetic analysis indicated enhanced properties, including a 5-fold increase in half-life, 44% higher recovery, 7-fold greater area under the curve, and 7-fold slower clearance, compared with recombinant FIX. Trough levels were maintained above 5% after 7 days when rIX-FP was administered at 25 IU/kg and after 14 days when given at 50 IU/kg, suggesting that schedules involving weekly dosing or dosing every 2 weeks are feasible. These results represent the first reported experience with rIX-FP in humans, and suggest that rIX-FP therapy is feasible and well tolerated in patients with hemophilia B. Phase II/III studies evaluating rIX-FP are underway.


Kinetic theory and Vlasov simulation of nonlinear ion-acoustic waves in multi-ion species plasmas.
The theory of damping and nonlinear frequency shifts from particles resonant with ion-acoustic waves (IAWs) is presented for multi-ion species plasma and compared to driven wave Vlasov simulations. Two distinct IAW modes may be supported in multi-ion species plasmas, broadly classified as fast and slow by their phase velocity relative to the constituent ion thermal velocities. In current fusion-relevant long pulse experiments, the ion to electron temperature ratio, T(i)/T(e), is expected to reach a level such that the least damped and thus more readily driven mode is the slow mode, with both linear and nonlinear properties that are shown to differ significantly from the fast mode. The lighter ion species of the slow mode is found to make no significant contribution to the IAW frequency shift despite typically being the dominant contributor to the Landau damping.


The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation.
The platelet receptor for von Willebrand factor, the glycoprotein Ib-IX (GPIb-IX) complex, mediates platelet adhesion at sites of vascular injury and transmits signals leading to platelet activation. von Willebrand factor/GPIb-IX interaction sequentially activates the Src family kinase Lyn (SFK), phosphoinositide 3-kinase (PI3K), and Akt, leading to activation of integrin α(IIb)β(3) and integrin-dependent stable platelet adhesion and aggregation. It remains unclear how Lyn activates the PI3K/Akt pathway after ligand binding to GPIb-IX. Using platelet-specific Rac1(-/-) mice and the Rac1 inhibitor NSC23766, we examined the role of Rac1 in GPIb-IX-dependent platelet activation. Rac1(-/-) mouse platelets and NSC23766-treated human platelets were defective in GPIb-dependent stable adhesion to von Willebrand factor under shear stress, integrin activation, thromboxane A(2) synthesis, and platelet aggregation. Interestingly, GPIb-induced activation of Rac1 and the guanine nucleotide exchange factor for Rac1, Vav, was abolished in both Lyn(-/-) and SFK inhibitor-treated platelets but was unaffected by the PI3K inhibitor LY294002, indicating that Lyn mediates activation of Vav and Rac1 independently of PI3K. Furthermore, GPIb-induced activation of Akt was abolished in Rac1-deficient platelets, suggesting that Rac1 is upstream of the PI3K/Akt pathway. A Lyn-Vav-Rac1-PI3K-Akt pathway mediates von Willebrand factor-induced activation of integrin α(IIb)β(3) to promote GPIb-IX-dependent platelet activation.


Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development.
Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-kappaB ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.


Flattening filter free in intensity-modulated radiotherapy (IMRT) - Theoretical modeling with delivery efficiency analysis.
The flattening filter (FF) has traditionally been used to flatten beams or create uniform fields in conformal and intensity-modulated radiation therapy (IMRT) but reduces the dose rate. Many studies have confirmed improvement in delivery efficiency by removing the FF, also known as flattening filter free (FFF), especially for small field stereotactic body radiation therapy (SBRT); but it is unclear if large treatment fields still favor the FFF beam. We propose a novel, unified approach to quantify delivery efficiency of the FFF and flattened beams. We modeled the FF effect by inverse conical filters and systematically studied delivery efficiency (beam-on time, BOT) by varying the filter thickness, including the FF and FFF mode. We formulated the BOT of different beams for any arbitrary fluence map in linear programming to solve the optimal inverse conical filter that minimizes the BOT. One-dimensional optimal filters of minimum BOT were also derived in closed form for conical fluence to gain insight for arbitrary clinical fluence maps. We evaluated the BOT of the FFF beam and flattened beam for conformal treatment fields of various dimensions ranging from 5 cm × 5 cm to 25 cm × 25 cm. We also analyzed the BOT for 698 clinical IMRT prostate fluence maps of field size 10 cm × 10 cm, 17 head-and-neck fluence maps of field size 15 cm × 15 cm, and additional realistic test data from 90° rotation and up to 40 cm × 40 cm enlargement of these clinical fluence maps, which were all initially generated with flattened beams. The FFF beam minimized the BOT for A field size less than 20 cm in single leaf pair cases and for conformal fields of dimension less than 20 cm × 20 cm. The FFF beam also minimized the BOT for all tested prostate and head-and-neck cases. The median BOT ratios of the FFF beam to the flattened beam were 0.56 and 0.61 for prostate and head-and-neck cases, respectively. The FFF beam minimized the BOT for field size up to 30 cm × 30 cm and had similar BOTs to those of the flattened beam for field size greater than 30 cm × 30 cm in those clinically realistic test data. The filter modeling and BOT calculation enable us to quantify delivery efficiency of the FFF beam and flattened beam in a unified approach. The FFF beam minimized the BOT both theoretically and in simulations for all clinically relevant field sizes and fluence maps in IMRT. The results for conformal fields imply that the FFF beam requires less BOT than the flattened beam for volumetric modulated arc therapy (VMAT) treatments. The delivery efficiency consideration favors the FFF beam in intensity-modulated treatments and may eventually lead to removal of the FF in all future linear accelerator head designs.


Nanoscale Surface Modifications of Medical Implants for Cartilage Tissue Repair and Regeneration.
Natural cartilage regeneration is limited after trauma or degenerative processes. Due to the clinical challenge of reconstruction of articular cartilage, research into developing biomaterials to support cartilage regeneration have evolved. The structural architecture of composition of the cartilage extracellular matrix (ECM) is vital in guiding cell adhesion, migration and formation of cartilage. Current technologies have tried to mimic the cell's nanoscale microenvironment to improve implants to improve cartilage tissue repair. This review evaluates nanoscale techniques used to modify the implant surface for cartilage regeneration. The surface of biomaterial is a vital parameter to guide cell adhesion and consequently allow for the formation of ECM and allow for tissue repair. By providing nanosized cues on the surface in the form of a nanotopography or nanosized molecules, allows for better control of cell behaviour and regeneration of cartilage. Chemical, physical and lithography techniques have all been explored for modifying the nanoscale surface of implants to promote chondrocyte adhesion and ECM formation. Future studies are needed to further establish the optimal nanoscale modification of implants for cartilage tissue regeneration.


Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells.
Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.


Scalable production in human cells and biochemical characterization of full-length normal and mutant huntingtin.
Huntingtin (Htt) is a 350 kD intracellular protein, ubiquitously expressed and mainly localized in the cytoplasm. Huntington's disease (HD) is caused by a CAG triplet amplification in exon 1 of the corresponding gene resulting in a polyglutamine (polyQ) expansion at the N-terminus of Htt. Production of full-length Htt has been difficult in the past and so far a scalable system or process has not been established for recombinant production of Htt in human cells. The ability to produce Htt in milligram quantities would be a prerequisite for many biochemical and biophysical studies aiming in a better understanding of Htt function under physiological conditions and in case of mutation and disease. For scalable production of full-length normal (17Q) and mutant (46Q and 128Q) Htt we have established two different systems, the first based on doxycycline-inducible Htt expression in stable cell lines, the second on "gutless" adenovirus mediated gene transfer. Purified material has then been used for biochemical characterization of full-length Htt. Posttranslational modifications (PTMs) were determined and several new phosphorylation sites were identified. Nearly all PTMs in full-length Htt localized to areas outside of predicted alpha-solenoid protein regions. In all detected N-terminal peptides methionine as the first amino acid was missing and the second, alanine, was found to be acetylated. Differences in secondary structure between normal and mutant Htt, a helix-rich protein, were not observed in our study. Purified Htt tends to form dimers and higher order oligomers, thus resembling the situation observed with N-terminal fragments, although the mechanism of oligomer formation may be different.


Topological solutions in gauge theory and their computer graphic representation.
A diverse range of physical phenomena, both observed and hypothetical, are described by topological solutions to nonlinear gauge field theories. Computer-generated color graphic displays can provide a clear and detailed representation of some of these solutions, which might otherwise be physically unintelligible because of their mathematical complexity. Graphical representations are presented here for two topological solutions: (i) the solutions of a model that represents the filaments of quantized magnetic flux in a superconductor, and (ii) the solutions of an SO(3) gauge theory corresponding to a pair of separated magnetic monopoles. An introduction is provided to the gauge field theories giving rise to these solutions.


Gliquidone Alleviates Diabetic Nephropathy by Inhibiting Notch/Snail Signaling Pathway.
Diabetic nephropathy is a common complication of diabetes. This study explored the renal protective effect and possible mechanism of gliquidone in mice with diabetic nephropathy. Animal model of diabetic nephropathy was established in KKAy mice. The renal protective effect of gliquidone was studied by evaluating the kidney function through measures of urinary protein, blood urea nitrogen (BUN), serum creatinine (Scr) and serum triglyceride (TG) that were performed using an automatic biochemical analyzer. The levels of oxidative stress indicators, such as nitric oxide (NO), superoxide dismutase (SOD) and malondialdehyde (MDA), were evaluated in renal tissue homogenates using the automatic biochemical analyzer. The inhibitory effect of gliquidone on renal interstitial fibrosis and its association with Notch / Snail1 signaling pathway in diabetic nephropathy was investigated using molecular biological techniques. It was found that low-, medium- and high-dose gliquidone improved the mice's general health condition, such as mental status, fur condition, eating, and drinking. Gliquidone reduced the body weight and the kidney weight /body weight ratio of mice. Gliquidone improved the kidney function, indicated by reductions in urinary protein, blood urea nitrogen, and serum creatinine and triglyceride. Gliquidone treatment increased levels of nitric oxide and superoxide dismutase, but decreased level of malondialdehyde. The expression of Jagged1/Notch1/hes1/Snail1/α-SMA decreased, while the expression of E-cadherin increased in gliquidone-treated kidneys. High dose gliquidone showed the best effect, one that was similar to that of the positive control drug irbesartan. Taken together, our results suggested that gliquidone can ameliorate the diabetic symptoms of diabetic nephropathy through inhibiting Notch / Snail1 signaling pathway, improving anti -oxidative response and delaying renal interstitial fibrosis. The efficacy of gliquidone is dose-dependent.


Small ubiquitin-related modifier (SUMO)-1, SUMO-2/3 and SUMOylation are involved with centromeric heterochromatin of chromosomes 9 and 1 and proteins of the synaptonemal complex during meiosis in men.
Post-transcriptional modification by SUMOylation is involved in numerous cellular processes including human spermatogenesis. For human male meiosis, we previously showed that the small ubiquitin-related modifier-1 (SUMO-1) protein localizes to chromatin axes in early pachytene spermatocytes, then to kinetochores as meiosis progresses. Here, we delineate possible functional roles based on subcellular localization for SUMO-1 and SUMO-2/3. Western and immunoprecipitation analyses were conducted on proteins isolated from the testis of two normal adult fertile men. Combinatorial immunofluorescence and chromosome-specific fluorescence in situ hybridization analyses were performed on male meiocytes obtained during testicular biopsy from four patients undergoing testicular sperm extraction for assisted reproduction technologies. The synaptonemal complex (SC) and SC proteins (SCP)-1 and SCP2, but not SCP3, are SUMOylated by SUMO-1 during the pachytene substage. Likewise, two distinct localization patterns for SUMO-1 are identified: a linear pattern co-localized with autosomal SCs and isolated SUMO-1 near the centromeric heterochromatin of chromosomes 9 and 1. In contrast to SUMO-1, which is not detectable prior to pachytene in normal tissue, SUMO-2/3 is identified as early as leptotene and zygotene and in some, but not all, pachytene cells; no linear patterns were detected. Similar to SUMO-1, SUMO-2/3 localizes in two predominant subnuclear patterns: a single, dense signal near the centromere of human chromosome 9 and small, individual foci co-localized with autosomal centromeres. Our data suggest that SUMO-1 may be involved in maintenance and/or protection of the autosomal SC. SUMO-2/3, though expressed similarly, may function separately and independently during pachytene in men.


Antioxidant activities of enzymatic extracts from brown seaweeds.
Potential antioxidative activities of enzymatic extracts from seven species of brown seaweeds were evaluated using four different reactive oxygen species (ROS) scavenging assays containing DPPH (1,1-diphenyl-2-pricrylhydrazyl) free radical, superoxide anion, hydroxyl radical and hydrogen peroxide scavenging assay. The brown seaweeds were enzymatically hydrolyzed to prepare water-soluble extracts by using five carbohydrate degrading enzymes (Viscozyme, Celluclast, AMG, Termamyl and Ultraflo) and five proteases (Protamex, Kojizyme, Neutrase, Flavourzyme and Alcalase) of commercial and inexpensive enzymes obtained from Novozyme Co. (Novozyme Nordisk, Bagsvaerd, Denmark). The enzymatic extracts exhibited more prominent effects in hydrogen peroxide scavenging activity (approximately 90%) compared to the other scavenging activities and the activity of enzymatic extracts was even higher than that of the commercial antioxidants. In particular, Ultraflo and Alcalase extracts of S. horneri were dose-dependent and thermally stable. Moreover the two enzymatic extracts strongly inhibited DNA damage (approximately 50%). Those extracts showed significantly (p<0.05) remarkable scavenging effects in DPPH free radical scavenging assay and the activity indicated a marked correlation with phenolic contents. From the results, enzymatic extracts of the brown seaweeds might be valuable antioxidative sources.


Mapping heatwave health risk at the community level for public health action.
Climate change poses unprecedented challenges, ranging from global and local policy challenges to personal and social action. Heat-related deaths are largely preventable, but interventions for the most vulnerable populations need improvement. Therefore, the prior identification of high risk areas at the community level is required to better inform planning and prevention. We aimed to demonstrate a simple and flexible conceptual framework relying upon satellite thermal data and other digital data with the goal of easily reproducing this framework in a variety of urban configurations. The study area encompasses Rennes, a medium-sized French city. A Landsat ETM + image (60 m resolution) acquired during a localized heatwave (June 2001) was used to estimate land surface temperature (LST) and derive a hazard index. A land-use regression model was performed to predict the LST. Vulnerability was assessed through census data describing four dimensions (socio-economic status, extreme age, population density and building obsolescence). Then, hazard and vulnerability indices were combined to deliver a heatwave health risk index. The LST patterns were quite heterogeneous, reflecting the land cover mosaic inside the city boundary, with hotspots of elevated temperature mainly observed in the city center. A spatial error regression model was highly predictive of the spatial variation in the LST (R² = 0.87) and was parsimonious. Three land cover descriptors (NDVI, vegetation and water fractions) were negatively linked with the LST. A sensitivity analysis (based on an image acquired on July 2000) yielded similar results. Southern areas exhibited the most vulnerability, although some pockets of higher vulnerability were observed northeast and west of the city. The heatwave health risk map showed evidence of infra-city spatial clustering, with the highest risks observed in a north-south central band. Another sensitivity analysis gave a very high correlation between 2000 and 2001 risk indices (r = 0.98, p < 10⁻¹²). Building on previous work, we developed a reproducible method that can provide guidance for local planners in developing more efficient climate impact adaptations. We recommend, however, using the health risk index together with hazard and vulnerability indices to implement tailored programs because exposure to heat and vulnerability do not require the same prevention strategies.


p38 MAP kinase mediates endotoxin-induced expression of cyclooxygenase-2 in enterocytes.
Necrotizing enterocolitis (NEC) occurs only after bacterial colonization of the intestine, suggesting that bacterial products, including lipopolysaccharide (endotoxin,) interact with enterocytes in the pathogenesis of this disease. Inflammatory molecules such as cyclooxygenase-2 (COX-2) are important mediators of the septic response leading to NEC. We therefore hypothesized that endotoxin activates production of COX-2 in enterocytes and explored the relative contributions of known mitogen-activated protein kinases (MAPK) pathways in this process. IEC-6 enterocytes were treated with 5 microg/mL endotoxin, or various stresses, or media alone, and COX-2 protein levels were assayed by immunoblots with anti-COX-2 antibodies. Activation of MAPK was examined by immunoblots with phospho-MAPK antibodies. MAPK activity was blocked by treatment with pharmacologic inhibitors or transfection with dominant-negative MAPK constructs. Endotoxin treatment caused increased expression of the COX-2 protein 24 hours after treatment. This was preceded by rapid and transient activation of the 3 major MAPKs: extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. SB203580, a specific inhibitor of p38, but not U0126 (ERK inhibitor) or SP600125 (JNK inhibitor), blocked endotoxin-induced accumulation of COX-2 protein. This response was also blocked by expression of dominant-negative p38 but not by the dominant-negative ERK construct. Genotoxic stress that activated p38 but not ERK was an effective inducer of COX-2, whereas stresses that activated both p38 and ERK were not effective. ERK inhibition by U1026 enhanced endotoxin-induced production of COX-2, consistent with negative regulation of COX-2 by ERK. These data point to p38 as the MAPK that mediates endotoxin-induced production of COX-2 in enterocytes. Endotoxin may be capable of inducing the production of COX-2 in enterocytes via the p38 MAPK pathway, which may be relevant to the development of NEC.


The protective effect of topical rifamycin treatment against sternal wound infection in diabetic patients undergoing on-pump coronary artery bypass graft surgery.
The aim of this study was to investigate the protective effect of topical rifamycin SV treatment against sternal wound infection (SWI) in diabetic patients undergoing on-pump coronary artery bypass graft (CABG) surgery. One hundred and fifty-nine diabetic patients who were scheduled to undergo isolated on-pump CABG surgery were included. Eight were excluded for various reasons. Of the 151 patients, 51 were on insulin therapy and 100 were on oral anti-diabetics. The risk of mediastinitis was assessed using the American College of Cardiology/American Heart Association 2004 guideline update for CABG surgery. According to the risk scores, patients were divided into two comparable groups: the rifamycin group (n = 78) received topical rifamycin treatment after on-pump CABG surgery, and the control group (n = 73) received no topical treatment. Deep sternal wound infection (mediastinitis) was not observed in either group (0/78 vs 0/73, p = 1.0). No superficial sternal wound infection was observed in the rifamycin group, however, it did occur in one patient in the control group (0/78 vs 1/73, p = 0.303). Wound culture was performed and coagulase-negative staphylococci were observed. The infection regressed on initiation of antibiotic therapy against isolated bacteria and the patient was discharged after a full recovery. Although the difference in rate of superficial sternal wound infection (SSWI) in the rifamycin and control groups was not statistically significant, locally applied rifamycin SV during closure of the sternum in the CABG operation may have had a protective affect against SWI.


End stage chronic obstructive pulmonary disease.
Many patients with chronic obstructive pulmonary disease (COPD) die each year as those with lung cancer but current guidelines make few recommendations on the care for the most severe patients i.e. those with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III and IV with chronic respiratory failure. Only smoking cessation and long term oxygen therapy (LTOT) improve survival in COPD. Although non invasive positive pressure ventilation (NPPV) may have an adjunctive role in the management of chronic respiratory insufficiency there is little evidence for its use in the routine management of stable hypercapnic COPD patients. At difference, several prospective, randomised, controlled studies, systematic reviews and meta-analyses show good level of evidence for clinical efficacy of NPPV in the treatment of acute on chronic respiratory failure due to acute exacerbations of COPD. NPPV is also alternative to invasive ventilation for symptom relief in end stage COPD. Surgical interventions for end stage COPD like bullectomy, different modalities of lung volume reduction surgery and lung transplantation are likely to be of value to only a small percentage of patients. Nevertheless, there are specific indications, which, when added to pulmonary rehabilitation will further advance exercise capacity and quality of life. As in other chronic diseases when severity of disease increases along the natural history, therapy aimed to prolong life becomes less and less important in comparison to palliative therapy aimed to relieve symptoms. The most effective treatments for dyspnoea are bronchodilators, although also opiates may improve dyspnoea. Supplemental oxygen reduce exertional breathlessness and improve exercise tolerance in hypoxaemic COPD patients. There are difficulties in treating with antidepressant the frail and elderly COPD patients. Good clinical care can prevent or alleviate suffering by assessing symptoms and providing psychological and social support to the patients and their families.


Ultrasonographic and hormonal characterization of reproductive health and disease in wild, semiwild, and aquarium-housed southern stingrays (Hypanus americanus).
To characterize physical examination, plasma biochemical, and ultrasonographic findings in aquarium-housed, managed semiwild, and wild southern stingrays (Hypanus americanus) with and without reproductive disease. Southern stingrays from aquarium (n = 48), lagoon (managed semiwild; 34), and wild (12) habitats. Limited, opportunistic prosections were performed of presumed anatomically normal wild southern stingrays and compared with findings for aquarium-housed stingrays with reproductive disease. Ultrasonographic video data from both groups were used to assign a score (1 to 5) indicating increasing severity of ovarian and uterine reproductive disease. Plasma total 17β-estradiol, estrone, progesterone, and testosterone concentrations were measured with enzyme immunoassays validated for use in southern stingrays. Ultrasonographic ovarian scores were significantly correlated with uterine scores. No reproductive disease was detected in semiwild or wild stingrays, but 65% (31/48) of aquarium-housed stingrays had developing or advanced reproductive disease (ie, ultrasonographic ovarian or uterine score of 4 or 5). Significant correlations were identified between ovarian and uterine disease status and plasma concentrations of all steroid hormones except testosterone. Findings suggested that ultrasonography and plasma hormone concentrations may be useful in the identification of reproductive disease and determination of disease severity in southern stingrays.


Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.
Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.


Biochemical, functional, and histopathologic characterization of lomustine-induced liver injury in dogs.
To characterize the biochemical, functional, and histopathologic changes associated with lomustine-induced liver injury in dogs. I0 healthy purpose-bred sexually intact female hounds. Dogs were randomly assigned to receive lomustine (approx 75 mg/m2, PO, q 21 d for 5 doses) alone (n = 5) or with prednisone (approx 1.5 mg/kg, PO, q 24 h for 12 weeks; 5). For each dog, a CBC, serum biochemical analysis, liver function testing, urinalysis, and ultrasonographic examination of the liver with acquisition of liver biopsy specimens were performed before and at predetermined times during and after lomustine administration. Results were compared between dogs that did and did not receive prednisone. 7 of the I0 dogs developed clinical signs of liver failure. For all dogs, serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, bile acid concentrations, and liver histologic score increased and hepatic reduced glutathione content decreased over time. Peak serum ALT (r = 0.79) and ALP (r = 0.90) activities and bile acid concentration (r = 0.68) were positively correlated with the final histologic score. Prednisone did not appear to have a protective effect on histologic score. In dogs, liver enzyme activities, particularly ALT and ALP activities, should be closely monitored during lomustine treatment and acute increases in those activities may warrant discontinuation of lomustine to mitigate liver injury. Nonspecific ultrasonographic findings and abnormal increases in liver function tests were not detected until the onset of clinical liver failure. Glutathione depletion may have a role in lomustine-induced hepatopathy and warrants further investigation.


Population genomic footprints of host adaptation, introgression and recombination in coffee leaf rust.
Coffee leaf rust, caused by Hemileia vastatrix (Hv), represents the biggest threat to coffee production worldwide and ranks amongst the most serious fungal diseases in history. Despite a recent series of outbreaks and emergence of hypervirulent strains, the population evolutionary history and potential of this pathogen remain poorly understood. To address this issue, we used restriction site-associated DNA sequencing (RADseq) to generate ∼19 000 single nucleotide polymorphisms (SNPs) across a worldwide collection of 37 Hv samples. Contrary to the long-standing idea that Hv represents a genetically unstructured and cosmopolitan species, our results reveal the existence of a cryptic species complex with marked host tropism. Using phylogenetic and pathological data, we show that one of these lineages (C3) infects almost exclusively the most economically valuable coffee species (tetraploids that include Coffea arabica and interspecific hybrids), whereas the other lineages (C1 and C2) are severely maladapted to these hosts, but successfully infect diploid coffee species. Population dynamic analyses suggest that the C3 group may be a recent 'domesticated' lineage that emerged via host shift from diploid coffee hosts. We also found evidence of recombination occurring within this group, which could explain the high pace of pathotype emergence despite the low genetic variation. Moreover, genomic footprints of introgression between the C3 and C2 groups were discovered and raise the possibility that virulence factors may be quickly exchanged between groups with different pathogenic abilities. This work advances our understanding of the evolutionary strategies used by plant pathogens in agro-ecosystems with direct and far-reaching implications for disease control.


Efficient planar fiber-to-chip coupler based on two-stage adiabatic evolution.
A new, efficient adiabatic in-plane fiber-to-chip coupler design is proposed. In this design, the light from the fiber is coupled into a low-index waveguide with matching mode size. The mode is first adiabatically reduced in size with a rib taper, and then transferred into a high-index (e.g. silicon) waveguide with an inverse taper. The two-stage design allows to reduce the coupler length multiple times in comparison with pure inverse taper-based couplers of similar efficiency. The magnitude of length reduction increases with the refractive index of the low-index waveguide and the fiber mode size.


Dispersal of the Japanese pine sawyer, Monochamus alternatus (Coleoptera: Cerambycidae), in mainland China as inferred from molecular data and associations to indices of human activity.
The Japanese pine sawyer, Monochamus alternatus Hope (Coleoptera: Cerambycidae), is an important forest pest as well as the principal vector of the pinewood nematode (PWN), Bursaphelenchus xylophilus (Steiner et Buhrer), in mainland China. Despite the economic importance of this insect-disease complex, only a few studies are available on the population genetic structure of M. alternatus and the relationship between its historic dispersal pattern and various human activities. The aim of the present study was to further explore aspects of human activity on the population genetic structure of M. alternatus in mainland China. The molecular data based on the combined mitochondrial cox1 and cox2 gene fragments from 140 individuals representing 14 Chinese populations yielded 54 haplotypes. Overall, a historical (natural) expansion that originated from China's eastern coast to the western interior was revealed by the haplotype network, as well as several recent, long-distant population exchanges. Correlation analysis suggested that regional economic status and proximity to marine ports significantly influenced the population genetic structure of M. alternatus as indicated by both the ratio of shared haplotypes and the haplotype diversity, however, the PWN distribution in China was significantly correlated with only the ratio of shared haplotypes. Our results suggested that the modern logistical network (i.e., the transportation system) in China is a key medium by which humans have brought about population exchange of M. alternatus in mainland China, likely through inadvertent movement of infested wood packaging material associated with trade, and that this genetic exchange was primarily from the economically well-developed east coast of China, westward, to the less-developed interior. In addition, this study demonstrated the existence of non-local M. alternatus in new PWN-infested localities in China, but not all sites with non-local M. alternatus were infested with PWN.


Comparative assessment of Graves' disease and main extrathyroidal manifestation, Graves' ophthalmopathy, by non-targeted metabolite profiling of blood and orbital tissue.
Graves' disease (GD) is an autoimmune disorder that causes the overproduction of thyroid hormones and consequent cascade of systemic metabolism dysfunction. Moreover, Graves' ophthalmopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). The goal of the study was to identify metabolic signatures in association with diagnostic biomarkers of GD without GO and GO, respectively. Ninety metabolites were profiled and analyzed based on a non-targeted primary metabolite profiling from plasma samples of 21 GD patients without GO, 26 subjects with GO, and 32 healthy subjects. Multivariate statistics showed a clear discrimination between healthy controls and disease group (R2Y = 0.518, Q2 = 0.478) and suggested a biomarker panel consisting of 10 metabolites. Among them, most of metabolites showed the positive association with the levels of thyrotropin receptor antibodies. With combination of proline and 1,5-anhydroglucitol, which were identified as GO-specific modulators, the re-constructed biomarker model greatly improved the statistical power and also facilitated simultaneous discrimination among healthy control, GO, and GD without GO groups (AUC = 0.845-0.935). Finally, the comparative analysis of tissue metabolite profiles from GO patients proposed putative metabolic linkage between orbital adipose/connective tissues and the biofluidic consequences, in which fumarate, proline, phenylalanine, and glycerol were coordinately altered with the blood metabolites.


The influence of advertising on compulsive buying - The role of persuasion knowledge.
The growing concern over compulsive buying (CB) among consumers has led to vast amount of research examining the antecedents of this maladaptive behaviour. The focus of previous research was, however, mainly on examining the internal, psychological factors contributing to CB. The current research, on the other hand, sheds light on one of the external triggers which can possibly stimulate CB, namely advertising. An online survey has been conducted to identify the attitudes and scepticism towards advertising as well as ad avoidance and persuasion knowledge among a sample of 582 Belgian consumers. Furthermore, all participants were screened with regard to compulsive buying tendencies. This research provides evidence that positive attitudes towards advertising can lead to CB. An important factor in this relation is persuasion knowledge. The study results lead to the conclusion that people higher in persuasion knowledge dispose less positive attitudes towards advertising which can subsequently prevent them from engaging in CB. Moreover high scores on scepticism towards advertising and ad avoidance among Belgian consumers in our sample point to a need for advertisers to modify their practices in order to gain more trust from consumers. This study also shows that advertising in particular attracts and seems to affect an already disadvantaged group of people - namely compulsive buyers.


Morphological and chemical analysis of bainite in Cu-17Al-11Mn (at.%) alloys by using orthogonal FIB-SEM and double-EDS STEM.
In this study, new microscopy techniques were developed for understanding the mechanism for the bainitic transformation in a Cu-17Al-11Mn (at%) alloy. An orthogonally arranged focused ion beam and a scanning electron microscope were employed to observe three-dimensional (3D) morphology of the bainite phase, in addition to compositional analysis by using a scanning transmission electron microscope equipped with a double-detector energy-dispersive X-ray spectrometer system. The 3D morphology of these samples was observed at different aging times and aging temperatures; the results obtained indicated that with increasing aging time and/or aging temperature, the bainite phase at the initial stage of formation exhibits a plate-like shape, which changes to a lenticular form. A habit plane was uniquely determined as ∼{9 3 2} by the combination of 3D image reconstruction and an electron back-scattered diffraction technique. The compositional analysis revealed the spatial distribution of the compositional variation between the bainite and matrix phases in the initial stages of the transformation. In the bainite phase, the Cu concentration was higher, while the concentrations of Al and Mn were lower than those in the surrounding matrix, indicative of the diffusion of the constituent elements with the growth of the bainite phase.


High thermoelectric performance of graphite nanofibers.
Graphite nanofibers (GNFs) have been demonstrated to be a promising material for hydrogen storage and heat management in electronic devices. Here, by means of first-principles and transport simulations, we show that GNFs can also be an excellent material for thermoelectric applications thanks to the interlayer weak van der Waals interaction that induces low thermal conductance and a step-like shape in the electronic transmission with mini-gaps, which are necessary ingredients to achieve high thermoelectric performance. This study unveils that the platelet form of GNFs in which graphite layers are perpendicular to the fiber axis can exhibit outstanding thermoelectric properties with a figure of merit ZT reaching 3.55 in a 0.5 nm diameter fiber and 1.1 in a 1.1 nm diameter one. Interestingly, by introducing 14C isotope doping, ZT can even be enhanced up to more than 5, and more than 8 if we include the effect of finite phonon mean free path, which demonstrates the amazing thermoelectric potential of GNFs.


Impact of pharmacist-conducted medication reconciliation at discharge on readmissions of elderly patients with COPD.
Beginning in fiscal year 2015, the Centers for Medicare and Medicaid Services will measure all-cause readmissions for patients admitted for exacerbation of chronic obstructive pulmonary disease (COPD). Hospitals will incur a payment penalty for unplanned 30-day readmissions. Elderly patients frequently present a challenge because of polypharmacy, which contributes to a greater risk for medication-related readmissions. To determine whether pharmacist-conducted medication reconciliation at discharge decreased medication discrepancies and reduced 30-day readmissions for elderly patients with COPD. Patients aged 65 years and older admitted for a COPD exacerbation between January 31, 2012, and February 29, 2012, were included. The pharmacist reviewed the discharge form for discrepancies. Patients who were readmitted within 30 days of discharge were identified. The rate of 30-day readmission was compared with baseline data. Length of stay and cost for admission versus readmission were also assessed. A total of 29 patients were admitted for a COPD exacerbation; 6 medication discrepancies were identified and reported to prescribers. Four patients were readmitted within 30 days of discharge. The 30-day readmission rate was lower than the baseline rate (16.0% vs 22.2%). When comparing admissions with readmissions, a slight reduction in average length of stay and slight increase in cost was observed. Pharmacist-conducted medication reconciliation at discharge decreased discrepancies for elderly patients admitted for exacerbation of COPD. The 30-day readmission rate could be decreased further by expanding pharmacist responsibilities during transitions of care. This includes patient counseling, tracking outpatient adherence, selecting affordable medications, and expanding the process to include other chronic disease states.


Wrist Accelerometer Cut Points for Classifying Sedentary Behavior in Children.
This study aimed to examine the validity and accuracy of wrist accelerometers for classifying sedentary behavior (SB) in children. Fifty-seven children (5-8 and 9-12 yr) completed an ~170-min protocol, including 15 semistructured activities and transitions. Nine ActiGraph (GT3X+) and two GENEActiv wrist cut points were evaluated. Direct observation was the criterion measure. The accuracy of wrist cut points was compared with that achieved by the ActiGraph hip cut point (≤25 counts per 15 s) and the thigh-mounted activPAL3. Analyses included equivalence testing, Bland-Altman procedures, and area under the receiver operating curve (ROC-AUC). The most accurate ActiGraph wrist cut points (Kim; vector magnitude, ≤3958 counts per 60 s; vertical axis, ≤1756 counts per 60 s) demonstrated good classification accuracy (ROC-AUC = 0.85-0.86) and accurately estimated SB time in 5-8 yr (equivalence P = 0.02; mean bias = 4.1%, limits of agreement = -20.1% to 28.4%) and 9-12 yr (equivalence P < 0.01; -2.5%, -27.9% to 22.9%). The mean bias of SB time estimates from Kim were smaller than ActiGraph hip (5-8 yr: 15.8%, -5.7% to 37.2%; 9-12 yr: 17.8%, -3.9% to 39.5%) and similar to or smaller than activPAL3 (5-8 yr: 12.6%, -39.8% to 14.7%; 9-12 yr: -1.4%, -13.9% to 11.0%), although classification accuracy was similar to ActiGraph hip (ROC-AUC = 0.85) but lower than activPAL3 (ROC-AUC = 0.92-0.97). Mean bias (5-8 yr: 6.5%, -16.1% to 29.1%; 9-12 yr: 10.5%, -13.6% to 34.6%) for the most accurate GENEActiv wrist cut point (Schaefer: ≤0.19 g) was smaller than ActiGraph hip, and activPAL3 in 5-8 yr, but larger than activPAL3 in 9-12 yr. However, SB time estimates from Schaefer were not equivalent to direct observation (equivalence P > 0.05) and classification accuracy (ROC-AUC = 0.79-0.80) was lower than for ActiGraph hip and activPAL3. The most accurate SB ActiGraph (Kim) and GENEActiv (Schaefer) wrist cut points can be applied in children with similar confidence as the ActiGraph hip cut point (≤25 counts per 15 s), although activPAL3 was generally more accurate.


A Monte Carlo investigation of low-Z target image quality generated in a linear accelerator using Varian's VirtuaLinac.
The focus of this work was the demonstration and validation of VirtuaLinac with clinical photon beams and to investigate the implementation of low-Z targets in a TrueBeam linear accelerator (Linac) using Monte Carlo modeling. VirtuaLinac, a cloud based web application utilizing Geant4 Monte Carlo code, was used to model the Linac treatment head components. Particles were propagated through the lower portion of the treatment head using BEAMnrc. Dose distributions and spectral distributions were calculated using DOSXYZnrc and BEAMdp, respectively. For validation, 6 MV flattened and flattening filter free (FFF) photon beams were generated and compared to measurement for square fields, 10 and 40 cm wide and at dmax for diagonal profiles. Two low-Z targets were investigated: a 2.35 MeV carbon target and the proposed 2.50 MeV commercial imaging target for the TrueBeam platform. A 2.35 MeV carbon target was also simulated in a 2100EX Clinac using BEAMnrc. Contrast simulations were made by scoring the dose in the phosphor layer of an IDU20 aSi detector after propagating through a 4 or 20 cm thick phantom composed of water and ICRP bone. Measured and modeled depth dose curves for 6 MV flattened and FFF beams agree within 1% for 98.3% of points at depths greater than 0.85 cm. Ninety three percent or greater of points analyzed for the diagonal profiles had a gamma value less than one for the criteria of 1.5 mm and 1.5%. The two low-Z target photon spectra produced in TrueBeam are harder than that from the carbon target in the Clinac. Percent dose at depth 10 cm is greater by 3.6% and 8.9%; the fraction of photons in the diagnostic energy range (25-150 keV) is lower by 10% and 28%; and contrasts are lower by factors of 1.1 and 1.4 (4 cm thick phantom) and 1.03 and 1.4 (20 cm thick phantom), for the TrueBeam 2.35 MV/carbon and commercial imaging beams, respectively. VirtuaLinac is a promising new tool for Monte Carlo modeling of novel target designs. A significant spectral difference is observed between the low-Z target beam on the Clinac platform and the proposed imaging beam line on TrueBeam, with the former providing greater diagnostic energy content.


Health Is Life in Balance: Students and Communities Explore Healthy Lifestyles in a Culturally Based Curriculum.
From exploring knowledge from wise members of the community to investigating the science of homeostasis, students learn healthy ways of living through a new hands-on curriculum, Diabetes Education in Tribal Schools: Health Is Life in Balance. The curriculum integrates science and Native American traditions to educate students about science, diabetes and its risk factors, and the importance of nutrition and physical activity in maintaining health and balance in life. Applying an inquiry-based approach to learning, the curriculum builds skills in observation, measurement, prediction, experimentation, and communication, and provides healthy lifestyle messages and innovative science activities for all students. The curriculum is now available to teachers and health educators at no cost through a federal grant.Health Is life in Balance incorporates interdisciplinary standards as well as storytelling to help children understand important messages. Implementation evaluation of the curriculum indicated improved knowledge and attitudes about science and health, positive teacher and student comments, and culturally relevant content. The lessons highlighted in this article give a glimpse into this hands-on curriculum which integrates science and Native American traditions, looking to our past and listening to the wisdom of our Elders, to gain powerful information for healthy, holistic living. The circle of balance is a theme in many indigenous belief systems and is woven into the lessons, providing enduring understandings of health behaviours that can prevent type 2 diabetes in the context of Native American cultural themes.


Effects of mindful-attention and compassion meditation training on amygdala response to emotional stimuli in an ordinary, non-meditative state.
The amygdala has been repeatedly implicated in emotional processing of both positive and negative-valence stimuli. Previous studies suggest that the amygdala response to emotional stimuli is lower when the subject is in a meditative state of mindful-attention, both in beginner meditators after an 8-week meditation intervention and in expert meditators. However, the longitudinal effects of meditation training on amygdala responses have not been reported when participants are in an ordinary, non-meditative state. In this study, we investigated how 8 weeks of training in meditation affects amygdala responses to emotional stimuli in subjects when in a non-meditative state. Healthy adults with no prior meditation experience took part in 8 weeks of either Mindful Attention Training (MAT), Cognitively-Based Compassion Training (CBCT; a program based on Tibetan Buddhist compassion meditation practices), or an active control intervention. Before and after the intervention, participants underwent an fMRI experiment during which they were presented images with positive, negative, and neutral emotional valences from the IAPS database while remaining in an ordinary, non-meditative state. Using a region-of-interest analysis, we found a longitudinal decrease in right amygdala activation in the Mindful Attention group in response to positive images, and in response to images of all valences overall. In the CBCT group, we found a trend increase in right amygdala response to negative images, which was significantly correlated with a decrease in depression score. No effects or trends were observed in the control group. This finding suggests that the effects of meditation training on emotional processing might transfer to non-meditative states. This is consistent with the hypothesis that meditation training may induce learning that is not stimulus- or task-specific, but process-specific, and thereby may result in enduring changes in mental function.


Low dose of valproate improves motor function after traumatic brain injury.
Traumatic brain injuries (TBIs) are a major health care problem worldwide. Approximately 1.5 million new TBI cases occur annually in the United States, with mortality rates ranging between 35% and 40% in severe patients. Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use. Several studies have indicated that 300 mg/kg or 400 mg/kg of valproate (VPA) exhibits neuroprotective effects in animal models. However, humans cannot tolerate high doses of VPA. This study aims to investigate whether 30 mg/kg of VPA administered to rats affects TBIs. We used a rat model to test the effects of 30 mg/kg of VPA on TBIs. Molecular identifications for histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) and phosphorylated extracellular signal regulated kinase (ERK) were performed. The results indicated that treating adult rats with VPA after TBIs significantly decreased the contusion volume and recovery of contusion-related skilled forelimb reaching deficits. Applying VPA also increased histone acetylation, p-ERK, and p-CREB expression in the brain. Furthermore, applying VPA reduced inflammation, glial fibrillary acidic protein activation, and apoptosis. Conclusion. This study found that 30 mg/kg of VPA assists in treating TBIs in rat models.


Patterns in reef fish assemblages: Insights from the Chagos Archipelago.
Understanding the drivers of variability in the composition of fish assemblages across the Indo-Pacific region is crucial to support coral reef ecosystem resilience. Whilst numerous relationships and feedback mechanisms between the functional roles of coral reef fishes and reef benthic composition have been investigated, certain key groups, such as the herbivores, are widely suggested to maintain reefs in a coral-dominated state. Examining links between fishes and reef benthos is complicated by the interactions between natural processes, disturbance events and anthropogenic impacts, particularly fishing pressure. This study examined fish assemblages and associated benthic variables across five atolls within the Chagos Archipelago, where fishing pressure is largely absent, to better understand these relationships. We found high variability in fish assemblages among atolls and sites across the archipelago, especially for key groups such as a suite of grazer-detritivore surgeonfish, and the parrotfishes which varied in density over 40-fold between sites. Differences in fish assemblages were significantly associated with variable levels of both live and recently dead coral cover and rugosity. We suggest these results reflect differing coral recovery trajectories following coral bleaching events and a strong influence of 'bottom-up' control mechanisms on fish assemblages. Species level analyses revealed that Scarus niger, Acanthurus nigrofuscus and Chlorurus strongylocephalos were key species driving differences in fish assemblage structure. Clarifying the trophic roles of herbivorous and detritivorous reef fishes will require species-level studies, which also examine feeding behaviour, to fully understand their contribution in maintaining reef resilience to climate change and fishing impacts.


Meropenem in children receiving continuous renal replacement therapy: clinical trial simulations using realistic covariates.
Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT.


Surface permeability of porous media particles and capillary transport.
We have established previously, in a lead-in study, that the spreading of liquids in particulate porous media at low saturation levels, characteristically less than 10% of the void space, has very distinctive features in comparison to that at higher saturation levels. In particular, we have found that the dispersion process can be accurately described by a special class of partial differential equations, the super-fast non-linear diffusion equation. The results of mathematical modelling have demonstrated very good agreement with experimental observations. However, any enhancement of the accuracy and predictive power of the model, keeping in mind practical applications, requires the knowledge of the effective surface permeability of the constituent particles, which defines the global, macroscopic permeability of the particulate media. In the paper, we demonstrate how this quantity can be determined through the solution of the Laplace-Beltrami Dirichlet problem, we study this using the well-developed surface finite-element method.


Nutritional intervention with omega-3 Fatty acids in a case of malignant fibrous histiocytoma of the lungs.
We present a case of a 78-yr-old man with malignant fibrous histiocytoma with multiple lesions in both lungs. Following diagnosis, he declined conventional chemotherapy and elected nutritional intervention by increasing intake of omega-3 fatty acids and lowering intake of omega-6 fatty acids. We estimated that he consumed 15 g of the long-chain omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) per day, and the ratio of linoleic acid/long-chain omega-3 fatty acids in his diet was 0.81. Serial computed tomography scans and pulmonary x-rays revealed remarkably a slow and steady decrease in the size and number of bilateral nodules. He has no apparent side effects from consuming large quantities of fish and algae oils rich in DHA and EPA and he remains asymptomatic.


Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection.
Clinical features of Coronavirus disease 2019 (COVID-19) are caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Acute infection management is a substantial healthcare issue, and the development of long-Covid syndrome (LCS) is extremely challenging for patients and physicians. It is associated with a variety of characteristics as impaired capillary microcirculation, chronic fatigue syndrome (CFS), proinflammatory cytokines, and functional autoantibodies targeting G-protein-coupled receptors (GPCR-AAbs). Here, we present a case report of successful healing of LCS with BC 007 (Berlin Cures, Berlin, Germany), a DNA aptamer drug with a high affinity to GPCR-AAbs that neutralizes these AAbs. A patient with a documented history of glaucoma, recovered from mild COVID-19, but still suffered from CFS, loss of taste, and impaired capillary microcirculation in the macula and peripapillary region. He was positively tested for various targeting GPCR-AAbs. Within 48 h after a single BC 007 treatment, GPCR-AAbs were functionally inactivated and remained inactive during the observation period of 4 weeks. This observation was accompanied by constant improvement of the fatigue symptoms of the patient, taste, and retinal capillary microcirculation. Therefore, the removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.


Physicians' perceptions on the impact of telemedicine on recruitment and retention in underserved areas: a descriptive study in Senegal.
Similar to many places, physicians in Senegal are unevenly distributed. Telemedicine is considered a potential solution to this problem. This study investigated the perceptions of Senegal's physicians of the impact of telemedicine on their recruitment to and retention in underserved areas. We conducted individual interviews with a random sample of 60 physicians in Senegal, including 30 physicians working in public hospitals and 30 physicians working in district health centres between January and June 2014, as part of a mixed methods study. Data were collected using a semi-structured interview guide comprising both open- and close-ended questions. Interviews were recorded, transcribed and coded thematically using NVivo 10 software using a priori and emergent codes. Participants' characteristics were analyzed descriptively using SPSS 23. The impact of telemedicine on physicians' recruitment and retention in underserved areas was perceived with some variability. Among the physicians who were interviewed, most (36) thought that telemedicine could have a positive impact on their recruitment and retention but many (24) believed the opposite. The advantages noted by the first included telemedicine's ability to break their professional isolation and reduce the stress related to this, facilitate their distance learning and improve their working conditions. They did acknowledge that it is not sufficient in itself, an opinion also shared by physicians who did not believe that telemedicine could affect their recruitment and retention. Both identified contextual, economic, educational, family, individual, organizational and professional factors as influential. Based on these opinions of physicians, telemedicine promotion is one intervention that, alongside others, could be promoted to assist in addressing the multiple factors that influence physicians' recruitment and retention in underserved areas.


Psychosomatic medicine in the 21st century: understanding mechanisms and barriers to utilization.
The psychosomatic approach arose in antiquity as mankind looked for explanations for illness and death. With the rise of modern medicine, the links between emotions and medical conditions, such as cardiac disease and diabetes, were described by astute clinical observers, but the mechanisms for these conditions were based on correlation from observations rather than on experimental design. Psychoanalytic theory was often utilized to explain many common diseases. For example, peptic ulcer disease was blamed upon anger and stress, but scientific methodology discovered Helicobacter pylori to be the significant causal factor of this disease and resulted in the development of more effective treatments. Nevertheless emotional factors are still linked to disease states and morbidity; for example, depression is a risk factor for mortality following myocardial infarction. Advances in neuroscience demonstrate that the reduction of telomere length by anxiety and stress leads to more rapid aging and potential disease vulnerability. Thus, neuroscientific probes may allow for the elucidation of psychosomatic mechanisms. Sadly, clinical barriers, in terms of time pressure upon physicians and the current separation of mental health services from primary care settings, continue the dualistic treatment of many conditions where psychological factors are important. It is not clear whether a mandate for the integration of behavioral health into primary care will remedy this partition and finally maximize a psychosomatic approach to medical care.


Analysis of cubic and orthorhombic C3A hydration in presence of gypsum and lime.
Field emission scanning electron microscopy (FE-SEM) and X-ray diffraction (XRD) have been used to study the microstructural changes and phase development that take place during the hydration of cubic (pure) and orthorhombic (Na-doped) tricalcium aluminate (C3A) and gypsum in the absence and presence of lime. The results demonstrate that important differences occur in the hydration of each C3A polymorph and gypsum when no lime is added; orthorhombic C3A reacts faster with gypsum than the cubic phase, forming longer ettringite needles; however, the presence of lime slows down the formation of ettringite in the orthorhombic sample. Additional rheometric tests showed the possible effects on the setting time in these cementitious mixes.


Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart.
Endocardial cushions are the precursors of the cardiac valves and form by a process of epithelial-mesenchymal transformation. Secreted growth factors from myocardium induce endocardial cells to transform into mesenchyme and invade the overlying extracellular matrix. Here, we show that the product of the Nf1 neurofibromatosis gene is required to regulate this event. In the absence of neurofibromin, mouse embryo hearts develop overabundant endocardial cushions due to hyperproliferation and lack of normal apoptosis. Neurofibromin deficiency in explant cultures is reproduced by activation of ras signaling pathways, and the Nf1(-/-) mutant phenotype is prevented by inhibiting ras in vitro. These results indicate that neurofibromin normally acts to modulate epithelial-mesenchymal transformation and proliferation in the developing heart by down regulating ras activity.


Comparative studies of paeoniflorin and albiflorin from Paeonia lactiflora on anti-inflammatory activities.
Paeonia lactiflora Pall. (Ranunculaceae) has been used for more than 1000 years in traditional Chinese medicine for the treatment of gynecological problems, cramp, pain, giddiness, and congestion. Paeoniflorin, monoterpene glycosides isolated from P. lactiflora, possesses a variety of pharmacological activities. However, the pharmacological activity of the pharmacological activity of albiflorin, another main monoterpene glycoside, has not been well studied. The present study investigated the anti-inflammatory activities of paeoniflorin and albiflorin using models of lipopolysaccharides (LPS) induced RAW 264.7 cells. Production of nitric oxide (NO) was measured by the Griess colorimetric method. In addition, prostaglandin E2 (PGE2), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) synthesis were analyzed using an enzyme-linked immunosorbent assay (ELISA). The protein expression of cyclooxygenase-2 (COX-2) was detected by a cell-based ELISA. The gene expression levels of inducible nitric oxide synthase (iNOS), COX-2, TNF-α, and IL-6 were detected by quantitative real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). Compared with the LPS-induced group, the inhibition rates of NO, PGE2, TNF-α, and IL-6 production were 17.61, 27.56, 20.57, and 29.01% by paeoniflorin and 17.35, 12.94, 15.29, and 10.78% by albiflorin. The IC50 values of paeoniflorin and albiflorin on NO production were 2.2 × 10(-4 )mol/L and 1.3 × 10(-2 )mol/L, respectively. The protein expression of COX-2 was reduced by 50.98% with paeoniflorin and 17.21% with albiflorin. The inhibition rates of gene expression of iNOS, COX-2, IL-6, and TNF-α were 35.65, 38.08, 19.72, and 45.19% by paeoniflorin and 58.36, 47.64, 50.70, and 12.43% by albiflorin, respectively. These results show that albiflorin has similar anti-inflammatory effects to paeoniflorin, which provides new evidence that albiflorin can serve as a new chemical marker for the quality control of Paeoniae Radix and the Chinese Pharmacopoeia can be updated.


Evidence of tool use in a seabird.
Documenting novel cases of tool use in wild animals can inform our understanding of the evolutionary drivers of the behavior's emergence in the natural world. We describe a previously unknown tool-use behavior for wild birds, so far only documented in the wild in primates and elephants. We observed 2 Atlantic puffins at their breeding colonies, one in Wales and the other in Iceland (the latter captured on camera), spontaneously using a small wooden stick to scratch their bodies. The importance of these observations is 3-fold. First, while to date only a single form of body-care-related tool use has been recorded in wild birds (anting), our finding shows that the wild avian tool-use repertoire is wider than previously thought and extends to contexts other than food extraction. Second, we expand the taxonomic breadth of tool use to include another group of birds, seabirds, and a different suborder (Lari). Third, our independent observations span a distance of more than 1,700 km, suggesting that occasional tool use may be widespread in this group, and that seabirds' physical cognition may have been underestimated.