Identification of S22 (ostarine) in human nails and hair using LC-HRMS. Application to two authentic cases.
Ostarine, also known as S22 or MK2866 and enobosarm, is a selective androgen receptor modulator (SARM). It has high anabolic potency, in addition to limited androgenic effects. At this time, ostarine has no therapeutic use, but can be abused for performance-enhancing purposes using the oral route, at dosages of 10-25 mg per day. As the drug can easily be obtained via the Internet or some fitness centers, athletes and more and more amateurs can use it without undergoing the deleterious physiological side effects that are generally associated with testosterone-related compounds. Since 2008, the World Anti-Doping Agency (WADA) has prohibited SARMs at-all-times in the category of "other anabolic agents" under section S1.2 of the WADA List. In a case of trafficking/abuse, ostarine was identified in nail (subject 1) and hair (subject 2) by LC/HRMS after incubation of 50 mg of matrix in a pH 9.5 buffer, followed by extraction with organic solvents. The drug was quantitated by LC-MS/MS. Ostarine tested positive at 61 pg/mg (toenails) and 111 pg/mg (fingernails) for subject 1. Ostarine was present at 146, 168, 93, and 101 pg/mg in the 4 × 3 cm hair sections of subject 2, clearly demonstrating long-term use.


Immunotherapeutic potential of extracellular vesicles.
Extracellular vesicle or EV is a term that encompasses all classes of secreted lipid membrane vesicles. Despite being scientific novelties, EVs are gaining importance as a mediator of important physiological and pathological intercellular activities possibly through the transfer of their cargo of protein and RNA between cells. In particular, exosomes, the currently best characterized EVs have been notable for their in vitro and in vivo immunomodulatory activities. Exosomes are nanometer-sized endosome-derived vesicles secreted by many cell types and their immunomodulatory potential is independent of their cell source. Besides immune cells such as dendritic cells, macrophages, and T cells, cancer and stem cells also secrete immunologically active exosomes that could influence both physiological and pathological processes. The immunological activities of exosomes affect both innate and adaptive immunity and include antigen presentation, T cell activation, T cell polarization to regulatory T cells, immune suppression, and anti-inflammation. As such, exosomes carry much immunotherapeutic potential as a therapeutic agent and a therapeutic target.


Differences in oral health behaviour between children from high and children from low SES schools in The Netherlands.
To identify the determinants of dental caries in relation to socio-economic status (SES) within oral health, children's eating habits and parental attitudes towards oral health. Dental screening data were collected from 6- and 10-year-old schoolchildren from low and high SES schools in The Netherlands in this cross-sectional study. The clinical examination was performed by trained dental hygiene students who collected the data on dental caries, dental plaque and duration of brushing. The paper questionnaire completed by the parents included 18 questions about oral health behaviour, eating habits and parental attitudes towards oral health. Two of the six parameters of oral health behaviour were statistically associated with the high caries prevalence in the low SES group (brushing frequency (p = 0.028) and age at the first visit to the dentist (p = 0.044)). High intake of fruit juices and/or soft drinks (p = 0.043) and low calcium intake (p = 0.028) were identified as risk determinants for caries with low SES. All parameters of parental attitudes towards oral health were associated with caries, but not with SES. This study confirmed that the high caries prevalence in children from low SES schools was associated with oral health behaviour and eating habits. The role of parents was indirectly associated with the occurrence of dental caries. Therefore, it is important to include parents in all intervention programmes in order to reduce the prevalence of caries.


Microdynamic changes of moisture-induced crystallization of amorphous calcium carbonate revealed via in situ FTIR spectroscopy.
Amorphous calcium carbonate (ACC) is the most important intermediate phase in the nucleation/crystallization process of CaCO3, and thus the proper interpretation of how ACC transforms into final crystals at the molecular level is crucial to understand various biomineralization phenomena. Herein, we successfully monitored the moisture-induced crystallization process of ACC via in situ FTIR spectroscopy, which is very sensitive to the specific changes of the different vibrational modes of carbonates and water molecules. In combination with the tools of perturbation correlation moving window and two-dimensional correlation spectroscopy, it is found that the driving force of ACC crystallization is the fracture of hydrogen bonds formed by H2OCO32-. The bending vibrations of carbonate are more sensitive to moisture permeation than the stretching modes, and the whole crystallization process can be divided into three sequential stages, i.e., the hydrated ACC first loses its structural water and converts to the dehydrated ACC, which then gradually transforms into vaterite, followed by the final growth of vaterite crystals. Anhydrous ACC microdomains are found to be already existing in the as-prepared ACCs.


The phylogenetic pattern of speciation and wing pattern change in neotropical Ithomia butterflies (Lepidoptera: nymphalidae).
Species level phylogenetic hypotheses can be used to explore patterns of divergence and speciation. In the tropics, speciation is commonly attributed to either vicariance, perhaps within climate-induced forest refugia, or ecological speciation caused by niche adaptation. Mimetic butterflies have been used to identify forest refugia as well as in studies of ecological speciation, so they are ideal for discriminating between these two models. The genus Ithomia contains 24 species of warningly colored mimetic butterflies found in South and Central America, and here we use a phylogenetic hypothesis based on seven genes for 23 species to investigate speciation in this group. The history of wing color pattern evolution in the genus was reconstructed using both parsimony and likelihood. The ancestral pattern for the group was almost certainly a transparent butterfly, and there is strong evidence for convergent evolution due to mimicry. A punctuationist model of pattern evolution was a significantly better fit to the data than a gradualist model, demonstrating that pattern changes above the species level were associated with cladogenesis and supporting a model of ecological speciation driven by mimicry adaptation. However, there was only one case of sister species unambiguously differing in pattern, suggesting that some recent speciation events have occurred without pattern shifts. The pattern of geographic overlap between clades over time shows that closely related species are mostly sympatric or, in one case, parapatric. This is consistent with modes of speciation with ongoing gene flow, although rapid range changes following allopatric speciation could give a similar pattern. Patterns of lineage accumulation through time differed significantly from that expected at random, and show that most of the extant species were present by the beginning of the Pleistocene at the latest. Hence Pleistocene refugia are unlikely to have played a major role in Ithomia diversification.


The gut microbiome, endocannabinoids and metabolic disorders.
Two complex systems are emerging as being deeply involved in the control of energy metabolism. The intestinal microbiota, with its warehouse of genes, proteins and small molecules, that is, the gut microbiome; and the endocannabinoid system, with its recent extension to a more complex signalling apparatus including more than 100 lipid mediators and 50 proteins, that is, the endocannabinoidome. Both systems can become perturbed following bad dietary habits and during obesity, thus contributing to exacerbating this latter condition and its consequences in both peripheral organs and the brain. Here, we discuss some of the multifaceted aspects of the regulation and dysregulation of the gut microbiome and endocannabinoidome in energy metabolism and metabolic disorders, with special emphasis on the emerging functional interactions between the two systems. The potential exploitation of this new knowledge for the development of new pharmacological and nutritional approaches against obesity and its consequences is also briefly touched upon.


Depressive symptoms predict mucosal wound healing.
There is mounting evidence that psychosocial stress can delay wound healing, but this literature almost exclusively pertains to dermal wound healing. Many surgical procedures involve damage to mucosal tissues and the time course and the role of repair processes, such as inflammation, in the healing of these tissues are markedly different from those in dermal healing. Feelings of depression and social isolation are common among surgical patients, and the present study therefore investigated if these factors predict the rate of mucosal wound healing. Undergraduate students were invited to participate in the study if they reported high or low levels of loneliness or depressive symptoms, corresponding to the upper or lower quintile of their peer group. The UCLA loneliness scale and the Beck Depression Inventory [short form] were used for this screening. A sample of 193 healthy young adults (age range 18-31 years) received a 3.5-mm circular wound on the oral hard palate, under local anesthesia. Healing was monitored by daily videographs of the wound. The median healing rate was 7 days. High dysphoric participants were, however, more likely to heal slower than this median healing rate (odds ratio 3.57 (1.58-8.07); p < .001). This association remained robust after correction for a broad range of demographic and behavioral variables, including gender, age, ethnicity, and health behaviors. High dysphoric individuals also exhibited significantly larger average wound sizes from day 2 post wounding onward. Loneliness and diurnal cortisol secretion (measured over 5 days) were unrelated to healing. Depressive symptoms predict the rate of mucosal wound healing in healthy young adults. We discuss potential pathways that warrant further investigation.


The resting brain: unconstrained yet reliable.
Recent years have witnessed an upsurge in the usage of resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity (fcMRI), both in normal and pathological populations. Despite this increasing popularity, concerns about the psychologically unconstrained nature of the "resting-state" remain. Across studies, the patterns of functional connectivity detected are remarkably consistent. However, the test-retest reliability for measures of resting state fcMRI measures has not been determined. Here, we quantify the test-retest reliability, using resting scans from 26 participants at 3 different time points. Specifically, we assessed intersession (>5 months apart), intrasession (<1 h apart), and multiscan (across all 3 scans) reliability and consistency for both region-of-interest and voxel-wise analyses. For both approaches, we observed modest to high reliability across connections, dependent upon 3 predictive factors: 1) correlation significance (significantly nonzero > nonsignificant), 2) correlation valence (positive > negative), and 3) network membership (default mode > task positive network). Short- and long-term measures of the consistency of global connectivity patterns were highly robust. Finally, hierarchical clustering solutions were highly reproducible, both across participants and sessions. Our findings provide a solid foundation for continued examination of resting state fcMRI in typical and atypical populations.


One-pot organometallic synthesis of alumina-embedded Pd nanoparticles.
Herein we report a one pot organometallic strategy to access alumina-embedded Pd nanoparticles. Unexpectedly, the decomposition of the organometallic complex tris(dibenzylideneacetone)dipalladium(0), Pd2(dba)3, by dihydrogen in the presence of aluminum isopropoxide, Al(iPrO)3, and without extra stabilizers, was found to be an efficient method to generate a Pd colloidal solution. Careful characterization studies revealed that the so-obtained Pd nanoparticles were stabilized by an aluminum isopropoxide tetramer and 1,5-diphenyl-pentan-3-one, which was produced after reduction of the dba ligand from the organometallic precursor. Moreover, calcination of the obtained nanomaterial in air at 773 K for 2 h resulted in a nanocomposite material containing Pd nanoparticles embedded in Al2O3. This stabilization strategy opens new possibilities for the preparation of transition metal nanoparticles embedded in oxides.


2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3.
The transient receptor potential (TRP) superfamily contains a large number of proteins encoding cation permeable channels that are further divided into TRPC (canonical), TRPM (melastatin), and TRPV (vanilloid) subfamilies. Among the six TRPV members, TRPV1, TRPV2, TRPV3, and TRPV4 form heat-activated cation channels, which serve diverse functions ranging from nociception to osmolality regulation. Although chemical activators for TRPV1 and TRPV4 are well documented, those for TRPV2 and TRPV3 are lacking. Here we show that in the absence of other stimuli, 2-aminoethoxydiphenyl borate (2APB) activates TRPV1, TRPV2, and TRPV3, but not TRPV4, TRPV5, and TRPV6 expressed in HEK293 cells. In contrast, 2APB inhibits the activity of TRPC6 and TRPM8 evoked by 1-oleolyl-2-acetyl-sn-glycerol and menthol, respectively. In addition, low levels of 2APB strongly potentiate the effect of capsaicin, protons, and heat on TRPV1 as well as that of heat on TRPV3 expressed in Xenopus oocytes. In dorsal root ganglia neurons, supra-additive stimulations were evoked by 2APB and capsaicin or 2APB and acid. Our data suggest the existence of a common activation mechanism for TRPV1, TRPV2, and TRPV3 that may serve as a therapeutic target for pain management and treatment for diseases caused by hypersensitivity and temperature misregulation.


Two Neural Circuits to Point Towards Home Position After Passive Body Displacements.
A challenge in motor control research is to understand the mechanisms underlying the transformation of sensory information into arm motor commands. Here, we investigated these transformation mechanisms for movements whose targets were defined by information issued from body rotations in the dark (i.e., idiothetic information). Immediately after being rotated, participants reproduced the amplitude of their perceived rotation using their arm (Experiment 1). The cortical activation during movement planning was analyzed using electroencephalography and source analyses. Task-related activities were found in regions of interest (ROIs) located in the prefrontal cortex (PFC), dorsal premotor cortex, dorsal region of the anterior cingulate cortex (ACC) and the sensorimotor cortex. Importantly, critical regions for the cognitive encoding of space did not show significant task-related activities. These results suggest that arm movements were planned using a sensorimotor-type of spatial representation. However, when a 8 s delay was introduced between body rotation and the arm movement (Experiment 2), we found that areas involved in the cognitive encoding of space [e.g., ventral premotor cortex (vPM), rostral ACC, inferior and superior posterior parietal cortex (PPC)] showed task-related activities. Overall, our results suggest that the use of a cognitive-type of representation for planning arm movement after body motion is necessary when relevant spatial information must be stored before triggering the movement.


Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis.
The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-α) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.


The association of bone density and calcified atherosclerosis is stronger in women without dyslipidemia: the multi-ethnic study of atherosclerosis.
We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years), who were not taking lipid-lowering medications or estrogen were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides. Participants were a random sample from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease. Spine BMD at the L3 vertebrate was performed by computer tomography (CT). CAC prevalence was measured by CT. The total cholesterol to HDL ratio (TC:HDL) ≥ 5.0 was used as the primary marker of hyperlipidemia. The association of BMD with CAC differed in women with TC:HDL < 5.0 versus higher (p-interaction = 0.01). In age- and race-adjusted models, among women with TC:HDL < 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (prevalence ratio [PR] 0.75, 95% confidence interval [CI] 0.63-0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82-1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men, irrespective of the TC:HDL ratio (p interaction 0.54). The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis.


Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes.
Whether nucleic acids that circulate in blood have any patho-physiological functions in the host have not been explored.We report here that far from being inert molecules, circulating nucleic acids have significant biological activities of their own that are deleterious to healthy cells of the body. Fragmented DNA and chromatin (DNAfs and Cfs) isolated from blood of cancer patients and healthy volunteers are readily taken up by a variety of cells in culture to be localized in their nuclei within a few minutes. The intra-nuclear DNAfs and Cfs associate themselves with host cell chromosomes to evoke a cellular DNA-damage-repair-response (DDR) followed by their incorporation into the host cell genomes. Whole genome sequencing detected the presence of tens of thousands of human sequence reads in the recipient mouse cells. Genomic incorporation of DNAfs and Cfs leads to dsDNA breaks and activation of apoptotic pathways in the treated cells. When injected intravenously into Balb/C mice, DNAfs and Cfs undergo genomic integration into cells of their vital organs resulting in activation of DDR and apoptotic proteins in the recipient cells. Cfs have significantly greater activity than DNAfs with respect to all parameters examined, while both DNAfs and Cfs isolated from cancer patients are more active than those from normal volunteers. All the above pathological actions of DNAfs and Cfs described above can be abrogated by concurrent treatment with DNase I and/or anti-histone antibody complexed nanoparticles both in vitro and in vivo. Taken together, our results suggest that circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications to ageing and a multitude of human pathologies including initiation of cancer.


Hypotensive Epidural Anesthesia Reduces Blood Loss in Pelvic and Sacral Bone Tumor Resections.
Resection of pelvic and sacral tumors can cause severe blood loss, complications, and even postoperative death. Hypotensive epidural anesthesia has been used to mitigate blood loss after elective arthroplasty, but to our knowledge, it has not been studied as an approach that might make resection of pelvic and sacral tumors safer. The purposes of this study were (1) to compare the blood loss and blood product use for patients undergoing pelvic and sacral tumor surgery under standard anesthesia or hypotensive epidural anesthesia; (2) to assess the frequency of end-organ damage with the two techniques; and (3) to compare 90-day mortality between the two techniques. Between 2000 and 2014, 285 major pelvic and sacral resections were performed at one center. A total of 174 (61%) had complete data sets for analysis of blood loss, transfusion use, complications, and mortality at 90 days. Of those, 102 (59%) underwent hypotensive epidural anesthesia, whereas the remainder received standard anesthetic care. The anesthetic approach was determined by the anesthetists in charge of the case with hypotensive epidural anesthesia exclusively performed by one of two subspecialty trained anesthetists as their routine for major pelvic or sacral surgery. The groups were comparable in terms of potential confounding variables such as age, gender, tumor volume, and operation performed. Hypotensive epidural anesthesia was defined as a technique using an extensive epidural block up to T2-3 dermatome, peripherally administered low-concentration intravenous adrenaline infusion, and using unimpeded spontaneous respiration to achieve controlled hypotension, precise rate control of the heart, and enhanced velocity of venous return, all aggregated thus to minimize blood loss during pelvic surgery while preserving vital perfusion. The groups were assessed for perioperative blood loss calculated from pre- and postsurgery hemoglobin and transfusion use as well as postoperative complications, morbidity, and mortality at 90 days. There was less mean blood loss in the hypotensive epidural anesthesia group (1457 mL, SD 1721, 95% confidence interval [CI], 1114-1801 versus 2421 mL, SD 2297, 95% CI, 1877-2965; p = 0.003). Patients in the hypotensive epidural anesthesia group on average received fewer packed red cell transfusions (2.7 units, SD 2.9, 95% CI, 2.1-3.2 versus 3.9 units, SD 4.4, 95% CI, 2.9-5.0; p = 0.03). There were no differences in the proportions of patients experiencing end-organ injury (7%, n = seven of 102 versus 6%, n = four of 72; p = 0.72). With the numbers available, there was no difference in 90-day mortality rate between groups (1.9%, n = two of 102 versus 1.3%, n = one of 72; p = 0.77). We found that hypotensive epidural anesthesia resulted in less blood loss, fewer transfusions, and no apparent increase in serious complications in pelvic and sacral tumor surgery performed in the setting of a high-volume tertiary sarcoma referral hospital. We recommend that further collaborative studies be undertaken to confirm our results with hypotensive epidural anesthesia in surgery for pelvic tumors. Level III, therapeutic study.


Effects of vegetation type on microbial biomass carbon and nitrogen in subalpine mountain forest soils.
Microbial biomass plays an important role in nutrient transformation and conservation of forest and grassland ecosystems. The objective of this study was to determine the microbial biomass among three vegetation types in subalpine mountain forest soils of Taiwan. Tatachia is a typical high-altitude subalpine temperate forest ecosystem in Taiwan with an elevation of 1800-3952 m and consists of three vegetation types: spruce, hemlock, and grassland. Three plots were selected in each vegetation type. Soil samples were collected from the organic layer, topsoil, and subsoil. Microbial biomass carbon (Cmic) was determined by the chloroform fumigation-extraction method, and microbial biomass nitrogen (Nmic) was determined from the total nitrogen (Ntot) released during fumigation-extraction. Bacteria, actinomycetes, fungi, cellulolytic microbes, phosphate-solubilizing microbes, and nitrogen-fixing microbes were also counted. The Cmic and Nmic were highest in the surface soil and declined with the soil depth. These were also highest in spruce soils, followed by in hemlock soils, and were lowest in grassland soils. Cmic and Nmic had the highest values in the spring season and the lowest values in the winter season. Cmic and Nmic had significantly positive correlations with total organic carbon (Corg) and Ntot. Contributions of Cmic and Nmic, respectively, to Corg and Ntot indicated that the microbial biomass was immobilized more in spruce and hemlock soils than in grassland soils. Microbial populations of the tested vegetation types decreased with increasing soil depth. Cmic and Nmic were high in the organic layer and decreased with the depth of layers. These values were higher for spruce and hemlock soils than for grassland soils. Positive correlations were observed between Cmic and Nmic and between Corg and Ntot.


Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach: a multi-institutional research study.
Gene fusion events resulting from chromosomal rearrangements play an important role in initiation of lung adenocarcinoma. The recent association of four oncogenic driver genes, ALK, ROS1, RET, and NTRK1, as lung tumor predictive biomarkers has increased the need for development of up-to-date technologies for detection of these biomarkers in limited amounts of material. We describe here a multi-institutional study using the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel to interrogate previously characterized lung tumor samples. Reproducibility between laboratories using diluted fusion-positive cell lines was 100%. A cohort of lung clinical research samples from different origins (tissue biopsies, tissue resections, lymph nodes and pleural fluid samples) were used to evaluate the panel. We observed 97% concordance for ALK (28/30 positive; 71/70 negative samples), 95% for ROS1 (3/4 positive; 19/18 negative samples), and 93% for RET (2/1 positive; 13/14 negative samples) between the AmpliSeq assay and other methodologies. This methodology enables simultaneous detection of multiple ALK, ROS1, RET, and NTRK1 gene fusion transcripts in a single panel, enhanced by an integrated analysis solution. The assay performs well on limited amounts of input RNA (10 ng) and offers an integrated single assay solution for detection of actionable fusions in lung adenocarcinoma, with potential savings in both cost and turn-around-time compared to the combination of all four assays by other methods.


Context-dependent biosonar adjustments during active target approaches in echolocating harbour porpoises.
Echolocating mammals generally target individual prey items by transitioning through the biosonar phases of search (slow-rate, high-amplitude outputs), approach (gradually increasing rate and decreasing output amplitude) and buzzing (high-rate, low-amplitude outputs). The range to the main target of interest is often considered the key or sole driver of such biosonar adjustments of acoustic gaze. However, the actively generated auditory scene of an echolocator invariably comprises a large number of other reflectors and noise sources that likely also impact the biosonar strategies and source parameters implemented by an echolocating animal in time and space. In toothed whales, the importance of context on biosonar adjustments is largely unknown. To address this, we trained two harbour porpoises to actively approach the same sound recording target over the same approach distance in two highly different environments: a PVC-lined pool and a semi-natural net pen in a harbour, while blind-folded and wearing a sound recording tag (DTAG-4). We show that the approaching porpoises used considerably shorter interclick intervals (ICIs) in the pool than in the net pen, except during the buzz phase, where slightly longer ICIs were used in the pool. We further show that average click source levels were 4-7 dB higher in the net pen. Because of the very low-level in-band ambient noise in both environments, we posit that the porpoises adapted their echolocation strategy to the different reverberation levels between the two settings. We demonstrate that harbour porpoises use different echolocation strategies and biosonar parameters in two different environments for solving an otherwise identical target approach task and thus highlight that biosonar adjustments are both range and context dependent.


Thrombus-specific theranostic nanocomposite for codelivery of thrombolytic drug, algae-derived anticoagulant and NIR fluorescent contrast agent.
Thrombolysis is a standard treatment for rapidly restoring blood flow. However, the application of urokinase-type plasminogen activator (Uk) in clinical therapy is limited due to its nonspecific distribution and inadequate therapeutic accumulation. Precise thrombus imaging and site-specific drug delivery can enhance the diagnostic and therapeutic efficacy for thrombosis. Accordingly, we developed a P-selectin-specific, photothermal theranostic nanocomposite for thrombus-targeted codelivery of Uk and indocyanine green (ICG, a contrast agent for near-infrared (NIR) fluorescence imaging). We evaluated its capabilities for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. Mesoporous silica-coated gold nanorods (Si-AuNRs) were functionalized with an arginine-rich peptide to create an organic template for the adsorption of ICG and fucoidan (Fu), an algae-derived anticoagulant. Uk was loaded into the SiO2 pores of the Si-AuNRs through the formation of a Fu-Uk-ICG complex on the peptide-functionalized template. The Fu-Uk/ICG@SiAu NRs nanocomposite increased the photostability of ICG and improved its targeting/accumulation at blood clot sites with a strong NIR fluorescence intensity for precise thrombus imaging. Furthermore, ICG incorporated into the nanocomposite enhanced the photothermal effect of Si-AuNRs. Fu, as a P-selectin-targeting ligand, enabled the nanocomposite to target a thrombus site where platelets were activated. The nanocomposite enabled a faster release of Uk for rapid clearing of blood clots and a slower release of Fu for longer lasting prevention of thrombosis regeneration. The nanocomposite with multiple functions, including thrombus-targeting drug delivery, photothermal thrombolysis, and NIR fluorescence imaging, is thus an advanced theranostic platform for thrombolytic therapy with reduced hemorrhaging risk and enhanced imaging/thrombolysis efficiency. STATEMENT OF SIGNIFICANCE: Herein, for the first time, a P-selectin specific, photothermal theranostic nanocomposite for thrombus-targeted co-delivery of urokinase and NIR fluorescence contrast agent indocyanine green (ICG) was developed. We evaluated the potential of this theranostic nanocomposite for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. The nanocomposite showed multiple functions including thrombus targeting and imaging, and photothermal thrombolysis. Besides, it allowed faster release of the thrombolytic urokinase for rapidly clearing blood clots and slower release of a brown algae-derived anticoagulant fucoidan (also acting as a P-selectin ligand) for prevention of thrombosis regeneration. The nanocomposite is thus a new and advanced theranostic platform for targeted thrombolytic therapy.


Nerve compression syndromes as models for research on osteopathic manipulative treatment.
Experimental and clinical studies of nerve compression syndromes show that ischemia or edema, singly or combined, causes responses in nerves that lead to alterations in impulse conduction and to commonly observed clinical signs. Because osteopathic manipulative treatment (OMT) is thought to affect microcirculation and anatomic positioning of structures, nerve compression syndromes appear ideal as models for studying how OMT accomplishes results. We recommend that researchers develop experimental protocols or clinical studies of nerve compression syndromes that will use anatomic, histologic, and physiologic criteria to monitor the effects of OMT. Techniques such as soft tissue, muscle energy, counterstrain, or myofascial release are appropriate for study in nerve compression syndromes. Such studies are necessary to understand the biologic basis of OMT.


3,3'-Diindolylmethane induces G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia cells.
Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G(1) phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.


Chiral self-sorting of active semiflexible filaments with intrinsic curvature.
Many-body interactions in systems of active matter can cause particles to move collectively and self-organize into dynamic structures with long-range order. In cells, the self-assembly of cytoskeletal filaments is critical for cellular motility, structure, intracellular transport, and division. Semiflexible cytoskeletal filaments driven by polymerization or motor-protein interactions on a two-dimensional substrate, such as the cell cortex, can induce filament bending and curvature leading to interesting collective behavior. For example, the bacterial cell-division filament FtsZ is known to have intrinsic curvature that causes it to self-organize into rings and vortices, and recent experiments reconstituting the collective motion of microtubules driven by motor proteins on a surface have observed chiral symmetry breaking of the collective behavior due to motor-induced curvature of the filaments. Previous work on the self-organization of driven filament systems have not studied the effects of curvature and filament structure on collective behavior. In this work, we present Brownian dynamics simulation results of driven semiflexible filaments with intrinsic curvature and investigate how the interplay between filament rigidity and radius of curvature can tune the self-organization behavior in homochiral systems and heterochiral mixtures. We find a curvature-induced reorganization from polar flocks to self-sorted chiral clusters, which is modified by filament flexibility. This transition changes filament transport from ballistic to diffusive at long timescales.


Near-infrared labeled, ovalbumin loaded polymeric nanoparticles based on a hydrophilic polyester as model vaccine: In vivo tracking and evaluation of antigen-specific CD8(+) T cell immune response.
Particulate antigen delivery systems aimed at the induction of antigen-specific T cells form a promising approach in immunotherapy to replace pharmacokinetically unfavorable soluble antigen formulations. In this study, we developed a delivery system using the model protein antigen ovalbumin (OVA) encapsulated in nanoparticles based on the hydrophilic polyester poly(lactide-co-hydroxymethylglycolic acid) (pLHMGA). Spherical nanoparticles with size 300-400 nm were prepared and characterized and showed a strong ability to deliver antigen to dendritic cells for cross-presentation to antigen-specific T cells in vitro. Using near-infrared (NIR) fluorescent dyes covalently linked to both the nanoparticle and the encapsulated OVA antigen, we tracked the fate of this formulation in mice. We observed that the antigen and the nanoparticles are efficiently co-transported from the injection site to the draining lymph nodes, in a more gradual and durable manner than soluble OVA protein. OVA-loaded pLHMGA nanoparticles efficiently induced antigen cross-presentation to OVA-specific CD8+ T cells in the lymph nodes, superior to soluble OVA vaccination. Together, these data show the potential of pLHMGA nanoparticles as attractive antigen delivery vehicles.


Pediatric thoracolumbar spine trauma.
Thoracolumbar spine trauma is an important cause of morbidity and mortality in pediatric patients. Special attention to this population is necessary because several unique features of the growing pediatric spine separate these patients from adult patients. These injuries are frequently associated with high-energy trauma and concurrent thoracic or abdominal injuries that require coordinated multidisciplinary care. Thoracolumbar spine trauma in pediatric patients may lead to compression fractures, burst fractures, flexion-distraction injuries (ie, Chance fracture), fracture-dislocation injuries, apophyseal fractures/herniations, and spinous process and transverse process fractures. Depending on the nature of the injury and the patient's level of skeletal maturity, thoracolumbar spinal injuries may have substantial ability to heal and remodel. Because the impact of thoracolumbar spinal injury on pediatric patients can be devastating, appropriate early diagnosis and management, as well as long-term follow-up, are imperative.


Improved function after combined physical and mental practice after stroke: a case of hemiparesis and apraxia.
This study describes change in functional performance and self-perception after participation in combined training with physical practice followed by mental practice. The patient was a 44-yr-old white man who experienced a single left ischemic stroke 7 mo before enrollment in the study. He engaged in physical and mental practice of two functional tasks: (1) reaching for and grasping a cup and (2) turning pages in a book with the more-affected arm. Practice took place 3 times per week during 60-min sessions for 6 consecutive wk. Primary outcome measures were the Arm Motor Ability Test (AMAT) and the Canadian Occupational Performance Measure (COPM). An abbreviated version of the Florida Apraxia Battery gesture-to-verbal command test approximated severity of ideomotor apraxia. After intervention, the patient demonstrated increased functional performance (AMAT) and self-perception of performance (COPM) despite persistent ideomotor apraxia. The results of this single-case report indicate functional benefit from traditional rehabilitation techniques despite comorbid, persisting ideomotor apraxia.


Effect of age on plasma membrane asymmetry and membrane fluidity in human leukocytes and platelets.
We determined whether ageing changes in plasma membrane phospholipid asymmetry were related to changes in membrane physical characteristics. Plasma membrane asymmetry was determined in polymorphonuclear leukocytes (PMN), lymphocytes, and platelets from 45 healthy young (mean 29 years, 26 male) and 28 healthy elderly (mean 70 years, 15 male) subjects by flow cytometric measurement of annexin V binding to cell surface phosphatidylserine. Membrane fluidity in lymphocytes and platelets from young and elderly subjects was determined by fluorescence polarization of 1,6-diphenyl- 1,3,5-hexatriene (DPH) and (4-trimethylammonium)-DPH (TMA). In elderly subjects, a higher proportion of lymphocytes had specific annexin V binding to phosphatidylserine (PS) than in young subjects (young: median percentage of cells with specific annexin V binding to PS 5.3 [second to fourth quintiles range 3.8-8.7]; elderly: 8.5 [5.2-17.2]; p = .028). No ageing change in annexin V binding to PMN was observed (young: 35.0% [21.8-53.5]; elderly: 39.6% [27.4-69.8]; p = .42). Platelets had no specific annexin V binding (young: median molecules of annexin V specific binding 3.8 [0.4-11.3]; elderly: -1.4 [-4.8-1.7]; p = .23). Superficial membrane fluidity was increased in lymphocytes (TMA anisotropy, young: 0.271 [0.259-0.289]; elderly: 0.262 [0.242-0.279];p = .004), but not in platelets (young: 0.273 [0.259-0.293]; elderly: 0.269 [0.248-0.284]; p = .12). Lymphocyte annexin V binding correlated with TMA (r = -.65, p = .022), but not DPH anisotropy (r = -.39, p = .18). Plasma membrane asymmetry is decreased with age in human lymphocytes, but not in human PMN or platelets. The increased proportion of lymphocytes with loss of plasma membrane asymmetry corresponds to the ageing changes in superficial membrane fluidity observed in lymphocytes. Such alterations in lymphocyte plasma membrane structure with age could account for changes in membrane-bound receptor function described with ageing, and may contribute to alterations in immune responsiveness and vascular thrombosis seen in older humans.


Load-bearing entanglements in polymer glasses.
Through a combined approach of experiment and simulation, this study quantifies the role of entanglements in determining the mechanical properties of glassy polymer blends. Uniaxial extension experiments on 100-nm films containing a bidisperse mixture of polystyrene enable quantitative comparison with molecular dynamics (MD) simulations of a coarse-grained model for polymer glasses, where the bidisperse blends allow us to systematically tune the entanglement density of both systems. In the MD simulations, we demonstrate that not all entanglements carry substantial load at large deformation, and our analysis allows the development of a model to describe the number of effective, load-bearing entanglements per chain as a function of blend ratio. The film strength measured experimentally and the simulated film toughness are quantitatively described by a model that only accounts for load-bearing entanglements.


Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.
Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE. We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQL™ guidelines, and the consolidated criteria for reporting qualitative research (COREQ). Both child (ages 8-12 and 13-18) and parent-proxy (ages 2-4, 5-7, 8-12, and 13-18) interviews were conducted. We conducted 75 interviews to construct the new instrument. Items were identified and developed from individual focus interviews, followed by cognitive interviews for face and content validation. Initial domains of symptom frequency and severity were developed, and open-ended questions were used to generate specific items during the focus interviews. Once developed, the instrument construct, instructions, timeframe, scoring, and specific items were systematically reviewed with a separate group of patients and their parents during the cognitive interviews. To capture the full impact of pediatric EoE, both histologic findings and PROs need to be included as equally important outcome measures. We have developed the face and content validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS™ v2.0). The PEESS™ v2.0 metric is now undergoing multisite national field testing as the next iterative instrument development phase.


Effects of posture on dynamic back loading during a cable lifting task.
This study evaluated spinal loads associated with lifting and hanging heavy mining cable in a variety of postures. This electrical cable can weigh up to 10 kg per metre and is often lifted in restricted spaces in underground coal mines. Seven male subjects performed eight cable lifting and hanging tasks, while trunk kinematic data and trunk muscle electromyograms (EMGs) were obtained. The eight tasks were combinations of four postures (standing, stooping, kneeling on one knee, or kneeling on both knees) and two levels of cable load (0 N or 100 N load added to the existing cable weight). An EMG-assisted model was used to calculate forces and moments acting on the lumbar spine. A two-way split-plot ANOVA showed that increased load (p < 0.05) and changes in lifting posture (p < 0.05) independently affected trunk muscle recruitment and spinal loading. The increase in cable load resulted in higher EMG activity of all trunk muscles and increased axial and lateral bending moments on the spine (p < 0.05). Changes in posture caused more selective adjustments in muscle recruitment and affected the sagittal plane moment (p < 0.05). Despite the more selective nature of trunk EMG changes due to posture, the magnitude of changes in spinal loading was often quite dramatic. However, average compression values exceeded 3400 N for all cable lifting tasks.


The repressor element 1-silencing transcription factor is a novel molecular target for the neurotoxic effect of the polychlorinated biphenyl mixture aroclor 1254 in neuroblastoma SH-SY5Y cells.
Chronic exposure to polychlorinated biphenyls (PCBs), a class of ubiquitous environmental toxicants, causes neurocognitive anomalies. The transcription factor repressor element 1-silencing transcription factor (REST) plays a critical role in neuronal phenotype elaboration in both neural progenitor cells and non-neuronal cells. Here, we investigated the possible relationship between PCBs and REST in neuroblastoma SH-SY5Y cells. In these cells, chronic exposure to the PCB mixture Aroclor 1254 (A-1254; 5-30 μg/ml) caused dose-dependent cell death via the induction of calpain but not caspase-3. Intriguingly, this effect was prevented by the calpain inhibitor calpeptin. Furthermore, A-1254 enhanced REST mRNA and protein expression levels after both 24 and 48 h. REST down-regulation by small interfering RNA prevented A-1254-induced cell death. In addition, A-1254 enhanced the binding of REST to the synapsin 1 gene promoter, and synapsin 1 knockdown potentiated A-1254-induced cell death. A-1254 (10 μg/ml) also increased the expression of the two REST cofactors, the REST corepressor and the mammalian SIN3 homolog A transcription regulator. Moreover, the PCB mixture decreased acetylation of the histone proteins H3 and H4. It is noteworthy that the histone deacetylase inhibitor trichostatin A prevented such decreases and reduced the A-1254-induced neurotoxic effect. Collectively, these results suggest that A-1254 exerts its toxic effect via REST by down-regulating synapsin 1 and decreasing H3 and H4 acetylation.


Correlations between exercise and anger in college students.
In a sample of 76 students (56 women, 20 men) from an upper division psychology class at this large university, men's and women's scores on the Anger subscale of the Profile of Mood States and self-reported exercise (-.34 and -.39, respectively) were significantly correlated. Men also reported exercising for longer periods, while women reported exercising more intensely. Researchers might well examine behavioral measures of anger and exercise over an extended period of time in an experimental design.


A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response.
The Chk2-p53-PUMA pathway is a major regulator of DNA-damage-induced apoptosis in response to double-strand breaks in vivo. Through analysis of 53BP1 complexes we have discovered a new ubiquitin protease, USP28, which regulates this pathway. Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage. In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA. Our studies implicate DNA-damage-induced ubiquitination and deubiquitination as a major regulator of the DNA-damage response for Chk2, 53BP1, and a number of other proteins in the DNA-damage checkpoint pathway, including several mediators, such as Mdc1, Claspin, and TopBP1.


Identification of functional Tat signal sequences in Mycobacterium tuberculosis proteins.
The twin-arginine translocation (Tat) pathway is a system used by some bacteria to export proteins out from the cytosol to the cell surface or extracellular environment. A functional Tat pathway exists in the important human pathogen Mycobacterium tuberculosis. Identification of the substrates exported by the Tat pathway can help define the role that this pathway plays in the physiology and pathogenesis of M. tuberculosis. Here we used a reporter of Tat export, a truncated beta-lactamase, 'BlaC, to experimentally identify M. tuberculosis proteins with functional Tat signal sequences. Of the 13 proteins identified, one lacks the hallmark of a Tat-exported substrate, the twin-arginine dipeptide, and another is not predicted by in silico analysis of the annotated M. tuberculosis genome. Full-length versions of a subset of these proteins were tested to determine if the native proteins are Tat exported. For three proteins, expression in a Deltatat mutant of Mycobacterium smegmatis revealed a defect in precursor processing compared to expression in the wild type, indicating Tat export of the full-length proteins. Conversely, two proteins showed no obvious Tat export in M. smegmatis. One of this latter group of proteins was the M. tuberculosis virulence factor phospholipase C (PlcB). Importantly, when tested in M. tuberculosis a different result was obtained and PlcB was exported in a twin-arginine-dependent manner. This suggests the existence of an M. tuberculosis-specific factor(s) for Tat export of a proven virulence protein. It also emphasizes the importance of domains beyond the Tat signal sequence and bacterium-specific factors in determining if a given protein is Tat exported.


Reciprocal translocation t(4;7)(q14;q28) in cattle: molecular characterization.
Cytogenetic analysis of a phenotypically normal young bull from the Marchigiana breed revealed the presence of an abnormal chromosome. The finding of one oversize chromosome in all metaphases, associated with a 2n = 60, XY karyotype, suggested that a reciprocal translocation had occurred. RBG-banding and FISH analyses, using specific bovine BAC probes, identified a de novo reciprocal translocation t(4;7)(q14;q28). The presence of rcp(4;7) was confirmed by FISH experiments using BTA4 and BTA7 whole chromosome probes. An array-CGH analysis (Agilent 244A) using a bovine custom design was performed to investigate if the translocation was associated with loss or gain of genetic material. The absence of a concomitant deletion or duplication at the break points allowed the balanced state of the translocation to establish. The analysis also revealed the presence of several CNVs throughout the genome. To our knowledge this is the first time the balanced condition of a cattle RCP has been ascertained using the array-CGH approach.


On the feasibility of imaging peripheral nerves using acoustic radiation force impulse imaging.
Regional anesthesia is preferred over general anesthesia for many surgical procedures; however, challenges associated with poor image guidance limit its widespread acceptance as a viable alternative. In B-mode ultrasound images, the current standard for guidance, nerves can be difficult to visualize due to their similar acoustic impedance with surrounding tissues and needles must be aligned within the imaging plane at limited angles of approach that can impede successful peripheral nerve anesthesia. These challenges lead to inadequate regional anesthesia, necessitating intraoperative interventions, and can cause complications, including hemorrhage, intraneural injections and even nerve paralysis. ARFI imaging utilizes acoustic radiation force to generate images that portray relative tissue stiffness differences. Peripheral nerves are typically surrounded by many different tissue types (e.g., muscle, fat and fascia) that provide a mechanical basis for improved image contrast using ARFI imaging over conventional B-mode images. ARFI images of peripheral nerves and needles have been generated in cadaveric specimens and in humans in vivo. Contrast improvements of >600% have been achieved for distal sciatic nerve structures. The brachial plexus has been visualized with improved contrast over B-mode images in vivo during saline injection and ARFI images can delineate nerve bundle substructures to aid injection guidance. Physiologic motion during ARFI imaging of nerves near arterial structures has been successfully suppressed using ECG-triggered image acquisition and motion filters. This work demonstrates the feasibility of using ARFI imaging to improve the visualization of peripheral nerves during regional anesthesia procedures.


Knowledge, Attitudes and Perceptions of Secondary School Teenagers towards HIV Transmission and Prevention in Rural and Urban Areas of Central Uganda.
HIV/AIDS has remained a challenge in Uganda among adolescent despite the ABC strategy used globally to prevent HIV infection. The study assessed the knowledge, attitudes and perceptions of secondary school teenagers towards HIV transmission and prevention in rural and urban schools of central Uganda. A cross sectional study using self-administered questionnaires and structured interviews was used to collect data from adolescents in secondary schools in Kampala and Buikwe districts. Eight schools were randomly selected with 4 schools in each district. A total of 245 students from schools were recruited in the study with 120 and 125 students from urban Kampala and rural Buikwe district schools respectively. Data were analyzed using SPSS version 11. The results were expressed as percentages in a 2 × 2 tables. The mean age of the participants was 15.9 ± 2.5 years. Results showed that 95.1% participants had knowledge on HIV/AIDS in both urban and rural schools and 27.4% knew all the modes of HIV transmission. About 83.7% knew the ABC strategy for HIV prevention and 37.6% would talk about HIV/AIDS mainly with friends. For HIV cure, 62.0% of study participants reported non-cure and 24.9% were not sure. The remaining 13.1% of the study participants in both urban and rural schools reported that HIV can be cured. And the modes of curing HIV that were mentioned by participants included spiritual healing, transmitting it to others through sexual intercourse and that antiretroviral (ARVs) drugs can cure it as well as that it can be cured abroad. About 65.7% of participants reported recognition of one with HIV/ AIDS and by having red lips, being sickly; weight loss, skin rash and being very rich were mentioned. About 39.2% of the study participants mentioned that they cannot get infected with HIV and can't contract HIV at all and 18.4% believed that chances of getting HIV infection were high. On perception and attitude on condoms and their use, participants reported that it is a sign of mistrust, reduces sexual pleasures and they are embarrassing to buy. Majority of the participants in both urban and rural schools had some knowledge on HIV/AIDS and the ABC strategy for HIV prevention. However, there was a knowledge gap on the various modes of HIV transmission and prevention. There was misconception of the participants on HIV/AIDS cure, condom use and on the chances of contracting HIV. About the source of HIV/AIDS information, majority of the participants were getting information on HIV/AIDS from friends of which some information was misleading. This false information could be the reason for the increased HIV prevalence reported among the adolescents in the schools. Generally, participants had some knowledge on HIV/AIDS though they had knowledge gap on HIV transmission and prevention.


Interpersonal communication campaign promoting knowledge, attitude, intention, and consumption of iron folic acid tablets and iron rich foods among pregnant Indonesian women.
Indonesia's community health delivery system offers services such as prenatal care and supplementation. Despite accessibility to these services, compliance with supplementation is low, and childhood stunting rates remain high. To address undernutrition, a National Nutrition Communication Campaign (NNCC) - using interpersonal communication (IPC) strategies - was implemented to promote consumption of iron-folic acid (IFA) supplements and iron-rich foods (ATIKA). The purpose of this study was to understand how participation in IPC activities influenced knowledge, attitude/intention, and consumption of IFA supplements and ATIKA among pregnant Indonesian women. Cross-sectional data came from 766 pregnant women that participated in a survey that was based on the constructs from the Theory of Planned Behavior and Health Belief Model. Adjusted linear and logistic regression models were conducted to analyze the differences between self-reported IPC participants and non-IPC participants. Approximately 20% of women were exposed to the IFA portion of the IPC campaign, and 18% were exposed to the ATIKA portion. Women that were exposed to the campaign reported significantly higher knowledge of IFA tablets and ATIKA, and improved attitudes/intentions towards IFA, compared to non-exposed women. Exposure was not associated with actual consumption behaviors. These findings suggest that exposure to a low-intensity intervention can increase knowledge but may not be sufficient to impact behavior. As such, future efforts to reduce stunting through improved maternal nutrition should seek to increase exposure, address barriers, understand perceived susceptibility, and improve self-efficacy in order to expand intervention reach in Indonesia.


Serotonin Dysfunction, Aggressive Behavior, and Mental Illness: Exploring the Link Using a Dimensional Approach.
Aggressive individuals have higher rates of mental illness compared to non-aggressive individuals. Multiple factors, including psychosocial, genetic, and neurobiological determinants modulate the liability to both aggressive behavior and mental illness. Concerning the latter factors, multiple lines of evidence have shown a dysfunction in the serotonin (5-HT) system occurring in aggressive and in mentally ill individuals. In particular, reduced 5-HT activity has been associated with depression as well as with aggressive behavior, especially with impulsive aggression. Consistently, psychopharmacological interventions aimed at boosting the 5-HT system (e.g., with selective serotonin reuptake inhibitors) have demonstrated therapeutic efficacy in a high percentage of patients with either or both pathological conditions. Current knowledge does not yet allow to clearly disentangle whether 5-HT dysfunction, most often a 5-HT deficiency, is the cause or the consequence of the aggressive/violent behavior, of the underlying mental disease/s, or the expression of the comorbidity. Future studies are thus needed to clarify the association between changes in 5-HT levels, altered activity of 5-HT receptors and their intracellular signaling cascades, and modifications of 5-HT genes, and in particular the neurobiological link between the altered 5-HT machinery and aggressive behavior in the context or in the absence of mental illness. In this Review, we employ a dimensional approach to discuss the trivariate relationship among the 5-HT system, aggressive behavior, and mental illness, focusing our attention on 5-HT levels, 5-HT receptors, metabolic enzymes, and their genes. Emphasis is given to controversial findings, still unanswered questions, and future perspectives.


Deciduous and evergreen oaks show contrasting adaptive responses in leaf mass per area across environments.
Increases in leaf mass per area (LMA) are commonly observed in response to environmental stresses and are achieved through increases in leaf thickness and/or leaf density. Here, we investigated how the two underlying components of LMA differ in relation to species native climates and phylogeny, across deciduous and evergreen species. Using a phylogenetic approach, we quantified anatomical, compositional and climatic variables from 40 deciduous and 45 evergreen Quercus species from across the Northern Hemisphere growing in a common garden. Deciduous species from shorter growing seasons tended to have leaves with lower LMA and leaf thickness than those from longer growing seasons, while the opposite pattern was found for evergreens. For both habits, LMA and thickness increased in arid environments. However, this shift was associated with increased leaf density in evergreens but reduced density in deciduous species. Deciduous and evergreen oaks showed fundamental leaf morphological differences that revealed a diverse adaptive response. While LMA in deciduous species may have diversified in tight coordination with thickness mainly modulated by aridity, diversification of LMA within evergreens appears to be dependent on the infrageneric group, with diversification in leaf thickness modulated by both aridity and cold, while diversification in leaf density is only modulated by aridity.


Purification of an Intact Human Protein Overexpressed from Its Endogenous Locus via Direct Genome Engineering.
The overproduction and purification of human proteins is a requisite of both basic and medical research. Although many recombinant human proteins have been purified, current protein production methods have several limitations; recombinant proteins are frequently truncated, fail to fold properly, and/or lack appropriate post-translational modifications. In addition, such methods require subcloning of the target gene into relevant plasmids, which can be difficult for long proteins with repeated domains. Here we devised a novel method for target protein production by introduction of a strong promoter for overexpression and an epitope tag for purification in front of the endogenous human gene, in a sense performing molecular cloning directly in the human genome, which does not require cloning of the target gene. As a proof of concept, we successfully purified intact human Reelin protein, which is lengthy (3460 amino acids) and contains repeating domains, and confirmed that it was biologically functional.


Multifaceted programmed cell death in the mammalian fetal ovary.
From previous and more recent works reviewed in the present paper, it appears that mammalian fetal oocytes face several challenges to survive throughout the stages of meiotic prophase I up to the block at the diplotene/dictyate stage and the primordial follicle assembly. Depending on the period of development and experimental conditions, these oocytes can undergo different forms of programmed cell death (PCD) and cross-talking pathways. We hypothesize that they require the continuous support of growth factors to accomplish the activities required to overcome PCD during prophase I. An extraordinary level of DNA double strand break (DSB) tolerance characterizes oocytes during the first stages of meiotic prophase I. However, the activation of a p63/p53-and PCNA-dependent DNA damage checkpoint, plays a major role in eliminating defective oocytes when they reach the diplotene stage. Before oocytes are enclosed into a primordial follicle, the shortness of nutrients/growth factors might activate protective autophagy but this can turn into their death if starvation is prolonged. Actually, clarifying the relationships among growth factor signalling (mainly AKT cascade), apoptotic and autophagic proteins that seem to coexist in fetal oocytes, could be the key to understanding PCD in these cells.


Elasticity and physico-chemical properties during drinking water biofilm formation.
Atomic force microscope techniques and multi-staining fluorescence microscopy were employed to study the steps in drinking water biofilm formation. During the formation of a conditioning layer, surface hydrophobic forces increased and the range of characteristic hydrophobic forces diversified with time, becoming progressively complex in macromolecular composition, which in return triggered irreversible cellular adhesion. AFM visualization of 1 to 8 week drinking water biofilms showed a spatially discontinuous and heterogeneous distribution comprising an extensive network of filamentous fungi in which biofilm aggregates were embedded. The elastic modulus of 40-day-old biofilms ranged from 200 to 9000 kPa, and the biofilm deposits with a height >0.5 μm had an elastic modulus <600 kPa, suggesting that the drinking water biofilms were composed of a soft top layer and a basal layer with significantly higher elastic modulus values falling in the range of fungal elasticity.


Dispositional optimism and recovery from coronary artery bypass surgery: the beneficial effects on physical and psychological well-being.
The effect of dispositional optimism on recovery from coronary artery bypass surgery was examined in a group of 51 middle-aged men. Patients provided information at three points in time--(a) on the day before surgery, (b) 6-8 days postoperatively, and (c) 6 months postoperatively. Information was obtained relating to the patient's rate of physical recovery, mood, and postsurgical quality of life. Information was also gathered regarding the manner in which the patients attempted to cope with the stress of the surgery and its aftermath. As expected, dispositional optimism proved to be an important predictor of coping efforts and of surgical outcomes. More specifically, dispositional optimism (as assessed prior to surgery) correlated positively with manifestations of problem-focused coping and negatively with the use of denial. Dispositional optimism was also associated with a faster rate of physical recovery during the period of hospitalization and with a faster rate of return to normal life activities subsequent to discharge. Finally, there was a strong positive association between level of optimism and postsurgical quality of life at 6 months.


Consumption of a polyphenol-rich grape-wine extract lowers ambulatory blood pressure in mildly hypertensive subjects.
Polyphenols in grape and wine have been suggested to contribute to the cardiovascular health benefits of the Mediterranean lifestyle. The reported effects of grape products on blood pressure (BP) remain, however, equivocal. In a double-blind placebo controlled crossover study, the effect of two grape extracts on BP and vascular function was assessed in 60 untreated, mildly hypertensive subjects after four weeks intervention. Both extracts (grape-red wine and grape alone) had high concentrations of anthocyanins and flavonols, but the grape alone was relatively poor in catechins and procyanidins. Parameters measured included ambulatory and office BP, flow-mediated vasodilation, arterial distensibility, platelet function and plasma lipoproteins. Results showed that 24-hour ambulatory systolic/diastolic BPs were significantly lower in the grape-wine extract intervention (135.9 ± 1.3/84.7 ± 0.8 mmHg; mean ± SEM) compared to placebo (138.9 ± 1.3/86.6 ± 1.2 mmHg), predominantly during daytime. Plasma concentrations of the vasoconstrictor endothelin-1 decreased by 10%, but other measures of vascular function were not affected. Grape juice extract alone had no effect on BP or any measures of vascular function. Polyphenol-rich food products, and may be specifically catechins and procyanidins, may thus help sustain a healthy BP and contribute to the healthy Mediterranean lifestyle.


Isolation of ATMEKK1 (a MAP kinase kinase kinase)-interacting proteins and analysis of a MAP kinase cascade in Arabidopsis.
In plants, a number of MAP kinase (MAPK), MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK) homologues have been reported. However, there have been no reports of protein-protein interactions between these kinases or molecular analysis of MAPK cascades in higher plants. To analyze a possible MAPK cascade in Arabidopsis thaliana, we took two molecular approaches. One is the two-hybrid screening of ATMEKK1 (a MAPKKK)-interacting proteins; the other is an analysis of physical and functional interactions among isolated MAPK, MAPKK, and MAPKKK homologues from Arabidopsis. In two-hybrid screening using ATMEKK1 as bait, we isolated a novel MAPKK homologue, ATMKK2, a MAPK homologue, ATMPK4, and an unknown protein. ATMKK2 has high sequence similarity with MEK1 (a MAPKK) in Arabidopsis. Based on yeast two-hybrid analysis, we detected protein-protein interactions between ATMEKK1 and ATMKK2/MEK1 (MAPKKs), between ATMKK2/MEK1 and ATMPK4 (a MAPK), and between ATMPK4 and ATMEKK1. ATMPK4 and ATMKK2/MEK1 interacted with two distinct regions of ATMEKK1, the N-terminal regulatory domain and the C-terminal kinase domain, respectively. Coexpression of ATMEKK1 increased the ability of two closely related MAPKKs, ATMKK2 and MEK1, to complement a growth defect of the yeast pbs2 mutant. Coexpression of ATMPK4 and MEK1 complemented a growth defect of the yeast mpk1 and bck1 mutants. By contrast, other combinations of MAPKs and MAPKKs did not suppress these yeast mutations. These results suggest that ATMEKK1, ATMKK2/MEK1, and ATMPK4 may constitute a MAP kinase cascade.


Results From Sweden's 2016 Report Card on Physical Activity for Children and Youth.
The 2016 Swedish Report Card on Physical Activity (PA) for Children and Youth is a unique compilation of the existing physical and health related data in Sweden. The aim of this article is to summarize the procedure and results from the report card. Nationally representative surveys and individual studies published between 2005-2015 were included. Eleven PA and health indicators were graded using the Active Healthy Kids Canada grading system. Grades were assigned based on the percentage of children/youth meeting a defined benchmark (A: 81% to 100%, B: 61% to 80%, C: 41% to 60%, D: 21% to 40%, F: 0% to 20%, or incomplete (INC). The assigned grades were Overall Physical Activity, D; Organized Sport Participation, B+; Active Play, INC; Active Transportation, C+; Sedentary Behaviors, C; Family and Peers, INC; School, C+; Community and the Built Environment, B; Government Strategies and Investments, B; Diet, C-; and Obesity, D. The included data provides some support that overall PA is too low and sedentary behavior is too high for almost all age groups in Sweden, even with the many national policies as well as an environment that is favorable to the promotion of PA.


Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction.
Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology. Antigen-induced arthritis (AIA) was established in IL-10KO mice and wild-type controls. Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies, we explored the regulation of inflammasome components. These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays. In AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores. Here, focal bone erosions were associated with increased tartrate-resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1β. When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components. Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1. In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis. These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.


Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians.
Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5-20 years) and adulthood (ages 20-45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.


Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain.
The detrimental effect of neuronal cell death due to oxidative stress and mitochondrial dysfunction has been implicated in age-related cognitive decline and neurodegenerative disorders such as Alzheimer's disease. The Indian herb Bacopa monnieri is a dietary antioxidant, with animal and in vitro studies indicating several modes of action that may protect the brain against oxidative damage. In parallel, several studies using the CDRI08 extract have shown that extracts of Bacopa monnieri improve cognitive function in humans. The biological mechanisms of this cognitive enhancement are unknown. In this review we discuss the animal studies and in vivo evidence for Bacopa monnieri as a potential therapeutic antioxidant to reduce oxidative stress and improve cognitive function. We suggest that future studies incorporate neuroimaging particularly magnetic resonance spectroscopy into their randomized controlled trials to better understand whether changes in antioxidant status in vivo cause improvements in cognitive function.


Performance of Tuberculin Skin Test Measured against Interferon Gamma Release Assay as Reference Standard in Children.
Objectives. International guidelines differ in the threshold of tuberculin skin test (TST) induration regarded as indicating Mycobacterium (M.) tuberculosis infection. Interferon gamma release assay (IGRA) results were used as reference to assess performance of TST induration thresholds for detection of M. tuberculosis infection in children. Design. Systematic review which included studies containing data on TST, IGRA, and Bacillus Calmette-Guérin (BCG) status in children. Data bases searched were PubMed, EMBASE, and the Cochrane library. Specificities and sensitivities were calculated for TST thresholds 5, 10, and 15 mm and correlated with age and geographical latitude. Results. Eleven studies with 2796 children were included. For BCG immunised children diameters of 5, 10, and 15 mm had median sensitivities of 87, 70, and 75% and specificities of 67, 93, and 90%, respectively. In non-BCG immunised children median sensitivities were 94, 95, and 83% and specificities 91, 95, and 97%. At the 10 mm threshold age correlated negatively with sensitivity of TST (r = -0.65, P = 0.04) and latitude correlated positively (r = 0.71, P = 0.02). Conclusions. For the 10 mm threshold the sensitivity of the TST is lower in BCG immunised children. Younger age and higher geographical latitude were associated with higher sensitivity of the TST.


Inter-facility patient transfers in ontario: do you know what your local ambulance is being used for?
Little is known about inter-facility patient transfers in populations. In 2003, detailed information about inter-facility patient transfers began to be systematically collected in Ontario. The authors undertook a descriptive examination of inter-facility patient transfers using a newly created population-based information system. Approximately 1,000 inter-facility patient transfers occur in Ontario each day, and every day and a half, the total distance travelled for these transfers equals the distance around the earth's circumference. The annual cost for patient transfers is approximately $283 million. Most common were routine and non-urgent inter-facility patient transfers. Eighty-five thousand patients (24.3% of transferred patients) were transported between healthcare facilities for dialysis appointments, appointments with physicians and return trips home. Patients with circulatory conditions were the most commonly transferred diagnostic group. Although 70% of all transfers were within 25 kilometres, some were for longer distances: for example, those involving pregnant women and newborn babies required travelling a median distance of 40.3 kilometres for continued care. Cardiac patients (54,000 patient transfers per year) travelled a median of 24.2 kilometres to reach a catheterization lab for treatment and further investigation. There was considerable lateral movement between academic health sciences centres (AHSCs). Over 16,000 patients per year (4.7% of all transfers) were transferred from one AHSC to another, predominantly for cardiac care. Patients in Ontario are often transferred between healthcare facilities. Most transfers are for routine, non-life-threatening reasons, using the Emergency Medical Services (EMS) system. This practice diverts resources from more emergent requests. Although patient transportation is a necessary part of any healthcare system, the results of this study highlight the current demands on a system that was not intended for the volume of inter-facility patient transfers it is supporting. These results call into question the use of sophisticated, highly trained, expensive patient transfer resources to provide routine medical services in Ontario.


Varicose veins: facts and fantasy.
The high prevalence of varicose veins in Western countries contrasts with their relative rarity in traditionally living communities in the Third World. Evidence is presented in support of the hypothesis that a major causative factor is the transmission of raised intra-abdominal pressures to the veins of the legs. One important cause of these pressures is the abdominal straining necessitated to evacuate small firm stools, which in turn are the result of fiber-depleted diets.


Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis.
Ivacaftor (Kalydeco(®), Vertex Pharmaceuticals) is the first of a new class of drugs that target the underlying protein defect in cystic fibrosis (CF). It is aimed at patients with the G551D (glycine to aspartate change in nucleotide 1784 in exon 11) mutation; 5.7% of patients with CF in the UK have this mutation. To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged ≥ 6 years who have the G551D mutation. Ten databases, including MEDLINE and EMBASE, were searched from inception to July 2012. Studies that evaluated ivacaftor for the treatment of adults and children (≥ 6 years) with at least one G551D mutation were eligible. There were insufficient data to conduct a formal meta-analysis. The manufacturer of ivacaftor, Vertex Pharmaceuticals, submitted a deterministic patient-level simulation model for the assessment of the lifetime cost-effectiveness of ivacaftor. We modified the model where values were not UK-specific or not recent, or where better estimates could be found. The only change to the model structure was the addition of lung transplantations. We changed utility values, annual decline in percentage predicted forced expiratory volume in 1 second (FEV1), and the baseline exacerbation rate, and used data from the CF Registry to estimate the relation between costs, age and percentage predicted FEV1. Estimates of treatment effect of ivacaftor came from the clinical effectiveness review. We modelled three scenarios for the longer-term effects of ivacaftor. We also modelled an 'optimistic' scenario for patients aged < 12 years with little lung damage. We conducted a budget impact analysis to estimate the total cost to the NHS of introducing ivacaftor in England. Three studies were included: a randomised controlled trial (RCT) in adults (n = 167) (≥ 12 years), a RCT in children (n = 26) (6-11 years), and an open-label extension study of the two RCTs. Both RCTs reported significantly greater changes from baseline in all measures of lung function in patients receiving ivacaftor than in those receiving placebo. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults' study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children's study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group. The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M. The available evidence suggests that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor. This study is registered as PROSPERO CRD42012002516. The National Institute for Health Research Health Technology Assessment programme.


Assessment of codependency behavior in two health student groups.
The present study examines the relationship between codependency and caregiving to determine whether codependent persons tend to be attracted to caregiving professions. The study also examined the relationship between codependency, self-esteem, and locus of control, as measured by the Friel Co-Dependency Assessment Inventory (Friel, 1985; Friel & Friel, 1987), the Tennessee Self-Concept Scale (Fitts, 1965), and the Internal-External Locus of Control Scale (Rotter, 1966), respectively. Voluntary participants consisted of 15 occupational therapy students and 15 health information administration (HIA) students believed to be different from one another with respect to the caregiving aspects of their respective professions. The occupational therapy group scored significantly lower than the HIA group on the measure of codependency (m = 21.2 vs. m = 28.8, respectively) [t(28) = 2.258, p = 05]. No other significant differences were noted between groups for the other test scores. Only codependency scores between 31 and 60, that is, moderate-to-severe and severe concerns (n = 6), had a strong correlation with self-esteem scores (r = -.974) and a moderate correlation with locus of control scores (r = .683). No student in the occupational therapy group scored within the moderate-to-severe or severe range. The results did not support a relationship between codependency and choice of a caregiving-oriented profession. Further, only moderate-to-severe and severe codependency scores were indicative of low self-esteem and high external locus of control. Implications of this study suggest incorporation into the academic preparation of occupational therapy students information regarding codependency and self-assessment of codependency to facilitate awareness of the student's need to nurture others.(ABSTRACT TRUNCATED AT 250 WORDS)


Trypanotolerance in N'Dama x Boran crosses under natural trypanosome challenge: effect of test-year environment, gender, and breed composition.
Trypanosomosis, a protozoal disease affecting livestock, transmitted by Glossina (tsetse) flies is a major constraint to agricultural production in Sub-Saharan Africa. It is accepted that utilization of the native trypanotolerance exhibited in some of the African cattle breeds to improve trypanotolerance of more productive but susceptible breeds, will offer a cost effective and sustainable solution to the problem. The success of this approach is based on the premise that quantitative trait loci previously identified under relatively controlled situations confer useful trypanotolerance under natural field situations. As part of a study to authenticate this hypothesis, a population of 192 cattle, consisting of six batches of N'Dama and Kenya-Boran backcross animals [(N'Dama x Kenya-Boran) x Kenya-Boran] born over the period 2002 to 2006 was constructed. Some of the batches also included pure Kenya-Boran cattle, or N'Dama x Kenya- Boran F1 animals. Each batch was exposed as yearlings to natural field trypanosomosis challenge over a period of about one year; the entire challenge period extending from December 2003 to June 2007. Performance of the animals was evaluated by weekly or biweekly measurements of body weight, packed blood cell volume (PCV), parasitemia score, and number of trypanocide treatments. From these basic data, 49 phenotypes were constructed reflecting dynamics of body weight, packed cell volume (PCV) and parasitemia under challenge. Females were distinctly more trypanotolerant than males. F1, backcross and pure Kenya- Boran animals ranked in that order with respect to trypanotolerance. Overall batch effects were highly significant (p<0.001) for most traits, and were generally more significant than the gender or genetic type effects. The superior trypanotolerance of the F1 animals was expressed in all three components of animal defense strategies against pathogens: Avoidance resistance, and tolerance. The results show that trypanotolerance derived from the N'Dama is expressed under field conditions; and that the trait is primarily additive in nature, being expressed in heterozygous condition and in a three-quarters Boran genetic background. The results further, underscore the complexity of the trait in the field manifesting all three host disease-control strategies, and show the importance of gender and local environmental conditions in determining response to challenge.


Packaged, high-Q, microsphere-resonator-based add-drop filter.
In this Letter a packaged add-drop filter composed of a silica microsphere resonator and two fiber tapers is demonstrated theoretically and experimentally. A two-step fabrication process using an UV curable polymer is shown to stabilize the microsphere resonator with a diameter of 153 μm coupled to two tapered microfibers with diameters of 1.5 μm which are used as add and drop ports. A high loaded quality factor (Q-factor) of 0.9×10(5) and a free spectral range (FSR) of about 104 pm are obtained at around 1550 nm from the microsphere for the parallel coupling tapered fibers in the add-drop configuration. This device has a range of advantages, such as ease of fabrication, low-cost, and compatibility with traditional and commercial fiber systems.


New perspectives in human stem cell therapeutic research.
Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating beta islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.


Thiopental is better than propofol for electroconvulsive therapy.
electroconvulsive therapy is a psychiatric procedure requiring general anesthesia. The choice of the hypnotic agent is important because the success of the intervention is associated to the occurrence and duration of motor convulsion. However, all available anesthetic agents have anti-convulsant activity. We compared the effect of thiopental and propofol on seizures. We designed a retrospective study at Mood Disorders Unit of a teaching Hospital. Fifty-six consecutive patients undergoing electroconvulsive therapy were enrolled. Patients received fentanyl followed by either thiopental or propofol. We evaluated the incidence and the duration of seizure after electric stimulus at the first session of electroconvulsive therapy for each patient. Adverse perioperative effects were recorded. Patients were 60±12.1 years old and 64% was female. There was a statistically significant higher number of patients who had motor convulsion activity in the thiopental group when compared to the propofol group (25 vs 13, p=0.023). Seizure duration was statistically significant longer in the thiopental group than in the propofol group (35 sec vs 11 sec, p=0.046). No hemodynamic instability, oxygen desaturation episodes, prolonged recovery time from anesthesia and adverse effects related to anesthesia were recorded. Thiopental induction has a favourable effect on seizure when compared to propofol in patients undergoing electroconvulsive therapy.


The effects of long-term prenatal exposure to 900, 1800, and 2100 MHz electromagnetic field radiation on myocardial tissue of rats.
It is well-known that wireless communication technologies facilitate human life. However, the harmful effects of electromagnetic field (EMF) radiation on the human body should not be ignored. In the present study, we evaluated the effects of long-term, prenatal exposure to EMF radiation on the myocardium of rats at varying durations. Overall, 18 pregnant Sprague-Dawley rats were assigned into six groups (n = 3 in each group). In all groups other than the control group, three pregnant rats were exposed to EMF radiation (900, 1800 and 2100 MHz) for 6, 12 and 24 h over 20 days. After delivery, the newborn male pups were identified and six newborn male pups from each group were randomly selected. Then, histopathological and biochemical analysis of myocardial samples were performed. When 24-h/day prenatal exposures to 900, 1800, 2100 MHz EMF radiation were evaluated, myocardial damage was greater in the 2100 MHz EMF-24h group than the other groups. In addition, when malondialdehyde (MDA) and glutathione (GSH) levels associated with reactive oxidative species (ROS) were evaluated, the MDA level was higher in the 2100 MHz EMF-24h group compared with the other groups. The GSH level was also lower in the 2100 MHz EMF-24h group. When the 6, 12 and 24 h/day prenatal exposures to 1800 MHz EMF radiation were evaluated, myocardial damage was greater in 1800 MHz EMF-24h group than the remaining groups (p < 0.0001). Also, MDA level was greater in the 1800 MHz EMF-24h group compared with the other groups while the GSH level was lower in this group. It was shown that myocardial tissue was affected more by long-term exposure to EMF radiation at high frequencies. The data raise concerns that the harmful effects of non-ionizing radiation exposure on cardiac tissue will increase with 5G technology.


Rhinosurgery in children: basic concepts.
In newborns, the main supporting structure of the nose is the dorsoseptal cartilage, a T-bar-formed complex of septum and upper lateral cartilages, which is essentially an external extension of the cartilage of the anterior cranial base. Later the anatomic situation gradually changes -- a potential pitfall for surgeons and radiologists. The vulnerability of various processes underlying postnatal development of the facial skeleton is discussed. The cartilaginous septum is the dominant growth center. Loss of septal cartilage at different ages leads to different facial syndromes involving nose, maxilla, and orbita. The septal cartilage in children demonstrates thinner fracture-prone areas next to thicker growth zones. Septum fractures have a preference for the thinner regions, corresponding with the most frequent septum deviations observed in growing children. The essential problem in pediatric rhinosurgery is not the age-specific anatomy but the poor wound-healing capacity: fractured or transected septum cartilage will not heal, and disconnected ends tend to overlap, resulting in increasing or recurrent deviations. Based on clinical and experimental evidence, indications and "safe" and "unsafe" techniques of rhinosurgery are presented for children of various age groups.


Quantitation of extrahepatic metabolism. Pulmonary and intestinal conjugation of naphthol.
There is much evidence in the literature to indicate extrahepatic conjugation of naphthol by various isolated tissue preparations. Using in vivo methodology, where multiple sites of input are employed, it has been demonstrated that both lung and intestinal mucosa make a significant contribution in the conjugation of naphthol in the rat. Under the conditions studied, both of the above organs (pulmonary extraction ratio 0.44, intestinal extraction ratio 0.46) are more than twice as effective as the liver in eliminating naphthol (hepatic extraction ratio 0.18). This multiple sites of input method has been compared with a multiple sites of sampling method. Similar results have been obtained in quantifying pulmonary conjugation of naphthol. The relevant merits of the two approaches are discussed.