Task specificity of cross-tolerance between Delta9-tetrahydrocannabinol and anandamide analogs in mice.
Relatively few studies have compared the effects of tetrahydrocannabinols and anandamide-like cannabinoids following repeated dosing. Whereas pronounced tolerance develops to many of the in vivo pharmacological effects of Delta9-tetrahydrocannabinol with repeated dosing, tolerance to anandamide-induced effects is typically less noted. In the present study, we examined cross-tolerance between Delta9-tetrahydrocannabinol and anandamide-like compounds (anandamide, 2-methylanandamide, and O-1812) in a tetrad of in vivo tests sensitive to cannabinoid action, including spontaneous activity, tail flick, rectal temperature, and a ring immobility test of catalepsy. Six intraperitoneal injections of Delta9-tetrahydrocannabinol 10 mg/kg over a period of 4 days resulted in the development of pronounced tolerance to all of its in vivo effects. In contrast, task specificity was observed in cross-tolerance to anandamide and its analogs: antinociception (all three compounds), suppression of spontaneous activity (2-methylanandamide and O-1812), catalepsy (O-1812), and hypothermia (none of the compounds). Furthermore, when it occurred, the magnitude of cross-tolerance was notably smaller. These results suggest that anandamide-like cannabinoids may have a unique pharmacology that only partially overlaps with that of Delta9-tetrahydrocannabinol and other traditional cannabinoids. Although the basis for this unique pharmacology has not as yet been determined, it is possible that regional specificity of cannabinoid CB1 receptor downregulation and endocannabinoid release induced by repeated dosing with Delta9-tetrahydrocannabinol may play a role.


Brachial plexus trauma: the morbidity of hemidiaphragmatic paralysis.
Phrenic nerve palsy has previously been associated with brachial plexus root avulsion; severe unilateral phrenic nerve injury is not uncommonly associated with brachial plexus injury. Brachial plexus injuries can be traumatic (gunshot wounds, lacerations, stretch/contusion and avulsion injuries) or non-traumatic in aetiology (supraclavicular brachial plexus nerve block, subclavian vein catheterisation, cardiac surgeries, or obstetric complications such as birth palsy). Despite the known association, the incidence and morbidity of a phrenic nerve injury and hemidiaphragmatic paralysis associated with traumatic brachial plexus stretch injuries remains ill-defined. The incidence of an associated phrenic nerve injury with brachial plexus trauma ranges from 10% to 20%; however, because unilateral diaphragmatic paralysis often presents without symptoms at rest, a high number of phrenic nerve injuries are likely to be overlooked in the setting of brachial plexus injury. A case report is presented of a unilateral phrenic nerve injury associated with brachial plexus stretch injury presenting with a recalcitrant left lower lobe pneumonia.


A Taiwanese Propolis Derivative Induces Apoptosis through Inducing Endoplasmic Reticular Stress and Activating Transcription Factor-3 in Human Hepatoma Cells.
Activating transcription factor-(ATF-) 3, a stress-inducible transcription factor, is rapidly upregulated under various stress conditions and plays an important role in inducing cancer cell apoptosis. NBM-TP-007-GS-002 (GS-002) is a Taiwanese propolin G (PPG) derivative. In this study, we examined the antitumor effects of GS-002 in human hepatoma Hep3B and HepG2 cells in vitro. First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners. Several main apoptotic indicators were found in GS-002-treated cells, such as the cleaved forms of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). GS-002 also induced endoplasmic reticular (ER) stress as evidenced by increases in ER stress-responsive proteins including glucose-regulated protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153), phosphorylated eukaryotic initiation factor 2 α (eIF2 α ), phosphorylated protein endoplasmic-reticular-resident kinase (PERK), and ATF-3. The induction of ATF-3 expression was mediated by mitogen-activated protein kinase (MAPK) signaling pathways in GS-002-treated cells. Furthermore, we found that GS-002 induced more cell apoptosis in ATF-3-overexpressing cells. These results suggest that the induction of apoptosis by the propolis derivative, GS-002, is partially mediated through ER stress and ATF-3-dependent pathways, and GS-002 has the potential for development as an antitumor drug.


Elastic stability, free vibrations, and bending of optical glass fibers: effect of the nonlinear stress-strain relationship.
We evaluate the effect of the nonlinear stress-strain relationship on elastic stability, free vibrations, and bending of optical glass fibers. The analysis is carried out under an assumption that this relationship, obtained for the case of uniaxial tension is also valid in the case of compression, and is applicable to bending deformations as well. We examine low-temperature microbending of infinitely long dual-coated fibers, elastic stability of short bare fibers, free vibrations of long fused portions of light-wave couplers that are subjected to uniaxial tension, and bending deformations of optical fibers that experience large deflections. We conclude that the nonlinear stress-strain relationship in silica materials can have a significant effect on the mechanical behavior of optical fibers and that, since the experimental data were obtained for tensile strains not exceeding 5%, future experimental research should include evaluation of the nonlinear stress-strain relationship, both in tension and compression, for higher strains and for high-strength fibers (such as, for instance, fibers protected by metallic coatings).


Medication errors in intensive care units: nurses' training needs.
To describe which elements of nurses' knowledge, training, behaviour and attitude can prevent errors in intensive care units during all steps of the administration of intravenous medication. An anonymous questionnaire made up of 43 items was drafted and delivered to a sample of 123 nurses at 2 university hospitals in Rome. The majority of the sample (96.7%) stated that topics related to the preparation and administration of intravenous medications were covered during the basic nursing course. Just over 95% of the sample considered it important to improve their knowledge about preparation and administration of intravenous medications; 94.3% said that teaching about the use of intravenous medications should be enhanced during the degree course they attended and 91.1% agreed that specific postgraduate courses should be set up on the use of intravenous drugs. Pharmacological knowledge is a prerequisite for the proper administration of drugs and for the clinical evaluation of the effects on the patient. This knowledge implies the understanding of the theoretical and clinical principles of pharmacology, the ability to contextualise medication management according to the complex and changing needs of patients, and it also includes the appropriate skills of drug administration.


The dominant cold-sensitive Out-cold mutants of Drosophila melanogaster have novel missense mutations in the voltage-gated sodium channel gene paralytic.
Here we report the molecular characterization of Out-cold (Ocd) mutants of Drosophila melanogaster, which produce a dominant, X-linked, cold-sensitive paralytic phenotype. From its initial 1.5-Mb cytological location within 13F1-16A2, P-element and SNP mapping reduced the Ocd critical region to <100 kb and to six candidate genes: hangover, CG9947, CG4420, eIF2a, Rbp2, and paralytic (para). Complementation testing with para null mutations strongly suggests Ocd and para are allelic, as does gene rescue of Ocd semilethality with a wild-type para transgene. Pesticide resistance and electrophysiological phenotypes of Ocd mutants support this conclusion. The para gene encodes a voltage-gated sodium channel. Sequencing the Ocd lines revealed mutations within highly conserved regions of the para coding sequence, in the transmembrane segment S6 of domain III (I1545M and T1551I), and in the linker between domains III and IV (G1571R), the location of the channel inactivation gate. The G1571R mutation is of particular interest as mutations of the orthologous residue (G1306) in the human skeletal muscle sodium channel gene SCN4A are associated with cases of periodic paralysis and myotonia, including the human cold-sensitive disorder paramyotonia congenita. The mechanisms by which sodium channel mutations cause cold sensitivity are not well understood. Therefore, in the absence of suitable vertebrate models, Ocd provides a system in which genetic, molecular, physiological, and behavioral tools can be exploited to determine mechanisms underlying sodium channel periodic paralyses.


Magnesium in addiction - a general view.
Addiction is a dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and loss of control over drug-taking. Addiction is a brain disease. There is evidence that magnesium deficit is involved in addiction to various addictive substances (heroin, morphine, cocaine, nicotine, alcohol, caffeine, and others). Magnesium is involved in all the stages of addiction. Magnesium deficit enhances the vulnerability to psychoactive substance addiction. Stress and trauma reduce the brain magnesium level and at the same time favor addiction development. In experimental studies, administration of magnesium while inducing morphine dependence in rats reduced the dependence intensity. Magnesium reduces the NMDA receptor activity and the glutamatergic activity. Because stress and trauma induce hypomagnesemia with increased vulnerability to addiction, magnesium intake by people who are under prolonged stress could be a way to reduce this vulnerability and the development of addiction to different psychoactive substances. Anxiety and depression appear to be associated with increases in drug-related harm and addictive substance use. Magnesium anxiolytic effect could be important for the antiaddictive action. Addiction is characterized by relapses. Magnesium deficiency may be a contributing factor to these relapses.


The 5 R's: an emerging bold standard for conducting relevant research in a changing world.
Research often fails to find its way into practice or policy in a timely way, if at all. Given the current pressure and pace of health care change, many authors have recommended different approaches to make health care research more relevant and rapid. An emerging standard for research, the "5 R's" is a synthesis of recommendations for care delivery research that (1) is relevant to stakeholders; (2) is rapid and recursive in application; (3) redefines rigor; (4) reports on resources required; and (5) is replicable. Relevance flows from substantive ongoing participation by stakeholders. Rapidity and recursiveness occur through accelerated design and peer reviews followed by short learning/implementation cycles through which questions and answers evolve over time. Rigor is the disciplined conduct of shared learning within the specific changing situations in diverse settings. Resource reporting includes costs of interventions. Replicability involves designing for the factors that may affect subsequent implementation of an intervention or program in different contexts. These R's of the research process are mutually reinforcing and can be supported by training that fosters collaborative and reciprocal relationships among researchers, implementers, and other stakeholders. In sum, a standard is emerging for research that is both rigorous and relevant. Consistent and bold application will increase the value, timeliness, and applicability of the research enterprise.


Comparison of high and low intensity contact between secondary and primary care to detect people at ultra-high risk for psychosis: study protocol for a theory-based, cluster randomized controlled trial.
The early detection and referral to specialized services of young people at ultra-high risk (UHR) for psychosis may reduce the duration of untreated psychosis and, therefore, improve prognosis. General practitioners (GPs) are usually the healthcare professionals contacted first on the help-seeking pathway of these individuals. This is a cluster randomized controlled trial (cRCT) of primary care practices in Cambridgeshire and Peterborough, UK. Practices are randomly allocated into two groups in order to establish which is the most effective and cost-effective way to identify people at UHR for psychosis. One group will receive postal information about the local early intervention in psychosis service, including how to identify young people who may be in the early stages of a psychotic illness. The second group will receive the same information plus an additional, ongoing theory-based educational intervention with dedicated liaison practitioners to train clinical staff at each site. The primary outcome of this trial is count data over a 2-year period: the yield - number of UHR for psychosis referrals to a specialist early intervention in psychosis service - per primary care practice. There is little guidance on the essential components of effective and cost-effective educational interventions in primary mental health care. Furthermore, no study has demonstrated an effect of a theory-based intervention to help GPs identify young people at UHR for psychosis. This study protocol is underpinned by a robust scientific rationale that intends to address these limitations. Current Controlled Trials ISRCTN70185866.


Genetic and household determinants of predisposition to human hookworm infection in a Brazilian community.
Predisposition to heavy or light human hookworm infection is consistently reported in treatment-reinfection studies. A significant role for host genetics in determining hookworm infection intensity has also been shown, but the relationship between host genetics and predisposition has not been investigated. A treatment-reinfection study was conducted among 1302 individuals in Brazil. Bivariate variance components analysis was used to estimate heritability for pretreatment and reinfection intensity and to estimate the contribution of genetic and household correlations between phenotypes to the overall phenotypic correlation (ie, predisposition). Heritability for hookworm egg count was 17% before treatment and 25% after reinfection. Predisposition to heavy or light hookworm infection was observed, with a phenotypic correlation of 0.34 between pretreatment and reinfection intensity. This correlation was reduced to 0.23 after including household and environmental covariates. Genetic and household correlations were 0.41 and 1, respectively, and explained 88% of the adjusted phenotypic correlation. Predisposition to human hookworm infection in this area results from a combination of host genetics and consistent differences in exposure, with the latter explained by household and environmental factors. Unmeasured individual-specific differences in exposure did not contribute to predisposition.


Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial.
During the last 30 years, auricular acupuncture has been used as complementary treatment of cancer pain when analgesic drugs do not suffice. The purpose of this study is to examine the efficacy of auricular acupuncture in decreasing pain intensity in cancer patients. Ninety patients were randomly divided in three groups; one group received two courses of auricular acupuncture at points where an electrodermal signal had been detected, and two placebo groups received auricular acupuncture at points with no electrodermal signal (placebo points) and one with auricular seeds fixed at placebo points. Patients had to be in pain, attaining a visual analog score (VAS) of 30 mm or more after having received analgesic treatment adapted to both intensity and type of pain, for at least 1 month of therapy. Treatment efficacy was based on the absolute decrease in pain intensity measured 2 months after randomization using the VAS. The main outcome was pain assessed at 2 months, with the assessment at 1 month carried over to 2 months for the eight patients who interrupted treatment after 1 month. For three patients, no data were available because they withdrew from the study during the first month. Pain intensity decreased by 36% at 2 months from baseline in the group receiving acupuncture; there was little change for patients receiving placebo (2%). The difference between groups was statistically significant (P <.0001). The observed reduction in pain intensity measured on the VAS represents a clear benefit from auricular acupuncture for these cancer patients who are in pain, despite stable analgesic treatment.


CHARMM-GUI Free Energy Calculator for Practical Ligand Binding Free Energy Simulations with AMBER.
Alchemical free energy methods, such as free energy perturbation (FEP) and thermodynamic integration (TI), become increasingly popular and crucial for drug design and discovery. However, the system preparation of alchemical free energy simulation is an error-prone, time-consuming, and tedious process for a large number of ligands. To address this issue, we have recently presented CHARMM-GUI Free Energy Calculator that can provide input and postprocessing scripts for NAMD and GENESIS FEP molecular dynamics systems. In this work, we extended three submodules of Free Energy Calculator to work with the full suite of GPU-accelerated alchemical free energy methods and tools in AMBER, including input and postprocessing scripts. The BACE1 (β-secretase 1) benchmark set was used to validate the AMBER-TI simulation systems and scripts generated by Free Energy Calculator. The overall results of relatively large and diverse systems are almost equivalent with different protocols (unified and split) and with different timesteps (1, 2, and 4 fs), with R2 > 0.9. More importantly, the average free energy differences between two protocols are small and reliable with four independent runs, with a mean unsigned error (MUE) below 0.4 kcal/mol. Running at least four independent runs for each pair with AMBER20 (and FF19SB/GAFF2.1/OPC force fields), we obtained a MUE of 0.99 kcal/mol and root-mean-square error of 1.31 kcal/mol for 58 alchemical transformations in comparison with experimental data. In addition, a set of ligands for T4-lysozyme was used to further validate our free energy calculation protocol whose results are close to experimental data (within 1 kcal/mol). In summary, Free Energy Calculator provides a user-friendly web-based tool to generate the AMBER-TI system and input files for high-throughput binding free energy calculations with access to the full set of GPU-accelerated alchemical free energy, enhanced sampling, and analysis methods in AMBER.


The effect of simultaneous contractions of ipsilateral muscles on changes in corticospinal excitability induced by paired associative stimulation (PAS).
Consideration was given to means of increasing the reliability and muscle specificity of paired associative stimulation (PAS) by utilising the phenomenon of crossed-facilitation. Eight participants completed three separate sessions: isometric flexor contractions of the left wrist at 20% of maximum voluntary contraction (MVC) simultaneously with PAS (20s intervals; 14 min duration) delivered at the right median nerve and left primary motor cortex (M1); isometric contractions at 20% of MVC; and PAS only (14 min). Eight further participants completed two sessions of longer duration PAS (28 min): either alone or in conjunction with flexion contractions of the left wrist. Thirty motor potentials (MEPs) were evoked in the right flexor (rFCR) and extensor (rECR) carpi radialis muscles by magnetic stimulation of left M1 prior to the interventions, immediately post-intervention, and 10 min post-intervention. Both 14 and 28 min of combined PAS and (left wrist flexion) contractions resulted in reliable increases in rFCR MEP amplitude, which were not present in rECR. In the PAS only conditions, 14 min of stimulation gave rise to unreliable increases in MEP amplitudes in rFCR and rECR, whereas 28 min of PAS induced small (unreliable) changes only for rFCR. These results support the conclusion that changes in the excitability of the corticospinal pathway induced by PAS interact with those associated with contraction of the muscles ipsilateral to the site of cortical stimulation. Furthermore, focal contractions applied by the opposite limb increase the extent and muscle specificity of the induced changes in excitability associated with PAS.


Linker engineering for fusion protein construction: Improvement and characterization of a GLP-1 fusion protein.
Protein engineering has been successfully applied in protein drug discovery. Using this technology, we previously have constructed a fusion protein by linking the globular domain of adiponectin to the C-terminus of a glucagon-like peptide-1 (GLP-1) analog. Herein, to further improve its bioactivity, we reconstructed this fusion protein by introducing linker peptides of different length and flexibility. The reconstructed fusion proteins were overexpressed in Escherichia coli and purified using nickel affinity chromatography. Their agonist activity towards receptors of GLP-1 and adiponectin were assessed in vitro by using luciferase assay and AMP-activated protein kinase (AMPK) immunoblotting, respectively. The effects of the selected fusion protein on glucose and lipid metabolism were evaluated in mice. The fusion protein reconstructed using a linker peptide of AMGPSSGAPGGGGS showed high potency in activating GLP-1 receptor and triggering AMPK phosphorylation via activating the adiponectin receptor. Remarkably, the optimized fusion protein was highly effective in lowering blood glucose and lipids in mice. Collectively, these findings demonstrate that the bioactivity of this GLP-1 fusion protein can be significantly promoted by linker engineering, and indicate that the optimized GLP-1 fusion protein is a promising lead structure for anti-diabetic drug discovery.


Effect of Huaier on the proliferation and apoptosis of human gastric cancer cells through modulation of the PI3K/AKT signaling pathway.
The aim of the present study was to investigate the effect of Huaier on the proliferation and apoptosis of the MKN45 and SGC7901 gastric cancer cell lines. The MTT assay was used to measure the effects of Huaier on the growth of the cells, while cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. It was found that cell survival decreased with the increase in the concentration of Huaier, and the apoptosis rates were increased in a dose-dependent manner both in MKN45 and SGC7901 cells. The number of cells in the G2/M phase in the Huaier-treated groups was increased in a dose-dependent manner compared with that in the control group. Huaier inhibited phosphorylated- (p-)AKT1, phosphatidylinositol 3-kinase (PI3K), pyruvate dehydrogenase kinase isoform 1, p-phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase and B-cell lymphoma 2 expression and upregulated cleaved-caspase-9 expression in a dose-dependent manner. In conclusion, Huaier can strongly inhibit gastric cancer cell proliferation by inhibiting cyclin B1 expression, promoting G2/M-phase arrest and modulating the PI3K/AKT signaling pathway, and can induce gastric cancer cell apoptosis by modulating the PI3K/AKT signaling pathway in dose-dependent manner.


Molecular wheels as nanoporous materials: differing modes of gas diffusion through Ga10 and Ga18 wheels probed by hyperpolarized 129Xe NMR spectroscopy.
The study of crystals of molecular wheels as nanoporous materials is reported. Hyperpolarized (129)Xe NMR spectroscopy has been used to characterize the mode of molecular diffusion and Xe interactions within the supramolecular nanochannels formed upon crystallization of the molecular wheels [Ga(10)(OMe)(20)(O(2)CMe)(10)] and [Ga(18)(pd)(12)(pdH)(12)(O(2)CMe)(6)(NO(3))(6)](NO(3))(6). In agreement with expectations based on the collision diameter of the Xe atom relative to the differing internal diameters of the two types of gallium wheels, single-file diffusion occurs in the Ga(10) channels, whereas in the Ga(18) system the data are consistent with normal, Fickian diffusion. Information about the electronic environment inside the channels was probed by the Xe chemical shift. The interaction of the gas with the channel walls is found to be substantially stronger than the interaction in organic nanotubes and zeolites. The results establish the ability of crystals of molecular wheel compounds to function as a new class of porous nanotubular materials, and ones of a known and variable diameter, for studying the channel diameter dependence of molecular exchange and unidirectional diffusion on the micrometer length scale.


Evaluation of Drug Delivery and Efficacy of Ciprofloxacin-Loaded Povidone Foils and Nanofiber Mats in a Wound-Infection Model Based on Ex Vivo Human Skin.
Topical treatment of wound infections is often a challenge due to limited drug availability at the site of infection. Topical drug delivery is an attractive option for reducing systemic side effects, provided that a more selective and sustained local drug delivery is achieved. In this study, a poorly water-soluble antibiotic, ciprofloxacin, was loaded on polyvinylpyrrolidone (PVP)-based foils and nanofiber mats using acetic acid as a solubilizer. Drug delivery kinetics, local toxicity, and antimicrobial activity were tested on an ex vivo wound model based on full-thickness human skin. Wounds of 5 mm in diameter were created on 1.5 × 1.5 cm skin blocks and treated with the investigated materials. While nanofiber mats reached the highest amount of delivered drug after 6 h, foils rapidly achieved a maximum drug concentration and maintained it over 24 h. The treatment had no effect on the overall skin metabolic activity but influenced the wound healing process, as observed using histological analysis. Both delivery systems were efficient in preventing the growth of Pseudomonas aeruginosa biofilms in ex vivo human skin. Interestingly, foils loaded with 500 µg of ciprofloxacin accomplished the complete eradication of biofilm infections with 1 × 109 bacteria/wound. We conclude that antimicrobial-loaded resorbable PVP foils and nanofiber mats are promising delivery systems for the prevention or topical treatment of infected wounds.


Specialized membrane-localized chaperones prevent aggregation of polytopic proteins in the ER.
The integral endoplasmic reticulum (ER) membrane protein Shr3p is required for proper plasma membrane localization of amino acid permeases (AAPs) in yeast. In the absence of Shr3p AAPs are uniquely retained in the ER with each of their twelve membrane-spanning segments correctly inserted in the membrane. Here, we show that the membrane domain of Shr3p specifically prevents AAPs from aggregating, and thus, plays a critical role in assisting AAPs to fold and correctly attain tertiary structures required for ER exit. Also, we show that the integral ER proteins, Gsf2p, Pho86p, and Chs7p, function similarly to Shr3p. In cells individually lacking one of these components only their cognate substrates, hexose transporters, phosphate transporters, and chitin synthase-III, respectively, aggregate and consequently fail to exit the ER membrane. These findings indicate that polytopic membrane proteins depend on specialized membrane-localized chaperones to prevent inappropriate interactions between membrane-spanning segments as they insert and fold in the lipid bilayer of the ER membrane.


A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis.
The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.


A Strain Gauge Monitor (SGM) for Continuous Valve Gape Measurements in Bivalve Molluscs in Response to Laboratory Induced Diel-cycling Hypoxia and pH.
An inexpensive, laboratory-based, strain gauge valve gape monitor (SGM) was developed to monitor the valve gape behavior of bivalve molluscs in response to diel-cycling hypoxia. A Wheatstone bridge was connected to strain gauges that were attached to the shells of oysters (Crassostrea virginica). The recorded signals allowed for the opening and closing of the bivalves to be recorded continuously over two-day periods of experimentally-induced diel-cycling hypoxia and diel-cycling changes in pH. Here, we describe a protocol for developing an inexpensive strain gauge monitor and describe, in an example laboratory experiment, how we used it to measure the valve gape behavior of Eastern oysters (C. virginica), in response to diel-cycling hypoxia and cyclical changes in pH. Valve gape was measured on oysters subjected to cyclical severe hypoxic (0.6 mg/L) dissolved oxygen conditions with and without cyclical changes in pH, cyclical mild hypoxic (1.7 mg/L) conditions and normoxic (7.3 mg/L) conditions. We demonstrate that when oysters encounter repeated diel cycles, they rapidly close their shells in response to severe hypoxia and close with a time lag to mild hypoxia. When normoxia is restored, they rapidly open again. Oysters did not respond to cyclical pH conditions superimposed on diel cycling severe hypoxia. At reduced oxygen conditions, more than one third of the oysters closed simultaneously. We demonstrate that oysters respond to diel-cycling hypoxia, which must be considered when assessing the behavior of bivalves to dissolved oxygen. The valve SGM can be used to assess responses of bivalve molluscs to changes in dissolved oxygen or contaminants. Sealing techniques to better seal the valve gape strain gauges from sea water need further improvement to increase the longevity of the sensors.


Expression of beta-galactosidase in neurons of dorsal root ganglia which are latently infected with herpes simplex virus type 1.
Explanation into culture of dorsal root ganglia (DRG) latently infected with herpes simplex virus type 1 (HSV-1) causes reactivation of the virus. Previous studies have suggested that either latency-associated transcripts (LATs) were removed as an early consequence of reactivation or, alternatively, there was a population of latently infected cells which did not contain LATs. We have now attempted to detect this population of neurons by inserting a reporter gene (Escherichia coli lacZ gene), under the control of promoters other than LAT, into the HSV-1 strain 17 mutant in 1814, which was used in the earlier studies. One of these promoters, the human cytomegalovirus enhancer, resulted in weak expression of beta-galactosidase in DRG neurons for at least 5 months. The pattern of staining was predominantly homogeneous in neurons at 3 or 5 days post-infection or at 3 days post-explanation, and was predominantly speckled in latently infected neurons (1 to 5 months post-infection). About 30% of the beta-galactosidase-positive neurons did not contain LATs by in situ hybridization. However, the detergents used to enable penetration of the substrate for beta-galactosidase had also reduced the levels of the LATs; in neurons which originally had only small numbers of LATs this may have reduced levels to below those detectable by the methods used. There was, therefore, no unequivocal evidence for a population of latently HSV-1-infected cells which did not express LATs.


Hispano-Americans in Europe: what do we know about their health status and determinants? A scoping review.
Policy makers and health practitioners are in need of guidance to respond to the growing geographic mobility of Hispano-American migrants in Europe. Drawing from contributions from epidemiology, social sciences, demography, psychology, psychiatry and economy, this scoping review provides an up-to-date and comprehensive synthesis of studies addressing the health status and determinants of this population. We describe major research gaps and suggest specific avenues of further inquiry. We identified systematically papers that addressed the concepts "health" and "Hispano Americans" indexed in five data bases from Jan 1990 to May 2014 with no language restrictions. We screened the 4,464 citations retrieved against exclusion criteria and classified 193 selected references in 12 thematic folders with the aid of the reference management software ENDNOTE X6. After reviewing the full text of all papers we extracted relevant data systematically into a table template to facilitate the synthesising process. Most studies focused on a particular disease, leaving unexplored the interlinkages between different health conditions and how these relate to legislative, health services, environmental, occupational, and other health determinants. We elucidated some consistent results but there were many heterogeneous findings and several popular beliefs were not fully supported by empirical evidence. Few studies adopted a trans-national perspective and many consisted of cross-sectional descriptions that considered "Hispano-Americans" as a homogeneous category, limiting our analysis. Our results are also constrained by the availability and varying quality of studies reviewed. Burgeoning research has produced some consistent findings but there are huge gaps in knowledge. To prevent unhelpful generalisations we need a more holistic and nuanced understanding of how mobility, ethnicity, income, gender, legislative status, employment status, working conditions, neighbourhood characteristics and social status intersect with demographic variables and policy contexts to influence the health of the diverse Hispano-American populations present in Europe.


Effects of exogenous phytohormones on plastid tRNA modifications in ragi coleoptiles.
The effects of phytohormones on plastid tRNA modifications were investigated in ragi (Eleucine coracana) coleoptiles. Intact 7-day old dark-grown ragi seedlings were given phytohormone, indoleacetic acid (IAA) or isopentenyladenine (i6A) treatment and grown in the dark or under white fluorescent light; coleoptiles were harvested 24 hr following treatment, and plastid total tRNAs were isolated and analyzed for their content of modified nucleotides. A total of 14 modified nucleotides were identified in the total digests of ragi plastid total tRNA preparations; significant increases in the content of some modified nucleotides were observed following treatment of phytohormones in the dark and light. The relative amounts of pT, pm1G, pm7G and pm1A in IAA-treated dark-grown, pi6A, pm2G and pCm in IAA-treated light-grown, and pT and pm2G in i6A-treated light-grown ragi coleoptiles were 2 to 10 times higher than the untreated control coleoptile plastid total tRNA. In order to gain a better understanding of the effects of phytohormones on ragi plastid tRNA modifications, we purified plastid tRNA(Ile)(GAU) from coleoptiles of the aforementioned ragi seedlings and analyzed its modifed nucleotide content. We find that the content of pGm was 4 to 5 times higher in the tRNA(Ile)(GAU) purified from i6A- or IAA-treated dark-grown coleoptiles, and pm7G was 5 to 6 times higher in the tRNA(Ile)(GAU) of i6A-treated light-grown ragi coleoptiles. These results suggest that the synthesis or activity of some plastid-specific tRNA-modifying enzymes may be enhanced by i6A and IAA with two different modes of regulation, one operating in the light and the other operating in the dark.


A rare case of central nervous system amyloidoma treated with fractionated radiotherapy.
A 54-year-old female presented with multiple episodes of emesis, intractable headaches, worsening balance, and slowly progressive right facial weakness. Imaging demonstrated a 3-cm mass in the left internal capsule and corona radiata region with associated edema, mass effect, and midline shift concerning for high-grade glioma, lymphoma, or brain metastasis. Stereotactic biopsy of the mass was consistent with amyloid deposition. Systemic workup for amyloidosis was negative, and the mass was thought to represent a focal tumor-like deposit of amyloid, also referred to as "amyloidoma." In the absence of systemic disease, therapy, which can include surgery or radiotherapy, can be directed at the local process. The location of the patient's lesion was not amenable to resection; therefore, she was treated with fractionated radiotherapy of 30.6 Gy at 1.8 Gy per fraction. Serial brain MRI demonstrated stability 18 months out from therapy. To the authors' knowledge, this is the first documented case of focal fractionated radiotherapy for CNS amyloidoma. The authors concluded that radiotherapy can prevent further progression of amyloidomas in anatomical locations that prohibit resection.


Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein.
Prion disease is characterized by the alpha-->beta structural conversion of the cellular prion protein (PrP(C)) into the misfolded and aggregated "scrapie" (PrP(Sc)) isoform. It has been speculated that methionine (Met) oxidation in PrP(C) may have a special role in this process, but has not been detailed and assigned individually to the 9 Met residues of full-length, recombinant human PrP(C) [rhPrP(C)(23-231)]. To better understand this oxidative event in PrP aggregation, the extent of periodate-induced Met oxidation was monitored by electrospray ionization-MS and correlated with aggregation propensity. Also, the Met residues were replaced with isosteric and chemically stable, nonoxidizable analogs, i.e., with the more hydrophobic norleucine (Nle) and the highly hydrophilic methoxinine (Mox). The Nle-rhPrP(C) variant is an alpha-helix rich protein (like Met-rhPrP(C)) resistant to oxidation that lacks the in vitro aggregation properties of the parent protein. Conversely, the Mox-rhPrP(C) variant is a beta-sheet rich protein that features strong proaggregation behavior. In contrast to the parent Met-rhPrP(C), the Nle/Mox-containing variants are not sensitive to periodate-induced in vitro aggregation. The experimental results fully support a direct correlation of the alpha-->beta secondary structure conversion in rhPrP(C) with the conformational preferences of Met/Nle/Mox residues. Accordingly, sporadic prion and other neurodegenerative diseases, as well as various aging processes, might also be caused by oxidative stress leading to Met oxidation.


Nocturnal warming increases photosynthesis at elevated CO2 partial pressure in Populus deltoides.
• We measured night-time respiration and daytime photosynthesis of leaves in canopies of 4 m tall cottonwood (Populus deltoides) trees to investigate the link between leaf respiration and photosynthetic capacity. • Trees were grown at three CO2 partial pressures [p(CO2 )a ] (42, 80, 120 Pa) and experimentally exposed to differing nocturnal temperatures (15, 20 or 25°C), but constant daytime temperatures (30-32°C), in a short-term whole-ecosystem environmental manipulation. • Rates of night-time leaf dark respiration (Rd ) increased significantly at all growth CO2 partial pressures when nocturnal temperatures were increased from 15 to 25°C. Predawn leaf nonstructural carbohydrate (soluble sugars and starch) content was significantly lower at the higher night temperatures. Photosynthetic capacity (Amax ) during the day increased significantly between 15 and 25°C at 42 and 80 Pa, but not at 120 Pa. • These findings indicate that the previously determined relationships between elevated night-time temperature, dark respiration and increased photosynthetic capacity may also hold at elevated p(CO2 )a . This response may have a significant influence on plant and ecosystem carbon exchange under global change scenarios.


Correlations between subjective treatment responses and plantar pressure parameters of metatarsal pad treatment in metatarsalgia patients: a prospective study.
Metatarsalgia is related to repetitive high-pressure loading under the metatarsal head (MH) that causes pain. The high pressure under the MH can be reduced by adequately applying metatarsal pads (MPs). Plantar pressure measurements may provide a method to objectively evaluate pressure loading under the MH. However, it is still unclear if the decrease in plantar pressure under the MH after MP treatment is associated with subjective improvement. This study aims to explore the correlations between subjective pain improvement and outcome rating, and the plantar pressure parameters in metatarsalgia patients treated using MPs. Thirteen patients (a total of 18 feet) with secondary metatarsalgia were included in this study. Teardrop-shaped MPs made of polyurethane foam were applied just proximal to the second MH by an experienced physiatrist. Insole plantar pressure was measured under the second MH before and after MP application. Visual analog scale (VAS) scores of pain were obtained from all subjects before and after 2 weeks of MP treatment. The subjects rated using four-point subjective outcome scales. The Wilcoxon signed-rank test was used to analyze the difference between the plantar pressure parameters and VAS scores before and after treatment. The Kruskal-Wallis test was applied to compare the plantar pressure parameters in each outcome group. Pearson's correlation was applied to analyze the correlation between the changes in plantar pressure parameters and VAS scores. Statistical significance was set as p < 0.05. MP application decreased the maximal peak pressure (MPP) and pressure-time integral (PTI) under the second MH and also statistically improved subjective pain scores. However, neither the pre-treatment values of the MPP and PTI shift in the position of the MPP after treatment, nor the age, gender and body mass index (BMI) of the subjects were statistically correlated with subjective improvement. Declines in the PTI and MPP values after MP application were statistically correlated with the improvement in VAS scores (r = 0.77, R2 = 0.59, p < 0.001; r = 0.60, R2 = 0.36, p = 0.009). We found that the successful decline in the PTI and MPP under the second MH after MP application was correlated to subjective pain improvement. This study provides a strategy for the further design and application of MPs for metatarsalgia treatment.


Objective differentiation of neonatal EEG background grades using detrended fluctuation analysis.
A quantitative and objective assessment of background electroencephalograph (EEG) in sick neonates remains an everyday clinical challenge. We studied whether long range temporal correlations quantified by detrended fluctuation analysis (DFA) could be used in the neonatal EEG to distinguish different grades of abnormality in the background EEG activity. Long-term EEG records of 34 neonates were collected after perinatal asphyxia, and their background was scored in 1 h epochs (8 h in each neonate) as mild, moderate or severe. We applied DFA on 15 min long, non-overlapping EEG epochs (n = 1088) filtered from 3 to 8 Hz. Our formal feasibility study suggested that DFA exponent can be reliably assessed in only part of the EEG epochs, and in only relatively short time scales (10-60 s), while it becomes ambiguous if longer time scales are considered. This prompted further exploration whether paradigm used for quantifying multifractal DFA (MF-DFA) could be applied in a more efficient way, and whether metrics from MF-DFA paradigm could yield useful benchmark with existing clinical EEG gradings. Comparison of MF-DFA metrics showed a significant difference between three visually assessed background EEG grades. MF-DFA parameters were also significantly correlated to interburst intervals quantified with our previously developed automated detector. Finally, we piloted a monitoring application of MF-DFA metrics and showed their evolution during patient recovery from asphyxia. Our exploratory study showed that neonatal EEG can be quantified using multifractal metrics, which might offer a suitable parameter to quantify the grade of EEG background, or to monitor changes in brain state that take place during long-term brain monitoring.


TTM-based motivational counselling does not increase physical activity of low back pain patients in a primary care setting--A cluster-randomized controlled trial.
To investigate the effectiveness of a TTM-based motivational counselling approach by trained practice nurses to promote physical activity of low back pain patients in a German primary care setting. Data were collected in a cluster-randomized controlled trial with three study arms via questionnaires and patient interviews at baseline and after 6 and 12 months. We analysed total physical activity and self-efficacy by using random effect models to allow for clustering. A total of 1378 low back pain patients, many with acute symptoms, were included in the study. Nearly 40% of all patients reported sufficient physical activity at baseline. While there were significant improvements in patients' physical activity behaviour in all study arms, there was no evidence for an intervention effect. The outcome may be explained by insufficient performance of the practice nurses, implementation barriers caused by the German health care system and the heterogenous sample. Given the objective to incorporate practice nurses into patient education, there is a need for a better basic training of the nurses and for a change towards an organizational structure that facilitates patient-nurse communication. Counselling for low back pain patients has to consider more specificated aims for different subgroups.


Sequence-specific, nanomolar peptide binding via cucurbit[8]uril-induced folding and inclusion of neighboring side chains.
This paper describes the molecular recognition of the tripeptide Tyr-Leu-Ala by the synthetic receptor cucurbit[8]uril (Q8) in aqueous buffer with nanomolar affinity and exceptional specificity. This combination of characteristics, which also applies to antibodies, is desirable for applications in biochemistry and biotechnology but has eluded supramolecular chemists for decades. Building on prior knowledge that Q8 binds to peptides with N-terminal aromatic residues, a library screen of 105 peptides was designed to test the effects of residues adjacent to N-terminal Trp, Phe, or Tyr. The screen used tetramethylbenzobis(imidazolium) (MBBI) as a fluorescent indicator and resulted in the unexpected discovery that MBBI can serve not only as a turn-off sensor via the simultaneous inclusion of a Trp residue but also as a turn-on sensor via the competitive displacement of MBBI upon binding of Phe- or Tyr-terminated peptides. The unusual fluorescence response of the Tyr series prompted further investigation by (1)H NMR spectroscopy, electrospray ionization mass spectrometry, and isothermal titration calorimetry. From these studies, a novel binding motif was discovered in which only 1 equiv of peptide binds to Q8, and the side chains of both the N-terminal Tyr residue and its immediate neighbor bind within the Q8 cavity. For the peptide Tyr-Leu-Ala, the equilibrium dissociation constant value is 7.2 nM, whereas that of its sequence isomer Tyr-Ala-Leu is 34 μM. The high stability, recyclability, and low cost of Q8 combined with the straightforward incorporation of Tyr-Leu-Ala into recombinant proteins should make this system attractive for the development of biological applications.


Bicycle riding and erectile dysfunction: an increase in interest (and concern).
From 1999 to 2004, there had been 21 publications from multiple medical specialties (sexual medicine, urology, neurology, cardiology, biomedical engineering, sports medicine, emergency medicine, and officials from the National Institute for Safety and Occupational Health) investigating the relationship between bicycle riding and erectile dysfunction (ED). In the previous 18 years, there have been 14 such studies. The primary aim was to summarize accumulating data on the safety of bicycle riding based on medical evidence categorized by levels of evidence, including case reports, observational studies, case control studies, mechanistic studies, and population-based epidemiologic investigations. The secondary aim was to address the concerns of bicyclists and propose measures to minimize the risk of ED associated with bicycle riding. An English-language medical literature review was made of publications in peer review journals from 1981 to 2004, including published abstract presentations at major medical meetings. Ranked published epidemiologic data on bicycle riding and ED. Bicycle riding more than 3 hours per week was an independent relative risk (RR = 1.72) for moderate to severe ED. In case control studies, the prevalence of moderate to severe ED in bicyclists was 4.2% and 4% vs. age-matched runners 1.1% (P < or = 0.018) and swimmers 2% (P = 0.05), respectively. Therefore, bicycle riders should take precautionary measures to minimize the risk of ED associated with bicycle riding: change the bicycle saddle with a protruding nose to a noseless seat, change the posture to a more upright/reclining position, change the material of the saddle (GEL), and tilt the saddle/seat downwards. The mechanism is hypothetically related to the rider interaction with the bicycle saddle at the perineum-saddle interface. Straddling bicycle saddles with a nose extension is associated with suprasystolic perineal compression pressures, temporarily occluding penile perfusion and potentially inducing endothelial injury and vasculogenic ED.


Hepatitis C virus infection in the human immunodeficiency virus infected patient.
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same transmission routes; therefore, coinfection is frequent. An estimated 5-10 million individuals alone in the western world are infected with both viruses. The majority of people acquire HCV by injection drug use and, to a lesser extent, through blood transfusion and blood products. Recently, there has been an increase in HCV infections among men who have sex with men. In the context of effective antiretroviral treatment, liver-related deaths are now more common than Acquired Immune Deficiency Syndrome-related deaths among HIV-HCV coinfected individuals. Morbidity and mortality rates from chronic HCV infection will increase because the infection incidence peaked in the mid-1980s and because liver disease progresses slowly and is clinically silent to cirrhosis and end-stage-liver disease over a 15-20 year time period for 15%-20% of chronically infected individuals. HCV treatment has rapidly changed with the development of new direct-acting antiviral agents; therefore, cure rates have greatly improved because the new treatment regimens target different parts of the HCV life cycle. In this review, we focus on the epidemiology, diagnosis and the natural course of HCV as well as current and future strategies for HCV therapy in the context of HIV-HCV coinfection in the western world.


Diagnostic impact of percutaneous renal biopsy.
Ultrasound-guided percutaneous renal biopsy (PRB) is an important diagnostic tool for nephrologists. Athough widely used and without question of pivotal importance for the diagnosis of renal diseases, little systematic data regarding standardized indications, outcomes, or consequences for this procedure are available. The aim of this study was to compare the clinically suspected diagnosis with the morphological results and the potential impact of PRB on the treatment of the patient. 205 patients who underwent PRB of the native kidney within a 4-year period were included in this retrospective analysis. The biopsy results (BR), discharge diagnosis (DD), and the suspected diagnoses (SD) of the attending nephrologists prior to biopsy were documented. Mean age of the patients was 58 (range 44 - 77) years. The majority of patients (61%) received PRB during an acute disease phase, whereas 39% had elective PRB. Percutaneous biopsy of the native kidney led to a discharge diagnosis in 92% of the patients, with low complication rates (with 3 out of 205 patients had major bleeding complications). In ~ 2/3, the nephrologists were correct with the suspected diagnosis prior to the biopsy. In ~ 74% of the biopsies, a disease was identified that was potentially responsive to treatment modification. In summary, PRB was found to be a safe procedure that confirmed the suspected clinical diagnosis in two thirds of patients. As one third of the histopathological analyses demonstrated a non-suspected disease, the biopsies were of major importance for the correct treatment of the patients.


Transcriptome-referenced association study of clove shape traits in garlic.
Genome-wide association studies are a powerful approach for identifying genes related to complex traits in organisms, but are limited by the requirement for a reference genome sequence of the species under study. To circumvent this problem, we propose a transcriptome-referenced association study (TRAS) that utilizes a transcriptome generated by single-molecule long-read sequencing as a reference sequence to score population variation at both transcript sequence and expression levels. Candidate transcripts are identified when both scores are associated with a trait and their potential interactions are ascertained by expression quantitative trait loci analysis. Applying this method to characterize garlic clove shape traits in 102 landraces, we identified 22 candidate transcripts, most of which showed extensive interactions. Eight transcripts were long non-coding RNAs (lncRNAs), and the others were proteins involved mainly in carbohydrate metabolism, protein degradation, etc. TRAS, as an efficient tool for association study independent of a reference genome, extends the applicability of association studies to a broad range of species.


Excited state reactions of metals in clusters: pluridimensional harpoon and solvation effects.
Excited state reactions of metals produce electronically excited products efficiently, as revealed by studies performed both in the gas phase and in free Van der Waals complexes. The reaction mechanism is assigned to an excited state charge transfer from the metal to the molecular reactant (i.e. a harpoon mechanism). The present work uses the well established cluster isolated chemical reaction (CICR) technique and addresses these processes when the metal ... molecule Van der Waals pair is deposited at the surface of a large argon cluster. Such work is aimed at investigating the effect of the cluster substrate on the preparation and dynamics of the reaction. We have revisited the pluridimensional character of the harpoon reaction in these systems. More specifically, we studied the reaction of excited calcium with HBr near the calcium resonance line at 422.7 nm, forming CaBr in the A and B states. As in previous Van der Waals experiments, we could explore the dynamics of the reaction by recording action spectra. These spectra exhibit noticeable differences from those observed for unsupported Ca...HBr complexes. In particular the bending movement of the Ca...HBr complex which gives access to the transition state of the reaction is partly hindered by the presence of the argon cluster.


Gold Medal Award for Life Achievement in the Science of Psychology: Constance L. Hammen.
The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2018 recipient of the Gold Medal Award for Life Achievement in the Science of Psychology is Constance L. Hammen, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, American Psychological Association Board of Directors liaison. (PsycINFO Database Record


Longitudinal developmental profile of children from low socio-economic circumstances in Cape Town, using the 1996 Griffiths Mental Development Scales.
BACKGROUND: The Griffiths Mental Development Scales (GMDS) have not been standardised in South African children Neurodevelopmental scores of infants from deprived environments decline with age, but there is no evidence on how young South African children from such backgrounds perform on serial assessments. AIM: To describe the longitudinal developmental profile of infants from low socio-economic backgrounds at Tygerberg Children's Hospital by comparing the GMDS scores performed at 10 - 12 months and 20 - 22 months. METHODS: Infants born to HIV-uninfected women attending the public service programme were recruited from a vaccine study in Cape Town, South Africa. The GMDS 0 - 2 years and a neurological examination were performed between 10 and 12 months and between 20 and 22 months. RESULTS: Thirty-one infants (14 girls, 17 boys) were assessed. Their mean (standard deviation (SD)) age was 11.6 (0.8) months and 21.0 (0.5) months at the first and second assessments, respectively. The mean (SD) general quotient decreased significantly from 107.3 (11.7) to 95.0 (11.0) (p<0.001). All sub-quotients decreased significantly except for locomotor. The hearing and language sub-quotient was most affected, with a decrease in mean quotients from 113.0 to 93.2 (p<0.001). There was no evidence of intercurrent events to explain the decline. INTERPRETATION: Scores on the GMDS of this group of children from low socio-economic backgrounds were normal at 11 months and, other than locomotor, decreased significantly at 21 months, with language the most affected. Further research is needed to determine the specific reasons for the decline.


Suicidal Behavior Among People Living with HIV (PLHIV) in Medical Care in Estonia and Factors Associated with Receiving Psychological Treatment.
People living with HIV (PLHIV) have higher rates of suicidal behavior than the general population. This study assessed suicidal behavior (ideation and/or attempts, ever and in the past 12 months) among PLHIV receiving outpatient HIV medical care in Estonia and associations between suicidal behavior and psychological treatment. The cross-sectional study collected data from January to November 2013 using a self-report questionnaire. Eight hundred PLHIV participated, 39 % (n = 306) of whom had been suicidal. Lifetime prevalence was 36 % for suicidal ideation and 20 % for attempts. Younger age, incarceration, having ever abused alcohol and also injected drugs, having lived with HIV for more than 10 years, and being depressed were associated with lifetime suicidal behavior. Suicidal behavior within the past 12 months was reported by 20 % (n = 156) of respondents. Of these, 27 % received psychological treatment (counseling and/or psychotherapy), 20 % had taken antidepressants, and 49 % sedatives. Individuals perceiving a need for treatment were significantly more likely to receive psychological treatment when experiencing suicidal behavior (OR 25.65, 95 % CI 2.92-225.47). In conclusion, suicidal behavior is frequent among PLHIV but psychological treatment is not often received. One of the barriers to treatment is patients' lack of perceived need for help.


Association of FMO3 Variants with Blood Pressure in the Atherosclerosis Risk in Communities Study.
Flavin containing monooxygenase 3 [FMO3] encodes dimethylaniline monooxygenase [N-oxide-forming] 3, which breaks down nitrogen-containing compounds, and has been implicated in blood pressure regulation. Studies have reported conflicting results of the association of a common nonsynonymous variant, E158K (rs2266782), with hypertension. We examined the associations of E158K, along with rare and low frequency exonic variants (minor allele frequency [MAF]<5%) in FMO3 with hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP). We included 7,350 European Americans and 2,814 African Americans in the Atherosclerosis Risk in Communities (ARIC) study with exome sequencing of FMO3. The association of FMO3 variants with SBP and DBP was tested using single variant and gene-based tests followed by the replication or interrogation of significant variants in ancestry-specific cohorts based on Bonferroni corrected thresholds. E158K had significant association with higher SBP in African Americans in ARIC (p=0.03), and two low frequency variants had significant association with higher SBP in African Americans (rs200985584, MAF 0.1%, p=0.0003) and European Americans (rs75904274, MAF 1.7%, p=0.006). These associations were not significant with additional samples: E158K in a meta-analysis of SBP of African ancestry (N=30,841, p=0.43) that included ARIC participants and the two low frequency variants in an independent ancestry-specific exome sequencing study of blood pressure (rs200985584, p=0.94; rs75904274, p=0.81). Our study does not support the association of E158K and low frequency variants in FMO3 with blood pressure and demonstrates the importance of replication in genetic studies.


A case of therapy-related acute lymphoblastic leukemia with t(11;19)(q23;p13.3) and MLL/MLLT1 gene rearrangement.
Therapy-related ALL (t-ALL) is a rare secondary leukemia that develops after chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormalities are the most common karyotypic alterations in t-ALL. The t(11;19)(q23;p13) aberration is extremely rare and has not been confirmed at the molecular genetic level. Here, we report a case of t-ALL with t(11;19)(q23;p13.3) and MLL-MLLT1 (alias ENL) gene rearrangement confirmed by cytogenetic analysis, multiplex reverse transcription-PCR (multiplex RT-PCR), and DNA sequencing in a patient who had undergone treatment for breast cancer. A 40-yr-old woman developed acute leukemia 15 months after undergoing 6 cycles of adjuvant chemotherapy (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²), radiation therapy (dose, 5,900 cGy), and anticancer endocrine therapy with tamoxifen. The complete blood cell counts and bone marrow examination showed increased blasts and the blasts showed B lineage immunophenotype (positive for CD19, CD34, and cytoplasmic CD79a). Cytogenetic analysis revealed the karyotype 47,XX,+X,t(11;19)(q23;p13.3)[4]/46,XX[16]. FISH analyses, multiplex RT-PCR, and DNA sequencing confirmed the MLL-MLLT1 gene rearrangement. The patient underwent induction chemotherapy with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and achieved complete remission. Subsequently, she underwent consolidation chemotherapy, but died of brain ischemia in the pons and the region of the middle cerebral artery. To our knowledge, this is the first case report of t-ALL with t(11;19)(q23;p13.3) and the MLL-MLLT1 gene rearrangement.


2014 Update of the Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Treatment Recommendations for the Management of Spondyloarthritis. Part II: Specific Management Recommendations.
The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. Recommendations for the management of SpA were created. Part II: Specific Management Recommendations addresses management with nonpharmacologic methods, nonsteroidal anti-inflammatories and analgesics, disease-modifying antirheumatic drugs, antibiotics, tumor necrosis factor inhibitors, other biologic agents, and surgery. Also included are 10 modifications for application to juvenile SpA. These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that implementation of these recommendations will promote best practices in the treatment of SpA.


Monitoring the athlete training response: subjective self-reported measures trump commonly used objective measures: a systematic review.
Monitoring athlete well-being is essential to guide training and to detect any progression towards negative health outcomes and associated poor performance. Objective (performance, physiological, biochemical) and subjective measures are all options for athlete monitoring. We systematically reviewed objective and subjective measures of athlete well-being. Objective measures, including those taken at rest (eg, blood markers, heart rate) and during exercise (eg, oxygen consumption, heart rate response), were compared against subjective measures (eg, mood, perceived stress). All measures were also evaluated for their response to acute and chronic training load. The databases Academic search complete, MEDLINE, PsycINFO, SPORTDiscus and PubMed were searched in May 2014. Fifty-six original studies reported concurrent subjective and objective measures of athlete well-being. The quality and strength of findings of each study were evaluated to determine overall levels of evidence. Subjective and objective measures of athlete well-being generally did not correlate. Subjective measures reflected acute and chronic training loads with superior sensitivity and consistency than objective measures. Subjective well-being was typically impaired with an acute increase in training load, and also with chronic training, while an acute decrease in training load improved subjective well-being. This review provides further support for practitioners to use subjective measures to monitor changes in athlete well-being in response to training. Subjective measures may stand alone, or be incorporated into a mixed methods approach to athlete monitoring, as is current practice in many sport settings.


Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine.
Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0-10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017.


Efficacy of Meditation-Based Interventions on Post-Traumatic Stress Disorder (PTSD) Among Veterans: A Narrative Review.
Decades of research have documented post-traumatic stress disorder (PTSD) symptoms in war veterans. Current treatment options for PTSD are unappealing as they either require re-exposure to the traumatic event or medications that are greatly impacted by comorbidities. Meditation-based interventions are a promising alternative. However, there is a dearth of research examining their impact. The purpose of this study was to examine meditation-based interventions tested for efficacy in treating PTSD among veterans and provide collective evidence. Authors searched the MEDLINE and CINAHL databases for relevant studies using the following inclusion criteria: (1) published in peer-reviewed journals; (2) conducted between January 2014 and July 2020; (3) described the evaluation of interventions; and (4) incorporated quantitative or mixed methods. United States. U.S. Veterans. A total of 15 studies (ten articles) met the inclusion criteria. Four tested Transcendental Meditation (n = 4), three tested Mantra Meditation (n = 3), two tested Mindful Meditation (n = 2), one tested Breathing-based Meditation (n = 1), one tested Mindfulness-based Exposure Therapy (n = 1), one tested Cognitively-based Compassion Training Meditation (n = 1), one tested Mantra Meditation and Mindfulness-based Treatment (n = 1), one tested Mindfulness-based PTSD Treatment (n = 1), and one tested Primary Care Brief Mindfulness Program (n = 1). The most common duration was 8 weeks (n = 8) and the most common evaluation design was the randomized controlled trial (n = 10). The most common outcome measure was the Clinician Administered PTSD Scale (CAPS) (n = 12). All interventions reported improvements in PTSD symptoms. Based on this review, meditation-based therapy is a promising approach for managing PTSD, particularly among veterans resistant to trauma-focused therapies. Randomized control trials with large sample sizes that apply CAPS as their primary outcome measure, and take into account effect size, attrition rates, and blinding are recommended for further research.


Oxidative stress-induced TGF-beta/TAB1-mediated p38MAPK activation in human amnion epithelial cells.
Term and preterm parturition are associated with oxidative stress (OS)-induced p38 mitogen-activated protein kinase (p38MAPK)-mediated fetal tissue (amniochorion) senescence. p38MAPK activation is a complex cell- and stimulant-dependent process. Two independent pathways of OS-induced p38MAPK activation were investigated in amnion epithelial cells (AECs) in response to cigarette smoke extract (CSE: a validated OS inducer in fetal cells): (1) the OS-mediated oxidation of apoptosis signal-regulating kinase (ASK)-1 bound Thioredoxin (Trx[SH]2) dissociates this complex, creating free and activated ASK1-signalosome and (2) transforming growth factor-mediated activation of (TGF)-beta-activated kinase (TAK)1 and TGF-beta-activated kinase 1-binding protein (TAB)1. AECs isolated from normal term, not-in-labor fetal membranes increased p38MAPK in response to CSE and downregulated it in response to antioxidant N-acetylcysteine. In AECs, both Trx and ASK1 were localized; however, they remained dissociated and not complexed, regardless of conditions. Silencing either ASK1 or its downstream effectors (MKK3/6) did not affect OS-induced p38MAPK activation. Conversely, OS increased TGF-beta's release from AECs and increased phosphorylation of both p38MAPK and TAB1. Silencing of TAB1, but not TAK1, prevented p38MAPK activation, which is indicative of TAB1-mediated autophosphorylation of p38MAPK, an activation mechanism seldom seen. OS-induced p38MAPK activation in AECs is ASK1-Trx signalosome-independent and is mediated by the TGF-beta pathway. This knowledge will help to design strategies to reduce p38MAPK activation-associated pregnancy risks.


Severe measles pneumonia in adults with respiratory failure: role of ribavirin and high-dose vitamin A.
Although measles is usually considered a benign viral disease of childhood, adults may be affected at any age and may experience severe respiratory or neurologic consequences. We present three adult cases (one of whom was pregnant) admitted to our University Hospital who were diagnosed to have measles and who had uncommon clinical features such as hepatitis and hyponatremia. All patients were markedly hypoxic; one required mechanical ventilation. Two patients received therapy with intravenous ribavirin and all patients received high-dose vitamin A for 3 days. Therapy with intravenous ribavirin and vitamin A were well tolerated by our patients except one patient who developed acute renal failure and were associated with reversal of respiratory compromise. Life-threatening measles pneumonitis in adults may be more common than previously appreciated, regardless of the patient's immune status, and ribavirin and high-dose vitamin A might be a treatment option.


Additive value of diffusion-weighted MRI in the I-SPY 2 TRIAL.
The change in apparent diffusion coefficient (ADC) measured from diffusion-weighted imaging (DWI) has been shown to be predictive of pathologic complete response (pCR) for patients with locally invasive breast cancer undergoing neoadjuvant chemotherapy. To investigate the additive value of tumor ADC in a multicenter clinical trial setting. Retrospective analysis of multicenter prospective data. In all, 415 patients who enrolled in the I-SPY 2 TRIAL from 2010 to 2014 were included. 1.5T or 3T MRI system using a fat-suppressed single-shot echo planar imaging sequence with b-values of 0 and 800 s/mm2 for DWI, followed by a T1-weighted sequence for dynamic contrast-enhanced MRI (DCE-MRI) performed at pre-NAC (T0), after 3 weeks of NAC (T1), mid-NAC (T2), and post-NAC (T3). Functional tumor volume and tumor ADC were measured at each MRI exam; pCR measured at surgery was assessed as the binary outcome. Breast cancer subtype was defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. A logistic regression model was used to evaluate associations between MRI predictors with pCR. The cross-validated area under the curve (AUC) was calculated to assess the predictive performance of the model with and without ADC. In all, 354 patients (128 HR+/HER2-, 60 HR+/HER2+, 34 HR-/HER2+, 132 HR-/HER2-) were included in the analysis. In the full cohort, adding ADC predictors increased the AUC from 0.76 to 0.78 at mid-NAC and from 0.76 to 0.81 at post-NAC. In HR/HER2 subtypes, the AUC increased from 0.52 to 0.65 at pre-NAC for HR+/HER2-, from 0.67 to 0.73 at mid-NAC and from 0.72 to 0.76 at post-NAC for HR+/HER2+, from 0.71 to 0.81 at post-NAC for triple negatives. The addition of ADC to standard functional tumor volume MRI showed improvement in the prediction of treatment response in HR+ and triple-negative breast cancer. 2 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019;50:1742-1753.


Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials.
Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early-phase studies are due to chance or possibly are a drug effect.


Inhibition of N-2-fluorenylacetamide-induced mammary tumorigenesis in rats by dietary polybrominated biphenyls.
Female SD rats were maintained for approximately 1 year on diets containing 300 ppm N-2-fluorenylacetamide (2-FAA), 50 ppm polybrominated biphenyls (PBB), or a combination of these chemicals (PBB + 2-FAA). Ingestion of 2-FAA significantly reduced the average survival time of the rats; this effect was virtually blocked by the simultaneous ingestion of PBB. Simultaneous ingestion of PBB also significantly reduced the overall incidence of 2-FAA-induced tumors during the examination period. The lower incidence of tumorigenesis was accompanied by an increase in the latency time for tumor induction; tumors were found in 100% of the animals given 2-FAA after 29 weeks of carcinogen ingestion, whereas only 50% of the PBB + 2-FAA-fed animals had tumors at the end of the experiment (53 wk of carcinogen ingestion). PBB significantly reduced the incidence of 2-FAA-induced tumors at nonhepatic locations (mammary gland and ear duct) but did not affect the incidence of hepatic tumors to a statistically significant extent. PBB ingestion did not significantly increase the incidence of tumors when compared with controls; 1 tumor was found in 1 of 12 rats fed 50 ppm PBB for 57 weeks, and no tumors were detected in 8 controls.


Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection.
Liver inflammation, fibrosis, and dyslipidemia are common features in patients with chronic hepatitis C virus (HCV) infection. Because peroxisome proliferator-activated receptor alpha (PPARalpha) is highly expressed in the liver and is involved in the regulation of lipid metabolism and inflammation, we sought to determine whether HCV infection may locally impair PPARalpha expression and activity. PPARalpha expression was investigated in liver biopsy specimens of 86 untreated patients with HCV infection and controls, by using real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistochemistry. PPARalpha activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA). The influence of HCV core protein on PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid. Hepatic concentrations of PPARalpha and CPT1A expressed by hepatocytes were impaired profoundly in the livers of untreated patients with HCV infection compared with controls. A mean decrease of 85% in PPARalpha mRNA expression paralleled with a lack of CPT1A mRNA induction also were observed in HCV core-expressing HepG2 cells compared with controls. HCV infection is related to altered expression and function of the anti-inflammatory nuclear receptor PPARalpha. These results identify hepatic PPARalpha as one mechanism underlying the pathogenesis of HCV infection, and as a new therapeutic target in traditional treatment of HCV-induced liver injury.


A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice.
Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenicity, as a consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1(+/-) mutation, instead of Mlh1(-/-), in these methyltransferase-deficient mice. Mgmt(-/-) Mlh1(+/-) mice, with about half the amount of MLH1 protein as Mgmt(-/-) Mlh1(+/+) mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg body wt. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated Mgmt(-/-) Mlh1(+/-) mice had thymic lymphomas and there were no tumors in those mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways leading to mutation induction or to apototic cell death. Loss of Mlh1 expression was frequently observed in tumors of Mgmt(-/-) Mlh1(+/-) mice and this might be related to progression of the tumors.


Chemoprevention by isothiocyanates: molecular basis of apoptosis induction.
An important and promising group of compounds that have a cancer-chemopreventive property are organosulfur compounds, such as isothiocyanates (ITCs). Various ITCs are effective chemoprotective agents against chemical carcinogenesis in experimental animals. Several epidemiological studies also indicated that the dietary consumption of ITCs or ITC-containing foods inversely correlates with the risk of developing lung, breast, and colon cancers, providing evidence that they have a potential to prevent cancer in humans. Mechanistically, ITCs are capable of inhibiting both the formation and development of a cancer cell through multiple pathways; i.e. the inhibition of carcinogen-activating cytochrome P450 mono-oxygenases, induction of carcinogen-detoxifying phase 2 enzymes, induction of apoptosis, and inhibition of cell cycle progression. We have clarified the molecular mechanisms underlying the relationship between cell cycle regulation and apoptosis induced by benzyl ITC (BITC), a major ITC compound isolated from papaya (Carica papaya) fruit. We identified phosphorylated Bcl-2 as a key molecule linking p38 MAPK-dependent cell cycle regulation with the c-Jun N-terminal kinase activation by BITC. We also established that BITC exerts the cytotoxic effect more preferentially in the proliferating cells than in the quiescent cells. Furthermore, p53 was found to be a potential negative regulator of apoptosis induction by BITC in normal epithelial cells through inhibition of cell cycle progression at the G(0)/G(1) phase. In contrast, treatment with an excessive concentration of BITC resulted in necrotic cell death in an ATP-dependent manner. This review addresses the biological impact of cell death induction by BITC as well as other ITCs and the involved molecules regulating signal pathways.


G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo.
G protein-coupled receptors (GPCR) comprise the largest family of drug targets. This is not surprising as many signaling systems rely on this class of receptor to convert external and internal stimuli to intracellular responses. As is the case with other membrane proteins, GPCRs are subjected to a stringent quality control mechanism at the endoplasmic reticulum, which ensures that only correctly folded proteins enter the secretory pathway. Because of this quality control system, point mutations resulting in protein sequence variations may result in the production of misfolded and disease-causing proteins that are unable to reach their functional destinations in the cell. There is now a wealth of information demonstrating the functional rescue of misfolded mutant receptors by small nonpeptide molecules originally designed to serve as receptor antagonists; these small molecules ("pharmacoperones") serve as molecular templates, promoting correct folding and allowing the mutants to pass the scrutiny of the cellular quality control system and be expressed at the cell surface membrane. Two of these systems are especially well characterized: the gonadotropin-releasing hormone and the vasopressin type 2 receptors, which play important roles in regulating reproduction and water homeostasis, respectively. Mutations in these receptors can lead to well defined diseases that are recognized as being caused by receptor misfolding that may potentially be amenable to treatment with pharmacoperones. This review is focused on protein misfolding and misrouting related to various disease states, with special emphasis on these two receptors, which have proved to be of value for development of drugs potentially useful in regulating GPCR trafficking in healthy and disease states.


A comparison of muscle activation between a Smith machine and free weight bench press.
The bench press exercise exists in multiple forms including the machine and free weight bench press. It is not clear though how each mode differs in its effect on muscle activation. The purpose of this study was to compare muscle activation of the anterior deltoid, medial deltoid, and pectoralis major during a Smith machine and free weight bench press at lower (70% 1 repetition maximum [1RM]) and higher (90% 1RM) intensities. Normalized electromyography amplitude values were used during the concentric phase of the bench press to compare muscle activity between a free weight and Smith machine bench press. Participants were classified as either experienced or inexperienced bench pressers. Two testing sessions were used, each of which entailed either all free weight or all Smith machine testing. In each testing session, each participant's 1RM was established followed by 2 repetitions at 70% of 1RM and 2 repetitions at 90% of 1RM. Results indicated greater activation of the medial deltoid on the free weight bench press than on the Smith machine bench press. Also, there was greater muscle activation at the 90% 1RM load than at the 70% 1RM load. The results of this study suggest that strength coaches should consider choosing the free weight bench press over the Smith machine bench press because of its potential for greater upper-body muscular development.


Workload trends in otolaryngology: some statistical observations from medical record linkage.
Trends in admission rates, lengths of stay, and clinical case mix (adjusted for multiple admissions per person) for Otolaryngology from 1975 to 1985 are described using the Oxford Record Linkage Study. Person-based admission rates increased generally, most strikingly amongst children and adolescents. Both length of stay per episode and total number of days an individual stayed in hospital each year decreased. Operations on tonsils and adenoids decreased averaging 2.2% per annum; admissions for diagnoses for otitis media with effusion increased averaging 8.2% per annum; for the operations of myringotomy and tympanostomy tube insertion increased averaging 9.2% per annum; for other diagnoses related to the ear increased averaging 5.7% per annum; and admissions for malignant neoplasms decreased averaging 2.0% per annum. Clearly more people are being treated for a changing case mix. The largest increases are occurring with children and adolescents.


Can Marginal Rates of Substitution Be Inferred From Happiness Data? Evidence from Residency Choices.
We survey 561 students from U.S. medical schools shortly after they submit choice rankings over residencies to the National Resident Matching Program. We elicit (a) these choice rankings, (b) anticipated subjective well-being (SWB) rankings, and (c) expected features of the residencies (such as prestige). We find substantial differences between choice and anticipated-SWB rankings in the implied tradeoffs between residency features. In our data, evaluative SWB measures (life satisfaction and Cantril's ladder) imply tradeoffs closer to choice than does affective happiness (even time-integrated), and as close as do multi-measure SWB indices. We discuss implications for using SWB data in applied work.


Light tunable plasmonic metasurfaces.
Self-assembled plasmonic metasurfaces are promising optical platforms to achieve accessible flat optics, due to their strong light-matter interaction, nanometer length scale precision, large area, light weight, and high-throughput fabrication. Here, using photothermal continuous wave laser lithography, we show the spectral and spatial tuning of metasurfaces comprised of a monolayer of ligand capped hexagonally packed gold nanospheres. To tune the spectral response of the metasurfaces, we show that by controlling the intensity of a laser focused onto the metasurface that the absorption peak can be reconfigured from the visible to near-infrared wavelength. The irreversible spectral tuning mechanism is attributed to photothermal modification of the surface morphology. Combining self-assembled metasurfaces with laser lithography, we demonstrate an optically thin (λ/42), spectrally selective plasmonic Fresnel zone plate. This work establishes a new pathway for creating flat, large area, frequency selective optical elements using self-assembled plasmonic metasurfaces and laser lithography.


Video ergo sum: manipulating bodily self-consciousness.
Humans normally experience the conscious self as localized within their bodily borders. This spatial unity may break down in certain neurological conditions such as out-of-body experiences, leading to a striking disturbance of bodily self-consciousness. On the basis of these clinical data, we designed an experiment that uses conflicting visual-somatosensory input in virtual reality to disrupt the spatial unity between the self and the body. We found that during multisensory conflict, participants felt as if a virtual body seen in front of them was their own body and mislocalized themselves toward the virtual body, to a position outside their bodily borders. Our results indicate that spatial unity and bodily self-consciousness can be studied experimentally and are based on multisensory and cognitive processing of bodily information.


Whole genome pyrosequencing of rare hepatitis C virus genotypes enhances subtype classification and identification of naturally occurring drug resistance variants.
Infection with hepatitis C virus (HCV) is a burgeoning worldwide public health problem, with 170 million infected individuals and an estimated 20 million deaths in the coming decades. While 6 main genotypes generally distinguish the global geographic diversity of HCV, a multitude of closely related subtypes within these genotypes are poorly defined and may influence clinical outcome and treatment options. Unfortunately, the paucity of genetic data from many of these subtypes makes time-consuming primer walking the limiting step for sequencing understudied subtypes. Here we combined long-range polymerase chain reaction amplification with pyrosequencing for a rapid approach to generate the complete viral coding region of 31 samples representing poorly defined HCV subtypes. Phylogenetic classification based on full genome sequences validated previously identified HCV subtypes, identified a recombinant sequence, and identified a new distinct subtype of genotype 4. Unlike conventional sequencing methods, use of deep sequencing also facilitated characterization of minor drug resistance variants within these uncommon or, in some cases, previously uncharacterized HCV subtypes. These data aid in the classification of uncommon HCV subtypes while also providing a high-resolution view of viral diversity within infected patients, which may be relevant to the development of therapeutic regimens to minimize drug resistance.


A review of health system infection control measures in developing countries: what can be learned to reduce maternal mortality.
A functional health system is a necessary part of efforts to achieve maternal mortality reduction in developing countries. Puerperal sepsis is an infection contracted during childbirth and one of the commonest causes of maternal mortality in developing countries, despite the discovery of antibiotics over eighty years ago. Infections can be contracted during childbirth either in the community or in health facilities. Some developing countries have recently experienced increased use of health facilities for labour and delivery care and there is a possibility that this trend could lead to rising rates of puerperal sepsis. Drug and technological developments need to be combined with effective health system interventions to reduce infections, including puerperal sepsis. This article reviews health system infection control measures pertinent to labour and delivery units in developing country health facilities. Organisational improvements, training, surveillance and continuous quality improvement initiatives, used alone or in combination have been shown to decrease infection rates in some clinical settings. There is limited evidence available on effective infection control measures during labour and delivery and from low resource settings. A health systems approach is necessary to reduce maternal mortality and the occurrence of infections resulting from childbirth. Organisational and behavioural change underpins the success of infection control interventions. A global, targeted initiative could raise awareness of the need for improved infection control measures during childbirth.


Gene expression in the presence or absence of myelin assembly.
Regulation of myelin protein gene expression in the presence and absence of myelin assembly can be assessed using crushed or permanently transected adult sciatic nerves of rats. The P0 glycoprotein and the myelin basic protein (MBP) are the major myelin-specific proteins of the peripheral nervous system. The steady-state level of P0 and MBP messenger RNA was determined by dot-blot analysis of poly(A)+ RNA from crushed and transected nerves of rats at 35 days post operation. The rat P0-specific cDNA clone, pSN63c, and mouse MBP-specific cDNA clone, pHF43, were used as probes. The level and quality of the poly(A)+ RNA was assessed by in vitro translation and immunoprecipitation of the translation products with anti-chick P0 antibody. Comparison of the steady-state level of P0 and MBP transcripts and the level of anti-P0 immunoprecipitated translation products from RNA extracts of permanently transected, crushed, adult control and 21-day-old control rat nerves indicated that the level of P0 and MBP messages was significantly reduced in the permanently transected model, whereas it was restored to normal in the crushed sciatic nerve 35 days post injury. These results suggest that regulation of P0 and MBP gene expression most likely occurs at the transcriptional or post-transcriptional level in the two models of peripheral neuropathies. Northern blot analysis indicated the absence of differential splicing of the message in crushed or transected nerves. The experiments also indicate that these two important gene products required for myelin synthesis and assembly seem to be co-regulated. However, the data do not rule out the possibility that regulation of gene expression may also occur at the level of translation or post-translational processing.