N6-Isopentenyladenosine promoted HeLa cell apoptosis through inhibitions of AKT and transforming growth factor β-activated kinase 1 activation.
N6-Isopentenyladenosine, a member of the family of plant hormones, possesses anti-cancer activities on a number of cancer cell lines. However, its mode of action in cervical cancer cell remains poorly understood. Our computational docking studies showed that N6-Isopentenyladenosine could bind with the really interesting new gene domain of tumor necrosis factor receptor-associated factor 6, which is an ubiquitination E3 ligase. Tumor necrosis factor receptor-associated factor 6-mediated ubiquitination is known to activate both protein kinase B (also known as AKT) and transforming growth factor β-activated kinase 1, and the really interesting new gene domain comprises the core of the ubiquitin ligase catalytic domain. First, we evaluated the effects of iPA on cervical cancer cell line HeLa using MTT and flow cytometry. Second, we examined the effects of iPA on activation of tumor necrosis factor receptor-associated factor 6-mediated downstream targets using western blot or immunoprecipitation. iPA could reduce HeLa cell proliferation through apoptosis, and such anti-cancer activity is associated with inhibitions of both AKT and transforming growth factor β-activated kinase 1 signaling pathways. In addition, suppression of the anti-apoptotic protein Bcl-2 and elevation of the pro-apoptotic protein Bax were also observed. Anti-proliferation properties of iPA are likely due to its binding at the really interesting new gene domain of tumor necrosis factor receptor-associated factor 6 and loss of AKT and transforming growth factor β-activated kinase 1 activities as a result of functional modulations of tumor necrosis factor receptor-associated factor 6. These results support the emerging notion that tumor necrosis factor receptor-associated factor 6 could serve as a viable target for developing new cancer therapeutics.


Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats.
Species-specific recognition between the egg extracellular matrix (zona pellucida) and sperm is the first, crucial step of mammalian fertilization. Zona pellucida filament components ZP3 and ZP2 act as sperm receptors, and mice lacking either of the corresponding genes produce oocytes without a zona pellucida and are completely infertile. Like their counterparts in the vitelline envelope of non-mammalian eggs and many other secreted eukaryotic proteins, zona pellucida subunits polymerize using a 'zona pellucida (ZP) domain' module, whose conserved amino-terminal part (ZP-N) was suggested to constitute a domain of its own. No atomic structure has been reported for ZP domain proteins, and there is no structural information on any conserved vertebrate protein that is essential for fertilization and directly involved in egg-sperm binding. Here we describe the 2.3 ångström (A) resolution structure of the ZP-N fragment of mouse primary sperm receptor ZP3. The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the post-fertilization block to polyspermy and speciation. Moreover, it provides an important framework for understanding human diseases caused by mutations in ZP domain proteins and developing new methods of non-hormonal contraception.


Design of an allosterically regulated retroaldolase.
We employed a minimalist approach for design of an allosterically controlled retroaldolase. Introduction of a single lysine residue into the nonenzymatic protein calmodulin led to a 15,000-fold increase in the second order rate constant for retroaldol reaction with methodol as a substrate. The resulting catalyst AlleyCatR is active enough for subsequent directed evolution in crude cell bacterial lysates. AlleyCatR's activity is allosterically regulated by Ca(2+) ions. No catalysis is observed in the absence of the metal ion. The increase in catalytic activity originates from the hydrophobic interaction of the substrate (∼2000-fold) and the change in the apparent pKa of the active lysine residue.


Self assembled nano fibers of betulinic acid: A selective inducer for ROS/TNF-alpha pathway mediated leukemic cell death.
The main complication in betulinic acid (BA) based drug delivery has been observed due to its bulk structure. The present study demonstrates the potential effects of self assembled nano size betulinic acid (SA-BA) by treating human leukemic cell lines (KG-1A and K562) and its normal counterpart. Self assembly property of BA was investigated using SEM and DLS study which showed that the BA forms fibrous structure having few nanometers in diameter. Selective anti-leukemic efficacy study of SA-BA was investigated by cell viability assay. Mode of leukemic cell death and probable pathway of apoptosis was monitored by measuring ROS level, pro and anti-inflammatory cytokine status and expression of caspase-8 and caspage-3 by immunocytochemistry. Higher efficacy of SA-BA over non-assemble BA was monitored toward cancer cells, with no relevant toxicity to normal blood cells. SA-BA facilitated reactive oxygen species (ROS) mediated leukemic cell death, confirmed by pre-treatment of N-acetyl-L-cysteine. Induction of apoptosis by SA-BA treatment increased pro-inflammatory cytokines, specifically potentiated TNF-α mediated cell death, confirmed by expression of caspase-8 and caspage-3 by immunocytochemistry. This study explored the better anti-leukemic efficacy of SA-BA over BA and this modification will enrich the use of BA in cancer therapy.


Dynamics of the DNA binding domain of the fructose repressor from the analysis of linear correlations between the 15N-1H bond spectral densities obtained by nuclear magnetic resonance spectroscopy.
The spectral densities of the backbone and arginine side chain NH bonds of the DNA binding domain of the fructose repressor (FruR) were extensively analyzed in order to extract reliable motions parameters. An accurate measurement of 15N NMR relaxation rates allowed their calculation at three frequencies, zero, omegaN, and omegaH + omegaN, using a reduced matrix approach. Linear correlations were found between J(omegaN) and J(0) and between <J(omegaH)> and J(0). The analysis of the compatibility between the motions parameters obtained independently from the two correlation lines allowed further development of the linear correlation approach proposed recently [Lefèvre, J. F., Dayie, K. T., Peng, J. W., and Wagner, G. (1996) Biochemistry 35, 2674-2686]. The results demonstrate (i) the existence of a concerted motion along the whole backbone with a global correlation time equal to 5.95 ns.rad-1, and (ii) the presence of complex internal movements at an intermediate time scale around 1 ns. The extracted motion parameters have been related to those obtained with the extended Lipari and Szabo approach but are incompatible with those obtained using the usual simple Lipari and Szabo approach. They were correlated to the features of the NMR structure of FruR(1-57)*. Some residues in the turns and in the third helix experience slow motions in the micro- to millisecond time scale. Side-chain motions are not correlated to the backbone dynamics. A direct examination of spectral densities reveals a higher flexibility for the side chains of arginines that are not involved in ionic bridges.


Performance evaluation of the section of 3D reconstruction based on different PET/CT image fusion sequence.
In recent years, positron emission tomography imaging (PET) and Computed tomography (CT) fusion images can be observed metabolic information, they can get a more accurate spatial information. People have to construct 3D models in the first place when they try to examine images from different angles. Once a cross-section which we want to inspect has been revealed, it can be observed from any angles. However, a issue people encounter in above-mentioned procedures is that they have to either process images fusion at the beginning and then reconstruct the 3D models with these images to generate section or rebuilt the 3D models with these images and fuse section images as the second step. The main objective of this research is to discriminate the divergences and merits between two types of procedures.This research discovers that two different procedures will exactly bring about dissimilar types of images. Therefore, this research particularly aims at the analysis of two images and evaluates the extent of fringe and remaining information. We calculates entropy and standard deviation of the images. Nevertheless, finding section on 3D models first and fusing images secondly will generate the images which retain more information.


Correction: Nanoparticle-based photoacoustic analysis for highly sensitive lateral flow assays.
Correction for 'Nanoparticle-based photoacoustic analysis for highly sensitive lateral flow assays' by Yunfei Zhao et al., Nanoscale, 2016, 8, 19204-19210.


Designer antigens for elicitation of broadly neutralizing antibodies against HIV.
Broadly neutralizing antibodies (bNAbs) are a consistent protective immune correlate in human immunodeficiency virus (HIV) patients as well as in passive immunotherapy studies. The inability to elicit bNAbs is the core reason underlining the repeated failures in traditional HIV vaccine research. Rare monoclonal bNAbs against HIV, however, have been produced. The significance of producing and studying more monoclonal bNAbs against HIV is underlined by its capability of defining critical epitopes for antigen designs aimed at the development of a serum-neutralizing HIV vaccine. In this regard, traditional antigen preparations have failed. There is a need to clearly advocate the concept, and systematic study, of more sophisticated 'designer antigens' (DAGs), which carry epitopes that can lead to the elicitation of bNAbs. Using an extremely efficient cell-to-cell HIV infection model for the preparation of HIV prefusion intermediates, we have investigated a novel and systematic approach to produce (not screen for) potential bNAbs against HIV. We have established the concept and the experimental system for producing formaldehyde-fixed HIV DAGs that carry temperature-arrested prefusion intermediates. These prefusion intermediates are structures on the cell surface after viral attachment and receptor engagement but before fully functional viral entry. Using defined HIV prefusion DAGs, we have produced monoclonal antibodies (mAbs) specific to novel epitopes on HIV prefusion intermediates. These mAbs do not react with the static/native surface HIV or cellular antigens, but react with the DAGs. This is a paradigm shift from the current mainstream approach of screening elite patients' bNAbs.


Case report: A novel mutation in RTEL1 gene in dyskeratosis congenita.
Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a telomeropathy typically presenting as a triad of leukoplakia, nail dystrophy, and reticular hyperpigmentation. Reported genetic mutations linked to DKC include DKC1, TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53/TCAB1, and RTEL1. Homozygous, compound heterozygous, and heterozygous mutations in RTEL1 (RTEL1, regulator of telomere elongation helicase 1) gene on chromosome 20q13 are known to cause autosomal dominant as well as recessive DKC. Pathogenic variants of RTEL1 gene in DKC patients include c.2288G>T (p. Gly763Val), c.3791G>A (p. Arg1264His), and RTEL p. Arg981Trp. We report a novel homozygous variant of RTEL1, transcript ID: ENST00000360203.11, exon 24, c.2060C>T (p.Ala687Val), in a patient of DKC presenting with leukoplakia, dystrophic nails, reticulate pigmentation, and positive family history of a similar phenotype. The novel variant, reported as a variant of uncertain significance, may therefore be considered diagnostic for DKC in a Pakistani population.


Clinical features suggestive of non-classical 21-hydroxylase deficiency in children presenting with precocious pubarche.
Precocious pubarche (PP) is defined as the onset of pubic hair at 8 years of age in girls and at 9 years of age in boys. PP is idiopathic (IPP) in most children, but it is the earliest manifestation of non-classical congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency (NC21OHD) in 5%-20% of cases. 17-Hydroxyprogesterone (17OHP) levels after ACTH stimulation test are used to distinguish the two forms. We studied clinical indicators of NC21OHD in 289 PP children: 14 (4.8%) showed post-ACTH 17OHP levels >30 nmol/L and NC21OHD due to CYP21A2 gene mutations was confirmed. NC21OHD children were younger (p: 0.006) and thinner (p: 0.003) than IPP children. Height standard deviation score (SDS) was not different (p: 0.97). NC21OHD girls showed more advanced bone age than IPP girls (p<0.001). Earlier PP onset and bone age advance suggest NC21OHD, which requires confirmation by an ACTH stimulation test. Later, PP appearance in overweight children suggests IPP and could merit only clinical monitoring.


Methods for certification in colonoscopy - a systematic review.
Reliable, valid, and feasible assessment tools are essential to ensure competence in colonoscopy. This study aims to provide an overview of the existing assessment methods and the validity evidence that supports them. A systematic search was conducted in October 2016. Pubmed, EMBASE, and PsycINFO were searched for studies evaluating assessment methods to ensure competency in colonoscopy. Outcome variables were described and evidence of validity was explored using a contemporary framework. Twenty-five observational studies were included in the systematic review. Most studies were based on small sample sizes. The studies were categorized after outcome measures into five groups: Clinical process related outcome metrics (n = 2), direct observational colonoscopy assessment (n = 8), simulator based metrics (n = 11), automatic computerized metrics (n = 2), and self-assessment (n = 1). Validity score varied among the studies and only five studies presented sufficient evidence to recommend the tool for clinical assessment. The objectives vary throughout the presented tools. Some tools are global tools where others focus on procedural technical skill assessment or even part-task skills. There is a tendency in the most recent studies towards more specific assessment of technical skills. The majority of assessment methods lack sufficient validity evidence.


Effectiveness of Mental Health Literacy and Stigma Interventions for Latino/a Adults in the United States: A Systematic Review.
Latinos/as in the United States (U.S.), face persistent mental health care disparities, even after adjusting for education, health insurance, and socioeconomic factors. While there has been increased attention on mental health stigma and mental health literacy, no systematic literature review currently exists of interventions developed to reduce mental health stigma and improve mental health literacy in the Latino/a community. This review aimed to (1) examine the methodological rigor of these intervention studies, (2) describe the mental health literacy and stigma interventions developed for Latinos/as in the U.S., and (3) summarize the outcomes of these studies focusing on mental health literacy and stigma outcomes. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to inform our systematic literature review. The methodological rigor of each study was assessed using an adapted version of the Methodological Quality Rating Scale. Seven articles met the inclusion criteria for this review. The majority of studies were small pilot studies with small samples and short follow-up periods of less than a month. These interventions showed promising results for improving knowledge of mental disorders and mixed results for reducing stigma towards people with mental illness and mental health treatments. As the Latino/a population continues to grow, future research should continue investigating and developing more intensive and prolonged mental health stigma interventions that use multiple media platforms (e.g., radio, television, website, print, and social media) to help reduce mental health care disparities in this population.


[The rebel ambulance of 1914].
The story of the so-called Rebel Ambulance of 1914 covers a period of about 6 weeks. During this time a group of people in Bloemfontein endeavoured to provide medical cover and comforts for casualties among those who participated in the armed protest of 1914 in the Orange Free State. Information about relevant historical facts, the collection of funds and equipment, and the work of the field ambulance are presented.


Humibacillus xanthopallidus gen. nov., sp. nov.
Strain KV-663(T) was isolated from a soil sample collected from a paddy field in Japan by using GPM agar plates. Strain YM21-029 was obtained from a lake sediment sample by using HSV agar. The two novel strains were Gram-positive, catalase-positive, rod-shaped bacteria with ll-diaminopimelic acid as the diagnostic diamino acid of the cell-wall peptidoglycan. The major menaquinone was MK-8(H(4)). Mycolic acids were not detected. The G+C content of the DNA was 69-70 mol%. 16S rRNA gene sequence analysis revealed that these strains represent a novel lineage within the family Intrasporangiaceae, order Actinomycetales, and are related to members of the genera Intrasporangium and Terracoccus. Based on morphological, biochemical and chemotaxonomic properties, together with phylogenetic analysis based on 16S rRNA gene sequences, the two new strains are considered to represent a novel species of a new genus, for which the name Humibacillus xanthopallidus gen. nov., sp. nov. is proposed. The type strain of the type species, Humibacillus xanthopallidus, is KV-663(T) (=NRRL B-24471(T)=NBRC 101803(T)).


Association of uric acid with obesity and endothelial dysfunction in children and early adolescents.
Hyperuricemia in adults is known to be associated with hypertension, the metabolic syndrome and cardiovascular disease. The purpose of this study was to elucidate the factors associated with hyperuricemia in obese children and early adolescents and to investigate the threshold serum level of uric acid (UA) for the metabolic syndrome in children. We assessed anthropometric measurements, blood pressure, body composition and biochemical data in 1,559 obese children. To assess endothelial dysfunction, flow-mediated dilatation (FMD) was measured in 92 children. The correlations between serum UA levels and various parameters were examined. The threshold serum UA level for the metabolic syndrome was calculated by receiver-operating characteristic (ROC) curve analysis. Serum UA levels were positively correlated with lipids in both boys and girls, and they were inversely correlated with FMD in the boys but not the girls. The threshold serum UA level for the metabolic syndrome was 5.25 mg/dl in boys and 5.05 mg/dl in girls. However, the specificity and sensitivity of ROC curve analysis are not so striking. The correlation between UA and FMD showed gender differences and might be affected by the hormonal status. The cutoff level of serum UA as a marker of the metabolic syndrome in obese children was affected by both age and gender.


Clostridium difficile among hospitalized patients receiving antibiotics: a case-control study.
Clostridium difficile is the most common cause of infectious nosocomial diarrhea and can be found in up to 30% of asymptomatic hospitalized patients. Our primary aim was to compare the clinical characteristics of hospitalized patients who received antibiotics and developed C. difficile-associated diarrhea (CDAD) with those of hospitalized patients who received antibiotics and did not develop the disease. Case-control study comprising inpatients at a single institution. Case-patients were defined as patients who had diarrhea and tested positive for C. difficile. Control-patients (matched 4:1 to case-patients) were defined as patients who received antibiotics for at least 5 days and did not develop CDAD. On univariate analysis, nine variables were associated with CDAD. Only three of the variables, need for intensive care, length of stay, and macrolide antibiotic use, were found to be significant (P < .05) on logistic regression analysis. The odds ratios for status as a CDAD case were 3.68 (CI95, 1.44 to 9.40) for stay in the intensive care unit and 1.03 (CI95, 1.02 to 1.05) for each day of hospital stay. Receipt of macrolide antibiotics reduced risk significantly; the odds ratio was 0.23 (CI95, 0.19 to 0.87). We identified need for intensive care and length of stay as important risk factors for the development of CDAD. We also identified macrolide antibiotic use as protective against its development. Patients receiving intensive care may represent a population to study for targeted prophylaxis.


Timing of Perennial Canker Development in Apple Trees Caused by Neofabraea perennans and Neofabraea kienholzii.
Members of the genera Neofabraea and Phlyctema have been reported to incite canker diseases of apple trees and a postharvest decay of apple fruit referred to as "bull's-eye rot." Neofabraea kienholzii was recently identified as participating in the bull's-eye rot disease complex of apple and other pome fruit. In this study, apple twigs inoculated with N. kienholzii were shown to develop symptoms of a canker disease closely resembling perennial canker of pome fruit trees caused by N. perennans. Cankers resulting from infection by either Neofabraea spp. were more likely to be induced when twig inoculations occurred in October, and to a lesser degree in April, compared with all other inoculation dates evaluated in this study. Although N. kienholzii tended to induce cankers that were smaller in size compared with N. perennans, both pathogens shared similar seasonal trends in the initiation and expansion of tree cankers. N. perennans and N. kienholzii were recovered from inoculated twigs 6 months postinoculation regardless of when inoculations were conducted, indicating that both pathogens can survive on diseased twigs year-round. In addition, acervuli were observed more often on twigs inoculated in September and April compared with those inoculated in other months. Data from this work should help further our understanding of the epidemiology of N. kienholzii. This information also highlights the importance of proper branch pruning, canker removal, and aphid control. Such management activities should be conducted in a manner that helps minimize further spread of the pathogen.


Personality and regional cerebral blood flow.
The extraversion-introversion dimension of personality is believed to have an inverse relationship with cortical arousal. Brain capillary perfusion is a well established index of brain function and arousal. Regional cerebral blood flow was measured in 51 right-handed females whose personality structure was examined with the Eysenck Personality Inventory (EPI). Significant inverse correlations were found between the brain blood flow and the extraversion-introversion score of EPI.


Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aβ42.
The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aβ-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aβ42 into fibrils but also disintegrates the aggregated Aβ42 fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aβ42 at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aβ42. This is in sharp contrast to the β-sheet conformation of Aβ42 upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aβ42 showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer's disease.


NADH as Donor.
The number of NADH dehydrogenases and their role in energy transduction in Escherchia coli have been under debate for a long time. Now it is evident that E. coli possesses two respiratory NADH dehydrogenases, or NADH:ubiquinone oxidoreductases, that have traditionally been called NDH-I and NDH-II. This review describes the properties of these two NADH dehydrogenases, focusing on the mechanism of the energy converting NADH dehydrogenase as derived from the high resolution structure of the soluble part of the enzyme. In E. coli, complex I operates in aerobic and anaerobic respiration, while NDH-II is repressed under anaerobic growth conditions. The insufficient recycling of NADH most likely resulted in excess NADH inhibiting tricarboxylic acid cycle enzymes and the glyoxylate shunt. Salmonella enterica serovar Typhimurium complex I mutants are unable to activate ATP-dependent proteolysis under starvation conditions. NDH-II is a single subunit enzyme with a molecular mass of 47 kDa facing the cytosol. Despite the absence of any predicted transmembrane segment it has to be purified in the presence of detergents, and the activity of the preparation is stimulated by an addition of lipids.


[A strategy for increasing the efficiency of psychopharmacological treatment of hyperkinetic behavior disorder with pantogam].
To assess short-term efficiency of hopantenic acid (pantogam) in the treatment of children with hyperkinetic behavior disorder, in whom the previous treatment with atomoxetine was not efficient. Twenty-four children (16 boys and 8 girls), aged 6-11 years, diagnosed with hyperkinetic behavior disorder (ICD-10 item F90.1) were enrolled in this open non-randomized study. A short-term positive therapeutic dynamics was observed when introducing hopantenic acid (pantogam) augmentation strategy to existing atomoxetine therapy. Qualitative improvements in children's state were found not only in the ability to control symptoms but also in their social functioning levels and quality of life. The proposed therapeutic strategy can help to improve treatment outcomes for children with certain clinical forms of hyperkinetic behavior disorder.


Effects of inhaled corticosteroids on bone density and metabolism.
Oral corticosteroids have adverse effects on bone density and metabolism. With the increased use of inhaled corticosteroids together with the use of higher doses for the treatment of asthma, the long-term effects of inhaled corticosteroids on bone metabolism and density must be evaluated. This article discusses the markers of bone resorption and formation together with techniques used to measure cortical and trabecular bone density. The effects of inhaled corticosteroids on bone density and metabolism as determined by these techniques are described in detail. Overall, inhaled corticosteroids are extremely safe, even at high doses, with the long-term risk of bone loss being extremely small compared with oral corticosteroids. In particular, fluticasone propionate at the recommended doses appears to be free of effects on bone density and metabolism. Finally, the use of inhaled corticosteroids results in the control of asthma, allowing patients to exercise, which itself improves bone density and protects against osteoporosis.


Veterans Administration health care policies as a protective mechanism supporting an expected life trajectory after military service.
Changes in the American military since the end of military conscription, as well as the increasing number of service-connected disabilities, suggest the need for increased consideration of the effects of health policies when assessing the impact of military service on young Americans' life course. This study analyzes data from the most recent National Survey of Veterans to investigate the health status, health benefits, and health care utilization of 2,773 Gulf War veterans, in association with resumption of their civilian life trajectory. Findings suggest that this sample of veterans may have poorer health status than previous veteran cohorts and did not fully utilize veterans' health care benefits to which they were entitled. This article examines whether veterans may usefully be considered a group at risk for health disparities, in that they have greater health risks and potentially poorer health status and access than mainstream Americans.


The alpha-effect in reactions of sp-hybridized carbon atom: Michael-type reactions of 1-aryl-2-propyn-1-ones with primary amines.
[reaction: see text] Second-order rate constants (kN) have been measured for the Michael-type reaction of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of primary amines in H2O at 25.0 +/- 0.1 degree C. A linear Brønsted-type plot with a small beta(nuc) value (beta(nuc) = 0.30) has been obtained for the reactions of 1-phenyl-2-propyn-1-one (2c) with non-alpha-nucleophile amines. Hydrazine is more reactive than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester) and results in a positive deviation from the linear Brønsted-type plot. The reactions of 2a-f with hydrazine exhibit a linear Hammett plot, while those with non-alpha-nucleophile amines give linear Yukawa-Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction mechanism. The alpha-effect increases as the substituent X in the phenyl ring of 2a-f becomes a stronger electron-donating group. However, the magnitude of the alpha-effect for the reactions of 2a-f is small (e.g., kN(hydrazine)/kN(glycylglycine) = 4.6-13) regardless of the electronic nature of the substituent X. The small beta(nuc) has been suggested to be responsible for the small alpha-effect. A solvent kinetic isotope effect (e.g., kN(H2O)/kN(D2O) = 1.86) was observed for the reaction with hydrazine but absent for the reactions with non-alpha-nucleophile amines. The reactions with hydrazine and other primary amines have been suggested to proceed through a five-membered intramolecular H-bonding structure VI and a six-membered intermolecular H-bonding structure VII, respectively. The transition state modeled on VI can account for the substituent dependent alpha-effect and the difference in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary amines. It has been proposed that the beta(nuc) value is more important than the hybridization type of the reaction site to determine the magnitude of the alpha-effect.


Integrating Social and Medical Care: Could it Worsen Health and Increase Inequity?
As a result of a large and compelling body of evidence documenting the impacts of social determinants, such as income and education, on health outcomes, health care systems are beginning to incorporate social and economic risk data into health care delivery decisions. But there is a risk that some of these efforts could worsen health and widen health inequities. We highlight 3 examples- including recent policy changes in Medicaid, social needs, informed risk prediction models, and advances in precision medicine-where the inclusion of social risk information threatens to reduce care quality or health care access for some groups of patients. A new dialog is needed about both the opportunities and potential consequences of bringing information about patients' social circumstances into a market-based health care system.


Clinical implications of hypothermic ventricular fibrillation versus beating-heart technique during cardiopulmonary bypass for pulmonary valve replacement in patients with repaired tetralogy of Fallot.
This study aimed to compare the effects of hypothermic ventricular fibrillation and beating-heart techniques during cardiopulmonary bypass (CPB) on postoperative outcomes after simple pulmonary valve replacement in patients with repaired tetralogy of Fallot (TOF). We retrospectively reviewed the data of 47 patients with repaired tetralogy of Fallot at a single institution, who received pulmonary valve replacement under the ventricular fibrillation or beating-heart technique without cardioplegic cardiac arrest during CPB between January 2005 and April 2015. The patients were divided into fibrillation (n = 32) and beating-heart (n = 15) groups. On comparing these groups, the fibrillation group had a larger sinotubular junction (27.1 ± 4.6 vs 22.1 ± 2.4 mm), had a longer operation duration (396 ± 108 vs 345 ± 57 min), required more postoperative transfusions (2.1 ± 2.6 vs 5.0 ± 6.3 units) and had a higher vasoactive-inotropic score at intensive care unit admission (8.0 vs 10, all P < 0.05). Echocardiographic data indicated that the systolic internal diameter of the left ventricle was larger in the fibrillation group than in the beating-heart group immediately after surgery and at the 1-year follow-up. Major adverse cardiac events occurred in 3 cases, all from the fibrillation group. Among 7 patients from the fibrillation group with transoesophageal echocardiography data during CPB, 6 had fully opened aortic valves during fibrillation, causing flooding into the left ventricle and left ventricle distension. The postoperative outcomes are worse with the ventricular fibrillation technique than with the beating-heart technique during CPB for pulmonary valve replacement in patients with repaired tetralogy of Fallot.


Factors influencing the occurrence and severity of farm accidents: comparing work-related and nonwork-related events.
Economic incentives are emerging as useful preventive approaches to motivating farmers to adopt safer farming and managerial practices. The effectiveness of these programs and incentives will be enhanced by focusing resources on factors that play a critical role in contributing to farm accidents and the injury severity. A primary objective is to identify and assess the relative impact of factors that jointly influence the probability of work-related farm accidents relative to nonwork-related accidents and the severity of farm accidents. The model uses survey data on producer characteristics, farm organization, and work routines from the Georgia Healthy Farmers Project (GHFP). A probit model describing the factors that influence the probability of a work-related accident is estimated jointly with an ordered probit model for farm accident severity. The probit model indicates that older farmers and hired farm workers have higher probabilities of experiencing work-related accidents relative to nonwork-related events. Significant variables that influence the severity of farm accidents are more difficult to identify from the ordered probit models for both work-related and nonwork-related farm accidents.


Blockade of the stimulus properties of mescaline by a serotonin antagonist.
It is known that the effects of mescaline (3, 4, 5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus. The present investigation examined the ability of cinanserin, a serotinin antagonist, to block the stimulus properties of mescaline in the rat. After a reliable discrimination was established between the effects following the injection of mescaline (10 mg/kg) and those following administration of saline, subjects were pretreated with cinanserin HC1 (3 mg/kg) and then treated with mescaline. Such pretreatment was found to block discrimination, i.e., the response rate following the administration of mescaline plus cinanserin was appropriate for the saline condition. The present data suggest that antagonists of serotonin may be useful in furthering our understanding of phenethylamine hallucinogens.


Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway.
Cisplatin (CIS) is a broad-spectrum anti-carcinogen that causes cytotoxic effects both in normal and cancer cells. The purpose of this study was to test whether Hibiscus sabdariffa (HS) extract can reduce CIS-induced hepatotoxicity in rodents and to assess its anticancer activity in vitro. Treatment with HS extract at daily doses of 500 mg/kg before and after a single dose of CIS (10 mg/kg) reduced hepatotoxicity in Wistar male albino rats. HS extract reduced activity of hepatic damage marker enzymes ( i.e. alanine and aspartate aminotransferases), necrosis, and apoptosis in liver tissues of CIS-treated rats. This hepatic protection was associated with reduced oxidative stress in liver tissues. The antioxidant effects of HS were manifested as a normalization of malondialdehyde levels and glutathione levels which were all raised after CIS-induction. In addition, HS treatment resulted in a decrease of catalase, and superoxide dismutase activity. The combined effects of CIS and HS were also studied in two human lung cancer cell lines (A549 and H460). Treatment with HS (20 μg /mL) enhanced the cytotoxic activity of CIS both in A549 and H460 cell lines. Interestingly, HS increased CIS-induced apoptosis and oxidative stress more clearly in A549 cells indicating that HS extract in combination with CIS could increase the efficacy of CIS in the treatment of cancer.


Heterojunction engineering of graphitic carbon nitride (g-C3N4) via Pt loading with improved daylight-induced photocatalytic reduction of carbon dioxide to methane.
In this paper, noble-metal Pt nanoparticles of around 2.5 nm were deposited on graphitic carbon nitride (g-C3N4) synthesized by a chemical reduction process in ethylene glycol. Compared with pure g-C3N4, the resulting Pt-loaded g-C3N4 (Pt/CN) exhibited a considerable improvement in the photoreduction of CO2 to CH4 in the presence of water vapor at ambient temperature and atmospheric pressure under visible light irradiation. 2 wt% Pt-loaded g-C3N4 (2Pt/CN) nanocomposites produced the highest CH4 yield of 13.02 μmol gcatalyst(-1) after 10 h of light irradiation, which was a 5.1-fold enhancement in comparison with pure g-C3N4 (2.55 μmol gcatalyst(-1)). The remarkable photocatalytic activity of Pt/CN nanostructures in the CH4 production was ascribed to the enhanced visible light absorption and efficient interfacial transfer of photogenerated electrons from g-C3N4 to Pt due to the lower Fermi level of Pt in the Pt/CN hybrid heterojunctions as evidenced by the UV-Vis and photoluminescence studies. The enriched electron density on Pt favored the reduction of CO2 to CH4via a multi-electron transfer process. This resulted in the inhibition of electron-hole pair recombination for effective spatial charge separation, thus enhancing the photocatalytic reactions. Based on the experimental results obtained, a plausible mechanism for improved photocatalytic performance associated with Pt/CN was proposed.


ReaxFF molecular dynamics simulation of the thermal decomposition reaction of bio-based polyester materials.
Bio-based polyester elastomers have been widely studied by researchers in recent years because of their comprehensive sources of monomers and environmentally friendly characteristics. However, compared with traditional petroleum-based elastomers, the thermal decomposition temperature of bio-based polyester elastomers is generally low, limiting the application of bio-based elastomers. An effective strategy to increase the intrinsic thermal decomposition temperature (Td) of bio-based elastomers is to increase the length of the monomer carbon chain in the bio-based elastomers. In this work, the content of dodecanedioic acid (DDA) in a bio-based polyester elastomer composed of butanediol (BDO) and succinic acid (SUA) was increased to improve the Td of the bio-based polyester elastomer through the reaction force-field molecular dynamics (ReaxFF-MD) simulations. And the thermal decomposition mechanism of the bio-based polyester was analyzed in detail. By calculating the change rate of the molecular chain mean square displacement (MSD), it was determined that when the content of DDA was 50%, the Td of the bio-based elastomer was up to 718 K. By calculating the activation energy of thermal decomposition and further analyzing the thermal decomposition process, it is found that the thermal decomposition of the bio-based polyester elastomer is mainly through breaking the C-O bond in the backbone. This work is expected to provide theoretical guidance for designing and fabricating highly heat-resistant bio-based elastomers by systematically exploring the thermal decomposition mechanism of bio-based polyester elastomers.


Enhanced sensitivity to oxidative stress in transgenic tobacco plants with decreased glutathione reductase activity leads to a decrease in ascorbate pool and ascorbate redox state.
To investigate the possible mechanisms of glutathione reductase (GR) in protecting against oxidative stress, we obtained transgenic tobacco (Nicotiana tabacum) plants with 30-70% decreased GR activity by using a gene encoding tobacco chloroplastic GR for the RNAi construct. We investigated the responses of wild type and transgenic plants to oxidative stress induced by application of methyl viologen in vivo. Analyses of CO(2) assimilation, maximal efficiency of photosystem II photochemistry, leaf bleaching, and oxidative damage to lipids demonstrated that transgenic plants exhibited enhanced sensitivity to oxidative stress. Under oxidative stress, there was a greater decrease in reduced to oxidized glutathione ratio but a greater increase in reduced glutathione in transgenic plants than in wild type plants. In addition, transgenic plants showed a greater decrease in reduced ascorbate and reduced to oxidized ascorbate ratio than wild type plants. However, there were neither differences in the levels of NADP and NADPH and in the total foliar activities of monodehydroascorbate reductase and dehydroascorbate reductase between wild type and transgenic plant. MV treatment induced an increase in the activities of GR, ascorbate peroxidase, superoxide dismutase, and catalase. Furthermore, accumulation of H(2)O(2) in chloroplasts was observed in transgenic plants but not in wild type plants. Our results suggest that capacity for regeneration of glutathione by GR plays an important role in protecting against oxidative stress by maintaining ascorbate pool and ascorbate redox state.


Effect of anticoccidial and antimicrobial feed additives on prevention of Salmonella colonization of chicks treated with anaerobic cultures of chicken feces.
Chicks were treated orally on the day of hatch with either fresh or frozen competitive exclusion (CE) cultures (native gut microflora). Chicks were fed either unmedicated feed or one of five commercial broiler starter rations or nine experimental feed mixtures containing varying amounts and combinations of anticoccidial and antimicrobial medicaments. After 2 days, they were challenged with approximately 10(6) colony-forming units of a nalidixic-acid-resistant strain of Salmonella typhimurium. Six days later, chicks were sacrificed and ceca were analyzed for S. typhimurium. Colonization of 2-day-old chicks was prevented or at least greatly reduced in most instances by treatment of chicks with a CE culture, but the efficacy of CE broth cultures stored at -70 C diminished over time. Not all CE cultures tested gave equal protection against Salmonella colonization, and CE cultures were more susceptible to some feed additives than others. Of the commercial or experimental feed tested, only the feed containing the combination of nicarbazin and bacitracin interfered with the protective effect of the CE culture.


Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease.
Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices - fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences.


Effect of propofol on the malignant hyperthermia susceptible pig model.
Anaesthetic techniques for malignant hyperthermia susceptible (MHS) patients should include drugs which do not trigger MH and provide stress free conditions. Thus all new drugs should be screened for their susceptibility to trigger MH. We have screened propofol, using the MHS pig model. In none of the animals exposed to propofol, were there signs of MH, even after challenge with suxamethonium. However, the same animals developed MH when exposed to halothane alone or with suxamethonium. Despite the problems of extrapolating from this study to man, it is unlikely that propofol may trigger an episode of MH.


Hypoxia inducible factor-1 independent pathways in tumor angiogenesis.
Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.


Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides.
The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle-metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity ( Ka), enthalpy of binding (Δ H), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides.


Clinical Characteristics of Ratborne Seoul Hantavirus Disease.
Although Seoul orthohantavirus is the only globally spread hantavirus pathogen, few confirmed human infections with this virus have been reported in Western countries, suggesting lower medical awareness of the milder, transient, and often chameleon-like symptoms of this zoonosis. We describe lesser known clinical and laboratory characteristics to help improve underreporting of this virus.


The role of the thymus in a genetically controlled defect of the immune response at the carrier level.
The genetic control of the immune response may be either specific for antigenic carrier or for determinant. We describe here results which show that a carrier-dependent strain defect in immune response is reflected in thymocytes. These results are in agreement with our hypothesis that the genetic defect in the immune response is reflected in thymocytes when the poor response is at the carrier level, whereas it is expressed in the bone marrow population when the low responsiveness is strictly at the determinant level. SWR mice are low responders to multichain polyproline. Furthermore, this mouse strain does not produce antibodies to determinants such as peptides of phenylalanine and glutamic acid (Phe,Glu) or to the loop peptide of lysozyme when attached to polyproline, although they respond well to the same antigenic determinants when conjugated to multichain poly(DL-alanine). Transfer experiments in which irradiated SWR recipients were injected with excess of DBA/1 thymocytes (which do not exhibit a defect in response to polyproline) mixed with graded numbers of SWR marrow cells, prior to immunization with poly(Tyr,Glu)-poly(Pro)--poly(Lys), have indicated that the poor response potential of SWR mice to polyproline is not reflected in their bone marrow cells. Allogeneic transfers in which mixtures of thymocytes and marrow cells from high and low responders were injected into irradiated mice, followed by immunization with poly(Tyr,Glu)-poly(Pro)--poly(Lys) or poly(Phe,Glu)-poly(Pro)--poly(Lys) have demonstrated a clear defect in the thymus derived population of SWR mice when the response potential to polyproline and to determinants attached to it was tested.


PHBV/PCL microparticles for controlled release of resveratrol: physicochemical characterization, antioxidant potential, and effect on hemolysis of human erythrocytes.
Microparticles of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and poly(ε-caprolactone) (PCL) containing resveratrol were successfully prepared by simple emulsion/solvent evaporation. All formulations showed suitable encapsulation efficiency values higher than 80%. PHBV microparticles revealed spherical shape with rough surface and presence of pores. PCL microparticles were spherically shaped with smooth surface. Fourier-transformed infrared spectra demonstrated no chemical bond between resveratrol and polymers. X-ray powder diffraction patterns and differential scanning calorimetry analyses indicated that microencapsulation led to drug amorphization. These PHBV/PCL microparticles delayed the dissolution profile of resveratrol. Release profiles were better fitted to biexponential equation. The hypochlorous-acid-scavenging activity and 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation discoloration assay confirmed that the antioxidant activity of PHBV/PCL microparticles was kept, but was dependent on the microparticle morphology and dissolution profile. Resveratrol-loaded PHBV/PCL microparticles showed no cytotoxic effect on red blood cells.


Time-order-errors and duration ranges in the Episodic Temporal Generalization task.
The current model of the Episodic Temporal Generalization task, where subjects have to judge whether pairs of auditory stimuli are equal in duration, predicts that results are scale-free and unaffected by the presentation order of the stimuli. To test these predictions, we conducted three experiments assessing sub- and supra-second standards and taking presentation order into account. Proportions were spaced linearly in Experiments 1 and 2 and logarithmically in Experiment 3. Critically, we found effects of duration range and presentation order with both spacing schemes. Our results constitute the first report of presentation order effects in the Episodic Temporal Generalization task and demonstrate that future studies should always consider duration range, number of trials and presentation order as crucial factors modulating performance.


[The transactional stress model for the animal keeper].
A health problem of an animal or a group of animals represents a potential stress situation for the animal keeper. In this article, the transactional stress model, which was developed in social psychology was applied on the animal keeper and shows, how he perceives the influence of animal care. If veterinary help is considered relevant, it may lead to an improved coping, which affects the health of the animal keeper and the animal as well. This viewpoint leads to a cycle, in which cause, success, coping and utility are closely linked together.


Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver.
To clarify molecular mechanisms underlying liver carcinogenesis induced by aberrant activation of Wnt pathway, we isolated the target genes of beta-catenin from mice exhibiting constitutive activated beta-catenin in the liver. Adenovirus-mediated expression of oncogenic beta-catenin was used to isolate early targets of beta-catenin in the liver. Suppression subtractive hybridization was used to identify the leukocyte cell-derived chemotaxin 2 (LECT2) gene as a direct target of beta-catenin. Northern blot and immunohistochemical analyses demonstrated that LECT2 expression is specifically induced in different mouse models that express activated beta-catenin in the liver. LECT2 expression was not activated in livers in which hepatocyte proliferation was induced by a beta-catenin-independent signal. We characterized by mutagenesis the LEF/TCF site, which is crucial for LECT2 activation by beta-catenin. We further characterized the chemotactic property of LECT2 for human neutrophils. Finally, we have shown an up-regulation of LECT2 in human liver tumors that expressed aberrant activation of beta-catenin signaling; these tumors constituted a subset of hepatocellular carcinomas (HCC) and most of the hepatoblastomas that were studied. In conclusion, our results show that LECT2, which encodes a protein with chemotactic properties for human neutrophils, is a direct target gene of Wnt/beta-catenin signaling in the liver. Since HCC develops mainly in patients with chronic hepatitis or cirrhosis induced by viral or inflammatory factors, understanding the role of LECT2 in liver carcinogenesis is of interest and may lead to new therapeutic perspectives.


A microfibril-generating factor from the cellulase of Trichoderma reesei.
A combination of ionic strength reduction and diafiltration of Trichoderma reesei cellulate complex through a hollow fiber apparatus of 5000 molecular weight (MW) cutoff and subsequent passage of filtrate over a Spherogel-TSK 3000-SW column provided extracts that had the ability to generate microfibrils in filter paper and to disrupt filter paper and corn leaf tissue. Milligram quantities of material obtained from these extracts released small amounts of soluble carbohydrate from filter paper, required ferric iron for increased activity, and contained amino acids. Short fiber formation and disruption of filter paper during interaction with these extracts was enhanced by prior acid treatment and eliminated by prior base treatment. The amount of soluble carbohydrate hydrolyzed in 24 h from filter paper by whole cellulase complex was not changed by first disrupting the substrate with the extracts.


A parallel-group, randomised controlled trial of a multimedia, self-directed, coping skills training intervention for patients with cancer and their partners: design and rationale.
Coping skills training interventions have been found to be efficacious in helping both patients and their partners manage the physical and emotional challenges they face following a cancer diagnosis. However, many of these interventions are costly and not sustainable. To overcome these issues, a self-directed format is increasingly used. The efficacy of self-directed interventions for patients has been supported; however, no study has reported on the outcomes for their partners. This study will test the efficacy of Coping-Together-a multimedia, self-directed, coping skills training intervention for patients with cancer and their partners. The proposed three-group, parallel, randomised controlled trial will recruit patients diagnosed in the past 4 months with breast, prostate, colorectal cancer or melanoma through their treating clinician. Patients and their partners will be randomised to (1) a minimal ethical care (MEC) condition-selected Cancer Council New South Wales booklets and a brochure for the Cancer Council Helpline, (2) Coping-Together generic-MEC materials, the six Coping-Together booklets and DVD, the Cancer Council Queensland relaxation audio CD and login to the Coping-Together website or (3) Coping-Together tailored-MEC materials, the Coping-Together DVD, the login to the website and only those Coping-Together booklet sections that pertain to their direct concerns. Anxiety (primary outcome), distress, depression, dyadic adjustment, quality of life, illness or caregiving appraisal, self-efficacy and dyadic and individual coping will be assessed before receiving the study material (ie, baseline) and again at 3, 6 and 12 months postbaseline. Intention-to-treat and per protocol analysis will be conducted. This study has been approved by the relevant local area health and University ethics committees. Study findings will be disseminated not only through peer-reviewed publications and conference presentations but also through educational outreach visits, publication of lay research summaries in consumer newsletters and publications targeting clinicians. Australian New Zealand Clinical Trials Registry ACTRN12613000491763 (03/05/2013).


The Syphilis Epidemic Among Heterosexuals Is Accelerating: Evidence From King County, Washington.
We characterized the rapid increase in syphilis among cisgender women in King County, Washington, and compared it with trends among cisgender men who have sex with men. We used surveillance data from King County, 2007 to 2022, to describe incidence trends stratified by syphilis stage, gender, and gender of sex partners; trends in pregnant cases and congenital syphilis; and trends in rapid plasma reagin titer at diagnosis among late/unknown duration cases. We used joinpoint regression to analyze trends. Among cisgender women, all-stage syphilis incidence remained stable from 2007 to 2010 but then increased by 16.3% per year (95% CI, 12.0%-20.7%) from 2010 to 2020 and 90.1% per year (95% CI, 26.4%-185.9%) from 2020 to 2022. Early syphilis rates rose gradually from 2007 to 2017 (18% per year; 95% CI, 7.4%-29.6%) and then rapidly from 2017 to 2022 (62.5% per year; 95% CI, 24.1%-112.9%). In contrast, the increase in late/unknown duration syphilis incidence was delayed. Among cisgender men who have sex with women, all-stage syphilis remained stable from 2007 to 2014 and increased 25.0% per year (95% CI, 14.0%-37.0%) from 2014 to 2022. Syphilis incidence increased steadily among men who have sex with men, with all-stage incidence increasing 7.0% per year (95% CI, 4.8%-9.2%) from 2007 to 2022. Median rapid plasma reagin titer among late/unknown duration cases increased significantly over the analysis period. An explosive epidemic of syphilis is ongoing in King County. The delayed increase in asymptomatic late/unknown duration cases relative to early symptomatic cases suggests that there is a large and growing reservoir of recently acquired undiagnosed syphilis in women. New clinical and public health activities are urgently needed to control the growing epidemic.


Lung organoids: current uses and future promise.
Lungs are composed of a system of highly branched tubes that bring air into the alveoli, where gas exchange takes place. The proximal and distal regions of the lung contain epithelial cells specialized for different functions: basal, secretory and ciliated cells in the conducting airways and type II and type I cells lining the alveoli. Basal, secretory and type II cells can be grown in three-dimensional culture, with or without supporting stromal cells, and under these conditions they give rise to self-organizing structures known as organoids. This Review summarizes the different methods for generating organoids from cells isolated from human and mouse lungs, and compares their final structure and cellular composition with that of the airways or alveoli of the adult lung. We also discuss the potential and limitations of organoids for addressing outstanding questions in lung biology and for developing new drugs for disorders such as cystic fibrosis and asthma.


Mood after various brief exercise and sport modes: aerobics, hip-hop dancing, ice skating, and body conditioning.
To investigate the potential psychological benefits of brief exercise and sport activities on positive mood alterations, 45 Korean high school and 232 undergraduate students enrolled in physical education and stress management classes voluntarily participated and were randomly assigned to one of four activities: aerobic exercise, body conditioning, hip-hop dancing, and ice skating. Mood changes from before to after exercise (2 pm to 3 pm) were measured based on a Korean translation of the Subjective Exercise Experiences Scale. The findings suggested that the aerobics and hip-hop dancing groups rated positive well-being higher than the body conditioning and ice skating groups. Immediately after exercise, psychological distress was rated lower in the aerobics and hip-hop dancing groups, as was fatigue.


[Retrospective analysis of thalidomide therapy in patients with relapsed/refractory multiple myeloma].
Thalidomide is now recognized as an important agent for multiple myeloma. In this study, we retrospectively analyzed the effect of thalidomide therapy in 52 patients with relapsed/refractory multiple myeloma. Median age was 70 years. Eight patients were treated with thalidomide alone, 36 with dexamethasone, and 8 with chemotherapy. The maintenance dose of thalidomide was 100 mg/day in 42 cases. The probability of overall survival and progression-free survival one year after the start of thalidomide were 76.2% and 70.9%, respectively. Complete or partial response was obtained in 16 patients (31%). The probability of survival was better in patients who obtained a partial or complete response than in non-responders (P=0.04). Adverse effects (CTCAE criteria Grade 3-4) were somnolence (n=3), constipation (n=5), peripheral neuropathy (n=1), deep vein thrombosis (n=1), anemia (n=10), leukocytopenia (n=10), and thrombocytopenia (n=3). The high incidence of cytopenia in this study suggests that the Japanese population tends to display bone marrow suppression after thalidomide therapy. Some patients developed peripheral neuropathy at the early stage of administration and attention was necessary. In conclusion, thalidomide therapy is safe and effective in patients with refractory multiple myeloma.


Real-time processing of serial stimuli in classical conditioning of the rabbit's nictitating membrane response.
Real-time models contend that a conditioned stimulus (CS) gives rise to a cascade of hypothetical stimuli that govern conditioned responses (CRs) on a moment-by-moment basis. Experiments with the rabbit nictitating membrane response successfully extended these models to external stimuli. CSs were trained in sequence with an unconditioned stimulus (CSA-CSB-US). When the CSA-CSB interval was shortened, the CR was compressed; when the CSA-CSB interval was lengthened, the CR was broadened. Peaks appeared at 2 places, namely, 1 following CSA by a period equal to its CS-US interval and another following CSB by its CS-US interval. Outside the sequence, the individual CSs evoked CRs located between their respective CS-US intervals. When, however, the 2 CSs were trained separately, the CRs were appropriate to their respective CS-US intervals when tested alone or in sequence. The results are discussed in terms of the J.E. Desmond and J.W. Moore (1988) and S. Grossberg and N.A. Schmajuk (1989) models.


Microcarrier-based stem cell bioprocessing: GMP-grade culture challenges and future trends for regenerative medicine.
Recently, stem cell-based therapies have been proposed as an alternative for the treatment of many diseases. Stem cells (SCs) are well known for their capacity to preserve themselves, proliferate, and differentiate into multiple lineages. These characteristics allow stem cells to be a viable option for the treatment of diverse diseases. Traditional methodologies based on 2-dimensional culture techniques (T-flasks and Petri dishes) are simple and well standardized; however, they present disadvantages that limit the production of the cell yield required for regenerative medicine applications. Lately, microcarrier (MC)-based culture techniques have emerged as an attractive platform for expanding stem cells in suspension systems. Although the use of stem cell expansion on MCs has recently shown significant increase, their implementation for medical purposes is been hampered by bottlenecks in upstream and downstream processing. Therefore, there is an urgent need in the development of bioprocesses that simplify stem cell cultures under xeno-free conditions and detachment from MCs without diminishing their pluripotency and viability. A critical analysis of the factors that impact the up and downstream bioprocessing on MC-based stem cell cultures is presented in this review. This analysis aims to raise the awareness of the current drawbacks that limit MC-based stem cell bioprocessing in regenerative medicine and propose alternatives to overcome them.


Molecular and structural insight into the role of key residues of thrombospondin-1 and calreticulin in thrombospondin-1-calreticulin binding.
Thrombospondin-1 (TSP1) binding to calreticulin (CRT) on the cell surface signals focal adhesion disassembly, leading to the intermediate adhesive phenotype, cell migration, anoikis resistance, and collagen stimulation. Residues Lys 24 and 32 in TSP1 and amino acids 24-26 and 32-34 in CRT have been shown through biochemical and cell-based approaches to be critical for TSP1-CRT binding and signaling. This study investigated the molecular and structural basis for these key TSP1 and CRT residues in TSP1-CRT binding. On the basis of a validated TSP1-CRT complex structure, we adopted steered molecular dynamics simulations to determine the effect of mutation of these key residues on TSP1-CRT binding and validated the simulation results with experimental observations. We further performed 30 ns molecular dynamics simulations for wild-type TSP1, CRT, K24A/K32A mutant TSP1, and mutant CRT (residues 24-26 and 32-34 mutated to Ala) and studied the conformational and structural changes in TSP1 and CRT as the result of mutation of these critical residues. Results showed that mutation of residues 24 and 32 to Ala in TSP1 and of amino acids 24-26 and 32-34 to Ala in CRT results in a shortened β-strand in the binding site, decreased hydrogen bond occupancy for β-strand pairs that are located within or near the binding site, increased conformational flexibility of the binding site, a changed degree of dynamically correlated motion between the residues in the binding site and the other residues in protein, and a changed degree of overall correlated motion between the residues in the protein. These changes could directly contribute to the loss or weakened binding between TSP1 and CRT and the resultant effects on TSP1-CRT binding-induced cellular activities. Results from this study provide a molecular and structural insight into the role of these critical residues of TSP1 and CRT in TSP1-CRT binding.


Ankyloglossum superius syndrome: diagnosis and surgical management.
Ankyloglossum superius (or ankyloglossia superior) is a rare congenital craniofacial condition characterized by tongue tip adherence to the hard palate and associated limb abnormalities. There have been few reports of this condition in the literature. We present a patient with ankyloglossum superius syndrome and discuss diagnosis and surgical management.


Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia.
We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.


Endogenous gamma interferon-independent host resistance against Listeria monocytogenes infection in CD4+ T cell- and asialo GM1+ cell-depleted mice.
The effects of in vivo administration of antibodies against T-cell subsets and asialo GM1 (ASGM1)-bearing cells on endogenous gamma interferon (IFN-gamma) production and host defense in Listeria monocytogenes-infected mice were investigated. Endogenous IFN-gamma titers in the bloodstreams and spleen extracts of mice on day 2 of infection were partially suppressed by administration of rabbit anti-ASGM1 antibody, but not by anti-CD4 monoclonal antibody (MAb) or anti-CD8 MAb. Of the different combinations of these three antibodies, the most suppressive effect on IFN-gamma production was observed after administration of anti-CD4 Mab and anti-ASGM1 antibody, although anti-CD8 MAb combined with anti-CD4 MAb partially inhibited IFN-gamma production. In contrast, antilisterial resistance was suppressed by the administration of anti-CD8 MAb but not by anti-CD4 MAb or anti-ASGM1 antibody. Antilisterial resistance in mice in which both CD4+ cells and ASGM1+ cells had been depleted was performed as efficiently as in normal mice in spite of the fact that endogenous IFN-gamma production was markedly suppressed. Furthermore, these mice also eliminated L. monocytogenes cells efficiently from the spleens even when they were pretreated with anti-mouse IFN-gamma MAb. These results indicate that CD4+ T cells, CD8+ T cells, and ASGM1+ cells are all responsible for endogenous IFN-gamma production and that antilisterial resistance and endogenous IFN-gamma production are not absolutely correlated.


Improved Classification of Benign and Malignant Breast Lesions Using Deep Feature Maximum Intensity Projection MRI in Breast Cancer Diagnosis Using Dynamic Contrast-enhanced MRI.
To develop a deep transfer learning method that incorporates four-dimensional (4D) information in dynamic contrast-enhanced (DCE) MRI to classify benign and malignant breast lesions. The retrospective dataset is composed of 1990 distinct lesions (1494 malignant and 496 benign) from 1979 women (mean age, 47 years ± 10). Lesions were split into a training and validation set of 1455 lesions (acquired in 2015-2016) and an independent test set of 535 lesions (acquired in 2017). Features were extracted from a convolutional neural network (CNN), and lesions were classified as benign or malignant using support vector machines. Volumetric information was collapsed into two dimensions by taking the maximum intensity projection (MIP) at the image level or feature level within the CNN architecture. Performances were evaluated using the area under the receiver operating characteristic curve (AUC) as the figure of merit and were compared using the DeLong test. The image MIP and feature MIP methods yielded AUCs of 0.91 (95% CI: 0.87, 0.94) and 0.93 (95% CI: 0.91, 0.96), respectively, for the independent test set. The feature MIP method achieved higher performance than the image MIP method (∆AUC 95% CI: 0.003, 0.051; P = .03). Incorporating 4D information in DCE MRI by MIP of features in deep transfer learning demonstrated superior classification performance compared with using MIP images as input in the task of distinguishing between benign and malignant breast lesions.Keywords: Breast, Computer Aided Diagnosis (CAD), Convolutional Neural Network (CNN), MR-Dynamic Contrast Enhanced, Supervised learning, Support vector machines (SVM), Transfer learning, Volume Analysis © RSNA, 2021.


A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma.
Multiple myeloma is a plasma cell malignancy, which grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NET). Here, we investigated whether multiple myeloma cells induce NET formation and whether targeting this process would delay multiple myeloma progression. We demonstrated that murine and human multiple myeloma cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel-specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to multiple myeloma-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of multiple myeloma.


Trend analysis of the dosimetric impact of anatomical changes during proton therapy for maxillary sinus carcinoma.
Anatomical changes, such as shrinkage and aeration, can affect dose distribution in proton therapy (PT) for maxillary sinus carcinoma (MSC). These changes can affect the dose to the target and organs at risk (OARs); however, when these changes occur during PT is unclear. This study aimed to investigate the dosimetric impact of anatomical changes during PT. Fifteen patients with MSC were enrolled in this study. Initial PT plans were generated based on initial computed tomography (CT) images. Several repeat CT images were obtained to confirm anatomical changes during PT. Evaluation PT plans were generated by copying initial PT plans to repeat CT images. The dose differences of the target and OARs were evaluated by comparing both the plans. At 3-4 weeks after the initiation of PT, the target volume reduced by approximately 10% as compared with the initial volume. Consequently, the target volumes gradually varied until the end of treatment. The value of V95 (volume that received 95% of the prescription dose) in the clinical target volume of the evaluation PT plan was similar to that of the initial PT plan. However, the dose to OARs, such as the contralateral optic nerve, contralateral eyeball, brainstem, and optic chiasm, increased significantly from the middle to the later phases of the treatment course. In contrast, there was a slight dose difference in the ipsilateral optic apparatus. The trend analysis in this study showed that anatomical changes appeared 3-4 weeks after the start of PT, and the dose to the OARs tended to increase. Therefore, it is recommended to check the status of tumor 3-4 weeks after the start of treatment to avoid the deterioration of dose distribution due to these changes.


[Sequence analysis of the complete genome of bocavirus WLL-1].
Human bocavirus, which was firstly discovered in 2005, is a new human parvovirus associated with lower respiratory tract infection in children. In this study, a human bocavirus, named WLL-1 isolate, was identified in Wenlin County, Zhejiang Province. The genome of bocavirus WLL-1 has been sequenced and analyzed. Phylogenetic analyses showed that WLL-1 shares 99% homology with other bocaviruses recently reported, but also has some special variations.


Extended parallel backprojection for standard three-dimensional and phase-correlated four-dimensional axial and spiral cone-beam CT with arbitrary pitch, arbitrary cone-angle, and 100% dose usage.
We have developed a new approximate Feldkamp-type algorithm that we call the extended parallel backprojection (EPBP). Its main features are a phase-weighted backprojection and a voxel-by-voxel 180 degrees normalization. The first feature ensures three-dimensional (3-D) and 4-D capabilities with one and the same algorithm; the second ensures 100% detector usage (each ray is accounted for). The algorithm was evaluated using simulated data of a thorax phantom and a cardiac motion phantom for scanners with up to 256 slices. Axial (circle and sequence) and spiral scan trajectories were investigated. The standard reconstructions (EPBPStd) are of high quality, even for as many as 256 slices. The cardiac reconstructions (EPBPCI) are of high quality as well and show no significant deterioration of objects even far off the center of rotation. Since EPBPCI uses the cardio interpolation (CI) phase weighting the temporal resolution is equivalent to that of the well-established single-slice and multislice cardiac approaches 180 degrees CI, 180 degrees MCI, and ASSRCI, respectively, and lies in the order of 50 to 100 ms for rotation times between 0.4 and 0.5 s. EPBP appears to fulfill all required demands. Especially the phase-correlated EPBP reconstruction of cardiac multiple circle scan data is of high interest, e.g., for dynamic perfusion studies of the heart.


GPS Cycle Slip Detection Considering Satellite Geometry Based on TDCP/INS Integrated Navigation.
This paper presents a means of carrier phase cycle slip detection for an inertial-aided global positioning system (GPS), which is based on consideration of the satellite geometry. An integrated navigation solution incorporating a tightly coupled time differenced carrier phase (TDCP) and inertial navigation system (INS) is used to detect cycle slips. Cycle-slips are detected by comparing the satellite-difference (SD) and time-difference (TD) carrier phase measurements obtained from the GPS satellites with the range estimated by the integrated navigation solution. Additionally the satellite geometry information effectively improves the range estimation performance without a hardware upgrade. And the covariance obtained from the TDCP/INS filter is used to compute the threshold for determining cycle slip occurrence. A simulation and the results of a vehicle-based experiment verify the cycle slip detection performance of the proposed algorithm.


Lubiprostone: pharmacokinetic, pharmacodynamic, safety and regulatory aspects in the treatment of constipation-predominant irritable bowel syndrome.
Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide. This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system. Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C.


Effects of procaine on pharmaco-mechanical coupling mechanisms activated by acetylcholine in smooth muscle cells of porcine coronary artery.
The action of procaine on pharmaco-mechanical coupling activated by application of acetylcholine (ACh) was investigated using collagenase-treated dispersed intact and skinned smooth muscle cells and intact muscle tissues of the porcine coronary artery. ACh reduced stored 45Ca2+, and this action was prevented by procaine in intact dispersed cells. The maximum reduction in the level of stored 45Ca induced by caffeine (25 mM) or inositol 1,4,5-trisphosphate (InsP3; 3 microM) was also prevented by procaine in the skinned muscle cells in the presence or absence of ATP. However, inhibitions of the latter required higher concentrations of procaine than the former. Release by 10 microM ACh of Ca2+ from its store site in the presence or absence of extracellular Ca2+ was also inhibited by procaine and was detected using the quin2 fluorescence method. In these smooth muscle tissues, ACh (above 10 nM) reduced the amount of phosphatidylinositol 4,5-bisphosphate (PI-P2) and dose dependently increased the amount of phosphatidic acid. Procaine inhibited the hydrolysis of PI-P2 activated by ACh, thus reducing the amount of InsP3 and the release of Ca2+ from the store site. It is concluded that procaine has multiple actions on the porcine coronary artery, and one of the actions related with pharmacomechanical coupling appears through inhibition of hydrolysis of PI-P2 induced by ACh.


The value of three-dimensional radiotherapy planning in advanced carcinoma of the urinary bladder based on computed tomography.
Since 1987, radiotherapy planning of advanced bladder cancer T3-T4 has been based on computed tomography (CT), and since 1989 we have used a three-dimensional (3-D) planning system. The treatment plans of 110 patients referred to our department in 1989-1991 have been evaluated. The field sizes used after CT-based treatment planning were compared with the field sizes that would have been used after conventional planning alone (cystogram). The changes of the treatment plans are described. In 62 (60%) cases the treatment plans were altered because of the CT-scans, mainly as an enlargement of the fields. The field enlargements were mostly in the dorsal and caudal direction. In 10 (10%) cases the CT-scans provided diagnostic information which contra-indicated the proposed radical irradiation. The 3-D dose planning system has been of great value, especially the beams-eye view presentation which is an efficient tool for adjusting the field size.


Lack of diagnostic utility of the ECG-derived ventricular gradient in patients with suspected acute pulmonary embolism.
The YEARS algorithm was successfully developed to reduce the number of computed tomography pulmonary angiography (CTPA) investigations in the diagnostic management of patients with suspected pulmonary embolism (PE), although half of patients still needed to be referred for CTPA. We hypothesized that ECG derived ventricular gradient optimized for right ventricular pressure overload (VG-RVPO), an easy to use tool for detecting PE-induced pulmonary hypertension (PH), may further improve the efficiency of the YEARS algorithm. In this post-hoc analysis of the Years study, ECGs of 479 patients with suspected PE managed according to the YEARS algorithm were available for analysis. The diagnostic performance of VG-RVPO was assessed and likelihood ratios were calculated. PE was diagnosed in 88 patients (18%). In patients with confirmed PE, 34% had an abnormal VG-RVPO versus 24% of those without PE (odds ratio 1.6; 95%CI 0.94-2.6). The mean VG-RVPO was -22 ± 13 and did not differ between the two patient groups (-22 versus -20; mean difference - 2, 95% CI -4.8 to 1.3). The sensitivity of VG-RVPO for PE was 24% (95%CI 34-45), the specificity 76% (95%CI 71-80) and the c-statistic 0.45 (95% CI 0.38-0.51). When combined with the YEARS algorithm, the likelihood ratios of VG-RVPO remained close to 1.0. Ruling out PE in patients with an indication for CTPA based on a normal VG-RVPO would have resulted in 58 missed cases. The VG-RVPO has no diagnostic value for suspected acute PE, either as stand-alone diagnostic test or combined with the YEARS algorithm. This post-hoc analysis of the YEARS study failed to demonstrate incremental diagnostic value of VG-RVPO for acute PE, either as stand-alone diagnostic test or combined with the YEARS algorithm. Nevertheless, the role of VG-RVPO recorded on admission could potentially be valuable in the risk stratification of PE during hospitalization, although this remains to be studied.


Influence of left atrial size on the outcome of pulmonary vein isolation in patients with atrial fibrillation.
Atrial fibrillation (AF) is the most frequent sustained supraventricular tachyarrhythmia. Radiofrequency (RF) ablation is one of the options used to prevent the recurrence of AF. Despite thorough studies, the relation between left atrial (LA) size and the results of RF ablation remains controversial. To estimate the relation between LA size assessed by echocardiography and the AF recurrence rate after pulmonary vein isolation (PVI). Our analysis comprised 175 AF patients subjected to PVI between June 2011 and March 2012. Inclusion criteria comprised: symptomatic AF with no reversible cause, and age < 70, LA < 5.5 cm (anteroposterior). PVI was performed with a 4-mm non-irrigated catheter or irrigated catheter and circular mapping catheter (electroanatomic mapping with LocaLisa or CARTO systems). Recurrence was defined as any atrial tachyarrhythmia episode that lasted more than 30 s after three months of blanking period. Standard echocardiographic post-ablation anteroposterior LA measurements were performed with additional parameters such as systolic and diastolic LA area and volume (on sinus rhythm). The analysis included 198 procedures performed in 175 patients. Median follow-up time was 17 months. Median age was 56 years. After the first procedure, AF recurred in 88 (52.4%) patients. Efficacy after the last procedure was 55.2% (43.5% for persistent AF and 59.7% for paroxysmal AF). No significant relation between any of the LA parameters and the recurrence rate was found. Cox univariate and multivariate analysis revealed only very early AF recurrence as a prognostic factor for AF recurrence in the long term. In patients with AF, no relation could be observed between the recurrence rate after PVI and the echocardiographic LA measurement parameters.


Non-invasive assessment of liver fibrosis in chronic viral hepatitis.
Hyaluronic acid (HA), ASAT to Platelet Ratio Index (APRI), ASAT/ALAT ratio, Fibrosis 4 score (FIB4) and FibroScan were studied as non-invasive markers of liver fibrosis (F) in chronic viral hepatitis B (CHB) and C (CHC), in an attempt to avoid the complications of liver puncture biopsy, considered the gold standard in the evaluation of F. The aim of our research was to study whether HA, APRI, ASAT/ALAT ratio, FIB4 and FibroScan are useful non-invasive markers in predicting severe F in Romanian patients. This was a prospective multicenter transversal and observational study, which included 76 patients with CHB/CHC. The independent effect of studied markers was tested using multiple binary logistic regression. In patients with CHB and CHC, the APRI cut-off value for F4 was 0·70 ng/mL (Se = 77%, Sp = 78%), the FIB4 cut-off value was 2·01 (Se = 77%, Sp = 69%), and the FibroScan cut-off value was 13·15 (Se = 92%, Sp = 88%). For patients with CHB/CHC, there was a significant linear positive correlation between F and HA (r = 0·42, P = 0·001), FibroScan (r = 0·67, P < 0·001), APRI (r = 0·46, P < 0·001) and FIB4 (r = 0·51, P < 0·001). Considering age, sex and body mass index as possible confounding factors or covariates in multivariable logistic modelling, FibroScan was the unique test that able to significantly highlight the presence of F4 score in CHB/CHC patients (P = 0·009) while FIB4 test seems to have a tendency to statistical significance. FibroScan, APRI and FIB4 are useful non-invasive tests for the evaluation of F4 in patients with CHB and CHC.


Comparison of communication skills in medical residents with and without undergraduate communication skills training as provided by the Faculty of Medicine of Gadjah Mada University.
To promote better doctor-patient relationships in clinical practice, many medical faculties have introduced practical communication skills training programs for their students. This study is aimed at comparing the communication skills of graduates of the Faculty of Medicine of Gadjah Mada University, Indonesia, educated with and without communication skills training as perceived by their patients and by the graduates themselves. Over 300 patients were seen by 18 medical residents trained in communication skills before graduation and 30 residents who had not attended this training. After consultation patients and residents completed a 39-item questionnaire addressing the doctor's communication behavior skills. In the questionnaires completed by patients the desired communication behavior of doctors was also rated. Patients did not observe any differences in communication behavior skills among residents who received training and those who did not. These two groups of trained and non-trained residents assessed their own communication behavior skills. On 4/39 questionnaire items patients rated the communication behavior skills of trained residents lower than the residents themselves and the ratio was 13/39 for non-trained residents. A significant gap was noted between doctors' communication behavior skills as observed and desired by their patients (p < 0.001). Undergraduate communication skills training in the institution under study could not be demonstrated to illustrate a difference in the communication behavior skills of its graduates from graduates from the same institution who did not attend communication skills training. Trained graduates, however, were more aware of communication behavior skills as being preferred by their patients than their peers who were not trained in communication behavior skills training during their undergraduate studies.


Anxiety in an alcoholic population: a normative study.
While anxiety is part of the clinical picture for alcohol abusers, there are no published normative data available for this population on state and trait anxiety as assessed by the STAI (Form Y). Pre- and posttreatment STAI-Y scores were examined from 107 males who volunteered for treatment at a Veterans Administration Medical Center Alcohol Dependence Treatment Unit. Normative data on the STAI (Form Y) from an alcoholic sample are presented (N = 107). Comparison of pre-admission and posttreatment scores yielded significant differences for both state anxiety and trait anxiety. Use of the STAI-Y with alcoholic inpatients for assessing self-reported changes of both transitory (state) anxiety and stable (trait) anxiety seems appropriate. The need for further construct validation as well as systematic manipulation of treatment variables and situational factors with this population is discussed.


Antibody directed against the 142-148 sequence of the myosin heavy chain interferes with myosin-actin interaction.
It has been reported recently that the isolated and renatured 23-kDa N-terminal fragment of rabbit skeletal muscle myosin binds tightly to F-actin in an ATP-dependent manner [Muhlrad, A. (1989) Biochemistry 28, 4002-4010]. The binding to actin is of electrostatic nature and may involve a positively charged cluster of residues on the 23-kDa fragment stretching from Arg-143 to Arg-147. An octapeptide containing this positive cluster was synthesized and coupled to BSA through a cysteine residue added to the N-terminus of the peptide. Polyclonal antibody was raised against the BSA-coupled peptide in rabbits which recognized the N-terminal 23-kDa fragment of rabbit skeletal myosin subfragment 1, and a peptide comprised of residues 122-204 of the 23K fragment in Western blots. The purified antibody [IgG and F(ab)] inhibited the actin-activated ATPase activity of S1 without affecting its Mg2(+)- and K+(EDTA)-modulated ATPase activity. Both IgG and F(ab) decreased the binding of S1 to F-actin in a sedimentation assay, and actin inhibited the binding of both IgG and F(ab) to S1 in a competitive binding assay. The cysteine thiol of the synthetic octapeptide was labeled by the fluorescent thiol reagent monobromobimane, and the labeled peptide was found to bind to actin in a sedimentation assay. The results support the possibility that the positively charged Arg-143 to Arg-147 stretch of residues on the 23-kDa fragment participates in actin binding of myosin and may represent an essential constituent of the actin-S1 interface.


A Laboratory Study on Effects of Cycling Helmet Fit on Biomechanical Measures Associated With Head and Neck Injury and Dynamic Helmet Retention.
There is a scant biomechanical literature that tests, in a laboratory setting, whether or not determinants of helmet fit affect biomechanical parameters associated with injury. Using conventional cycling helmets and repeatable models of the human head and neck, integrated into a guided drop impact experiment at speeds up to 6 m/s, this study tests the hypothesis that fit affects head kinematics, neck kinetics, and the extent to which the helmet moves relative to the underlying head (an indicator of helmet positional stability). While there were a small subset of cases where head kinematics were statistically significantly altered by fit, when viewed as a whole our measures of head kinematics suggest that fit does not systematically alter kinematics of the head secondary to impact. Similarly, when viewed as a whole, our data suggest that fit does not systematically alter resultant neck compression and resultant moment and associated biomechanical measures. Our data suggest that backward fit helmets exhibit the worst dynamic stability, in particular when the torso is impacted before the helmeted head is impacted, suggesting that the typical certification method of dynamical loading of a helmet to quantify retention may not be representative of highly plausible cycling incident scenarios where impact forces are first applied to the torso leading to loading of the neck prior to the head. Further study is warranted so that factors of fit that affect injury outcome are uncovered in both laboratory and real-world settings.


Life and destruction: ubiquitin-mediated proteolysis in aging and longevity.
The ubiquitin/proteasome system (UPS) regulates the turnover of improperly folded and damaged proteins to maintain protein homeostasis (proteostasis), cellular function, and viability. It is commonly thought that an age-related impairment of the UPS affects general proteostasis networks, which causes enhanced protein aggregation and contributes to normal aging. Recent studies identified the existence of ubiquitin-dependent degradation pathways that specifically control lifespan regulators, suggesting additional roles for ubiquitylation in aging and longevity.