Cutting edge: developmental switches in chemokine responses during T cell maturation.
We show that developmental transitions during thymocyte maturation are associated with dramatic changes in chemotactic responses to chemokines. Macrophage-derived chemokine, a chemokine expressed in the thymic medulla, attracts thymocytes only during a brief window of development, between the late cortical and early medullary stages. All medullary phenotypes (CD4 or CD8 single positive) but not immature thymocytes respond to the medullary stroma-expressed (and secondary lymphoid tissue-associated) chemokines secondary lymphoid-tissue chemokine and macrophage inflammatory protein-3beta. The appearance of these responses is associated with the phenotypic stage of cortex to medulla migration and with up-regulation of mRNA for the receptors CCR4 (for macrophage-derived chemokine and thymus and activation-regulated chemokine) and CCR7 (for secondary lymphoid-tissue chemokine and macrophage inflammatory protein-3beta). In contrast, most immature and medullary thymocytes migrate to thymus-expressed chemokine, an ability that is lost only with up-regulation of the peripheral homing receptor L-selectin during the latest stages of thymocyte maturation associated with export to the periphery. Developmental switches in chemokine responses may help regulate critical migratory events during T cell development.


Occurrence of genes of putative fibrinogen binding proteins and hemolysins, as well as of their phenotypic correlates in isolates of S. lugdunensis of different origins.
Staphylococcus lugdunensis is an important human pathogen that causes potentially fatal endocarditis, osteomyelitis and skin and soft tissue infections similar to diseases caused by Staphylococcus aureus. Nevertheless, in contrast to S. aureus, data on pathogenicity factors of S. lugdunensis is scarce. Two adhesins, a fibrinogen and a von Willebrand factor binding protein, and a S. lugdunensis synergistic hemolysin (SLUSH) have been previously described. Moreover, the newly sequenced genome of S. lugdunensis revealed genes of other putative fibrinogen binding adhesins and hemolysins. The aim of this study was to gain more insight into the occurrence of genes likely coding for fibrinogen binding adhesins and hemolysins using clinical strains of S. lugdunensis. Most of the putative adhesin genes and hemolysin genes investigated in this study were highly prevalent, except for the SLUSH gene cluster. In contrast to previous reports, binding to fibrinogen was detected in 29.3% of the S. lugdunensis strains. In most strains, hemolysis on blood agar plates was weak after 24 h and distinct after 48 h of incubation. The fibrinogen binding and hemolysis phenotypes were also independent of the type of clinical specimen, from which the isolates were obtained. In this study we described a pyrrolidonyl arylamidase negative S. lugdunensis isolate. Our data indicate that a matrix-assisted laser desorption ionisation time-of-flight MS-based identification of S. lugdunensis or species-specific PCR's should be performed in favour of pyrrolidonyl arylamidase testing. In contrast to the high occurrence of putative fibrinogen binding protein genes, 29.3% of the S. lugdunensis strains bound to fibrinogen. Putative hemolysin genes were also prevalent in most of the S. lugdunensis strains, irrespective of their hemolysis activity on Columbia blood agar plates. Similar to a previous report, hemolysis after 48 h of incubation is also indicative for S. lugdunensis. The SLUSH gene cluster was detected in an estimated 50% of the strains, indicating that this locus is different or non-prevalent in many strains.


Mode-of-action-based dosimeters for interspecies extrapolation of vinyl acetate inhalation risk.
Vinyl acetate is used in the manufacture of many polymers. The Clean Air Act Amendments of 1990 require that an inhalation risk assessment be conducted to assess risks to human health from ambient exposures. Vinyl acetate is a nasal carcinogen in rats and induces olfactory degeneration in rats and mice. Because of the many unique aspects of the rodent nasal cavity compared to that of humans, conventional means for extrapolating dosimetry between species are not appropriate. Physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) modeling can address many of these unique aspects. A PBPK/PD model has been developed for vinyl acetate, but the choice of appropriate dosimeter(s) to use for interspecies extrapolation depends on a hypothesis regarding mode of action. This article summarizes the key studies that formulate a mode of action hypothesis for vinyl acetate. Dose-response relationships for vinyl acetate-induced nonneoplastic and neoplastic responses are highly nonlinear, suggesting complex kinetic processes. Carboxylesterase-dependent metabolism of vinyl acetate forms acetic acid, a potent cytotoxicant, and acetaldehyde, a weak clastogen. Cell death, proposed to be the result of intracellular acidification, results in restorative cell proliferation. In conjunction with sufficient genetic damage, induced by spontaneous mutation and acetaldehyde-induced DNA-protein cross-links (DPX), olfactory degeneration progresses to a state of elevated proliferation and eventually, at high vinyl acetate concentrations, to neoplastic transformation. Thus, reduction in intracellular pH (pHi) is proposed as the dosimeter most closely linked to the earliest stages of vinyl acetate toxicity. Consequently, risk assessments that are based on protection of nasal epithelium from intracellular acidification will be protective of all subsequent pathological responses related to vinyl acetate exposure. Proposing a reasonable mode of action is an important step in any risk assessment and is critical to the choice of dosimeter(s) to be used for interspecies dosimetry extrapolation.


Identification of a nuclear matrix targeting signal in the leukemia and bone-related AML/CBF-alpha transcription factors.
Transcription factors of the AML (core binding factor-alpha/polyoma enhancer binding protein 2) class are key transactivators of tissue-specific genes of the hematopoietic and bone lineages. Alternative splicing of the AML-1 gene results in two major AML variants, AML-1 and AML-1B. We show here that the transcriptionally active AML-1B binds to the nuclear matrix, and the inactive AML-1 does not. The association of AML-1B with the nuclear matrix is independent of DNA binding and requires a nuclear matrix targeting signal (NMTS), a 31 amino acid segment near the C terminus that is distinct from nuclear localization signals. A similar NMTS is present in AML-2 and the bone-related AML-3 transcription factors. Fusion of the AML-1B NMTS to the heterologous GAL4-(1-147) protein directs GAL4 to the nuclear matrix. Thus, the NMTS is necessary and sufficient to target the transcriptionally active AML-1B to the nuclear matrix. The loss of the C-terminal domain of AML-1B is a frequent consequence of the leukemia-related t(8;21) and t(3;21) translocations. Our results suggest this loss may be functionally linked to the modified interrelationships between nuclear structure and gene expression characteristic of cancer cells.


Association of occupational exposures with cardiovascular disease among US Hispanics/Latinos.
Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the USA. The role of occupational exposures to chemicals in the development of CVD has rarely been studied even though many agents possess cardiotoxic properties. We therefore evaluated associations of self-reported exposures to organic solvents, metals and pesticides in relation to CVD prevalence among diverse Hispanic/Latino workers. Cross-sectional data from 7404 employed individuals, aged 18-74 years, enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analysed. Participants from four US cities provided questionnaire data and underwent clinical examinations, including ECGs. CVD was defined as the presence of at least one of the following: coronary heart disease, atrial fibrillation, heart failure or cerebrovascular disease. Prevalence ratios reflecting the relationship between each occupational exposure and CVD as well as CVD subtypes were calculated using Poisson regression models. Hispanic/Latino workers reported exposures to organic solvents (6.5%), metals (8.5%) and pesticides (4.7%) at their current jobs. Overall, 6.1% of participants had some form of CVD, with coronary heart disease as the most common (4.3%) followed by cerebrovascular disease (1.0%), heart failure (0.8%) and atrial fibrillation (0.7%). For individuals who reported working with pesticides, the prevalence ratios for any CVD were 2.18 (95% CI 1.34 to 3.55), coronary heart disease 2.20 (95% CI 1.31 to 3.71), cerebrovascular disease 1.38 (95% CI 0.62 3.03), heart failure 0.91 (95% CI 0.23 to 3.54) and atrial fibrillation 5.92 (95% CI 1.89 to 18.61) after adjustment for sociodemographic, acculturation, lifestyle and occupational characteristics. Metal exposures were associated with an almost fourfold (3.78, 95% CI 1.24 to 11.46) greater prevalence of atrial fibrillation. Null associations were observed for organic solvent exposures. Our results suggest that working with metals and pesticides could be risk factors for CVD among Hispanic/Latino workers. Further work is needed to evaluate these relationships prospectively.


Development and psychometric evaluation of a new team effectiveness scale for all types of community adult mental health teams: a mixed-methods approach.
Defining 'effectiveness' in the context of community mental health teams (CMHTs) has become increasingly difficult under the current pattern of provision required in National Health Service mental health services in England. The aim of this study was to establish the characteristics of multi-professional team working effectiveness in adult CMHTs to develop a new measure of CMHT effectiveness. The study was conducted between May and November 2010 and comprised two stages. Stage 1 used a formative evaluative approach based on the Productivity Measurement and Enhancement System to develop the scale with multiple stakeholder groups over a series of qualitative workshops held in various locations across England. Stage 2 analysed responses from a cross-sectional survey of 1500 members in 135 CMHTs from 11 Mental Health Trusts in England to determine the scale's psychometric properties. Based on an analysis of its structural validity and reliability, the resultant 20-item scale demonstrated good psychometric properties and captured one overall latent factor of CMHT effectiveness comprising seven dimensions: improved service user well-being, creative problem-solving, continuous care, inter-team working, respect between professionals, engagement with carers and therapeutic relationships with service users. The scale will be of significant value to CMHTs and healthcare commissioners both nationally and internationally for monitoring, evaluating and improving team functioning in practice.


Optical Study of Solvatochromic Isocyanoaminoanthracene Dyes and 1,5-Diaminoanthracene.
Isocyanoaminoarenes (ICAAr-s) are a novel and versatile group of solvatochromic fluorophores. Despite their versatile applicability, such as antifungals, cancer drugs and analytical probes, they still represent a mostly unchartered territory among intramolecular charge-transfer (ICT) dyes. The current paper describes the preparation and detailed optical study of novel 1-isocyano-5-aminoanthrace (ICAA) and its N-methylated derivatives along with the starting 1,5-diaminoanthracene. The conversion of one of the amino groups of the diamine into an isocyano group significantly increased the polar character of the dyes, which resulted in a significant 50-70 nm (2077-2609 cm-1) redshift of the emission maximum and a broadened solvatochromic range. The fluorescence quantum yield of ICAAs is strongly influenced by the polarity of the solvent. The starting anthracene-diamine is highly fluorescent in every solvent (√f = 12-53%), while the isocyano derivatives are practically nonfluorescent in solvents more polar than dioxane. This phenomenon implies the potential application of ICAAs to probe the polarity of the medium and is favorable in practical applications, such as cell-staining, resulting in a reduced background fluorescence. The ICT character of the emission states of ICAAs are in good agreement with the computational findings presented in TD-DFT calculations and molecular electrostatic potential (MESP) isosurfaces.


Head, eye and arm coordination in table tennis.
The aim of this study was to determine the role of head, eye and arm movements during the execution of a table tennis forehand stroke. Three-dimensional kinematic analysis of line-of-gaze, arm and ball was used to describe visual and motor behaviour. Skilled and less skilled participants returned the ball to cued right or left target areas under three levels of temporal constraint: pre-, early- and late-cue conditions. In the pre- and early-cue conditions, both high and low skill participants tracked the ball early in flight and kept gaze stable on a location in advance of the ball before ball-bat contact. Skilled participants demonstrated an earlier onset of ball tracking and recorded higher performance accuracy than less skilled counterparts. The manipulation of cue condition showed the limits of adaptation to maintain accuracy on the target. Participants were able to accommodate the constraints imposed by the early-cue condition by using a shorter quiet eye duration, earlier quiet eye offset and reduced arm velocity at contact. In the late-cue condition, modifications to gaze, head and arm movements were not sufficient to preserve accuracy. The findings highlight the functional coupling between perception and action during time-constrained, goal-directed actions.


The role of human equilibrative nucleoside transporter 1 on the cellular transport of the DNA methyltransferase inhibitors 5-azacytidine and CP-4200 in human leukemia cells.
The nucleoside analog 5-azacytidine is an archetypical drug for epigenetic cancer therapy, and its clinical effectiveness has been demonstrated in the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). However, therapy resistance in patients with MDS/AML remains a challenging issue. Membrane proteins that are involved in drug uptake are potential mediators of drug resistance. The responsible proteins for the transport of 5-azacytidine into MDS/AML cells are unknown. We have now systematically analyzed the expression and activity of various nucleoside transporters. We identified the human equilibrative nucleoside transporter 1 (hENT1) as the most abundant nucleoside transporter in leukemia cell lines and in AML patient samples. Transport assays using [¹⁴C]5-azacytidine demonstrated Na⁺-independent uptake of the drug into the cells, which was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBTI), a hENT1 inhibitor. The cellular toxicity of 5-azacytidine and its DNA demethylating activity were strongly reduced after hENT1 inhibition. In contrast, the cellular activity of the 5-azacytidine derivative 5-azacytidine-5'-elaidate (CP-4200), a nucleoside transporter-independent drug, persisted after hENT1 inhibition. A strong dependence of 5-azacytidine-induced DNA demethylation on hENT1 activity was also confirmed by array-based DNA methylation profiling, which uncovered hundreds of loci that became demethylated only when hENT1-mediated transport was active. Our data establish hENT1 as a key transporter for the cellular uptake of 5-azacytidine in leukemia cells and raise the possibility that hENT1 expression might be a useful biomarker to predict the efficiency of 5-azacytidine treatments. Furthermore, our data suggest that CP-4200 may represent a valuable compound for the modulation of transporter-related 5-azacytidine resistances.


[Case report summary browsing system for education of pharmaceutical students through the Internet].
We have developed a patient case database at Gunma University Hospital. The transmission of the data contained in this database via the Internet is protected by SSH encryption technology. The database may also function as an education tool for medical and pharmaceutical students who can access this system through the Internet using a special browser system that we have also developed. In a survey questionnaire relating to our system conducted among graduate students, most responded positively to its usefulness as an opportunity for exposure to actual clinical practice. Because this system can introduce students to realistic and daily practices at hospitals, it might have a great impact on Japanese pharmaceutical education in universities or pharmaceutical colleges where early exposure to actual hospital practices is not appropriately included in the curriculum. In addition, our system will function to establish a mutual feedback system between hospitals and basic research institutions such as pharmaceutical universities.


High-Affinity Detection and Capture of Heavy Metal Contaminants using Block Polymer Composite Membranes.
Adsorptive membranes offer one possible solution to the challenge of removing and recovering heavy metal ion contaminants and resources from water supplies. However, current membrane-based sorbents suffer from low binding affinities, leading to issues when contaminants are present at trace concentrations or when the source waters have a high concentration of background electrolytes that compete for open binding sites. Here, these challenges are addressed in the design of a highly permeable (i.e., permeability of ∼2.8 × 104 L m-2 h-1 bar-1) sorbent platform based on polysulfone and polystyrene-b-poly(acrylic acid) composite membranes. The membranes possess a fully interconnected network of poly(acrylic acid)-lined pores, which enables the surface chemistry to be tailored through sequential attachment of polyethylenimine brushes and metal-binding terpyridine ligands. The polyethylenimine brushes increase the saturation capacity, while the addition of terpyridine enables high-affinity binding to a diversity of transition metal ions (i.e., Pd2+, Cd2+, Hg2+, Pb2+, Zn2+, Co2+, Ni2+, Fe2+, Nd3+, and Sm3+). This platform removes these metal contaminants from solution with a sorbent capacity of 1.2 mmol g-1 [based on Cu2+ uptake]. The metal capture performance of the functionalized membranes persists in spite of high concentrations of competitive ions, with >99% removal of Pb2+ and Cd2+ ions from artificial groundwater and seawater solutions. Breakthrough experiments demonstrate the efficient purification of feed solutions containing multiple heavy metal ions under dynamic flow conditions. Finally, fluorescence quenching of the terpyridine moiety upon metal ion complexation offers an in situ probe to monitor the extent of sorbent saturation with a Stern-Volmer association constant of 2.9 × 104 L mol-1. The permeability, capacity, and affinity of these membranes, with high-density display of a metal-binding ligand, offer a chemically tailored platform to address the challenges that arise in ensuring clean water.


Involvement of a Stat3 binding site in inflammation-induced enteric apelin expression.
Apelin is the endogenous ligand for the APJ receptor; both are expressed in the gastrointestinal tract. Experimental colitis in rodents and inflammatory bowel disease in humans are associated with increased intestinal apelin production. Our aim was to use LPS and proinflammatory cytokine-treated (IL-6 and IFN-gamma) rodents or enteric cells to identify signaling mechanisms underlying inflammation-induced enteric apelin expression. LPS, IL-6, or IFN-gamma treatment of rodents increased enteric apelin expression. Pharmacological blockade of Jak/Stat signaling or IL-6 antibody administration inhibited elevations in enteric apelin expression. Transient transfection experiments showed that LPS, IL-6, or IFN-gamma increased apelin expression by stimulation of apelin promoter activity, and blockade of Jak/Stat signaling abolished elevations in apelin promoter activity. A chromatin immunoprecipitation assay showed that IL-6 induced binding of phospho-Stat3 to a putative Stat3 site in the apelin promoter; mutation of this site abrogated the LPS-induced elevation in apelin promoter activity. Together, our findings indicate that binding of phospho-Stat3 to the apelin promoter is the final step underlying proinflammatory cytokine-induced enteric apelin expression during intestinal inflammation.


Redesigning primary care processes to improve the offering of mammography. The use of clinic protocols by nonphysicians.
To develop, within the framework of continuous quality improvement, new processes for offering mammography and determine whether protocols executed completely by nonphysicians would increase mammography utilization. A prospective follow-up study with patients from an intervention clinic and two control clinics. Three general internal medicine clinics in a large, urban teaching hospital in Detroit, Michigan. A total of 5,934 women, aged 40 through 75 years, making 16,546 visits to one of the clinics during the study period (September 1, 1992, through November 31, 1993). Medical assistants and licensed practical nurses in the intervention clinic were trained to identify women due for screening mammography, and to directly offer and order a mammogram if patients agreed. Patients were considered up-to-date with screening if they had a mammogram within 1 year (if age 50-75) or 2 years (if age 40-49) prior to the visit or a mammogram within 60 days after the visit. The proportion of visits each month in which a woman was up-to-date with mammography was calculated using computerized billing records. Prior to the intervention, the proportion of visits in which women were up-to-date was 68% (95% confidence interval [CI] 63%, 73%) in the intervention clinic and 66% (95% CI 61%, 71%) in each of the control clinics. At the end of the evaluation, there was an absolute increase of 9% (95% CI 2%, 16%) in the intervention clinic, and a difference of 1% (95% CI -5%, 7%) in one of the control clinics and -2% (95% CI -3%, 5%) in the other. In the intervention clinic, the proportion of visits in which women were up-to-date with mammography increased over time and was consistent with a linear trend (p = .004). Redesigning clinic processes to make offering of mammography by medical assistants and licensed practical nurses a routine part of the clinic encounter can lead to mammography rates that are superior to those seen in physicians' usual practice, even when screening levels are already fairly high. Physicians need not be considered the sole, or even the primary, member of the health care team who can effectively deliver some preventive health measures.


Genotypic typing and phylogenetic analysis of Salmonella paratyphi B and S. java with IS200.
Salmonella paratyphi B and Salmonella java are biovars of common serotype 1,4,[5],12:b:1,2 which respectively cause human paratyphoid fever and gastroenteritis. In order to define genotypes and phylogenetic relationships in this group, we examined representative strains for restriction fragment length polymorphisms (RFLPs) in and around the 16S ribosomal RNA (rrn) genes, and the five to eleven insertion sites of the Salmonella-specific DNA insertion sequence IS200. One of four 16S rrn profiles was predominant, and was shared by the majority of strains, irrespective of their designation as S. paratyphi B or S. java. On the other hand, thirteen unique IS200 profiles were found and this technique was able to distinguish, for the first time, distinct genotypes for S. paratyphi B and S. java. One of the S. paratyphi B profiles, Spj-IP1.0, represented a globally-distributed clone. Greater diversity was detected within IS200 profiles of S. java than within those of S. paratyphi B. IS200 profiles described a phylogenetic complex in which strains of both biovars could be placed. They constituted reproducible molecular fingerprints, which could be compared in a band-matching database suitable for molecular epidemiological typing.


Genetic dissection of the developmental behaviours of plant height in wheat under diverse water regimes.
Plant height (PH), a crucial trait related to yield potential in crop plants, is known to be typically quantitatively inherited. However, its full expression can be inhibited by a limited water supply. In this study, the genetic basis of the developmental behaviour of PH was assessed in a 150-line wheat (Triticum aestivum L.) doubled haploid population (Hanxuan 10 x Lumai 14) grown in 10 environments (year x site x water regime combinations) by unconditional and conditional quantitative trait locus (QTL) analyses in a mixed linear model. Genes that were expressed selectively during ontogeny were identified. No single QTL was continually active in all periods of PH growth, and QTLs with additive effects (A-QTLs) expressed in the period S1|S0 (the period from the original point to the jointing stage) formed a foundation for PH development. Additive main effects (a effects), which were mostly expressed in S1|S0, were more important than epistatic main effects (aa effects) or QTL x environment interaction (QE) effects, suggesting that S1|S0 was the most significant development period affecting PH growth. A few QTLs, such as QPh.cgb-6B.7, showed high adaptability for water-limited environments. Many QTLs, including four A-QTLs (QPh.cgb-2D.1, QPh.cgb-4B.1, QPh.cgb-4D.1, and QPh.cgb-5A.7) coincident with previously identified reduced height (Rht) genes (Rht8, Rht1, Rht2, and Rht9), interacted with more than one other QTL, indicating that the genetic architecture underlying PH development is a network of genes with additive and epistatic effects. Therefore, based on multilocus combinations in S1|S0, superior genotypes were predicted for guiding improvements in breeding for PH.


Measuring sense of presence and user characteristics to predict effective training in an online simulated virtual environment.
Virtual-reality solutions have successfully been used to train distributed teams. This study aimed to investigate the correlation between user characteristics and sense of presence in an online virtual-reality environment where distributed teams are trained. A greater sense of presence has the potential to make training in the virtual environment more effective, leading to the formation of teams that perform better in a real environment. Being able to identify, before starting online training, those user characteristics that are predictors of a greater sense of presence can lead to the selection of trainees who would benefit most from the online simulated training. This is an observational study with a retrospective postsurvey of participants' user characteristics and degree of sense of presence. Twenty-nine members from 3 Air Force National Guard Medical Service expeditionary medical support teams participated in an online virtual environment training exercise and completed the Independent Television Commission-Sense of Presence Inventory survey, which measures sense of presence and user characteristics. Nonparametric statistics were applied to determine the statistical significance of user characteristics to sense of presence. Comparing user characteristics to the 4 scales of the Independent Television Commission-Sense of Presence Inventory using Kendall τ test gave the following results: the user characteristics "how often you play video games" (τ(26)=-0.458, P<0.01) and "television/film production knowledge" (τ(27)=-0.516, P<0.01) were significantly related to negative effects. Negative effects refer to adverse physiologic reactions owing to the virtual environment experience such as dizziness, nausea, headache, and eyestrain. The user characteristic "knowledge of virtual reality" was significantly related to engagement (τ(26)=0.463, P<0.01) and negative effects (τ(26)=-0.404, P<0.05). Individuals who have knowledge about virtual environments and experience with gaming environments report a higher sense of presence that indicates that they will likely benefit more from online virtual training. Future research studies could include a larger population of expeditionary medical support, and the results obtained could be used to create a model that predicts the level of presence based on the user characteristics. To maximize results and minimize costs, only those individuals who, based on their characteristics, are supposed to have a higher sense of presence and less negative effects could be selected for online simulated virtual environment training.


Influence of a Non-Ionic Surfactant in the Microstructure and Rheology of a Pickering Emulsion Stabilized by Cellulose Nanofibrils.
Emulsion stabilization is a broad and relevant field with applications in oil, polymer and food industries. In recent years, the use of solid particles to stabilize emulsions or Pickering emulsions have been studied for their kinetic and physical properties. Nanomaterials derived from natural sources are an interesting alternative for this application. Cellulose nanofibrils (CNFs) have been widely explored as a Pickering emulsifier with potential food applications, however, in some cases the presence of surfactants is unavoidable, and the literature is devoid of an evaluation of the effect of a non-ionic food-grade surfactant, such as polysorbate 80, in the stabilization of a vegetable oil by CNFs. To better assess the possible interactions between CNFs and this surfactant emulsions containing coconut oil, an emerging and broadly used oil, were processed with and without polysorbate 80 and evaluated in their qualitative stability, morphological and physical properties. Fluorescence microscopy, dynamic light scattering and rheology were used for this assessment. Results indicate in absence of the surfactant, emulsion stability increased at higher CNFs content, creaming was observed at 0.15 and 0.3 wt.% of CNFs, while it was not evidenced when 0.7 wt.% was used. After the addition of surfactant, the droplets are covered by the surfactant, resulting in particles with a smaller diameter, entrapped in the cellulosic structure. Rheology indicates a lower network stiffness after adding polysorbate 80.


Analysis of phosphorylation-dependent modulation of Kv1.1 potassium channels.
The voltage-gated potassium channel Kv1.1 contains phosphorylation sites for protein kinase A (PKA) and protein kinase C (PKC). To study Kv1.1 protein expression and cellular distribution in regard to its level of phosphorylation, the effects of PKA and PKC activation on Kv1.1 were investigated in HEK 293 cells stably transfected with Kv1.1 (HEK 293/1). Without kinase activation, HEK 293/1 cells carry unphosphorylated Kv1.1 protein in the plasma membranes, whereas large amounts of phosphorylated and unphosphorylated Kv1.1 protein were located intracellularly. Activation of PKA resulted in phosphorylation of intracellular Kv1.1 protein, followed by a rapid translocation of Kv1.1 into the plasma membrane. Patch-clamp analysis revealed an increase in current amplitude upon PKA activation and demonstrated differences in the voltage dependence of current activation between unphosphorylated and phosphorylated Kv1.1 channels. In contrast to PKA, even prolonged activation of PKC did not lead to direct phosphorylation of Kv1.1, but induced Kv1.1 protein synthesis. Thus, protein kinases have direct and indirect effects on the functional expression of voltage-gated potassium channels. Our data suggest that the synergistic action of protein kinases may play an important role in the fine-tuning of Kv channel function.


Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases.
Doripenem (S-4661), a new parenteral carbapenem, was tested against over 250 clinical isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp., selected or derived for their beta-lactamase expression characteristics. Imipenem, meropenem, and ertapenem were tested as comparators, along with cephalosporins and piperacillin-tazobactam, by using National Committee for Clinical Laboratory Standards agar dilution methodology. Doripenem MICs were from 0.03 to 0.25 microg/ml for Klebsiella isolates, irrespective of the presence of extended-spectrum beta-lactamases (ESBLs) or plasmid-mediated AmpC or hyperproduced K1 beta-lactamase. Similarly, MICs of doripenem for both AmpC-inducible and -derepressed Enterobacter isolates were 0.06 to 0.5 microg/ml. ESBL production did not raise the MICs of doripenem for Escherichia coli transconjugants, and studies with known expression mutants confirmed that neither inducible nor depressed AmpC beta-lactamase expression was protective in Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, or Morganella morganii. In all of these respects, doripenem resembled meropenem and imipenem, whereas the MICs of ertapenem were raised (but still < or =1 microg/ml) for many ESBL-producing klebsiellas and AmpC-derepressed E. cloacae and C. freundii strains. Resistance to all carbapenems, including doripenem (MICs of mostly 16 to 64 microg/ml, compared with 0.25 to 1 microg/ml for typical strains), was seen in Acinetobacter isolates with metallo-beta-lactamases or OXA-carbapenemases. Isolates of Klebsiella and Serratia spp. with IMP, KPC, and SME beta-lactamases also were resistant to doripenem (MICs, 8 to >64 microg/ml) and to other carbapenems, although the continued apparent susceptibility (MICs, < or =0.5 microg/ml) of E. coli derivatives with cloned IMP-1 and NMC-A beta-lactamases suggested that carbapenem resistance might require other factors besides the enzymes.


Programmatic effectiveness of a university-based implant training program: long-term, patient-centered outcomes.
The University of Kentucky College of Dentistry established a formal implant program in 1999. The program utilizes a single system (Straumann) and a team concept in which implants are placed by residents in period ontology or oral and maxillofacial surgery and restored by predoctoral dental students. The program features stringent patient inclusion and exclusion criteria, incremental structured learning experiences, formal standardized protocols, and hands-on preclinical learning experiences. The use of a single system simplified training protocols and inventory requirements. Complete and partially edentulous patients requiring single and multiple implants are eligible for the program, although maxillary anterior sites are excluded. There is a formal quality assurance program to assess patient-centered outcomes. The current report includes data for patients who had implants placed in the period from January 2000 through December 2002. During that period, 192 patients received dental implants, of which 116 patients (248 implants) were available for analysis. The mean follow-up was 7.05 years (median = 7.32 years). The implant survival rate was 98.4%, while the success rate was 93.15%. Success was determined by the absence of pain or mobility, as well as self-reported patient satisfaction with function, appearance, and surgical experience.


Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage.
Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up.


Exocrine pancreatic function tests.
Despite the development in the last two decades of new imaging techniques for the detection of pancreatic disease, discrepancies between functional and morphological findings can be remarkable. Pancreatic function tests may aid in the detection of disease at an earlier stage in some patients and can assess the degree of functional damage which is helpful in assessing patients for supplemental therapy. While direct intubation methods are invasive and time consuming, they remain the gold standard against which the other investigations have to be assessed. An indirect test, such as the pancreolaural test, has been shown to be a useful addition to ultrasound for the screening of pancreatic disease. Pancreatic markers and radioisotope methods have failed to live up to early promise, but fecal tests can be used effectively to monitor enzyme replacement. A judicious combination of pancreatic function tests and imaging techniques may be able to rationalize investigation and treatment of pancreatic disease.


Thyroid Hormone Economy in the Perinatal Mouse Brain: Implications for Cerebral Cortex Development.
Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in neurodevelopment; however, the mechanisms underlying T3 brain delivery during mice fetal development are not well known. This work has explored the sources of brain T3 during mice fetal development using biochemical, anatomical, and molecular approaches. The findings revealed that during late gestation, a large amount of fetal brain T4 is of maternal origin. Also, in the developing mouse brain, fetal T3 content is regulated through the conversion of T4 into T3 by type-2 deiodinase (D2) activity, which is present from earlier prenatal stages. Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8. Notably, the gene encoding for D2 (Dio2) was mainly expressed at the blood-cerebrospinal fluid barrier (BCSFB). Overall, these data signify that T4 deiodinated by D2 may be the only source of T3 during neocortical development. We therefore propose that D2 activity at the BCSFB converts the T4 transported across the choroid plexus into T3, thus supplying the brain with active hormone to maintain TH homeostasis.


Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus.
Connectivity in the developing hippocampus displays a functional organization particularly effective in supporting network synchronization, as it includes superconnected hub neurons. We have previously shown that hub network function is supported by a subpopulation of GABA neurons. However, it is unclear whether hub cells are only transiently present or later develop into distinctive subclasses of interneurons. These questions are difficult to assess given the heterogeneity of the GABA neurons and the poor early expression of markers. To circumvent this conundrum, we used "genetic fate mapping" that allows for the selective labeling of GABA neurons based on their place and time of origin. We show that early-generated GABA cells form a subpopulation of hub neurons, characterized by an exceptionally widespread axonal arborization and the ability to single-handedly impact network dynamics when stimulated. Pioneer hub neurons remain into adulthood, when they acquire the classical markers of long-range projecting GABA neurons.


Spine fusion cross-link causing delayed dural erosion and CSF leak: case report.
The past 2 decades have seen a considerable increase in the number of lumbar spinal fusion surgeries. To enhance spinal stabilization and fusion, make the construct resistant to or stiffer for axial stress loading, lateral bending, and torsional stresses, cross-links and connectors were designed and included in a rod-screw construct. The authors present the case of a 49-year-old woman who presented 11 years after undergoing an L4-5 decompression and fusion in which a pedicle screw-rod construct with an integrated cross-link was designed to attach onto the pedicle screws. The patient's response at the time to the initial surgery was excellent; however, at the time of presentation 11 years later, she had significant postural headaches, severe neurogenic claudication, and radiculopathy. Imaging revealed canal compression across the instrumented levels and a possible thickened adherent filum terminale. Reexploration of the level revealed a large erosive dural defect with a CSF leak, spinal canal compression, and a thickened filum at the level of the cross-link. To the author's knowledge, such complications have not been reported in literature. The authors discuss this rare complication of spinal fusion and the need to avoid dural compression when cross-links are used.


Autoregulation of adenovirus E1A gene expression.
We examined E1A gene expression by two evolutionarily divergent human adenoviruses, type 5 (subgroup C) and type 3 (subgroup B). Adenovirus type 3 (Ad3)-infected A549 cells contained much larger amounts of E1A-specific RNA than adenovirus type 5 (Ad5)-infected cells, from very early (3 h) through the late stages (20 h) after infection. The appearance of such abundant Ad3 E1A transcripts was delayed after infection of Ad5 E1A-expressing 293 cells, suggesting a down regulation of the Ad3 E1A gene by Ad5 E1A gene products. In a reciprocal manner, coinfection of A549 cells led to typically early and intense Ad3 E1A transcription and strongly inhibited transcription of the Ad5 E1A gene. Transient expression assays were developed so that the autoregulation of the E1A gene could be studied apart from the more complex background of infected cells. The DNA sequence surrounding the transcription start site of the Ad3 E1A gene was placed 5' to the sequence which encodes the bacterial chloramphenicol acetyltransferase gene. Cotransfection of HeLa cells with Ad3 or Ad5 E1A-expression plasmids increased the expression of the Ad3 E1A promoter-driven chloramphenicol acetyltransferase gene. Taken together, these results suggest dual autoregulatory features of adenovirus E1A gene expression. The positive and negative effects appear to be temporally distinguished under different conditions, both in viral infection and in transient assays with plasmid-cloned genes.


Collapse transitions in thermosensitive multi-block copolymers: a Monte Carlo study.
Monte Carlo simulations are performed on a simple cubic lattice to investigate the behavior of a single linear multiblock copolymer chain of various lengths N. The chain of type (AnBn)m consists of alternating A and B blocks, where A are solvophilic and B are solvophobic and N = 2nm. The conformations are classified in five cases of globule formation by the solvophobic blocks of the chain. The dependence of globule characteristics on the molecular weight and on the number of blocks, which participate in their formation, is examined. The focus is on relative high molecular weight blocks (i.e., N in the range of 500-5000 units) and very differing energetic conditions for the two blocks (very good-almost athermal solvent for A and bad solvent for B). A rich phase behavior is observed as a result of the alternating architecture of the multiblock copolymer chain. We trust that thermodynamic equilibrium has been reached for chains of N up to 2000 units; however, for longer chains kinetic entrapments are observed. The comparison among equivalent globules consisting of different number of B-blocks shows that the more the solvophobic blocks constituting the globule the bigger its radius of gyration and the looser its structure. Comparisons between globules formed by the solvophobic blocks of the multiblock copolymer chain and their homopolymer analogs highlight the important role of the solvophilic A-blocks.


Polyethylene-glycol suppresses colon cancer and causes dose-dependent regression of azoxymethane-induced aberrant crypt foci in rats.
Dietary polyethylene-glycol (PEG) 8000, a nonfermented polymer laxative, strongly suppresses azoxymethane-induced aberrant crypt foci (ACF) in the colon of rats, as shown in a previous study (D. E. Corpet et al., Carcinogenesis (Lond.), 20: 915-918, 1999). In the present study, we tested the effect of PEG administered during either initiation or postinitiation, the dose-response effect of PEG, the regressive effect of PEG on established ACF, and the preventive effect of PEG on colon cancers in rats. The general design was to initiate carcinogenesis in F344 rats by a single injection of azoxymethane (20 mg/kg) and to randomize the animals 7 days later to AIN-76 diets containing 5% PEG or no PEG (control). At termination, ACF and tumors were scored blindly by a single observer. The administration of 5% PEG for 32 days to groups of 10 female rats in either food or drinking water reduced the number of ACF by a factor of 8 (P = 0.0002) and reduced the number of large ACF by a factor of 20-30 (P = 0.002). No protection was afforded when PEG was given only during the initiation phase. Diets containing 0%, 0.5%, 2%, or 5% PEG fed for 35 days to four groups of male rats inhibited ACF in a dose-dependent manner (P < 0.0001). The administration of a 5% PEG diet for 41 days, starting 42 days after carcinogen injection, led to a 73% decrease in the number of ACF (P < 0.0001). Dietary PEG thus caused the regression of established ACF. Macroscopic tumors were evaluated by histology in rats that had been fed a high-fat diet containing cooked casein to promote tumor growth for 81 days. In this accelerated model of carcinogenesis, dietary PEG suppressed the occurrence of colon adenomas and carcinomas: the incidence of tumors decreased from 70% to 10% (P = 0.005); and the multiplicity decreased from 2.1 to 0.1 tumor(s)/rat (P = 0.003). No cancer was detected in the PEG-fed rats. Taken together, these results suggest that PEG could be a potent anticancer agent in the postinitiation phase of carcinogenesis. Because PEG is a substance that is generally recognized as safe (GRAS list, Food and Drug Administration), its cancer-preventive features could be tested in humans.


Ultrastructural changes in mesenteric arteries from spontaneously hypertensive rats. A morphometric study.
Morphometric measurements at the electron microscope level were carried out on three categories of mesenteric arteries representing elastic (superior mesenteric), muscular and arteriolar vessels, from 10- to 12-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto normotensive rats (WKY). Changes were observed only in muscular and arteriolar vessels of SHR, mainly as thickening of the vessel wall due to hypertrophy of the media. In muscular arteries, hypertrophy of the endothelial cells, widening of the subendothelial space, increased volume of the internal elastic lamina (IEL), and both hyperplasia and hypertrophy of the smooth muscle cells (SMC) in the media contributed to the wall thickening. In arteriolar vessels, increase in the subendothelial space and IEL, and hyperplasia of the SMC in the media were involved in the increased thickness of the vessel wall. There was no difference in the collagen content in all vessels, but elastin was increased in the muscular and arteriolar vessels of SHR. Nerve density was also increased in arteriolar vessels of SHR. These changes, especially the increase of SMC in muscular and arteriolar vessels, may be related to the elevated blood pressure in SHR.


Recent progress in studies on autoantigens for various autoimmune blistering skin diseases.
Autoimmune blistering skin diseases develop separation either between epidermal keratinocytes or dermo-epidermal junction. Recent studies have revealed that the autoantigens for these diseases are components of either the desmosome, the cell adhesion junction between keratinocytes, or the hemidesmosome complex, cell adhesion machinery at the dermo-epidermal junction. Thus, the major pemphigus antigens are desmogleins, one of desmosomal cadherins. Both the 230 kD and 180 kD bullous pemphigoid antigens are present in the hemidesmosome, and epidermal basement membrane zone-specific extracellular matrices, epiligrin and type VII collagen, are detected by sera of cicatricial pemphigoid and epidermolysis bullosa acquisita, respectively. Furthermore, animal model studies using newborn mice have revealed that these autoantibodies are really pathogenic and can induce blister formation by passive transfer into mice. Therefore, these skin diseases seem to be a typical model for various autoimmune diseases, for most of which the role of autoantibodies has not yet been revealed.


Quantitative FDG PET/CT in the community: experience from interpretation of outside oncologic PET/CT exams in referred cancer patients.
Tertiary care institutions often deal with patients who have had a baseline positron emission tomography (PET)/computed tomography (CT) scan performed elsewhere. Little data exist regarding the quality of these PET/CT scans and whether they are fully suitable for qualitative or quantitative interpretation. We evaluated outside PET/CT scans from cancer patients referred to our institution and compared them with PET/CT scans acquired locally. This Health Insurance Portability and Accountability Act-compliant retrospective study was approved by our institutional review board. Informed consent requirements were waived. One hundred seventy recent whole-body outside PET/CT exams from many sites were digitally imported into our radiology imaging system and reviewed for key quality metrics including time from injection until imaging, availability of patient height and weight information, serum glucose level and [(18) F]fluoro-2-deoxy-D-glucose (FDG) dose. The standardised uptake value (SUV) and SUV based on lean body mass (SUL) in the liver were measured whenever possible. These were compared with 170 internal studies performed at our centre during the same period. Missing data were common in outside scans with height in 62%, weight 35%, uptake time 25%, FDG dose 28% and glucose levels in 64% of cases. In quantitatively evaluable cases, mean liver SUL, SUV, FDG dose and uptake time were much more variable in outside than in internal studies. Approximately one-third of the outside PET/CT studies submitted digitally for analysis lacked key information required to secure any quantitative imaging data. Only about a third of these studies had all necessary information available for accurate SUL determination and had acceptable quality that was comparable with locally acquired scans. This suggests that many of PET studies performed in the community cannot be relied upon to provide quantitative image data that can be applied in a different centre. Greater standardisation of oncologic PET/CT studies among different centres must still be pursued.


Modulation of the UGT2B7 enzyme activity by C-terminally truncated proteins derived from alternative splicing.
The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 5' region but alternative 3' ends namely UGT2B7_v5 (containing a novel terminal exon 6b) and _v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (K(m)). Finally, coimmunoprecipitation experiments support a direct protein-protein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.


Preconditioning and Perturbative Estimators in Full Configuration Interaction Quantum Monte Carlo.
We propose the use of preconditioning in FCIQMC which, in combination with perturbative estimators, greatly increases the efficiency of the algorithm. The use of preconditioning allows a time step close to unity to be used (without time-step errors), provided that multiple spawning attempts are made per walker. We show that this approach substantially reduces statistical noise on perturbative corrections to initiator error, which improve the accuracy of FCIQMC but which can suffer from significant noise in the original scheme. Therefore, the use of preconditioning and perturbatively corrected estimators in combination leads to a significantly more efficient algorithm. In addition, a simpler approach to sampling variational and perturbative estimators in FCIQMC is presented, which also allows the variance of the energy to be calculated. These developments are investigated and applied to benzene (30e, 108o), an example where accurate treatment is not possible with the original method.


Serotonin syndrome. A common but often unrecognized psychiatric condition.
This case illustrates that compliance with the basic principles of geriatric pharmacology (start low, go slow, and avoid polypharmacy) might have prevented a clinical syndrome that could have caused serious complications. Fortunately, serotonin syndrome was recognized early, the offending agents were discontinued, and supportive treatment was provided. The patient was ultimately treated with mirtazapine, an antidepressant not associated with serotonergic effects.


Methods for Economic Evaluations of Novel Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review.
Atrial fibrillation (AF) is a severe epidemiological and public health concern among the elderly population worldwide, with substantial economic and social burdens. Economic evaluations can play an essential role in optimizing the utilization of scarce resources. In recent years, the number of economic evaluation studies related to AF has increased due to the rising number of AF patients, the continuous updating of clinical data, and the emergence of real-world evidence. However, there are still deficiencies in model settings and parameter sources in relevant studies. This study aims to review the existing economic evaluations of novel oral anticoagulants (NOACs) in patients with AF and summarize the evidence and methods applied. A comprehensive and systematic search was conducted on electronic databases, including PubMed, Embase, Web of Science (WOS), and The Cochrane Library, from the date of database creation to November 2022. The reporting quality of included literature was assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement. A total of 102 studies were included in the review, with 200 comparisons between NOACs and vitamin K antagonists (VKAs), as well as 58 comparisons between different NOACs. The healthcare sector and payer perspectives were the most common, and accordingly, the majority of the evaluations considered only direct medical costs. Most studies used Markov cohort models with the number of health states ranging from 4 to 29. Of included studies, 80 (78%) considered event recurrence and complications, and 78 (76%) considered discontinuation and second-line therapy. All of the studies applied uncertainty analysis to explore the robustness of the results. Of all 200 NOACs-VKAs comparisons, 149 (75%) showed that NOACs were more cost-effective; this proportion was 84% (139 out of 165) in high-income countries but decreased to 29% (10 out of 35) in middle- and low-income countries. Most (82%) of the 28 items in the CHEERS 2022 checklist were elucidated in the majority of included studies. A minority (only 39%) of included studies demonstrated high reporting quality. NOACs may be more cost-effective than VKAs in patients with AF, but this conclusion applies to high-income countries, whereas VKAs may be more cost-effective in middle- and low-income countries. The reporting quality of included studies was variable, and certain methodological issues were presented. This study highlights the economic evaluation methodology of NOACs in patients with AF and provides recommendations for modeling methods and future studies.


Comparison of levalbuterol and racemic albuterol in hospitalized patients with acute asthma or COPD: a 2-week, multicenter, randomized, open-label study.
The National Heart, Lung, and Blood Institute guideline recommends that dosing racemic albuterol be administered every 1 to 4 hours for treating patients with asthma or chronic obstructive pulmonary disease (COPD) in the hospital. Previously published preliminary and retrospective studies suggested that levalbuterol can be administered every 8 hours for the treatment of bronchoconstriction in hospitalized patients. However, it is unclear how the different dosing regimens affect the total number of nebulizations (scheduled plus as-needed treatments) and the costs of treatment of bronchoconstriction in a hospital setting. Moreover, it is not clear how the different dosing regimens affect symptom outcomes and health status in hospitalized patients with asthma or COPD. The aim of this study was to evaluate these issues in hospitalized patients with acute asthma or COPD. In this prospective, multicenter, randomized, open-label study, hospitalized patients aged > or = 18 years were randomly assigned to receive 14-day treatment with levalbuterol 1.25 mg q6-8h or racemic albuterol 2.5 mg q1-4h, administered per routine hospital practice at each institution. The primary efficacy end point was total number of nebulizations during hospitalization. Pulmonary function, symptom evaluation (subject general well-being score [SGWB], disease symptom assessment [DSA], and beta-mediated adverse effect scores), hospital costs (excluding medication costs) and hospital length of stay (LOS) were also evaluated. In the intent-to-treat population (n = 479; levalbuterol, 241;racemic albuterol, 238), the mean (SE) age was 55.3 (16.9) years, the majority of patients were white (57.8%), and the mean (SE) weight was 80.9 (24.5) kg. Demographic characteristics were similar between the 2 treatment groups, except that there were more females with COPD in the levalbuterol treatment group (63.88%) compared with the racemic albuterol treatment group (45.5%) (P = 0.005). Patients treated with levalbuterol required significantly fewer median total nebulizations (10 vs 12; P = 0.031) and scheduled nebulizations (9 vs 11; P = 0.009) compared with those in the racemic albuterol group. The 2 treatment groups required 0 rescue nebulizations. Mean (SD) forced expiratory volume in 1 second improved from baseline with both levalbuterol and racemic albuterol (0.06 [0.43] and 0.10 [0.37] L, respectively); these improvements were maintained throughout the hospital stay (0.11 [0.48] and 0.16 [0.52] L). DSA and SGWB scores improved significantly from baseline in both treatment groups, and beta-mediated adverse effects mean scores were significantly greater with levalbuterol versus racemic albuterol (P < 0.001). In the levalbuterol and racemic albuterol treatment groups, hospital LOS (70.6 and 65.7 hours, respectively), time to discharge (66.0 and 62.8 hours), and total hospital costs (least squares mean [SE], US $4869.30 [$343.58] and $4899.41 [$343.20]) were similar. In these hospitalized patients with acute asthma or COPD treated with levalbuterol every 6 to 8 hours or racemic albuterol every 1 to 4 hours, significantly fewer total nebulizations were required with levalbuterol, without an increased need for rescue nebulizations during 14 days of hospitalization. Both treatments were associated with improvements from baseline in symptoms and health status. The costs of treating bronchoconstriction in hospitalized patients were similar between the levalbuterol and racemic albuterol groups.


Zika-prevention Knowledge among Hispanic Women Living in Puerto Rico: A Cross-sectional Study.
To describe the level of knowledge about Zika virus exposure, symptoms, complications, and transmission prevention in Hispanic women living in Puerto Rico. A sample of 168 women aged 21 to 64 at the general community, consented to complete a self-administered questionnaire of 112 questions from October 2016 to July 2017. A univariate analysis showed that the participating women recognized that the Zika virus was transmitted through mosquito bites (95.2%), sexual intercourse (78.0%), and from a mother to her fetus (41.1%); participants also believed that other, incorrect, routes of transmission were plausible. Regarding their knowledge of Zika infection prevention, the participants' correct answers included the following: using mosquito repellent (94.1%), eliminating standing water (83.9%), and using condoms (83.3%). When asked about fetal risks associated with Zika, they believed that the fetus would not develop normally (75.6%), would be born with a disability (69.6%), or would experience nervous system problems (54.2%). Only 22.6% of the participants had taken precautions to prevent pregnancy during the Zika outbreak, of which 65.8% reported that they had used condoms during all sexual relationships. There is a need to educate the general population about the Zika virus to reduce the misconceptions about disease prevention and transmission as well as about the complications associated with Zika during pregnancy. Awareness efforts should emphasize the prevention of infections during pregnancy and the use of available contraceptive methods.


Relationship between stressful life events, stigma and life satisfaction with the willingness of disclosure of psychotic illness: A community study in Hong Kong.
The preference of and potential barriers to disclosure of psychotic illness vary across cultures. Studying its patterns and correlates can guide the design of future culture-specific intervention and public education approaches to improve willingness to disclose and thereby reducing the duration of untreated psychosis (DUP). A population-based, random telephone survey was conducted with a total of 1514 respondents in Hong Kong in January 2018. Cross-sectional data on willingness to disclose psychotic illness, life satisfaction, stigmatizing attitude and recent experience of stressful life events (SLEs) were analysed against age and gender using structural equation modelling (SEM). Unwillingness to disclose to anyone was reported by 12% of the participants. Family was reported as the preferred disclosure candidate by most respondents. Our model, which showed a good fit to the data demonstrated that stigmatizing attitude and life satisfaction were directly associated with willingness to disclose illness. Younger age was correlated with more recent experience of SLEs, lower life satisfaction and less willingness to disclose illness. Women's disclosure willingness was positively associated with their life satisfaction, which was sensitive to recent exposure to single SLE. In contrast, men's was negatively associated with their stigmatizing attitude, which increased significantly upon exposure to two or more recent SLEs. Encouraging the public to help their family to seek treatment should be a focal point of a successful mental health public education campaign. Cultural-specific and integrated interventions should be developed targeting the vulnerable groups including people with high recent life stress, particularly woman and those with younger age.


Transcriptome-wide N 6-Methyladenosine Methylome Profiling Reveals m6A Regulation of Skeletal Myoblast Differentiation in Cattle (Bos taurus).
N 6 -methyladenosine (m6A) is the most prevalent methylation modification of eukaryotic mRNA, and it plays an important role in regulating gene expression. Previous studies have found that m6A methylation plays a role in mammalian skeletal muscle development. However, the effect of m6A on bovine skeletal myogenesis are still unclear. Here, we selected proliferating myoblasts (GM) and differentiated myotubes (on the 4th day of differentiation, DM) for m6A-seq and RNA-seq to explore the m6A methylation modification pattern during bovine skeletal myogenesis. m6A-seq analysis revealed that m6A methylation was an abundant modification of the mRNA in bovine myoblasts and myotubes. We scanned 5,691-8,094 m6A-modified transcripts, including 1,437 differentially methylated genes (DMGs). GO and KEGG analyses revealed that DMGs were primarily involved in transcriptional regulation and RNA metabolism, as well as insulin resistance and metabolic pathways related to muscle development. The combined analysis further identified 268 genes that had significant changes at both m6A and mRNA levels, suggesting that m6A modification may regulate myoblast differentiation by mediating the expression of these genes. Furthermore, we experimentally confirmed four genes related to myogenesis, including MYOZ2, TWIST1, KLF5 and MYOD1, with differential changes in both m6A and mRNA levels during bovine myoblast differentiation, indicating that they can be potential candidate targets for m6A regulation of skeletal myogenesis. Our results may provide new insight into molecular genetics and breeding of beef cattle, and provide a reference for investigating the mechanism of m6A regulating skeletal muscle development.


Metabolism of reactive nitrogen species in pea plants under abiotic stress conditions.
Nitric oxide (*NO) is a key signaling molecule in different physiological processes of animals and plants. However, little is known about the metabolism of endogenous *NO and other reactive nitrogen species (RNS) in plants under abiotic stress conditions. Using pea plants exposed to six different abiotic stress conditions (high light intensity, low and high temperature, continuous light, continuous dark and mechanical wounding), several key components of the metabolism of RNS including the content of *NO, S-nitrosothiols (RSNOs) and nitrite plus nitrate, the enzyme activities of l-arginine-dependent nitric oxide synthase (NOS) and S-nitrosogluthathione reductase (GSNOR), and the profile of protein tyrosine nitration (NO(2)-Tyr) were analyzed in leaves. Low temperature was the stress that produced the highest increase of NOS and GSNOR activities, and this was accompanied by an increase in the content of total *NO and S-nitrosothiols, and an intensification of the immunoreactivity with an antibody against NO(2)-Tyr. Mechanical wounding, high temperature and light also had a clear activating effect on the different indicators of RNS metabolism in pea plants. However, the total content of nitrite and nitrate in leaves was not affected by any of these stresses. Considering that protein tyrosine nitration is a potential marker of nitrosative stress, the results obtained suggest that low and high temperature, continuous light and high light intensity are abiotic stress conditions that can induce nitrosative stress in pea plants.


Clinical evaluation of the branched DNA assay for hepatitis B virus DNA detection in patients with chronic hepatitis B lacking hepatitis B e antigen and treated with interferon-alpha.
The aim of this study was to evaluate the Chiron branched DNA (bDNA) assay for detection of serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis B lacking hepatitis B e antigen (HBeAg) and undergoing interferon (IFN) therapy. Results obtained with the bDNA assay were compared with those obtained using the Abbott liquid hybridization (LH) assay and the polymerase chain reaction (PCR). Serial samples (274) from 34 patients were analysed. Analysis of variance results indicated that bDNA values were more significantly correlated than LH values with both PCR positive/negative results (probability of artifact (Prob > F) = 0.7 and 0.09 for LH and bDNA assays, respectively) and presence/absence of precore mutations (Prob > F = 0.21 and 0.001 for LH and bDNA assays, respectively). Both bDNA and LH results correlated highly with alanine aminotransferase (ALT) values (both had Prob > F values of 0.0) while PCR was not correlated with ALT (Prob > F = 0.05). In 26 evaluable patients, a model based on a generalized Knodell score was used to predict response to IFN therapy, as defined by normalization of ALT values during therapy. This model discriminated well between non-responders and responders. The bDNA results correlated well with the generalized Knodell score, while the LH results did not (Prob > F = 0.04 and 0.19 for the bDNA and LH assays, respectively). In conclusion, the bDNA assay appears to be useful for quantification of HBV DNA levels in HBeAg-negative chronic hepatitis as it correlates with biochemical and histological indications of disease severity as well as with response to IFN therapy.


Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders.
The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H(1) and the H(3) receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H(1) receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H(3) receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss the existing studies on various antihistamines and antagonists of the H(1) receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders. In addition, we review the current data available on the use of ligands at H(3) receptors for the modulation of sleep and wake.


Heat stress induces RIP1/RIP3-dependent necroptosis through the MAPK, NF-κB, and c-Jun signaling pathways in pulmonary vascular endothelial cells.
Necroptosis represents a newly defined form of regulated necrosis and participates in various human inflammatory diseases. It remains unclear whether necroptosis is presented in heatstroke-induced lung injury. We show that heat stress(HS) triggered an significant upregulation of receptor-interacting protein 1 (RIP1) and mixed lineage kinase domain-like protein (MLKL) expression in a time-dependent manner, without a significant change of receptor-interacting protein 3 (RIP3). Furthermore, co-immunoprecipitation assays showed that RIP1 binds to RIP3 to form the necrosome in heat stress-induced PMVECs. In vitro, necrostatin-1 (Nec-1) pre-treatment reduced heat stress-induced PMVECs necroptosis, which also inhibited HMGB1 translocation from the nucleus into the cytoplasm. Similarly, inhibition for ERK (PD98059), NF-κB (BAY11-7082) and c-Jun (c-Jun peptide), respectively, also suppressed the HMGB1 cytoplasm translocation. Furthermore, siRNA-mediated RIP1/RIP3 knockdown negatively regulated the release of HMGB1 in HS-induced necroptosis through the ERK, NF-κB, and c-Jun signaling pathways. Our study reveals that HS induces RIP1/RIP3-dependent necroptosis through the MAPK, NF-κB, and c-Jun signaling pathways in PMVECs.


Basis for the permeability barrier abnormality in lamellar ichthyosis.
The basis for the permeability barrier abnormality in lamellar ichthyosis (LI) is not known. LI is caused by mutations in the gene that encodes the enzyme, transglutaminase 1 (TGI), which is responsible for assembly of the cornified envelope (CE). TG1 also has been suggested recently to catalyze the covalent attachment of omega-hydroxyceramides (omega-OHCer) to the CE, forming the corneocyte-lipid envelope (CLE). We first assessed the barrier function and the permeability pathway of the water-soluble tracer, colloidal lanthanum, across the stratum corneum (SC) in patients with LI with absent (n = 4) or low (n = 2) TG1 activity/protein. Increased movement of tracer through the SC correlated with increased transcutaneous water loss, and tracer remained restricted to the SC interstices. Enhanced extracellular permeability, in turn, was explicable by truncation and fragmentation of extracellular lamellar membrane arrays. The resultant clefts in the SC interstices represent the likely pathway for increased water permeability. Moreover, tracer movement remained restricted to the interstices, despite the demonstration of increased corneocyte fragility associated with widespread variations in CE structure. Regardless of variability in CE structure, however, CLE structure and bound omega-OHCer content were normal. The normal CLE in LI may explain both the restriction of tracer to the SC interstices, as well as the presence of foreshortened membrane arrays with near-normal interlamellar dimensions. Finally, the demonstration of a normal CLE in LI also raises questions about the putative role of TG1 in forming the CLE. These results demonstrate: (1) the extracellular nature of increased permeability in LI; (2) discontinuities in extracellular membrane structures that account for the enhanced permeability in LI; (3) that these membrane abnormalities are both associated with and explained by abnormalities in the subjacent CE scaffold; and (4) an intact CLE is present in LI, despite abnormalities in the CE, which may restrict water movement to the SC interstices in LI.


In-vivo disposition characteristics of PEG niosome and its interaction with serum proteins.
Three different nonionic surfactants (Brij 72, Span 20 and Tween 60) were used to prepare various naked and PEG niosomes. In-vivo study demonstrated that PEGylation dramatically increased the AUC and decreased the affinity to the liver of Brij 72 and Span 20 niosomes in rats. Liver perfusion experiments suggested that the hepatic uptake of naked Brij 72 and Span 20 niosomes could mainly be ascribed to the receptor-mediated uptake, while PEGylation of these niosomes could diminish the receptor-mediated hepatic disposition. Evaluation of serum proteins associated with niosomes revealed that PEGylation of these niosomes significantly reduced the association of serum proteins with them, including typical opsonins such as IgG and C3. On the other hand, in the case of Tween 60 niosomes, naked Tween 60 niosome showed large AUC and its PEGylation did not show any additional effect on the in-vivo pharmacokinetics. Furthermore, PEGylation of Tween 60 niosome did not significantly affect the hepatic disposition or the association of serum proteins with Tween 60 niosome. These results demonstrated that niosomes would exhibit distinct in-vivo disposition characteristics depending on the physicochemical properties of surfactants used and that PEGylation of niosomes with adequate compositions would be a powerful tool to improve their in-vivo behavior.


Study of the radionuclide deposition in the radioactive ion line of the Selective Production of Exotic Species (SPES) facility.
SPES (Selective Production of Exotic Species) is a second generation facility for the production of radioactive ion beams that is going to be commissioned at the Laboratori Nazionali di Legnaro of INFN at Legnaro, Padua, Italy. Radioactive neutron-rich isotopes are expected to be produced by nuclear fission induced by a 40 MeV, 200 μA primary proton beam impinging on a 238UCx target. The expected reaction rate is about 1013 fission/s. Radioactive ion beams are produced using the isotope separation on-line technique. The production of such an amount of radioactive species raises radiological issues throughout the life cycle of the facility. A study of the radioactive contamination of the components of the radioactive ion beam line is performed with the FLUKA Monte Carlo simulation code, under realistic hypotheses for the produced isobaric beams. The present results complete previous studies focused on the radiological impact of the production target irradiation, the residual activation of the primary proton beam line and the radioactive contamination of the ion source complex. The overall ambient dose equivalent rate due to the different radiation sources is calculated at several positions inside the production bunker and at different times after a typical one-year operating period of the facility with the 238UCx target at full power. The obtained results and the developed methodology provide the guidelines and the needed tools to plan ordinary and extraordinary interventions as well as final decommissioning of the SPES facility.


High-prevalence and high-estimated incidence of HIV infection among new injecting drug users in Estonia: need for large scale prevention programs.
To examine HIV risk behavior and HIV infection among new injectors in Tallinn, Estonia. Design and methods Data from two cross-sectional surveys of injecting drug users (IDUs) recruited from a syringe exchange program (N = 162, Study 1) or using respondent driven sampling (N = 350, Study 2). Behavioral surveys were administered; serum samples were collected for HIV testing. Subjects were categorized into new injectors (injecting < or = 3 years) and long-term injectors (injecting > 3 years). Twenty-eight of 161 (17%, Study 1) and 73/350 (21%, Study 2) of the study subjects were new injectors. HIV infection was substantial among the newer injectors: HIV prevalence was 50% (Study 1) and 34% (Study 2), and estimated HIV incidence 31/100 PY and 21/100 PY, respectively. In Study 2, new injectors were more likely to be female and ethnic Estonian and less likely to be injecting daily compared with long-term injectors. No significant difference was found among two groups on sharing injecting equipment or reported number of sexual partners. A continuing HIV epidemic among new injectors is of critical public health concern. Interventions to prevent initiation into injecting drug use and scaling up HIV prevention programs for IDUs in Estonia are of utmost importance.


Multiple forms of amine oxidase in perfused rabbit lung.
The biogenic monoamines, phenylethylamine and 5-hydroxytryptamine are rapidly and extensively deaminated when perfused in Krebs' solution through rabbit lung. Deamination of phenylethylamine is inhibited approximately 70% by 10(-5) M pargyline and 30% by 10(-3) M semicarbazide. Deamination of this monoamine is unaffected by 10(-6) M harmaline whereas deamination of 5-hydroxytryptamine is inhibited about 75%. These data indicate that the intact perfused rabbit lung contains three forms of amine oxidase two of which are analogous to the A and B forms of the mitochondrial enzyme, monoamine oxidase described previously only in broken cell preparations of lung and other tissues. The third form of amine oxidase is similar to the enzyme found in plasma and several large arteries. Since uptake and metabolism of these amines, as well as loss of their deaminated metabolites, occurs very rapidly, it is suggested that all these forms of monoamine oxidase are associated with vascular endothelium.


Translation, cross-cultural adaptation, and validation of the Turkish version of the Harris Hip Score.
The Harris Hip Score (HHS) developed to assess function and pain from the perspective of patients hip pathologies. The purpose of this study was to translate and culturally adapt the HHS into Turkish, and thereby determine the reliability and validity of the translated version. The HHS was translated into Turkish in accordance with the stages recommended by Beaton. The measurement properties of the HHS were tested in 80 patients; 52 males, mean age 51 years (range 21-75 years) suffering from different hip pathologies. The test-retest reliability was tested in 58 patients; 28 males mean age, 52 years (range 30-73 years) after an interval of seven days. The Cronbach's Alpha was used to assess internal consistency and the intra-class correlation coefficient (ICC) was used to estimate the test-retest reliability. Patients were asked to answer the Oxford Hip Score (OHS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the VAS and the Short Form-36 (SF-36) for the validity of the estimation. The Turkish version of the HHS showed sufficient internal consistency (Cronbach's alpha,0.70) and test-retest reliability (ICC = 0.91). The correlation coefficients between the HHS, the WOMAC and the OHS were 0.64 and 0.89 respectively. The highest correlations between the HHS and SF-36 were with the physical function scale (r = 0.72), and the lowest correlations were with the mental function scale (r = 0.10). We observed no floor or ceiling effects. The Turkish version of the HHS has sufficient reliability and validity to measure patient-reported outcome for Turkish-speaking individuals with a variety of hip disorders.


Prescribing for the elderly: ethical considerations.
This article reports on a few ethical considerations associated with prescribing for the elderly. A large number of elderly people are on several medications for the treatment of various chronic conditions that develop with age. Most of these treatments involve symptom management and prevention of symptoms likely to occur from untreated diseases. Serious consideration should be given when prescribing for the elderly. These include: allowing the elderly and their families to be involved in their treatment; social support; and cost-benefit considerations. A lack of clear therapeutic guidelines exists for prescribing in this group of people that is confounded by factors such as quality of life and life expectancy.


[Distribution of 5'-nucleotidase activity in the subcellular fractions of rabbit brain cortex].
The specific activity of 5'-nucleotidase was measured in the fractions of myelin, synaptic membranes, heavy and light synaptosomes and purified mitochondria of brain cortex of intact rabbits. The enzyme specific activity in these fractions was practically the same and made up to 2.2, 2.1, 1.98 and 1.8 mkmoles of Pn per mg of protein per hr. The differences between the specific activities of the four fractions were statistically insignificant. The 5'-nucleotidase activity of the heavy synaptosome fraction was 2 times as low as that of the other fractions as was equal to 0.92 mkmoles of Pn per mg of protein per hr. This value is statistically different from those obtained during the analysis of the other fractions.


Electrical and mechanical responses of guinea-pig bladder muscle to nerve stimulation.
1 The electrical and mechanical responses to transmural stimulation of intrinsic nerves have been recorded from smooth muscle strips dissected from the dome of the guinea-pig bladder, by use of intracellular microelectrodes, and conventional tension recording techniques. 2 Stimulation of intrinsic nerves evoked action potentials in all cells studied. Hyperpolarization of the cells by extracellular current injection revealed subthreshold excitatory junction potentials (e.j.ps) in about a quarter of the cells studied. 3 Action potentials could still be evoked in the presence of atropine and neostigmine, but were abolished after desensitization of the cells to alpha, beta-methylene ATP, a stable analogue of ATP. 4 In the presence of neostigmine, the evoked action potential was followed by a slow depolarization of the membrane. The mechanical response increased in amplitude and duration. 5 The contractile response to transmural nerve stimulation was reduced but not abolished in the presence of either atropine or desensitizing doses of alpha, beta-methylene ATP. Atropine was more effective at high frequencies of stimulation (greater than or equal to 30 Hz), and alpha, beta-methylene ATP at low frequencies (less than or equal to 15 Hz). In combination the drugs abolished the response. 6 The results suggest that the mechanical response to excitatory nerve stimulation is biphasic. The early transient response is elicited by e.j.ps and evoked spikes, is resistant to atropine, but sensitive to desensitization of purinoceptors. The late response is mediated through muscarinic receptors, involves little membrane depolarization, and is unaffected by desensitization of purinoceptors. These responses are analogous to the responses seen in rabbit bladder, and in the sympathetically innervated rat tail artery and guinea-pig vas deferens.


A preference-based single-item measure of quality of life following medial opening wedge high tibial osteotomy: large improvements similar to arthroplasty.
Improvements in generic and disease specific scores have been reported with medial opening wedge high tibial osteotomy (MOW HTO). However, meaningful comparisons between competing surgical interventions have been hampered by the lack of a preference based single index of health related quality of life (HRQoL). The primary aim of this study was to derive and report a single index measure of HRQoL for patients undergoing MOW HTO, preoperatively and at 12 and 24 postoperatively. Secondary aims were to evaluate changes in various additional measures of quality of life at these time points. The impact of MOW HTO was evaluated using generic and disease specific instruments. One hundred thirty eight patients completed the Medical Outcomes Study short form health survey (SF-12) and Knee Osteoarthritis Outcomes Score (KOOS) before, 12 and 24 months after surgery. A preference-based single index measure of HRQoL was calculated and changes were evaluated. The mean change in the HRQoL suggested large, clinically significant improvements from 0.69 preoperatively to 0.82 (p<0.001) and 0.8 at 12 and 24 months postoperatively respectively. All dimensions of the SF-12, except role mental health, and all dimensions of the KOOS also demonstrated statistically significant improvements between pre and postoperative measurements. The preoperative HRQoL of young patients with mechanical varus alignment and medial compartment knee osteoarthritis is similar to older patients with knee osteoarthritis. Medial opening wedge high tibial osteomoty results in significant improvements in HRQoL, the magnitude of which is comparable to other surgical interventions for knee osteoarthristis.


Development and Evaluation of an Objective Tympanic Membrane Visualization Assessment Technique.
To introduce an inexpensive method for objectively evaluating otoscopic visualization of the tympanic membrane wherein learners match what they visualize in standardized patients to tympanic membrane photographs. Two standardized patients had photographs taken of their tympanic membranes using a commercially-available digital otoscope. First- and third-year medical students were asked to perform an otoscopic examination on each patient using a conventional handheld otoscope and to match what they saw with the correct tympanic membrane image among distractor photographs belonging to other patients. The ability of students to match the standardized patients' tympanic membrane to the correct photographs was assessed before and after a didactic training session. These measurements were compared between the two cohort groups for construct validity. Fifty-one first-year medical students (with no previous otoscopy experience) and 44 third-year medical students (with otoscopy experience from completing pediatric and family medicine clinical clerkships) were recruited to voluntarily participate in this study. At baseline, a larger percentage of third-year students correctly matched both tympanic membranes compared to first-year students (27% vs 8%, P < .01). After otoscopy training, correct matching of both tympanic membranes significantly improved among both first-year students (8-31%, P < .01) and third-year students (27-54%, P < .01). The use of tympanic membrane photographs from standardized patients provides a novel technique for objectively assessing proficiency in otoscopic visualization of the middle ear. The concept is low cost, uses live patients, and can be easily implemented in pre-clinical instruction and beyond.


Factors affecting the foraging behaviour of the European shag: implications for seabird tracking studies.
Seabird tracking has become an ever more popular tool to aid environmental procedures such as the designation of marine protected areas and environmental impact assessments. However, samples used are usually small and little consideration is given to experimental design and sampling protocol. European shags Phalacrocorax aristotelis were tracked using GPS technology over three breeding seasons and the following foraging trip characteristics: trip duration, trip distance, maximum distance travelled from the colony, size of area used and direction travelled from colony were determined for each foraging trip. The effect of sex, year of study, breeding site, number and age of chicks and the timing of tracking on foraging behaviour were investigated using a General Estimation Equation model. A range of sampling scenarios reflecting likely field sampling were also tested to compare how foraging behaviour differed depending on composition of the sample of birds tracked. Trip distance, trip duration, maximum distance travelled and size of area used were all significantly affected by the breeding site, and the number of chicks a tracked adult was raising. The effect of sex was also seen when examining trip distance, trip duration and the maximum distance travelled. The direction travelled on a foraging trip was also significantly affected by breeding site. This study highlights the importance of sampling regime and the influence that year, sex, age, number of chicks and breeding site can have on the foraging trip characteristics for this coastal feeding seabird. Given the logistical and financial constraints in tracking large numbers of individuals, this study identifies the need for researchers to consider the composition of their study sample to ensure any identified foraging areas are as representative as possible of the whole colony's foraging area.


Impact of the COVID-19 Lockdown on a Long-Term Care Facility: The Role of Social Contact.
(1) Background: Long-term care facilities (LTCFs) have been harmed by the coronavirus, and older adults have remained isolated for a long time with many restrictions. The aim of this study was to measure the decline in cognitive, functional, and affective status in a care facility after the lockdown in the first wave of the COVID-19 pandemic and to compare it with previous measures in order to determine if this decline was accelerated. (2) Methods: Ninety-eight participants were recruited. Data from three retrospective pre-lockdown assessments and an additional post-lockdown assessment were analyzed. Mixed ANOVA analyses were performed according to the Clinical Dementia Rating levels, considering social-contact frequency during the lockdown as a covariate. (3) Results: The cognitive and functional scores were lower and depression scores were higher after the strict lockdown, accelerating a general pattern of decline that was already present in LTCF residents. The frequency of social contact eliminated the measurement differences in the cognitive and functional scores and the group differences in depression scores. (4) Conclusions: The effects of the SARS-CoV-2 lockdown in an LTCF were mediated by the frequency of contact. Clinical implications: Preventive measures must be taken to ensure social contact with relatives and friends and reduce the negative consequences of social isolation in LTCFs.


A Mixed-Methods, Randomized Clinical Trial to Examine Feasibility of a Mindfulness-Based Stress Management and Diabetes Risk Reduction Intervention for African Americans with Prediabetes.
African Americans have disproportionately high rates of stress-related conditions, including diabetes and diabetes-related morbidity. Psychological stress may negatively influence engagement in risk-reducing lifestyle changes (physical activity and healthy eating) and stress-related physiology that increase diabetes risk. This study examined the feasibility of conducting a randomized trial comparing a novel mindfulness-based stress management program combined with diabetes risk-reduction education versus a conventional diabetes risk-reduction education program among African American adults with prediabetes and self-reported life stress. Participants were recruited in collaboration with community partners and randomized to the mindfulness-based diabetes risk-reduction education program for prediabetes (MPD; n = 38) or the conventional diabetes risk-reduction education program for prediabetes (CPD; n = 30). The mindfulness components were adapted from the Mindfulness-based Stress Reduction Program. The diabetes risk-reduction components were adapted from the Power to Prevent Program and the Diabetes Prevention Program. Groups met for eight weeks for 2.5 hours, with a half-day retreat and six-monthly boosters. Mixed-methods strategies were used to assess feasibility. Psychological, behavioral, and metabolic data were collected before the intervention and at three and six months postintervention to examine within-group change and feasibility of collecting such data in future clinical efficacy research. Participants reported acceptability, credibility, and cultural relevance of the intervention components. Enrollment of eligible participants (79%), intervention session attendance (76.5%), retention (90%), and postintervention data collection attendance (83%, 82%, and 78%, respectively) demonstrated feasibility, and qualitative data provided information to further enhance feasibility in future studies. Both groups exhibited an A1C reduction. MPD participants had reductions in perceived stress, BMI, calorie, carbohydrate and fat intake, and increases in spiritual well-being. Considering the high prevalence of diabetes and diabetes-related complications in African Americans, these novel findings provide promising guidance to develop a larger trial powered to examine efficacy of a mindfulness-based stress management and diabetes risk-reduction education program for African Americans with prediabetes.


Subsidence of the femoral prosthesis. A stereophotogrammetric evaluation.
A quantitative three-dimensional measurement method, radiographic stereophotogrammetry (SPG), was employed to assess the relation between early subsidence of the femoral prosthesis after total hip arthroplasty (THA) and subsequent clinical course. The SPG technique and the authors' error control mechanisms are described in 15 patients in the early postoperative period, and the findings are correlated with those of follow-up clinical examinations. Among the 12 patients who remained clinically asymptomatic with respect to pain, only one had an SPG estimate of subsidence in excess of 1 mm at any point in time. Each of the three patients who later became symptomatic had SPG estimates of subsidence in excess of 1.75 mm within six months of the operation. Thus far, the patient with the largest estimate of subsidence is the only one who required surgical revision.


Review. The incentive sensitization theory of addiction: some current issues.
We present a brief overview of the incentive sensitization theory of addiction. This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these systems cause pathological incentive motivation ('wanting') for drugs. We address some current questions including: what is the role of learning in incentive sensitization and addiction? Does incentive sensitization occur in human addicts? Is the development of addiction-like behaviour in animals associated with sensitization? What is the best way to model addiction symptoms using animal models? And, finally, what are the roles of affective pleasure or withdrawal in addiction?