Wavefront ablation profiles in refractive surgery: description, results, and limitations.
To provide an overview of the clinical results of different ablation profiles based on wavefront technology and discuss their characteristics and limitations. Literature review of studies reporting results of ablation profiles based on wavefront technology in virgin healthy eyes. Over the past 10 years, a large number of studies comparing different treatment algorithms and newer excimer laser platforms have been published. Thirty-six clinical studies including 3637 eyes analyzing the clinical results obtained after wavefront-guided, wavefront-optimized, and Q-factor profiles have been reviewed. Although wavefront-driven profiles allowed reduction of the amount of induced optical aberrations with conventional ablations, thereby improving the quality of vision, it appears that no algorithm of treatment or excimer laser platform has demonstrated a clear superiority over another. Wound healing and unexpected biomechanical response to surgery affect the accuracy of customized treatments and produce variable results. In addition, it is difficult to rigorously analyze and compare findings among different studies because of the diverse variety in which the data are reported. Despite several technological improvements over the years, wavefront ablation profiles have not consistently demonstrated superiority in terms of visual acuity and lower order aberrations compared to the standard procedure, although the induction of higher order aberrations has been reduced. The concept of an individualized eye model has emerged recently, based on the optical ray tracing algorithm, and could theoretically provide a higher level of customization, thus fulfilling the promise of "super vision."


Impact of a patient incentive program on receipt of preventive care.
Patient financial incentives are being promoted as a mechanism to increase receipt of preventive care, encourage healthy behavior, and improve chronic disease management. However, few empirical evaluations have assessed such incentive programs. In South Africa, a private health plan has introduced a voluntary incentive program which costs enrollees approximately $20 per month. In the program, enrollees earn points when they receive preventive care. These points translate into discounts on retail goods such as airline tickets, movie tickets, or cell phones. We chose 8 preventive care services over the years 2005 to 2011 and compared the change between those who entered the incentive program and those that did not. We used multivariate regression models with individual random effects to try to address selection bias. Of the 4,186,047 unique individuals enrolled in the health plan, 65.5% (2,742,268) voluntarily enrolled in the incentive program. Joining the incentive program was associated with statistically higher odds of receiving all 8 preventive care services. The odds ratio (and estimated percentage point increase) for receipt of cholesterol testing was 2.70 (8.9%); glucose testing 1.51 (4.7%); glaucoma screening 1.34 (3.9%); dental exam 1.64 (6.3%); HIV test 3.47 (2.6%); prostate specific antigen testing 1.39 (5.6%); Papanicolaou screening 2.17 (7.0%); and mammogram 1.90 (3.1%) (P < .001 for all 8 services). However, preventive care rates among those in the incentive program was still low. Voluntary participation in a patient incentive program was associated with a significantly higher likelihood of receiving preventive care, though receipt of preventive care among those in the program was still lower than ideal.


The At Home/Chez Soi trial protocol: a pragmatic, multi-site, randomised controlled trial of a Housing First intervention for homeless individuals with mental illness in five Canadian cities.
Introduction Housing First is a complex housing and support intervention for homeless individuals with mental health problems. It has a sufficient knowledge base and interest to warrant a test of wide-scale implementation in various settings. This protocol describes the quantitative design of a Canadian five city, $110 million demonstration project and provides the rationale for key scientific decisions. Methods A pragmatic, mixed methods, multi-site field trial of the effectiveness of Housing First in Vancouver, Winnipeg, Toronto, Montreal and Moncton, is randomising approximately 2500 participants, stratified by high and moderate need levels, into intervention and treatment as usual groups. Quantitative outcome measures are being collected over a 2-year period and a qualitative process evaluation is being completed. Primary outcomes are housing stability, social functioning and, for the economic analyses, quality of life. Hierarchical linear modelling is the primary data analytic strategy. Ethics and dissemination Research ethics board approval has been obtained from 11 institutions and a safety and adverse events committee is in place. The results of the multi-site analyses of outcomes at 12 months and 2 years will be reported in a series of core scientific journal papers. Extensive knowledge exchange activities with non-academic audiences will occur throughout the duration of the project. Trial registration number This study has been registered with the International Standard Randomised Control Trial Number Register and assigned ISRCTN42520374.


Epidermal growth factor receptor stimulation of diacylglycerol kinase.
The epidermal growth factor receptor (EGFR) activates formation of the phospholipid signal messenger phosphatidic acid (PA) on ligand binding. We explored the effects of chronic EGF stimulation on cellular PA in NIH3T3 cells expressing intact EGFR a mutant EGFR (EGFRvIII). The presence of EGFRvIII increased PA levels to twice those induced by chronic EGFR activation. Fatty acid methyl ester analysis revealed a marked increase in oleic acid containing PA. No apparent increase in phospholipase D (PLD) activity was detected, and diacylglycerol (DAG) kinase assays demonstrated a marked preference for dioleoyl DAG in the presence of activated EGFR or EGFRvIII. Levels of PA which were lower than would be predicted by DAG kinase activation are explained by increased phosphatidate phosphohydrolase activity. Specific inhibitors of EGFR kinase and DAG kinase suppressed DAG kinase activation and PA production by EGFRvIII. EGFR kinase activation by chronic exposure to ligand or by deletional mutation stimulates formation of a specific form of signalling PA.


Biphasic activation of PKBalpha/Akt in platelets. Evidence for stimulation both by phosphatidylinositol 3,4-bisphosphate, produced via a novel pathway, and by phosphatidylinositol 3,4,5-trisphosphate.
Stimulation of platelet thrombin receptors or protein kinase C causes fibrinogen-dependent aggregation that is a function of integrin alphaIIb beta3 activation. Such platelets rapidly and transiently form phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and a small amount of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2). After aggregation, a larger amount of PtdIns(3,4)P2 is generated. We report that this latter PtdIns(3,4)P2 arises largely through wortmannin-inhibitable generation of PtdIns3P and then phosphorylation by PtdIns3P 4-kinase (PtdIns3P 4-K), a novel pathway apparently contingent upon the activation of the Ca2+-dependent protease calpain. Elevation of cytosolic Ca2+ by ionophore, without integrin/ligand binding, is insufficient to activate the pathway. PtdIns3P 4-K is not the recently described "PIP5KIIalpha." Cytoskeletal activities of phosphatidylinositol 3-kinase and PtdIns3P 4-K increase after aggregation. Prior to aggregation, PtdIns3P 4-K can be regulated negatively by the beta gamma subunit of heterotrimeric GTP-binding protein. After aggregation, PtdIns3P 4-K calpain-dependently loses its susceptibility to Gbeta gamma and is, in addition, activated. Both PtdIns(3,4,5)P3 and PtdIns(3,4)P2 have been shown to stimulate PKBalpha/Akt phosphorylation and activation by phosphoinositide-dependent kinase 1. We find that activation of PKBalpha/Akt in platelets is phosphorylation-dependent and biphasic; the initial phase is PtdIns(3,4,5)P3-dependent and more efficient, whereas the second phase depends upon PtdIns(3,4)P2 generated after aggregation. There is thus potential for both pre- and post-aggregation-dependent signaling by PKBalpha/Akt.


Potential Drug-Drug Interactions Between Anti-Cancer Drugs and Other Medications in Lung Cancer Patients: A Retrospective Study.
Cancer patients are more vulnerable to developing drug-drug interactions as multiple medications are administered concomitantly with cytotoxic agents to treat the underlying comorbidities. These drug-drug interactions often receive less medical attention and consequently are associated with adverse clinical outcomes. We intended to comprehensively characterize the drug-drug interactions among anticancer drugs and other concomitantly prescribed drugs in hospitalized lung cancer patients. A retrospective, observational, single-centre study was conducted on lung cancer inpatients from the medical records department of Kasturba Hospital, Manipal, India. Drug-drug interactions were identified using the drug interaction checkers of two drug information databases, Micromedex and Epocrates. These drug-drug interactions were categorized based on the source from which they were identified, mechanism, severity/significance, adverse consequences, and management strategies required. Among 196 patients, 555 drug-drug interactions were identified in 185 patients using Micromedex and Epocrates. Based on the mechanism of action, 74% and 22% of the drug-drug interactions were classified as pharmacodynamic and pharmacokinetic respectively. 112 drug-drug interactions were recorded from Micromedex alone, while 549 interactions were found using Epocrates. The oral chemotherapeutic drug gefitinib was found to be associated with the highest number of drug-drug interactions. Drug-drug interactions were highly prevalent among hospitalized lung cancer patients. Structured screening and monitoring for these potentially clinically relevant drug-drug interactions by oncologists in collaboration with clinical pharmacists should be carried out prior to initiation and during anticancer treatment to prevent adverse clinical outcomes.


Age-related Changes in Eye, Brain and Visuomotor Behavior in the DBA/2J Mouse Model of Chronic Glaucoma.
Although elevated intraocular pressure (IOP) and age are major risk factors for glaucoma, their effects on glaucoma pathogenesis remain unclear. This study examined the onset and progression of glaucomatous changes to ocular anatomy and physiology, structural and physiological brain integrity, and visuomotor behavior in the DBA/2J mice via non-invasive tonometry, multi-parametric magnetic resonance imaging (MRI) and optokinetic assessments from 5 to 12 months of age. Using T2-weighted MRI, diffusion tensor MRI, and manganese-enhanced MRI, increasing IOP elevation at 9 and 12 months old coincided with anterior chamber deepening, altered fractional anisotropy and radial diffusivity of the optic nerve and optic tract, as well as reduced anterograde manganese transport along the visual pathway respectively in the DBA/2J mice. Vitreous body elongation and visuomotor function deterioration were observed until 9 months old, whereas axial diffusivity only decreased at 12 months old in diffusion tensor MRI. Under the same experimental settings, C57BL/6J mice only showed modest age-related changes. Taken together, these results indicate that the anterior and posterior visual pathways of the DBA/2J mice exhibit differential susceptibility to glaucomatous neurodegeneration observable by in vivo multi-modal examinations.


Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation.
G protein-coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.


Dissociation between the calcium-induced and voltage-driven motility in cochlear outer hair cells from the waltzing guinea pig.
The waltzing guinea pig, possessing an hereditary progressive deafness, shows pathology to the actin-bearing structures within the hair cells of the organ of Corti. In particular, the affected structures include the stereocilia, the cuticular plate and, as shown in the present study, swollen and disorganized subsurface cisternae. To test whether this pathology affected outer hair cell motility, cells were isolated from waltzing guinea pigs and their age-matched controls and were subjected to either electrical or chemical stimulation. Visual detection thresholds and the magnitude of the electrically-induced length changes were equivalent for both groups. However, when intracellular calcium was increased with either the calcium ionophore, ionomycin or Ca2+/ATP (under permeabilized conditions with DMSO), length changes were significantly reduced for the outer hair cells from waltzing guinea pigs compared to the controls. The average percent length increase induced by 10 microM ionomycin for the outer hair cells from control animals was 2.3 +/- 1.7 whereas for postnatal day 4 waltzing guinea pigs it was 1.3 +/- 1.7. Postnatal day 7 and 10 waltzing guinea pigs responded with significantly smaller percent length changes. The intracellular concentration of ionic calcium increased similarly for both groups after the application of ionomycin as revealed with the indicator fluo-3. In the permeabilized cells in the presence of Ca2+/ATP, control cells responded with a percent length change of 3.5, whereas, age-matched waltzing outer hair cells responded with barely detectable length changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression.
The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRHPVN) and hypocretin neurons in the lateral hypothalamus (HcrtLH). CRHPVN neurons directly innervate HcrtLH neurons, and optogenetic stimulation of LH-projecting CRHPVN neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the crh gene in CRHPVN neurons abolishes hyperarousal induced by stimulating LH-projecting CRHPVN neurons. Genetic ablation of Hcrt neurons or crh gene knockdown significantly counteracts restraint stress-induced hyperarousal. Single-cell mass cytometry by time of flight (CyTOF) revealed extensive changes to immune cell distribution and functional responses in peripheral blood during hyperarousal upon optogenetic stimulation of CRHPVN neurons simulating stress-induced insomnia. Our findings suggest both central and peripheral systems are synergistically engaged in the response to stress via CRHPVN circuitry.


Transient 2D IR Spectroscopy and Multiscale Simulations Reveal Vibrational Couplings in the Cyanobacteriochrome Slr1393-g3.
Cyanobacteriochromes are bistable photoreceptor proteins with desirable photochemical properties for biotechnological applications, such as optogenetics or fluorescence microscopy. Here, we investigate Slr1393-g3, a cyanobacteriochrome that reversibly photoswitches between a red-absorbing (Pr) and green-absorbing (Pg) form. We applied advanced IR spectroscopic methods to track the sequence of intermediates during the photocycle over many orders of magnitude in time. In the conversion from Pg to Pr, we have revealed a new intermediate with distinct spectroscopic features in the IR, which precedes Pr formation using transient IR spectroscopy. In addition, stationary and transient 2D IR experiments measured the vibrational couplings between different groups of the chromophore and the protein in these intermediate states, as well as their structural disorder. Anharmonic QM/MM calculations predict spectra in good agreement with experimental 2D IR spectra of the initial and final states of the photocycle. They facilitate the assignment of the IR spectra that serve as a basis for the interpretation of the spectroscopic results and suggest structural changes of the intermediates along the photocycle.


Inferring demographic parameters in bacterial genomic data using Bayesian and hybrid phylogenetic methods.
Recent developments in sequencing technologies make it possible to obtain genome sequences from a large number of isolates in a very short time. Bayesian phylogenetic approaches can take advantage of these data by simultaneously inferring the phylogenetic tree, evolutionary timescale, and demographic parameters (such as population growth rates), while naturally integrating uncertainty in all parameters. Despite their desirable properties, Bayesian approaches can be computationally intensive, hindering their use for outbreak investigations involving genome data for a large numbers of pathogen isolates. An alternative to using full Bayesian inference is to use a hybrid approach, where the phylogenetic tree and evolutionary timescale are estimated first using maximum likelihood. Under this hybrid approach, demographic parameters are inferred from estimated trees instead of the sequence data, using maximum likelihood, Bayesian inference, or approximate Bayesian computation. This can vastly reduce the computational burden, but has the disadvantage of ignoring the uncertainty in the phylogenetic tree and evolutionary timescale. We compared the performance of a fully Bayesian and a hybrid method by analysing six whole-genome SNP data sets from a range of bacteria and simulations. The estimates from the two methods were very similar, suggesting that the hybrid method is a valid alternative for very large datasets. However, we also found that congruence between these methods is contingent on the presence of strong temporal structure in the data (i.e. clocklike behaviour), which is typically verified using a date-randomisation test in a Bayesian framework. To reduce the computational burden of this Bayesian test we implemented a date-randomisation test using a rapid maximum likelihood method, which has similar performance to its Bayesian counterpart. Hybrid approaches can produce reliable inferences of evolutionary timescales and phylodynamic parameters in a fraction of the time required for fully Bayesian analyses. As such, they are a valuable alternative in outbreak studies involving a large number of isolates.


On how to deal with deep uncertainties in a risk assessment and management context.
Recently, several authors have presented interesting contributions on how to meet deep or severe uncertainties in a risk analysis setting. In this article, we provide some reflections on some of the foundational pillars that this work is based on, including the meaning of concepts such as deep uncertainty, known probabilities, and correct models, the aim being to contribute to a strengthening of the scientific platform of the work, as well as providing new insights on how to best implement management policies meeting these uncertainties. We also provide perspectives on the boundaries and limitations of analytical approaches for supporting decision making in cases of deep uncertainties. A main conclusion of the article is that deep uncertainties call for managerial review and judgment that sees beyond the analytical frameworks studied in risk assessment and risk management contexts, including those now often suggested to be used, such as robust optimization techniques. This managerial review and judgment should be seen as a basic element of the risk management.


Fever-range hyperthermia promotes cGAS-STING pathway and synergizes DMXAA-induced antiviral immunity.
Background: Fever-range hyperthermia or fever-range temperature (hereafter FRT) improves survival and shortens disease duration in microbial infections. However, the mechanisms of these beneficial effects still remain elusive. We hypothesized that FRT might enhance cell responsiveness to infections by promoting cGAS-STING signaling to cause enhanced production of IFN-β. Objective: To investigate the effect fever-range hyperthermia on cGAS-STING pathway. Methods: RAW 264.7 and cGAS-/- RAW 264.7 cells, stimulated with 5μg/ml herring testis DNA (htDNA), were heated to 39.5°C and analyzed for the expression of cGAS, STING, IFN-β, and the synthesis of cGAMP and IRF3 phosphorylation. In vivo, wild type C57BL/6J mice were subjected to whole body hyperthermia (WBH) at 39.5°C. The mice were then challenged with influenza virus and analyzed for antiviral response in term of IFN-β expression, body weight and survival. Results: We found that 39.5°C FRT upregulated the expression of cGAS and STING, and induced the synthesis of cGAMP and production of IFN-β in htDNA-transfected RAW 264.7 cells more potently as compared to 37°C. Moreover, FRT+DMXAA-treated cells were better protected from vesicular stomatitis virus (VSV)-induced cytotoxicity in vitro in contrast to the nonprotected control (no FRT and DMXAA) or DMXAA treatment alone. In vivo, FRT at 39.5°C, co-administered with DMXAA, significantly induced the expression of IFN-β, showed reduced weight loss mice and exhibited 25% more survival over the course of 14 days as compared to DMXAA treated mice 37°C. Conclusion: We conclude that fever-range hyperthermia promotes cGAS-STING pathway to cause increased expression of IFN-β and mediate its antiviral effects.


Ultrastructure of soybean nodules. I: release of rhizobia from the infection thread.
Root nodules on soybeans (var. Clark 63) were examined by transmission electron microscopy 10-12 days after seed inoculation and planting. The cell infection process appeared identical in both effective nodules, induced by Rhizobium japonicum strain 138 (USDA) and in ineffective nodules, induced by strain 8-0 (Iowa). Electron micrographs are presented which suggest that rhizobia are freed from the infection thread by disintegration of the thread wall and compartmentalization of the distintegrated wall material in membrane-bound vesicles derived from the membrane surrounding the thread. As the thread wall is removed in this manner, the bacteria are released into the host cytoplasm by a process which encloses each in an envelope also dervide from the thread membrane. Any thread wall material remaining around a bacterium after it has dissociated from the thread is removed from the envelope space by vesiculation of the membrane envelope. thus, it appears that endocytosis of both the bacteria and the material composing the infection thread wall occurs during release of rhizobia into the host cell.


[Anesthetic maintenance of renal transplantation in children].
For many children with severe renal excretory dysfunction, renal transplantation is the sole method of life prolongation. The purpose of the investigation was to analyze the specific features of anesthetic maintenance of transplantation of related and cadaver kidney at 1 to 5 years. The investigation involved a detailed analysis of the specific features of 101 anesthesias made in children aged 1 to 16 years (mean 9.6+/-4.87 years) during transplantation of kidneys from corpses and apparently healthy relatives. The duration of surgery and anesthesia was 5.6+/-1.00 and 7.6+/-1.42 hours, respectively. Operations were made under balanced general anesthesia using a low-flow inhalational isoflurane or sevoflurane (0.5-2.0 MAC) technology. After inclusion of a graft into the bloodstream, a plasmapheresis procedure was initiated in 1-1.5 circulating blood volumes. All the children underwent invasive hemodynamic monitoring: the radial artery and internal jugular vein were catheterized. In 19 cases, the pulmonary artery was catheterized using a Swan-Ganz catheter. In children, the initial period of anesthesia during renal transplantation was marked by a drastic hemodynamic instability tended for hypotension and significant tachycardia in the presence of marked hypovolemia (central venous pressure = 0+/-2.0 mm Hg). The major component of infusion therapy was freshly frozen plasma (up to 50% of the volume). Inclusion of a cold renal graft into systemic circulation and washout of residues of preservative solution and necrobiolysis products from it were accompanied by a 0.5-1.3 degrees C temperature reduction and progression of metabolic acidosis. Safe and successful anesthetic maintenance of renal transplantation in children requires an obligatory informative invasive hemodynamic monitoring, continuous laboratory screening, and knowledge of stage-specific features. Continuous plasmapheresis by means of a plasma filter is preferred.


Neuronal coding by cortical cells of the frequency of oscillating peripheral stimuli.
One class of neurons in the somatic sensory cortex of unanesthetized monkeys is rhythmically entrained by sinusoidal mechanical stimulation of the skin of the hand at low frequencies. A second class, which is linked to Pacinian afferents, increases its rate of discharge in response to high-frequency peripheral stimuli but is not entrained. The vibratory sense is served by two distinct classes of cortical cells. The code for the group sensitive to low-frequency stimuli is the temporal order of impulses; for the high-frequency group the code is the labeled line.


Precompetition warm-up in elite and subelite rhythmic gymnastics.
The aim of this study was to investigate which precompetition warm-up methodologies resulted in the best overall performance in rhythmic gymnastics. The coaches of national and international clubs (60 elite and 90 subelite) were interviewed. The relationship between sport performance and precompetition warm-up routines was examined. A total of 49% of the coaches interviewed spent more than 1 hour to prepare their athletes for the competition, including 45 minutes dedicated to warm-up exercises. In spite of previous studies' suggestions, the time between the end of warm-up and the beginning of competition was more than 5 minutes for 68% of those interviewed. A slow run was the activity of choice used to begin the warm-up (96%). Significant differences between elite and subelite gymnasts were found concerning the total duration of warm-up, duration of slow running, utilization of rhythmic steps and leaps during the warm-up, the use of dynamic flexibility exercises, competition performances repetition (p < 0.01), and utilization of imagery (p < 0.05). A precompetition warm-up in rhythmic gymnastics would include static stretching exercises at least 60 minutes prior to the competition starting time and the active stretching exercises alternated with analytic muscle strengthening aimed at increasing muscle temperature. Rhythmic gymnastics coaches at all levels can use this data as a review of precompetition warm-up practices and a possible source of new ideas.


Mode of antibacterial action of cefprozil, a new cephalosporin, on Escherichia coli, Serratia marcescens and Morganella morganii.
The mode of antibacterial action of cefprozil (CFPZ, BMY-28100), a newly developed cephalosporin, was investigated using Escherichia coli K12, Serratia marcescens IFO 12648 and Morganella morganii IFO 3848 as test organisms, in comparison with the action of cefaclor (CCL). The minimum inhibitory concentrations (MICs) of CFPZ for these organisms were 1.56, 800 and 25 micrograms/ml, whereas those of CCL were 1.56, 800 and 100 micrograms/ml, respectively. The addition of a subinhibitory concentration (1/4 MIC) of ethylenediaminetetraacetic acid (EDTA), which damages the permeability barrier of the outer membrane, markedly reduced the MICs of CFPZ for E. coli and S. marcescens, compared with those of CCL, whereas the MICs of both antibiotics for M. morganii were hardly affected by the presence of EDTA. CFPZ was more stable to beta-lactamase activities from these organisms than CCL. The cross-linking reactions of peptidoglycan synthesis catalyzed by the ether-treated cells from these organisms were inhibited by a lower concentration of CFPZ than of CCL.


Development of a high-throughput quantitative assay for detecting herpes simplex virus DNA in clinical samples.
We have developed a high-throughput, semiautomated, quantitative fluorescence-based PCR assay to detect and type herpes simplex virus (HSV) DNA in clinical samples. The detection assay, which uses primers to the type-common region of HSV glycoprotein B (gB), was linear from <10 to 10(8) copies of HSV DNA/20 microl of sample. Among duplicate samples in reproducibility runs, the assay showed less than 5% variability. We compared the fluorescence-based PCR assay with culture and gel-based liquid hybridization system with 335 genital tract specimens from HSV type 2 (HSV-2)-seropositive persons attending a research clinic and 380 consecutive cerebrospinal fluid (CSF) samples submitted to a diagnostic virology laboratory. Among the 162 culture-positive genital tract specimens, TaqMan PCR was positive for 157 (97%) specimens, whereas the quantitative-competitive PCR was positive for 144 (89%) specimens. Comparisons of the mean titer of HSV DNA detected by the two assays revealed that the mean titer detected by the gel-based system was slightly higher (median, 1 log). These differences in titers were in part related to the fivefold difference in the amount of HSV DNA used in the amplicon standards with the two assays. Among the 380 CSF samples, 42 were positive by both assays, 13 were positive only by the assay with the agarose gel, and 3 were positive only by the assay with the fluorescent probe. To define the subtype of HSV DNA detected in the screening assay, we also designed one set of primers which amplifies the gG regions of both types of HSV and probes which are specific to either HSV-1 (gG1) or HSV-2 (gG2). These probes were labeled with different fluorescent dyes (6-carboxyfluorescein for gG2 and 6-hexachlorofluorescein for gG1) to enable detection in a single PCR. In mixing experiments the probes discriminated the correct subtype in mixtures with up to a 7-log-higher concentration of the opposite subtype. The PCR typing results showed 100% concordance with the results obtained by assays with monoclonal antibodies against HSV-1 or HSV-2. Thus, while the real-time PCR is slightly less sensitive than the gel-based liquid hybridization system, the high throughput, the lack of contamination during processing, the better reproducibility, and the better ability to type the isolates rapidly make the real-time PCR a valuable tool for clinical investigation and diagnosis of HSV infection.


Zeta waves: a distinctive type of intermittent delta wave studied prospectively.
Zeta waves are a distinctive form of sharply contoured biphasic delta waves that have been associated with underlying structural lesions. We have prospectively interpreted the EEGs of 840 consecutive patients blinded for clinical details. Thirty three patients had zeta waves in at least one recording and 87% of these had an underlying structural lesion on neuroimaging. By excluding those with bifrontal intermittent rhythmic delta activity and bifrontal zeta waves, the positive predictive value of zeta waves for an underlying structural lesion increases to 96%. We conclude that zeta waves are distinctive and easily recognisable delta waves which are highly predictive of recent or residual cerebral damage from a variety of causes, including cerebral trauma and infarction.


Characterization of Site-Specific N-Glycopeptide Isoforms of α-1-Acid Glycoprotein from an Interlaboratory Study Using LC-MS/MS.
Glycoprotein conformations are complex and heterogeneous. Currently, site-specific characterization of glycopeptides is a challenge. We sought to establish an efficient method of N-glycoprotein characterization using mass spectrometry (MS). Using alpha-1-acid glycoprotein (AGP) as a model N-glycoprotein, we identified its tryptic N-glycopeptides and examined the data reproducibility in seven laboratories running different LC-MS/MS platforms. We used three test samples and one blind sample to evaluate instrument performance with entire sample preparation workflow. 165 site-specific N-glycopeptides representative of all N-glycosylation sites were identified from AGP 1 and AGP 2 isoforms. The glycopeptide fragmentations by collision-induced dissociation or higher-energy collisional dissociation (HCD) varied based on the MS analyzer. Orbitrap Elite identified the greatest number of AGP N-glycopeptides, followed by Triple TOF and Q-Exactive Plus. Reproducible generation of oxonium ions, glycan-cleaved glycopeptide fragment ions, and peptide backbone fragment ions was essential for successful identification. Laboratory proficiency affected the number of identified N-glycopeptides. The relative quantities of the 10 major N-glycopeptide isoforms of AGP detected in four laboratories were compared to assess reproducibility. Quantitative analysis showed that the coefficient of variation was <25% for all test samples. Our analytical protocol yielded identification and quantification of site-specific N-glycopeptide isoforms of AGP from control and disease plasma sample.


Dilation of esophageal strictures induced by radiation therapy for cancer of the esophagus.
During a 2-year period, 103 consecutive patients undergoing dilation of esophageal strictures induced by radiation therapy for cancer of the esophagus were prospectively studied. The length of the strictures ranged from 0.5 to 13.5 cm (median, 5 cm) and the luminal diameter from 1 to 11 mm (median, 6 mm). Patients were referred for dilation from 2 weeks to 5 years (median, 2 months) after completion of radiation therapy. The guide wire was placed using fluoroscopy in 21 patients, endoscopy in 61, and a combination of endoscopy and fluoroscopy in 21. At least one dilator larger than the stricture could be passed in 101 (98%) patients. Five strictures were dilated to 16 mm, 29 to 15 mm, 28 to 14 mm, 16 to 12.8 mm, and 23 to 12 mm or less during the initial procedure. Development of complications and severe resistance were the limiting factors for optimal dilation. Relief of dysphagia was adequate in 66% of patients. The duration of dysphagia relief was 3 to 84 weeks (median, 16 weeks). Complications included persistent pain in 7 patients, unexplained fever in 2, perforation in 2, and delayed tracheo-esophageal fistula in 1. Two patients died of treatment-related complications. Repeated dilation was required in 32 of the 75 patients on long-term follow-up. We conclude that adequate palliation of dysphagia can be achieved by dilation in two-thirds of patients with radiation therapy-induced strictures of the esophagus. Dilation of these strictures is relatively simple and safe if performed with care.


The purported effects of alcohol on appetite and weight in lung cancer patients.
Loss of appetite and weight predict poor outcomes in patients with advanced cancer. Effective and affordable palliative strategies are lacking; but because an emerging non-cancer literature suggests that alcohol can increase appetite and weight, this study explored associations between alcohol and clinical outcomes in lung cancer patients. Among 404 consecutive lung cancer patients enrolled in the Mayo Clinic Lung Cancer Cohort between 2004 and 2008, alcohol consumption (within 6 mo of diagnosis) was as follows: 199 (49%) used none, 158 (14%) were moderate users (7 drinks per wk or less), and 47 (12%) were heavier consumers (more than 7 drinks per wk). Only heavier consumers had a lower likelihood of anorexia (odds ratio: 0.49; 95% CI: 0.25, 0.94; P = 0.03) and weight loss (odds ratio: 0.43; 95% CI: 0.20, 0.91; P = 0.03) compared to those who consumed no alcohol. These conclusions were sustained in multivariate analyses. Neither moderate nor heavier consumption was associated with better or worse survival, although, in univariate analyses, a drop in alcohol consumption was associated with worse survival. This report suggests a need for further study of alcohol as a palliative agent for cancer-associated loss of appetite and weight.


Elucidating the Structural and Minimal Protective Epitope of the Serogroup X Meningococcal Capsular Polysaccharide.
Despite the considerable progress toward the eradication of meningococcal disease with the introduction of glycoconjugate vaccines, previously unremarkable serogroup X has emerged in recent years, recording several outbreaks throughout the African continent. Different serogroup X polysaccharide-based vaccines have been tested in preclinical trials, establishing the principles for further improvement. To elucidate the antigenic determinants of the MenX capsular polysaccharide, we generated a monoclonal antibody, and its bactericidal nature was confirmed using the rabbit serum bactericidal assay. The antibody was tested by the inhibition enzyme-linked immunosorbent assay and surface plasmon resonance against a set of oligosaccharide fragments of different lengths. The epitope was shown to be contained within five to six α-(1-4) phosphodiester mannosamine repeating units. The molecular interactions between the protective monoclonal antibody and the MenX capsular polysaccharide fragment were further detailed at the atomic level by saturation transfer difference nuclear magnetic resonance (NMR) spectroscopy. The NMR results were used for validation of the in silico docking analysis between the X-ray crystal structure of the antibody (Fab fragment) and the modeled hexamer oligosaccharide. The antibody recognizes the MenX fragment by binding all six repeating units of the oligosaccharide via hydrogen bonding, salt bridges, and hydrophobic interactions. In vivo studies demonstrated that conjugates containing five to six repeating units can produce high functional antibody levels. These results provide an insight into the molecular basis of MenX vaccine-induced protection and highlight the requirements for the epitope-based vaccine design.


Prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen: a randomized controlled trial.
To estimate the rate of endometrial pathology with the prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen. This was a randomized contro-lled trial of 129 Chinese women who attended a university hospital in Hong Kong and required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy. Women were randomized to treatment (prophylactic levonorgestrel-releasing intrauterine system insertion before the commencement of tamoxifen) or control group. The uterine cavity was examined by hysteroscopy and endometrial sampling before the commencement of tamoxifen and at 12, 24, 45, and 60 months afterward. Any endometrial polyps or submucosal fibroids were resected through hysteroscopy at each assessment and specimens were sent for histologic confirmation. A total of 94 women completed 5-year follow-up. There was no significant difference in the occurrence of submucosal fibroids (1 [1.8%] compared with 2 [3.4%]) and endometrial hyperplasia (both 0) in the treatment and control groups, respectively. Levonorgestrel-releasing intrauterine system significantly reduced de novo endometrial polyps (hazard ratio 0.19, 95% confidence interval 0.07-0.48) over the course of 5 years on an intention-to-treat basis. There was no statistically significant increase in breast cancer recurrence rate (10 [17.2%] compared with 6 [10.0%]) or cancer-related deaths (6 [10.3%] compared with 5 [8.3%]) in the treatment group, but the study was underpowered in this regard. Prophylactic levonorgestrel-releasing intrauterine system prevents de novo endometrial polyps in women using tamoxifen. However, its role in the prevention of endometrial hyperplasia and adenocarcinoma as well as its effect on risk of breast cancer recurrence remain uncertain. Chinese Clinical Trial Registry, http://www.chictr.org/en/, ChiCTR-TRC-09000625. I.


Changing outcome of angioplasty in the elderly.
This study sought to determine whether in-hospital and intermediate-term posthospital outcomes have changed in elderly patients undergoing percutaneous transluminal coronary angioplasty from the period 1980 through 1989 to the period 1990 through 1992. Although elderly patients have a higher incidence of procedure-related deaths and late recurrence of angina after coronary angioplasty, recent complication rates for angioplasty seem to be lower. From 1980 to 1989, 982 patients > or = 65 years old underwent nonemergent coronary angioplasty (group A). They were compared with 768 similar patients who had coronary angioplasty from 1990 to 1992 (group B). Patients in group B were older than those in group A and had a higher mean concomitant disease score, a higher proportion of men and a greater proportion of patients with a previous myocardial infarction and previous coronary artery bypass surgery. Despite the increased complexity of the group B cohort, procedural success rates were higher, and rates of important in-hospital complications were much lower than those in group A. For group A versus group B, respectively, the technical success rate was 88.1% versus 93.5% (p < 0.001), in-hospital death rate 3.3% versus 1.4% (p = 0.014), emergency bypass surgery rate 5.5% versus 0.65% (p < 0.001) and incidence of in-hospital death or myocardial infarction 6.3% versus 3.4% (p < 0.005). However, intermediate-term posthospital event-free rates in hospital survivors did not decrease. The rate of death or myocardial infarction at 6 months was 4.7% in group A versus 7.1% in group B (p < 0.05). Survival free of acute myocardial infarction, bypass surgery, repeat coronary angioplasty or severe angina at 1 year was 66.7% in group A versus 54.9% in group B (p < 0.001). The combined in-hospital death/myocardial infarction rate plus that for the first 6 months after hospital dismissal was essentially equivalent for the two groups (10.3% vs. 9.9%, p = NS). An increase in technical success rates and a reduction in short-term complication rates for coronary angioplasty in the elderly in recent years have not translated into an improved event-free survival rate, which continues to be influenced by important baseline characteristics of these high risk patients.


Artificial intelligence for molecular neuroimaging.
In recent years, artificial intelligence (AI) or the study of how computers and machines can gain intelligence, has been increasingly applied to problems in medical imaging, and in particular to molecular imaging of the central nervous system. Many AI innovations in medical imaging include improving image quality, segmentation, and automating classification of disease. These advances have led to an increased availability of supportive AI tools to assist physicians in interpreting images and making decisions affecting patient care. This review focuses on the role of AI in molecular neuroimaging, primarily applied to positron emission tomography (PET) and single photon emission computed tomography (SPECT). We emphasize technical innovations such as AI in computed tomography (CT) generation for the purposes of attenuation correction and disease localization, as well as applications in neuro-oncology and neurodegenerative diseases. Limitations and future prospects for AI in molecular brain imaging are also discussed. Just as new equipment such as SPECT and PET revolutionized the field of medical imaging a few decades ago, AI and its related technologies are now poised to bring on further disruptive changes. An understanding of these new technologies and how they work will help physicians adapt their practices and succeed with these new tools.


Protein⁻Protein Interactions with Connexin 43: Regulation and Function.
Connexins are integral membrane building blocks that form gap junctions, enabling direct cytoplasmic exchange of ions and low-molecular-mass metabolites between adjacent cells. In the heart, gap junctions mediate the propagation of cardiac action potentials and the maintenance of a regular beating rhythm. A number of connexin interacting proteins have been described and are known gap junction regulators either through direct effects (e.g., kinases) or the formation of larger multifunctional complexes (e.g., cytoskeleton scaffold proteins). Most connexin partners can be categorized as either proteins promoting coupling by stimulating forward trafficking and channel opening or inhibiting coupling by inducing channel closure, internalization, and degradation. While some interactions have only been implied through co-localization using immunohistochemistry, others have been confirmed by biophysical methods that allow detection of a direct interaction. Our understanding of these interactions is, by far, most well developed for connexin 43 (Cx43) and the scope of this review is to summarize our current knowledge of their functional and regulatory roles. The significance of these interactions is further exemplified by demonstrating their importance at the intercalated disc, a major hub for Cx43 regulation and Cx43 mediated effects.


Ceramic liner fracture after cementless alumina-on-alumina total hip arthroplasty.
Advances in technology have reduced the risk of fracture of ceramic total hip arthroplasty implants, but concerns remain about fracture of both components. We retrospectively reviewed 133 patients (157 hips) who had cementless alumina-on-alumina total hip arthroplasties with a sandwich-type acetabular component. Six patients (seven hips) died and five patients (six hips) were interviewed by telephone (95% followup). The 122 patients (144 hips) examined had a minimum followup of 36 months (average, 45 months; range, 36-68 months). All acetabular cups and femoral stems were radiographically stable at the last followup. Five hips in five patients (3.5%) were revised because of ceramic liner fractures. Ceramic liner fractures occurred at a mean of 35 months (range, 24-48 months) postoperatively. Acetabular cups in the fracture group (n = 5) were more anteverted than those in the nonfracture group (n = 139). In three patients the fracture apparently occurred during squatting, resulting in hyperflexion and wide hip abduction. Early ceramic liner fracture was associated with impingement associated with excessive anteversion of the acetabular cup in Korean patients who habitually squat.


The impact of socioeconomic status and race on trial participation for older women with breast cancer.
Older women, and older minorities in particular, are under represented in breast cancer trials. Although socioeconomic status (SES) is associated with both race and age, to the authors' knowledge little is known regarding the impact of SES on trial enrollment among older women with breast cancer. The authors performed a case-control study comparing women who were participants in National Cancer Institute cooperative group breast cancer trials (cases) with a population-based sample of breast cancer patients (controls) obtained from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data base. The sample was restricted to women age >/= 65 years who were living in SEER areas. Proxies for SES included the proportion of the population below poverty level (by zip code) and unemployed (by county) as well those with Medicaid insurance coverage. A multivariable logistic regression model was used to test the association of SES with trial participation after accounting for other patient and county characteristics. In bivariate analysis, trial participants were significantly less likely than community cancer patients to reside in high-poverty zip codes (20.9% vs. 24.9%, respectively; P < 0.001) or to have Medicaid insurance (2.0% vs. 10.0%; P < 0.0001). After adjusting for race, age, and county, trial participation remained inversely related to residing in areas with high poverty (odds ratio [OR] vs. residents of remaining counties, 0.78; 95% confidence interval [95% CI], 0.62-0.98), high unemployment rates (OR vs. residents of residents of counties in the lowest quartile, 0.50; 95% CI, 0.35-0.71), and having Medicaid insurance (OR vs. women without Medicaid, 0.22; 95% CI, 0.13-0.37); black race was not found to be related to trial participation (OR for black vs. white, 1.0; 95% CI, 0.67-1.47). Low SES was associated inversely with trial enrollment for older women with breast cancer and appeared to account for the enrollment disparities between black patients and white patients. Future efforts to enhance enrollment of elderly women in cancer research should identify specific barriers related to SES that may be amenable to intervention.


Wheat-germ-agglutinin and Ricinus communis-agglutinin-binding sites of BHK cells compared with each other and with 140 kDa fibronectin receptors.
We compared the wheat-germ agglutinin (WGA) and Ricinus communis agglutinin (RCA) binding sites of baby-hamster kidney (BHK) cells. There were 1.01 X 10(8) WGA-binding sites per cell (Kd = 0.027 nM) and 6 X 10(6) RCA-binding sites per cell (Kd = 0.014 nM). Binding of WGA or RCA to BHK cells resulted in more than 75% of the cell-surface binding sites becoming associated with the cytoskeleton (i.e. resistant to extraction with detergent), although no more than 10% of these sites were associated with the cytoskeleton before addition of the lectins. After binding of WGA to the cells, the cell surface was cross-linked so extensively that it remained intact even after detergent extraction of the treated cells, and could be observed by electron microscopy. A similar cross-linking effect did not occur after binding of RCA to cells, which may be because there were so many more binding sites for WGA than for RCA. The composition of WGA- and RCA-binding molecules was analysed by lectin affinity chromatography of metabolically radiolabelled BHK cells. We found that in the WGA-binding-molecule preparations there were eight major polypeptides, ranging in molecular mass from 93 to 340 kDa, and that the RCA-binding molecules were a subpopulation of the WGA-binding molecules. A polyclonal antibody against the 140 kDa fibronectin (FN) receptors of Chinese-hamster ovary (CHO) cells immunoblotted a 145 kDa polypeptide component in both WGA- and RCA-binding-molecule preparations. The results indicated that the 145 kDa component was present in at least two FN-receptor complexes that differed in glycosylation, only one of which was able to bind to RCA affinity columns. The oligomeric nature of the FN-receptor complex, which contained three polypeptides with molecular masses of 120-145 kDa, was demonstrated by using anti-(CHO-cell FN receptor) antibodies to immunoprecipitate extracts prepared from radioiodinated BHK cells.


Fermi level dependence of gas-solid oxygen defect exchange mechanism on TiO2 (110) by first-principles calculations.
In the same way that gases interact with oxide semiconductor surfaces from above, point defects interact from below. Previous experiments have described defect-surface reactions for TiO2(110), but an atomistic picture of the mechanism remains unknown. The present work employs computations by density functional theory of the thermodynamic stabilities of metastable states to elucidate possible reaction pathways for oxygen interstitial atoms at TiO2(110). The simulations uncover unexpected metastable states including dumbbell and split configurations in the surface plane that resemble analogous interstitial species in the deep bulk. Comparison of the energy landscapes involving neutral (unionized) and charged intermediates shows that the Fermi energy EF exerts a strong influence on the identity of the most likely pathway. The largest elementary-step thermodynamic barrier for interstitial injection trends mostly downward by 2.1 eV as EF increases between the valence and conduction band edges, while that for annihilation trends upward by 2.1 eV. Several charged intermediates become stabilized for most values of EF upon receiving conduction band electrons from TiO2, and the behavior of these species governs much of the overall energy landscape.


Essential Oil Based PVP-CMC-BC-GG Functional Hydrogel Sachet for 'Cheese': Its Shelf Life Confirmed with Anthocyanin (Isolated from Red Cabbage) Bio Stickers.
'Gouda cheese' is one of the most popular varieties of cheese eaten worldwide. The preservation problem of gouda arises due to microbial contamination and infestation. Therefore, essential oil (EO) based PVP-CMC-BC-GG hydrogel film was prepared to solve the problem and to extend the shelf-life of 'Gouda cheese'. Anthocyanin (isolated from red cabbage) based pH stickers are integrated into the packaging system to recognize the spoilage of 'cheese'. EOs (clove and/or cinnamon) are added to PVP-CMC-BC-GG hydrogel film to improve its antimicrobial, physical, mechanical, and thermal properties as well as shelf-life of cheese. The films are assessed based on their physical, structural, and functional properties, real-time assessment on cheese, and biodegradability. The results revealed that although the addition of oils to the PVP-CMC-BC-GG hydrogel films enhanced its mechanical, hydrophobic, and antimicrobial properties, the biodegradability of PVP-CMC-BC-GG films declined with the addition of EOs. The thermal properties remained the same irrespective of the addition of EOs. The shelf life of cheese was extended for more than 10-12 days, inside the PVP-CMC-BC-GG hydrogel sachet compared to the conventional PE packaging system. Hence the use of the PVP-CMC-BC-GG sachet (containing EO or without EO) is recommended for cheese packaging along with the use of PVP-CMC-BC-GG anthocyanin bio stickers for monitoring the quality of cheese.


Transforming growth factor-beta 1 responsiveness of human articular chondrocytes in vitro: normal versus osteoarthritis.
The transforming growth factor-beta 1 was known as having the most important influence on chondrocytes among various growth factors, being abundant in articular chondrocytes and osteocytes. We performed in vitro monolayer cultures of human articular chondrocytes from normal and osteoarthritic patients and studied the transforming growth factor-beta 1 responsiveness of those chondrocytes. The cell-growth curve indicated that the primary osteoarthritic chondrocyte culture with transforming growth factor-beta 1 showed a more rapid growth pattern than normal chondrocytes with or without TGF-beta 1 and osteoarthritic chondrocytes without TGF-beta 1. The osteoarthritic group showed a sharp decline in growth pattern with subsequent culture. The shape of osteoarthritic chondrocytes was bigger and more bizarre compared to those of normal chondrocytes. With subsequent culture, this change became prominent. The transforming growth factor-beta 1 increased the [3H]-TdR uptake in each group. The phenotypes of chondrocytes were more clearly expressed in the normal group. The chondrocytes lost their phenotype (production of collagen type II) following subculture in each group. The transforming growth factor-beta 1 could not inhibit or delay the dedifferentiation process (loss of phenotype).


The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest.
To discuss 3 potential mechanisms for loss of peripheral vasomotor tone during vasodilatory shock; review vasopressin physiology; review the available animal experimental and human clinical studies of vasopressin in vasodilatory shock and cardiopulmonary arrest; and make recommendations based on review of the data for the use of vasopressin in vasodilatory shock and cardiopulmonary arrest. Human clinical studies, veterinary experimental studies, forum proceedings, book chapters, and American Heart Association guidelines. HUMAN AND VETERINARY DATA SYNTHESIS: Septic shock is the most common form of vasodilatory shock. The exogenous administration of vasopressin in animal models of fluid-resuscitated septic and hemorrhagic shock significantly increases mean arterial pressure and improves survival. The effect of vasopressin on return to spontaneous circulation, initial cardiac rhythm, and survival compared with epinephrine is mixed. Improved survival in human patients with ventricular fibrillation, pulseless ventricular tachycardia, and nonspecific cardiopulmonary arrest has been observed in 4 small studies of vasopressin versus epinephrine. Three large studies, though, did not find a significant difference between vasopressin and epinephrine in patients with cardiopulmonary arrest regardless of initial cardiac rhythm. No veterinary clinical trials have been performed using vasopressin in cardiopulmonary arrest. Vasopressin (0.01-0.04 U/min, IV) should be considered in small animal veterinary patients with vasodilatory shock that is unresponsive to fluid resuscitation and catecholamine (dobutamine, dopamine, and norepinephrine) administration. Vasopressin (0.2-0.8 U/kg, IV once) administration during cardiopulmonary resuscitation in small animal veterinary patients with pulseless electrical activity or ventricular asystole may be beneficial for myocardial and cerebral blood flow.


Structural and functional characterization of tnpI, a recombinase locus in Tn21 and related beta-lactamase transposons.
A novel discrete mobile DNA element from Tn21 from the plasmid R100.1 is described, and its mobilization function was confirmed experimentally. In addition, the element behaves as a recombinase-active locus (tnpI) which facilitates insertions of antibiotic resistance genes as modules or cassettes at defined hot spots or integration sites. A similar tnpI sequence was detected by DNA hybridization in a series of beta-lactamase transposons and plasmids and localized on their physical maps. The genetic function of the locus cloned from Tn21 into pACYC184 was tested for conduction and integration into the plasmids R388 and pOX38Km, and the results suggested recombinase-integrase activity and recA independence. DNA sequence analysis of the tnpI locus revealed no inverted or direct terminal repeats or transposition features of class I and class II transposons. The coding capacity revealed three putative open reading frames encoding 131, 134, and 337 amino acids. Orf3 encoded a putative polypeptide product of 337 amino acids that shared highly significant identity with the carboxyl region of integrase proteins. A comparison and an alignment of the tnpI locus from Tn21 and its flanking sequences identified similar sequences in plasmids and in transposons. The alignment revealed discrete nucleotide changes in these tnpI-like loci and a conserved 3' and 5' GTTA/G hot spot as a duplicated target site. Our data confirm the remarkable ubiquity of tnpI associated with antibiotic resistance genes. We present a model of transposon modular evolution into more complex multiresistant units via tnpI and site-specific insertions, deletions, and DNA rearrangements at this locus.


Working as frontline health facilitators, service providers, program supporters, and social health activists in Indian hilly terrain areas: A qualitative study of accredited social health activists' experiences before and during the COVID-19 pandemic.
Community health workers (CHW) contribute to achieving health targets of the Sustainable Development Goals (SDG) and Universal Health Care (UHC) in low- and middle-income countries (LMICs). In India, accredited social health activists (ASHAs) function as health facilitators, service providers, and programme supporters for rural and tribal communities and are at the frontline during the COVID-19 pandemic. We aimed to describe the ASHAs' work roles both before and during the COVID-19 pandemic, explore the tasks ASHAs performed throughout the pandemic, and understand its effects on the evolving role of ASHAs. We used qualitative data from a pre-COVID-19 study conducted in 2018-2019 including face-to-face interviews with purposively sampled ASHAs and their health care supervisors (n = 18) from rural Maharashtra state (India), and a follow-up study during the COVID-19 pandemic using telephonic interviews with a subset of participants from the pre-COVID-study (n = 8). Data were analysed thematically using MAXQDA v11.00. The primary theme in the pre-COVID-19 study was ASHAs' role as described above, except as social health activists, linking beneficiaries to the local maternal and child health care services, distributing medicines for common illnesses, access to government schemes, and engaging in multiple health surveys. During the pandemic, raising awareness, screening of at-risk populations, arranging referrals, providing treatment and follow-up to COVID-19 patients, and supporting their family members. These activities increased the workload and health risks to ASHAs and their family, causing stress and tension among them. However, they had effectively carried out the new duties. ASHAs have improved their status, earning praise from families, society, and the government. They were honoured with the Global Health Leaders Award at the 75th World Health Assembly. ASHAs' contribution to the health system improved the indicators related to maternal and child health during the pre-COVID-19 pandemic. Additionally, they maintained frontline health care during the COVID-19 pandemic, demonstrating resilience despite the challenges of increased workload and stress. However, the COVID-19 pandemic highlights the need to respond to and understand the implications of ASHAs' evolving roles.


Radio Reflection by Free Radicals in Earth's Atmosphere.
Reflections of megacycle-per-second radio signals by free radicals in Earth's ionosphere are observed having about the intensity predicted for induced magnetic-dipole transitions. It seems that magnetic atoms, ions, and molecules in planetary atmospheres may be detected by this method. These cbservations were made with the topside ionosonder of the Canadian satellite Alouette II.


Impact of Two Types of Board Games on Drug-Use Prevention in Adolescents at Senior High Schools.
Objective: A technology-assisted teaching tool with interactive features may improve the outcomes of illegal drug-use prevention strategies. This study explores augmented reality (AR) and paper board games incorporating a brief antidrug educational program for students without drug-use problems to increase their antidrug knowledge, attitude, life skills, subjective norms, perceived behavioral control, and intention to avoid using drugs. Materials and Methods: A total of 600 students were recruited, and 578 completed the intervention program and pre-and post-tests. The participants were randomly assigned to one of the following three groups: AR board game, paper board games, and comparison groups. The brief educational program consisted of two sessions. Generalized estimation equations were used to assess group differences in outcome variables. The paired t-tests were used to assess improvements in outcome variables of the two experimental groups. Results: The study found that the students who received the brief educational program featuring the AR board game was significantly different from the comparison group in outcome variables, including antidrug knowledge (P = 0.001), life skills (P = 0.004), subjective norms (P < 0.001), perceived behavioral control (P < 0.001), and intention (P = 0.02). The group with the paper board games also revealed similar findings as to the AR board game group in outcome variables, except for antidrug knowledge. There were no group differences in antidrug attitude between experimental and comparison groups. Conclusion: The results of this study support the efficacy of the two types of board games incorporated with a brief educational program. Results suggest that schools can adopt AR or paper board games as learning tools to assist in drug-use prevention programs and reduce the likelihood of students using illegal drugs.


A comparison of methods for estimating directions in egocentric space.
A central issue for researchers of human spatial knowledge, whether focused on perceptually guided action or cognitive-map acquisition, is knowledge of egocentric directions, directions from the body to objects and places. Several methods exist for measuring this knowledge. We compared two particularly important methods, manual pointing with a dial and whole-body rotation (body heading), under various conditions of sensory or memory access to targets. In two experiments, blindfolded body rotation resulted in the greatest variability of performance (variable error), while the manual dial resulted in greater consistent bias (constant error). The variability of performance with body rotation was no greater than that of the dial when subjects' memory loads for directions to targets was reduced by allowing them to peek at targets in between trials, point to concurrent auditory targets, or point with their eyes open. In both experiments, errors with the manual dial were greater for directions to targets that were further from the closest orthogonal axis (ahead, behind, right, left), while errors with body rotation with restricted perceptual access were greater for directions to targets that were further from an axis straight ahead of subjects. This suggests that the two methods will produce evidence of different organizational frameworks for egocentric spatial knowledge. Implications for the structures and processes that underlie egocentric spatial knowledge, and are involved in estimating directions, are discussed, as is the value of decomposing absolute errors into variable and constant errors.


[Analysis of the performance of system indicators for coping with family violence and the sexual exploitation of children and adolescents].
A critical review of a descriptive/discursive nature was conducted to analyze the methodological performance of a system of 41 indicators created in 2007 in partnership with the United Nations Fund for Children. It was geared to the monitoring and analysis for evaluating the performance of municipalities in addressing domestic violence and the sexual exploitation of children and adolescents. The following criteria were considered in the evaluation: validity, reliability, sensitivity, communication, social relevance and feasibility of obtaining data. Each indicator was analyzed individually, based on the comparison of research results in three cities in the state of Rio de Janeiro: Rio de Janeiro, Belford Roxo and São Gonçalo. The difficulties encountered in the application of the indicators were the lack of data for their calculation and the low quality of institutional records. The article presents the revised system of 32 indicators as a management tool for the evaluation and monitoring of municipal strategies for coping with family violence and the sexual exploitation of children and adolescents. These included prevention, attention to children and family members, qualification of notification and registration, bolstering the rights assurance system and accountability for perpetrators.


Superior Carrier Mobility Enabled by the Charge Channel Leads to Enhanced Thermoelectric Performance in BiCuSeO Composites.
BiCuSeO oxyselenides possess a highlighted thermoelectric performance among oxides, which originates from their intrinsically low thermal conductivity. However, intrinsic factors causing low thermal transport are also detrimental to carrier transport, leading to ultralow carrier mobility and relatively low electrical transport properties. Here, high-conductivity single-wall carbon nanotubes (SWCNTs) are adopted as the charge channels to be embedded in a BiCuSeO-based matrix, providing a transport pathway for charge carriers. The results show that carrier mobility is increased to 188 cm2 V-1 s-1 due to the SWCNTs composited, triggering an enhancement in electrical transport properties. Besides, the SWCNTs embedded in the matrix introduce abundant interfaces, suppressing phonon transport and depressing lattice thermal conductivity. With these achievements, a maximum zT of 0.84 at 818 K is realized in the composite with 0.1 wt% SWCNTs. The mechanical property of the composites is strengthened as well because of the SWCNTs. The work indicates that the SWCNTs, as the charge channels, propose an effective approach for enhancing carrier mobility in BiCuSeO-based materials, finally optimizing the thermoelectric performance as well as the mechanical property.


Structure and properties of metal-exchanged zeolites studied using gradient-corrected and hybrid functionals. I. Structure and energetics.
The structural and energetic properties of purely siliceous, proton-, and Cu- and Co-exchanged chabazite have been studied using periodic density-functional (DFT) calculations with both conventional gradient-corrected exchange-correlation functionals and hybrid functionals mixing exact (i.e., Hartree-Fock) and DFT exchange. Spin-polarized and fixed-moment calculations have been performed to determine the equilibrium and excited spin-configurations of the metal-exchanged chabazites. For the purely siliceous chabazite, hybrid functionals predict a slightly more accurate cell volume and lattice geometry. For isolated Al/Si substitution sites, gradient-corrected functionals predict that the lattice distortion induced by the substitution preserves the local tetrahedral symmetry, whereas hybrid functionals lead to a distorted Al coordination with two short and two long Al-O bonds. Hybrid functionals yield a stronger cation-framework binding that conventional functionals in metal-exchanged zeolites, they favor shorter cation-oxygen bonds and eventually also a higher coordination of the cation. Both types of functionals predict the same spin in the ground-state. The structural optimization of the excited spin-states shows that the formation of a high-spin configuration leads to a strong lattice relaxation and a weaker cation-framework bonding. For both Cu- and Co-exchanged chabazite, the prediction of a preferred location of the cation in a six-membered ring of the zeolite agrees with experiment, but the energy differences between possible cation locations and the lattice distortion induced by the Al/Si substitution and the bonding of the cation depends quite significantly on the choice of the functional. All functionals predict similar energy differences for excited spin states. Spin-excitations are shown to be accompanied by significant changes in the cation coordination, which are more pronounced with hybrid functionals. The consequences of electronic spectra and chemical reactivity are analyzed in the following papers.


Clinical and pathologic characteristics of serous carcinoma confined to the endometrium: a multi-institutional study.
The objective of this study was to analyze the clinical and pathologic factors in patients with uterine serous carcinoma confined to the endometrium. A total of 236 uterine serous carcinoma patients from the pathology databases of 4 large academic institutions were included in the study. Clinical and pathologic variables were analyzed, including patient demographics, tumor size (≤2 vs. >2 cm), myometrial invasion, lymphovascular invasion, lymph node status, tumor location (endometrium vs. polyp), cervical involvement, lower uterine segment involvement, FIGO stage, pelvic washings, recurrence, overall survival, and progression-free survival. Of 236 patients, 55 (23%) had tumors limited to the endometrium. Forty-four patients (80%) had Stage IA tumors. The tumor was confined to a polyp in 17 (30.9%) patients. Twenty patients (36.4%) had tumor sizes >2 cm and 12 (21.8%) exhibited lymphovascular invasion. Only 3 patients (5.4 %) had cervical stromal involvement. Thirty-three (66%) patients underwent pelvic and para-aortic lymphadenectomy with 2 positive para-aortic lymph nodes identified. Seven (12.7%) patients had positive washings, whereas 8 patients (14.5 %) had disease recurrence. At a median follow-up of 46 months, there was no difference in overall survival (P = 0.216) or progression-free survival (P=0.063) between patients with tumors confined to a polyp, patients with tumors confined to the endometrium, and patients with tumors present in both polyp and the endometrium. Uterine serous carcinoma with only endometrial involvement, even when confined to a polyp, can be associated with poor prognosis, further stressing the importance of complete surgical staging and adjuvant treatment in this setting.


Prognostic role of EGR1 in breast cancer: a systematic review.
EGR1 (early growth response 1) is dysregulated in many cancers and exhibits both tumor suppressor and promoter activities, making it an appealing target for cancer therapy. Here, we used a systematic multi-omics analysis to review the expression of EGR1 and its role in regulating clinical outcomes in breast cancer (BC). EGR1 expression, its promoter methylation, and protein expression pattern were assessed using various publicly available tools. COSMIC-based somatic mutations and cBioPortal-based copy number alterations were analyzed, and the prognostic roles of EGR1 in BC were determined using Prognoscan and Kaplan-Meier Plotter. We also used bc-GenEx- Miner to investigate the EGR1 co-expression profile. EGR1 was more often downregulated in BC tissues than in normal breast tissue, and its knockdown was positively correlated with poor survival. Low EGR1 expression levels were also associated with increased risk of ER+, PR+, and HER2- BCs. High positive correlations were observed among EGR1, DUSP1, FOS, FOSB, CYR61, and JUN mRNA expression in BC tissue. This systematic review suggested that EGR1 expression may serve as a prognostic marker for BC patients and that clinicopathological parameters influence its prognostic utility. In addition to EGR1, DUSP1, FOS, FOSB, CYR61, and JUN can jointly be considered prognostic indicators for BC. [BMB Reports 2021; 54(10): 497-504].


Origins and Status of American Botanists.
The biographical data on botanists in the ninth edition of American Men of Science, supplemented by limited information from other sources, show a trend toward reduced numbers in the younger age groups, except for a continued increase in physiologists and a stabilized supply of pathologists. The 2640 botanists with bachelor's degrees from American colleges represent 401 undergraduate institutions, but more than half of them are alumni of a group of 37 large universities supported by public funds and 14 privately endowed colleges. More than 86 percent of the botanists have taken doctorates from 92 graduate schools, but 12 of the largest ones, located chiefly in the state universities, have provided two-thirds of these degrees; more than three-fourths of the candidates came from other colleges for their advanced training. Their fields of employment are predominantly in education and in government service, but appreciable numbers are doing research work for industry or in nonindustrial laboratories.


Ethics, standards, and TQM.
The most important ethical issue for our profession is the responsibility to assure the care delivered by our colleagues and ourselves meets a self-imposed standard of excellence. There is anecdotal and experimental evidence that we have not fulfilled this obligation. Peer review has proven, for a number of reasons, to be ineffective; however, improvements in the epidemiologic sciences should provide better standards and total quality management (TQM) might prove to be of value in monitoring, comparing and improving the decisions made by physicians. Its promise lies in its emphasis on statistical analysis, its focus on systematic rather than human error, and its use of outcomes as standards. These methods, however, should not diminish our other professional responsibilities: Altruism, peer review, and in Hippocrates' words "to prescribe regimens for the good of our patients-and never do harm to anyone."


HIV testing and intimate partner violence among non-pregnant women in 15 US states/territories: findings from behavioral risk factor surveillance system survey data.
Intimate partner violence (IPV) has been shown to be associated with higher rates of HIV infection among women, underscoring the importance of encouraging IPV victims to receive HIV testing. However, we do not know how much HIV testing behavior is influenced by IPV victimization. The current study characterized the association between individual types of IPV and HIV testing in a large sample of non-pregnant women in 15 US states/territories. The 2005 Behavioral Risk Factor Surveillance System data were analyzed after restricting the sample to non-pregnant women. The dependent variable, whether a woman ever had an HIV test, was examined in relation to individual types of IPV victimization (threatened physical violence; attempted physical violence; completed physical violence; and unwanted sex). Associations between HIV testing and types of IPV were assessed using adjusted risk ratios (aRR) that controlled for demographics and HIV-related risk factors (intravenous drug use, sexually transmitted diseases, exchange sex, unprotected anal sex). Approximately 28.6 % of women reported ever having experienced IPV, and 52.8 % of these women reported being tested for HIV. Among women who had not experienced IPV, 32.9 % reported ever having been tested for HIV. HIV testing was associated with lifetime experience of threatened violence (aRR = 1.43; 95 % CI = 1.24-1.65), attempted violence (aRR = 1.43; 95 % CI = 1.20-1.69), completed physical violence (aRR = 1.30; 95 % CI = 1.13-1.48), and unwanted sex (aRR = 1.66; 95 % CI = 1.48-1.86). Women who experienced each type of IPV were more likely to have been ever tested for HIV compared to women with no IPV history. However, nearly half of those reporting IPV, even though at greater risk for HIV infection, had never been tested. Additional efforts are needed to address barriers to testing in this group.


[Lipoid pneumonia related to an accidental aspiration of gas-oil].
A 35-year-old non smoker man with no known history of chronic pulmonary disease, was treated at our hospital after accidental aspiration of gas-oil. He had developed an acute lipoid pneumonia in a few hours. Computed tomography of the chest showed a ground-glass pattern in middle lobe; given the immediate epidemiological precedent, it was possible to confirm a definitive diagnosis. One year later the patient is asymptomatic although small signs of acute process remain in the computed tomography.


Alterations in plasma essential trace elements selenium, manganese, zinc, copper, and iron concentrations and the possible role of these elements on oxidative status in patients with childhood asthma.
The aim of the present study is to evaluate the status of plasma essential trace element selenium (Se), manganese (Mn), copper (Cu), zinc (Zn), and iron (Fe) concentrations and the effect of these elements on oxidative status in patients with childhood asthma. Plasma Se, Mn, Cu, and Zn concentrations were determined by atomic absorption spectrophotometry (AAS) and Fe concentrations, malondialdehyde (MDA), and total antioxidant capacity (TAC) were determined by the colorimetric method. The plasma MDA/TAC ratio was calculated as an index of oxidative status. Plasma albumin levels were measured to determine nutritional status. Plasma Fe concentrations, MDA levels and the MDA/TAC ratio were significantly higher (p<0.001, p<0.001, and p<0.01, respectively) and Se and Mn concentrations and TAC were lower (p<0.01, p<0.05, and p<0.01, respectively) in patients when compared to the healthy subjects. Plasma Zn, Cu, and albumin levels were not found to be significantly different in patients and controls (p>0.05). There were positive relationships between plasma MDA and Fe (r=0.545, p<0.001) and TAC and Se (r= 0.485, p<0.021), and a negative correlation between TAC and MDA values (r= -0.337, p<0.031) in patients with childhood asthma. However, there was no correlation between these trace elements and albumin content in patient groups. These observations suggest that increased Fe and decreased Se concentrations in patients with childhood asthma may be responsible for the oxidant/antioxidant imbalance.


Motor Imagery during Action Observation: A Brief Review of Evidence, Theory and Future Research Opportunities.
Motor imagery (MI) and action observation (AO) have traditionally been viewed as two separate techniques, which can both be used alongside physical practice to enhance motor learning and rehabilitation. Their independent use has largely been shown to be effective, and there is clear evidence that the two processes can elicit similar activity in the motor system. Building on these well-established findings, research has now turned to investigate the effects of their combined use. In this article, we first review the available neurophysiological and behavioral evidence for the effects of combined action observation and motor imagery (AO+MI) on motor processes. We next describe a conceptual framework for their combined use, and then discuss several areas for future research into AO+MI processes. In this review, we advocate a more integrated approach to AO+MI techniques than has previously been adopted by movement scientists and practitioners alike. We hope that this early review of an emergent body of research, along with a related set of research questions, can inspire new work in this area. We are optimistic that future research will further confirm if, how, and when this combined approach to AO+MI can be more effective in motor learning and rehabilitation settings, relative to the more traditional application of MI or AO independently.


Radiological and endoscopic imaging methods in the management of cystic pancreatic neoplasms.
The management of cystic pancreatic neoplasm (CPN) is a clinical dilemma because of its clinical presentations and malignant potential. Surgery is the best treatment choice ; however, pancreatic surgery still has high complication rates, even in experienced centers. Imaging methods have a definitive role in the management of CPN and computed tomography, magnetic resonance imaging, and endoscopic ultrasonography are the preferred methods since they can reveal the suspicious features for malignancy. Therefore, radiologists, gastroenterologists, endoscopists, and surgeons should be aware of the common features of CPN, its discrete presentations on imaging methods, and the limitations of these modalities in the management of the disease. This study aims to review the radiological and endoscopic imaging methods used for the management of CPN.


Exploring phytochemical constituents of Achillea arabica Kotschy. ethanolic flower extract by LC-MS/MS and its possible antioxidant and antidiabetic effects in diabetic rats.
The aim of this study was to reveal the antidiabetic and antioxidant effects of ethanolic lyophilized extract of Achillea arabica flower extract against streptozotosine (STZ)-induced in diabetic rats and to determine its phytochemical content by liquid chromatography with tandem mass spectrometry (LC-MS/MS). After toxicity test, 35 female rats were divided into five groups. Control, diabetes mellitus (DM), A.arabica (400 mg/kg) extract, DM + A. arabica (400 mg/kg) extract and DM + Glibenclamide (2 mg/kg). It was determined that while diabetic rats treated A.arabica plant extract significantly decreased blood glucose level, serum glucose, HbA1c, liver and kidney damage biomarker levels, and malondialdehyde (MDA) content compared to the DM group, it caused fluctuations in antioxidant enzyme levels. According to LC-MS/MS results of A. arabica flower extract, quinic acid (2439.9 μg/g), cyranoside (858.4 μg/g), chlorogenic acid (698.7 μg/g), and cosmosiin (347.8 μg/g) were determined as major compounds, respectively. In addition, two new compounds were determined in this extract according to nuclear magnetic resonance (NMR) and Mass analyses and these compounds were named edremitine and achillosine, respectively. Thus, A.arabica flower extract has possible therapeutic effects to prevent high blood glucose level and oxidative stress caused by DM in liver and kidney via its high phenolic content.


Expression of multiple gamma-glutamyltransferase genes in man.
In clinical and pharmacological laboratories, the assay for gamma-glutamyltransferase (GGT) activity is an important diagnostic test, but one with high biological variability. Although the human genome contains multiple GGT genomic sequences, the diagnostic tests generally assume that only a single GGT gene is active. In the current study, segments encompassing parts of seven different potential human GGT genes have been molecularly cloned. Based on sequence determination of exons within these distinct genomic clones, oligonucleotide primers were designed which would prime and PCR-amplify putative mRNA of all seven potential GGT genes, if expressed. Gene-specific oligonucleotide probes were then utilized to assay the transcriptional status of the seven possible GGT genes in a wide variety of human RNAs. Our results show that a single GGT gene exhibits ubiquitous expression in all RNAs tested, including those from fetal and adult liver. A surprisingly large number of four additional GGT genes is expressed in man. Interestingly, these novel GGT genes are expressed in a tissue-restricted manner, which suggests that their corresponding gene products exhibit distinct functions in these specific tissues.


Anticoccidial activity of Lasalocid in control of moderate and severe coccidiosis.
The fermentation product lasalocid ("Antibiotic X-537A," Hoffmann-LaRoche) showed good anticoccidial activity when administered via feed at 50 or 75 ppm in a replicated floor-pen experiment. Lasalocid was compared with monensin (121 ppm) ("positive control") and also with unmedicated ("negative") controls in pens heavily seeded or indirectly seeded with eight species of coccidia (Eimeria acervulina, E. brunetti, E. hagani, E. maxima, E. mitati, E. necatrix, E. praecox, and E. tenella). Under severe coccidiosis exposure (litter seeded by infected birds) both anticoccidials permitted significantly increased weights, improved feed conversions, and reduced lesion scores. Shank depigmentation was numerically less in anticoccidial-treated birds than in unmedicated controls, though not significantly. Coccidiosis mortality (lesions or parasites demonstrated) was 10% in unmedicated controls. Lasaloic reduced this mortality significantly to 0.8% at 50 ppm and 0.4% at 75 ppm. No coccidiosis mortality occurred with monensin-fed birds. With moderate exposure (indirect seeding) both anticoccidials permitted significantly greater weight gains and less shank depigmentation than in unmedicated controls. In unmedicated pens severity of coccidiosis was significantly greater in the intentionally seeded pens than in indirectly seeded pens with all parameters except depigmentation. This design provided a practical procedure for testing anticoccidials in a single experiment against severe and moderate exposures to coccidiosis as are normal in broiler production.


Giving birth and becoming a parent during the COVID-19 pandemic: A qualitative analysis of 806 women's responses to three open-ended questions in an online survey.
When Europe was hit by the COVID-19 pandemic, changes were made in maternity care to reduce infections. In Norway, hospital maternity wards, postnatal wards, and neonatal units' companions and visitors were restricted. We aimed to explore the experiences of being pregnant, giving birth and becoming a parent in Norway during the COVID-19 pandemic. The study is based on the responses from women who provided in-depth qualitative accounts to the ongoing Babies Born Better survey version 3 during the first year of the COVID-19 pandemic. The responses were analysed with inductive thematic analysis. In all, 806 women were included, regardless of parity and mode of birth. They gave birth in 42 of 45 available birthing units across Norway. The analysis resulted in four themes: 1) Pregnancy as a stressful waiting period; 2) Feeling lonely, isolated, and disempowered without their partner; 3) Sharing experiences and becoming a family; and 4) Busy postnatal care without compassion. The COVID-19 pandemic seems to have affected women's experiences of giving birth and becoming a parent in Norway. The restrictions placed on companionship by the healthcare facilities varied between hospitals. However, the restrictions seem to have affected a range of aspects related to women's experiences of late pregnancy, early labour and birth and the early postpartum period. Postnatal care was already poor, and the pandemic has highlighted the shortcomings, especially where companionship was banned.


The anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells.
The administration of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the expected cancer therapeutics. However, improvements are required in therapies against TRAIL-resistant tumor cells. We report, here, that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in hormone-refractory prostate cancer (HRPC) cells through two different pathways. The combination of orlistat and TRAIL remarkably induced apoptosis in TRAIL-resistant HRPC, DU145 and PC3 cells. Orlistat induced the expression of death receptor (DR) 5, which is one of the TRAIL receptors, at both the mRNA and protein levels. The suppression of DR5 with siRNA reduced the apoptosis induced by the combination of orlistat and TRAIL, suggesting that the apoptosis was at least partially due to the upregulation of DR5. Although the upregulation by orlistat of CHOP at both mRNA and protein levels was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of CHOP and DR5 expression in both cell lines. These results suggest that there are two pathways of upregulation of DR5 by orlistat, which are the ROS-CHOP pathway and the ROS-direct pathway. In conclusion, orlistat promotes the sensitivity to TRAIL by ROS-mediated pathways in prostate cancer cells, especially in TRAIL-resistant cells. We believe that the combination of orlistat and TRAIL in HRPC is promising as a new chemotherapeutic strategy.


Multifractal feature descriptor for histopathology.
Histologic image analysis plays an important role in cancer diagnosis. It describes the structure of the body tissues and abnormal structure gives the suspicion of the cancer or some other diseases. Observing the structural changes of these chaotic textures from the human eye is challenging process. However, the challenge can be defeat by forming mathematical descriptor to represent the histologic texture and classify the structural changes via a sophisticated computational method. In this paper, we propose a texture descriptor to observe the histologic texture into highly discriminative feature space. Fractal dimension describes the self-similar structures in different and more accurate manner than topological dimension. Further, the fractal phenomenon has been extended to natural structures (images) as multifractal dimension. We exploited the multifractal analysis to represent the histologic texture, which derive more discriminative feature space for classification. We utilized a set of histologic images (belongs to liver and prostate specimens) to assess the discriminative power of the multifractal features. The experiment was organized to classify the given histologic texture as cancer and non-cancer. The results show the discrimination capability of multifractal features by achieving approximately 95% of correct classification rate. Multifractal features are more effective to describe the histologic texture. The proposed feature descriptor showed high classification rate for both liver and prostate data sample datasets.


Process and outcome evaluation of a community intervention for orphan adolescents in western Kenya.
We conducted a 2-year pilot randomized controlled trial (N = 105) in a high HIV-prevalence area in rural western Kenya to test whether providing young orphan adolescents with uniforms, school fees, and community visitors improves school retention and reduces HIV risk factors. The trial was a community intervention, limited to one community. In this paper, we examined intervention implementation and its association with outcomes using longitudinal data. We used both quantitative and qualitative methods to evaluate the community-based model for orphan HIV prevention, with recommendations for future studies. Despite promising effects after 1 year, GEE analyses showed null effects after 2 years. Volunteer community visitors, a key element of the intervention, showed little of the expected effect although qualitative reports documented active assistance to prevent orphans' school absence. For future research, we recommend capturing the transition to high school, a larger sample size, and biomarker data to add strength to the research design. We also recommend a school-based intervention approach to improve implementation and reduce infrastructure costs. Finally, we recommend evaluating nurses as agents for improving school attendance and preventing dropout because of their unique ability to address critical biopsychosocial problems.


Identification and resolution of artifacts in the interpretation of imprinted gene expression.
Genomic imprinting refers to genes that are epigenetically programmed in the germline to express exclusively or preferentially one allele in a parent-of-origin manner. Expression-based genome-wide screening for the identification of imprinted genes has failed to uncover a significant number of new imprinted genes, probably because of the high tissue- and developmental-stage specificity of imprinted gene expression. A very large number of technical and biological artifacts can also lead to the erroneous evidence of imprinted gene expression. In this article, we focus on three common sources of potential confounding effects: (i) random monoallelic expression in monoclonal cell populations, (ii) genetically determined monoallelic expression and (iii) contamination or infiltration of embryonic tissues with maternal material. This last situation specifically applies to genes that occur as maternally expressed in the placenta. Beside the use of reciprocal crosses that are instrumental to confirm the parental specificity of expression, we provide additional methods for the detection and elimination of these situations that can be misinterpreted as cases of imprinted expression.


Cloning and characterization of tomato leaf senescence-related cDNAs.
Senescence-related cDNA clones designated SENU1, 4, 5 (senescence up-regulated) and SEND32, 33, 34, 35 and 36 (senescence down-regulated) isolated from a tomato leaf cDNA library [9] were characterized. Southern analysis showed that SEND32 is encoded by a single-copy gene while SEND33, 34, 35, 36 and SENU1 and SENU5 are members of small gene families. DNA and protein database searches revealed that SEND32, SEND35, SENU1 and SENU5 are novel cDNAs of unknown function. SEND33 encodes ferredoxin, SEND34 encodes a photosystem II 10 kDa polypeptide and SEND36 encodes catalase. The SENU4 sequence is identical to the P6 tomato protein previously reported to be pathogenesis-related [46]. The mRNA levels of SENU1, 4 and 5 increased during leaf senescence and SENU1 and SENU5 were also expressed at high levels during leaf development and in other plant organs. The SENU4 mRNA was associated more specifically with leaf senescence, although low expression was also detected in green fruit. The mRNAs for all SEND clones decreased during tomato leaf development and senescence and all except SEND32 were expressed at low levels in other plant organs. The accumulation of mRNA homologous to SENU4 and the decrease in abundance of SEND32 provide good molecular markers for leaf senescence.


Seroprevalence and awareness of human papillomavirus infection and cervical cancer screening results among reproductive-aged Georgian women.
As is the case in many developing countries, more than half of the new cervical cancer cases in Georgia are late-stage diagnoses, thus reducing the opportunity for effective treatment. A state cancer screening programme was launched in Tbilisi in 2006; 5 years later the programme had expanded to other regions in Georgia. This study was designed to estimate awareness about human papillomavirus (HPV), cervical cancer screening, the HPV vaccine, and the seroprevalence of HPV infection among reproductive-aged Georgian women. Study participants were recruited from four women's consultation centres in different regions of Georgia. Data were collected through interviewer-administered questionnaires and HPV seroprevalence was assessed for HPV types 6/11/16/18. Of the 500 study participants, 52.0% were aware of HPV and 36.4% stated that the main cause of cervical cancer is HPV. Of those aware of HPV, 78% reported attending for cervical cancer screening at least once during their lifetime. Half (50.8%) of all respondents were unaware of the HPV vaccine. Of the women who agreed to be tested for anti-HPV antibodies (n=317), 21.1% were positive. Women reporting no condom use were more likely to have HPV antibodies (prevalence ratio 2.77; 95% confidence interval 1.79-4.27). Awareness of cervical cancer screening was significantly associated with HPV seropositivity. With multivariate analysis, both absence of condom use and lack of knowledge about cervical cancer screening were independently associated with HPV seropositivity. More comprehensive public awareness campaigns should be developed to raise awareness about HPV screening and prevention.