The effects of celeration lines on visual data analysis.
Previous visual analysis research reported that the overall agreement between visual analysis and statistical analysis was poor. In response, some researchers suggested the use of celeration lines to improve the accuracy and reliability of visual analysis. However, subsequent research reported little or no improvement in accuracy with such lines. The present study presented 5 board-certified behavior analysts with a series of behavioral graphs. The participants were asked to answer questions similar to those posed in previous studies but were also asked to talk aloud as they viewed each graph. Results indicate that the participants made accurate decisions for only 72% of the graphs and that celeration lines did not improve overall accuracy. The verbal protocol analysis suggests that participants were as likely to attend to trend when celeration lines were absent as they were when they were present, with the most differences attributable to varying participant competencies and not graph (i.e., celeration line) characteristics.


[Right ventricular myxoma simulating pulmonary valve stenosis. A case report].
A 17 year old girl was asymptomatic until 3 months ago, when she noticed palpitations and chest pain. Physical examination revealed a systolic murmur + + +/6 in the pulmonary area. Chest X-ray showed discrete dilatation of the pulmonary trunk and the electrocardiogram a first degree heart block. The diagnosis of myxoma was established after echocardiogram and cardiac catheterization when a mobile cardiac mass was identified in the right ventricular outflow tract. The tumor was removed using extracorporeal circulation and the ventricular access through the right atrium. After a 16 month follow-up the patient is dealing a normal life and there are no signs of recurrence.


1H and (13)C NMR spectroscopic analysis of human saliva.
We have explored the ability of high-resolution NMR techniques to (1) index salivary biomolecules and (2) provide valuable data regarding intra- and inter-subject variability in the concentrations of a series of components readily determinable by this technique (organic acids and malodorous amines). Experiments were conducted on 'whole' saliva samples collected from 20 patients, either randomly during their daily activities, or, for investigations involving the quantification of salivary biomolecules, immediately after they woke in the morning throughout a three-day period. These NMR techniques permitted us to detect greater than 60 metabolites, together with agents arising from dietary, oral health care product, and pharmaceutical sources. Highly significant "between-subject" differences in the a.m. waking salivary metabolite concentrations were found for 9 out of 11 components monitored. It is concluded that NMR spectroscopy serves as a powerful technique for the multicomponent analysis of human saliva.


Refining quality of life: validating a multidimensional factor measure in the severe mentally ill.
Quality of life measurement has historically been characterized by a focus on physical functionality, great variability in definitions and insufficient attention to psychometric properties of measures. The present study examined four core subscales of the Quality of Life Enjoyment Scale (Q-LES-Q) designed to assess subjective quality of life (i.e. physical health, subjective feelings, leisure activities and social relationships) administered to 151 male and female subjects with severe mental illness admitted to a residential community treatment center or a university psychiatric hospital. The use of factor analysis is a common approach to examining construct validity of instruments through the examination of correlated clusters of item responses. Those sets of highly correlated item responses should identify a construct or dimension of related items (i.e. a factor). Two factor approaches, exploratory (i.e. the maximum number of possible factor is unspecified) and restricted (i.e. the maximum number of factors allowed is specified), were employed to examine construct validity of the four Q-LES-Q subscales. In addition, both orthogonal (i.e. independence between factors is maximized) and oblique (i.e. correlated factors are allowed) rotations (arrangements) of factor structure were also investigated to define subscale validity further. Results supported good construct validity for each subscale with either factor approach, i.e. the four proposed subscales were clearly identifiable in the factors (groupings) of correlated item responses from the sample. In both cases, the orthogonal (independent) rotation produced the simplest structure, i.e. the clearest groupings of items. These results indicate that the Q-LES-Q does appear to measure valid dimensions matching those proposed by the subscales and, thus, may be a useful and reliable tool for clinical applications.


Membership and attendance patterns in Tavistock Clinic general practitioner seminars.
Patterns of recruitment and attendance (1951-79) of general practitioners at seminars at the Tavistock Clinic are analysed. Latterly about 40 general practitioners have attended each week; a turnover of about 15 join or leave each year; about 60 per cent stay at least two years and 40 per cent stay over three years. Half come from outside London. The ratio of men and women reflects the prevailing ratio in the profession. Most join five to 10 years after qualifying and younger general practitioners tend to leave early. At least seven per cent of recent members have left general practice; but the proportion involved in training, course organizing and the Royal College of General Practitioners is far above the average for all general practitioners.


Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies.
Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target. To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies. Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells. Results of testing for splice site mutation, haplotypes, and alternate transcripts. The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing. The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.


Pain Management for Ambulatory Arthroscopic Anterior Cruciate Ligament Reconstruction: Evidence-Based Recommendations From the Society for Ambulatory Anesthesia.
Ambulatory arthroscopic anterior cruciate ligament reconstruction is associated with moderate pain, even when nonopioid oral analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs are used. Regional analgesia can supplement nonopioid oral analgesics and reduce postoperative opioid requirements, but the choice of regional analgesia technique for anterior cruciate ligament reconstruction remains controversial. Femoral nerve block, adductor canal block, and local instillation analgesia have all been proposed and are supported by some evidence from randomized controlled trials. Consequently, regional analgesia practice in patients undergoing anterior cruciate ligament reconstruction remains mixed. Published systematic reviews were used to identify the regional analgesia modality that would provide a balance between analgesic efficacy and associated potential risks in the setting of nonopioid multimodal analgesic strategies. Based on the evidence available, local instillation analgesia provides the best balance of analgesic efficacy and associated risks (strong recommendation, moderate level of evidence) when used as a component of multimodal analgesic technique in the first 24 hours after outpatient arthroscopic anterior cruciate ligament reconstruction. In the absence of local instillation analgesia, clinicians might use adductor canal block or femoral nerve block (weak recommendation, weak level of evidence). These recommendations have been endorsed by the Society of Ambulatory Anesthesia and approved by its board of directors.


Nuclease-hypersensitive sites in the chromatin domain of the chicken lysozyme gene.
We have examined the chromatin structure of a 22 kilobase-pair chromosomal region containing the lysozyme gene in laying hen. Nuclease-hypersensitive sites were probed with DNAase I by using an indirect end-labeling technique. Eight DNAase I-hypersensitive sites could be mapped in the flanking regions of the gene in oviduct cells, in which the gene is expressed. The same sensitive sites were detected by utilization of an endogenous nuclease activity present in oviduct nuclei. Only one hypersensitive site was detected in the chromatin from erythrocytes, in which the gene is not expressed. The 3'-terminus of the lysozyme gene is highly exposed in nuclei from both tissues. Of special interest is the hypersensitive site at the 5'-terminus of the actively transcribed gene since it maps at the region of multiple initiation sites of transcription and the putative control regions of steroid hormones. DNAase I-hypersensitive chromatin structures also at a greater distance from the gene may take part in the control of gene expression.


Overexpression and Activation of αvβ3 Integrin Differentially Affects TGFβ2 Signaling in Human Trabecular Meshwork Cells.
Studies from our laboratory have suggested that activation of αvβ3 integrin-mediated signaling could contribute to the fibrotic-like changes observed in primary open angle glaucoma (POAG) and glucocorticoid-induced glaucoma. To determine how αvβ3 integrin signaling could be involved in this process, RNA-Seq analysis was used to analyze the transcriptomes of immortalized trabecular meshwork (TM) cell lines overexpressing either a control vector or a wild type (WT) or a constitutively active (CA) αvβ3 integrin. Compared to control cells, hierarchical clustering, PANTHER pathway and protein-protein interaction (PPI) analysis of cells overexpressing WT-αvβ3 integrin or CA-αvβ3 integrin resulted in a significant differential expression of genes encoding for transcription factors, adhesion and cytoskeleton proteins, extracellular matrix (ECM) proteins, cytokines and GTPases. Cells overexpressing a CA-αvβ3 integrin also demonstrated an enrichment for genes encoding proteins found in TGFβ2, Wnt and cadherin signaling pathways all of which have been implicated in POAG pathogenesis. These changes were not observed in cells overexpressing WT-αvβ3 integrin. Our results suggest that activation of αvβ3 integrin signaling in TM cells could have significant impacts on TM function and POAG pathogenesis.


Tsunami: scientific frontiers, mitigation, forecasting and policy implications.
Tsunamis are an ever-present threat to lives and property along the coasts of most of the world's oceans. As the Sumatra tsunami of 26 December 2004 reminded the world, we must be more proactive in developing ways to reduce their impact on our global society. This article provides an overview of the state of knowledge of tsunamis, presents some challenges confronting advances in the field and identifies some promising frontiers leading to a global warning system. This overview is then used to develop guidelines for advancing the science of forecasting, hazard mitigation programmes and the development of public policy to realize a global system. Much of the information on mitigation and forecasting draws upon the development and accomplishments of a joint state/federal partnership that was forged to reduce tsunami hazards along US coastlines-the National Tsunami Hazard Mitigation Programme. By integrating hazard assessment, warning guidance and mitigation activities, the programme has created a roadmap and a set of tools to make communities more resilient to local and distant tsunamis. Among the tools are forecasting, educational programmes, early warning systems and design guidance for tsunami-resilient communities. Information on international cooperation is drawn from the Global Earth Observing System of Systems (GEOSS). GEOSS provides an international framework to assure international compatibility and interoperability for rapid exchange of data and information.


Detection and quantification of beta2AR internalization in living cells using FAP-based biosensor technology.
Ligand-dependent receptor internalization is a feature of numerous signaling systems. In this article, the authors describe a new kind of live-cell biosensor of receptor internalization that takes advantage of fluorogen-activating protein (FAP) technology. Recombinant genes that express the human beta2 adrenergic receptor (beta2AR) with FAP domains at their extracellular N-termini were transduced into mammalian cells. Exposure of the cells to membrane-impermeant fluorogens led to a strong fluorescent signal from the cell surface. Agonist-dependent translocation of the receptor from the surface to the cell interior was readily observed and quantified by fluorescence microscopy or flow cytometry in a homogeneous format without wash or separation steps. The approach described here is generalizable to other receptors and cell surface proteins and is adaptable to a variety of fluorescence-based high-throughput screening platforms.


Cyanide concentrations in blood after amygdalin (laetrile) administration in rats.
Toxic amounts of cyanide are released into the blood of rats following the oral administration of amygdalin (laetrile); cyanide blood concentrations and toxicity are markedly less when amygdalin is given intravenously. Analysis of the time course of cyanogenesis suggests that cyanide could accumulate in blood after repeated oral doses of amygdalin.


Light responsive metal-organic frameworks as controllable CO-releasing cell culture substrates.
A new carbon monoxide (CO)-releasing material has been developed by embedding a manganese carbonyl complex, MnBr(bpydc)(CO)3 (bpydc = 5,5'-dicarboxylate-2,2'-bipyridine) into a highly robust Zr(iv)-based metal-organic framework (MOF). Efficient and controllable CO-release was achieved under exposure to low intensity visible light. Size-controllable nanocrystals of the photoactive MOF were obtained and their CO-releasing properties were correlated with their crystal sizes. The photoactive crystals were processed into cellular substrates with a biocompatible polymer matrix, and the light-induced delivery of CO and its subsequent cellular uptake were monitored using a fluorescent CO-probe. The results discussed here demonstrate a new opportunity to use MOFs as macromolecular scaffolds towards CO-releasing materials and the advantage of MOFs for high CO payloads, which is essential in future therapeutic applications.


Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium.
This study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice. Longitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers. Seventy-nine patients with 656 visits were observed for a median of 7.1 months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46 months (per follow-up month) at OM centers and 0.78 months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of ≥1 (P < 0.001, odds ratio: 5.1) and mouth pain (P = 0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P = 0.03). Oral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions.


Thin-film-based field penetration engineering for surface plasmon resonance biosensing.
Penetration depth defines the measurable range in evanescent-wave-based sensing techniques such as surface plasmon resonance (SPR). We investigate penetration depth variation implemented with dielectric layers in a SPR sensing structure. The results show that the penetration depth can be controlled to increase or decrease depending on a specific configuration. Effective medium theory was introduced to describe the field penetration in dielectric multilayer designs. Comparison was made with the field penetration of a localized SPR structure based on periodic nanowires. The penetration depth variation in response to environmental changes was also explored.


Immunogold demonstration of GABA in synaptic terminals of intracellularly recorded, horseradish peroxidase-filled basket cells and clutch cells in the cat's visual cortex.
To identify the putative transmitter of large basket and clutch cells in the cat's visual cortex, an antiserum raised against GABA coupled to bovine serum albumen by glutaraldehyde and a postembedding, electron microscopic immunogold procedure were used. Two basket and four clutch cells were revealed by intracellular injection of horseradish peroxidase. They were identified on the basis of the distribution of their processes and their synaptic connections. Large basket cells terminate mainly in layer III, while clutch cells which have a more restricted axon, terminate mainly in layer IV. Both types of neuron have a small radial projection. They establish type II synaptic contacts and about 20-30% of their synapses are made with the somata of other neurons, the rest with dendrites and dendritic spines. Altogether 112 identified, HRP-filled boutons, the dendrites of three clutch cells and myelinated axons of both basket and clutch cells were tested for the presence of GABA. They were all immunopositive. The postsynaptic neurons received synapses from numerous other GABA-positive boutons in addition to the horseradish peroxidase-filled ones. Dendritic spines that received a synapse from a GABA-positive basket or clutch cell bouton also received a type I synaptic contact from a GABA-negative bouton. A few of the postsynaptic dendrites, but none of the postsynaptic somata, were immunoreactive for GABA. The fine structural characteristics of the majority of postsynaptic targets suggested that they were pyramidal and spiny stellate cells. These results provide direct evidence for the presence of immunoreactive GABA in identified basket and clutch cells and strongly suggest that GABA is a neurotransmitter at their synapses. The laminar distribution of the synaptic terminals of basket and clutch cells demonstrates that some GABAergic neurons with similar target specificity segregate into different laminae, and that the same GABAergic cells can take part in both horizontal and radial interactions.


Dual-wavelength GaN-based LEDs grown on truncated hexagonal pyramids formed by selective-area regrowth on Si-implanted GaN templates.
GaN-based blue light-emitting diodes (LEDs) with micro truncated hexagonal pyramid (THP) array were grown on selective-area Si-implanted GaN (SIG) templates. The GaN epitaxial layer regrown on the SIG templates exhibited selective growth and subsequent lateral growth to form the THP array. The observed selective-area growth was attributed to the different crystal structures between the Si-implanted and implantation-free regions. Consequently, LEDs grown on the GaN THP array emitted broad electroluminescence spectra with multiple peaks. Spatially resolved cathodoluminescence revealed that the broad spectra originated from different areas within each THP. Transmission electron microscopy showed the GaN-based epitaxial layers, including InGaN/GaN multi-quantum wells regrown at different growth rates (or with different In content in the InGaN wells) between the semi-polar and c-face planes of each THP.


Intramuscular Nerves of the Inferior Rectus Muscle: Distribution and Characteristics.
Knowledge of the distribution of intramuscular nerves of the extraocular muscles is crucial for understanding their function. The purpose of this study was to elucidate the intramuscular distribution of the oculomotor nerve within the inferior rectus muscle (IRM) using Sihler's staining. Ninety-three IRM from 50 formalin-embalmed cadavers were investigated. The IRM including its branches of the oculomotor nerve was finely dissected from its origin to the point where it inserted into the sclera. The intramuscular nerve course was investigated after performing Sihler's whole-mount nerve staining technique that stains the nerves while rendering other soft tissues either translucent or transparent. The oculomotor nerve enters the IRM around the distal one-fourth of the muscle and then divides into multiple smaller branches. The intramuscular nerve course finishes around the distal three-fifth of the IRM in gross observations. The types of branching patterns of the IRM could be divided into two subcategories based on whether or not topographic segregation was present: (1) no significant compartmental segregation (55.9% of cases) and (2) a several-zone pattern with possible segregation (44.1% of cases). Possible compartmentalization was less clear for the IRM, which contained overlapping mixed branches between different trunks. Sihler's staining is a useful technique for visualizing the gross nerve distribution of the IRM. The new information about the nerve distribution and morphological features provided by this study will improve the understanding of the biomechanics of the IRM, and could be useful for strabismus surgery.


Endovascular balloon-assisted embolization of intracranial and cervical arteriovenous malformations using dual-lumen coaxial balloon microcatheters and Onyx: initial experience.
Ethylene vinyl alcohol copolymer (Onyx) is widely used for the embolization of arteriovenous malformations (AVMs) of the brain, head, and neck. Balloon-assisted Onyx embolization may provide additional unique advantages in the treatment of AVMs in comparison with traditional catheter-based techniques. To report our initial experience in performing balloon-assisted AVM embolization for brain and neck AVMs with the use of the new Scepter-C and Scepter-XC coaxial dual-lumen balloon microcatheters. Balloon-assisted transarterial embolization was performed in a series of 7 patients with AVMs (4 with brain AVMs, 1 with a dural arteriovenous fistula, and 2 with neck AVMs) by using Onyx delivered through the lumen of Scepter-C or Scepter XC coaxial balloon microcatheters. Following the initial balloon-catheter navigation into a feeding artery and the subsequent inflation of the balloon, the embolization was performed by using Onyx 18, Onyx 34, or both. A total of 12 embolization sessions were performed via 17 arterial feeders in these 7 patients. In 1 patient, there was an arterial perforation from the inflation of the balloon; in all others, the embolization goals were successfully achieved with no adverse events. The balloon microcatheters showed excellent navigability, and there were no problems with retrieval or with the repeated inflation and deflation of the balloons. A proximal Onyx plug, which is crucial in many AVM embolizations, was not necessary with this technique. Additionally, fluoroscopy and procedural times seemed lower with this technique compared with conventional embolization methods.


The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis.
Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/LAMTOR (lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin [mTOR] activator/regulator) complex, thereby contributing to the signal transduction of the extracellular signaling-regulated kinase (ERK) and the mTOR cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Because p14 participates in the regulation of endosomal trafficking, growth factor signaling, and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knockout mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo.


Trait variations of ground flora species disentangle the effects of global change and altered land-use in Swedish forests during 20 years.
Northern forest ecosystems are exposed to a range of anthropogenic processes including global warming, atmospheric deposition, and changing land-use. The vegetation of northern forests is composed of species with several functional traits related to these processes, whose effects may be difficult to disentangle. Here, we combined analyses of spatio-temporal dynamics and functional traits of ground flora species, including morphological characteristics, responses to macro- and microclimate, soil conditions, and disturbance. Based on data from the Swedish National Forest Inventory, we compared changes in occurrence of a large number of ground flora species during a 20-year period (1994-2013) in boreal and temperate Sweden respectively. Our results show that a majority of the common ground flora species have changed their overall frequency. Comparisons of functional traits between increasing and declining species, and of trends in mean trait values of sample plots, indicate that current floristic changes are caused by combined effects of climate warming, nitrogen deposition and changing land-use. Changes and their relations with plant traits were generally larger in temperate southern Sweden. Nutrient-demanding species with mesotrophic morphology were favored by ongoing eutrophication due to nitrogen deposition in the temperate zone, while dwarf shrubs with low demands on nitrogen decreased in frequency. An increase of species with less northern and less eastern distribution limits was also restricted to temperate Sweden, and indicates effects of a moister and milder macroclimate. A trend toward dense plantation forests is mirrored by a decrease of light-demanding species in both vegetation zones, and a decrease of grassland species in the temperate zone. Although denser tree canopies may buffer effects of a warmer climate and of nitrogen deposition to some extent, traits related to these processes were weakly correlated in the group of species with changing frequency. Hence, our results indicate specific effects of these often confounded anthropogenic processes.


A general framework for analyzing the genetic architecture of developmental characteristics.
The genetic architecture of growth traits plays a central role in shaping the growth, development, and evolution of organisms. While a limited number of models have been devised to estimate genetic effects on complex phenotypes, no model has been available to examine how gene actions and interactions alter the ontogenetic development of an organism and transform the altered ontogeny into descendants. In this article, we present a novel statistical model for mapping quantitative trait loci (QTL) determining the developmental process of complex traits. Our model is constructed within the traditional maximum-likelihood framework implemented with the EM algorithm. We employ biologically meaningful growth curve equations to model time-specific expected genetic values and the AR(1) model to structure the residual variance-covariance matrix among different time points. Because of a reduced number of parameters being estimated and the incorporation of biological principles, the new model displays increased statistical power to detect QTL exerting an effect on the shape of ontogenetic growth and development. The model allows for the tests of a number of biological hypotheses regarding the role of epistasis in determining biological growth, form, and shape and for the resolution of developmental problems at the interface with evolution. Using our newly developed model, we have successfully detected significant additive x additive epistatic effects on stem height growth trajectories in a forest tree.


Sequencing and functional annotation of the Bacillus subtilis genes in the 200 kb rrnB-dnaB region.
The 200 kb region of the Bacillus subtilis chromosome spanning from 255 to 275 degrees on the genetic map was sequenced. The strategy applied, based on use of yeast artificial chromosomes and multiplex Long Accurate PCR, proved to be very efficient for sequencing a large bacterial chromosome area. A total of 193 genes of this part of the chromosome was classified by level of knowledge and biological category of their functions. Five levels of gene function understanding are defined. These are: (i) experimental evidence is available of gene product or biological function; (ii) strong homology exists for the putative gene product with proteins from other organisms; (iii) some indication of the function can be derived from homologies with known proteins; (iv) the gene product can be clustered with hypothetical proteins; (v) no indication on the gene function exists. The percentage of detected genes in each category was: 20, 28, 20, 15 and 17, respectively. In the sequenced region, a high percentage of genes are implicated in transport and metabolic linking of glycolysis and the citric acid cycle. A functional connection of several genes from this region and the genes close to 140 degrees in the chromosome was also observed.


Traumatic brain injury alters long-term hippocampal neuron morphology in juvenile, but not immature, rats.
Pediatric traumatic brain injury (TBI) represents a prominent yet understudied medical condition that can profoundly impact brain development. As the juvenile injured brain matures in the wake of neuropathological cascades during potentially critical periods, circuit alterations may explain neurological consequences, including cognitive deficits. We hypothesize that experimental brain injury in juvenile rats, with behavioral deficits that resolve, will lead to quantifiable structural changes in hippocampal neurons at chronic time points post-injury. Controlled cortical impact (CCI), a model of focal TBI with contusion, was used to induce brain injury on post-natal day (PND) 17 juvenile rats. The histological consequence of TBI was quantified in regions of the hippocampus at post-injury day 28 (PID28) on sections stained using a variation of the Golgi-Cox staining method. Individual neuronal morphologies were digitized from the dentate gyrus (DG), CA3, and CA1 regions. Soma area in the ipsilateral injured DG and CA3 regions of the hippocampus increased significantly at PID28 in comparison to controls. In CA1, dendritic length and dendritic branching decreased significantly in comparison to controls and the contralateral hemisphere, without change in soma area. To extend the study, we examined neuronal morphology in rats with CCI at PND7. On PID28 after CCI on PND7 rats, CA1 neurons showed no injury-induced change in morphology, potentially indicating an age-dependent morphological response to injury. Long-lasting structural alterations in hippocampal neurons of brain-injured PND17 juvenile animals, but not PND7 immature animals, suggest differential plasticity depending on age-at-injury, with potential consequences for later function.


An integrated framework reinstating the environmental dimension for GWAS and genomic selection in crops.
Identifying mechanisms and pathways involved in gene-environment interplay and phenotypic plasticity is a long-standing challenge. It is highly desirable to establish an integrated framework with an environmental dimension for complex trait dissection and prediction. A critical step is to identify an environmental index that is both biologically relevant and estimable for new environments. With extensive field-observed complex traits, environmental profiles, and genome-wide single nucleotide polymorphisms for three major crops (maize, wheat, and oat), we demonstrated that identifying such an environmental index (i.e., a combination of environmental parameter and growth window) enables genome-wide association studies and genomic selection of complex traits to be conducted with an explicit environmental dimension. Interestingly, genes identified for two reaction-norm parameters (i.e., intercept and slope) derived from flowering time values along the environmental index were less colocalized for a diverse maize panel than for wheat and oat breeding panels, agreeing with the different diversity levels and genetic constitutions of the panels. In addition, we showcased the usefulness of this framework for systematically forecasting the performance of diverse germplasm panels in new environments. This general framework and the companion CERIS-JGRA analytical package should facilitate biologically informed dissection of complex traits, enhanced performance prediction in breeding for future climates, and coordinated efforts to enrich our understanding of mechanisms underlying phenotypic variation.


Molecularly imprinted solid-phase extraction for selective trace analysis of trifluoperazine.
In this study, a novel sample clean-up technique based on the molecularly imprinted solid-phase extraction procedure is described for the determination of trifluoperazine (TFP) in biological fluids. The water-compatible molecularly imprinted polymers (MIPs) were prepared by using methacrylic acid as functional monomer, ethylene glycol dimethacrylate as cross-linker, chloroform as porogen and TFP as the template molecule. The novel imprinted polymer was used as a solid-phase extraction sorbent for the extraction of TFP from human serum and urine samples. Various parameters affecting the extraction efficiency of the polymer were evaluated. The selectivity of MIPs was evaluated by checking several substances with molecular structures similar to the template. The limits of detection and quantification for TFP in urine samples were 0.06 and 0.2 µg/L, respectively. These limits for TFP in serum samples were 0.15 and 0.4 µg/L, respectively. The recovery values for serum and urine samples were higher than 92 and 93%, respectively.


Characterization by means of Delaunay triangulation and Voronoi paving of the influence of anti-hormone and/or anti-growth factor antibodies on the in vitro cell growth of human colorectal neoplastic cell lines.
A new tool is described which makes it possible to evaluate directly the influence of various growth factors on in vitro neoplastic cell growth on the one hand and to look at a concept of differentiation in terms of population dynamics, on the other. This tool relies upon the digital cell image analyses of Feulgen-stained nuclei and the mathematical method of Voronoi paving. This technique enabled us to characterize the influence on the proliferation and the differentiation of the HCT-15 and LoVo colorectal cell lines of anti-gastrin (G), anti-estradiol (E(2)), anti-epidermal growth factor (EGF), anti-luteinizing hormone-releasing hormone (LHRH), and anti-transforming growth factor alpha (TGF alpha) and beta (TGF beta) antibodies. Two variants were set up with respect to each of the two cell lines, i.e, one growing in culture medium supplemented with 5% fetal calf serum (FCS) and another supplemented with 1% FCS+10 nM G+10 nM E(2). The data show that it is possible to characterize the cell clone structure and to assess growth rate concomitantly by direct cell counts. It further appears that while the anti-hormone and/or anti-growth factor antibody-induced effects on growth were relatively similar, these effects were in sharp contrast at the level of cell clone architecture.


Adenovirus-based vaccines: comparison of vectors from three species of adenoviridae.
In order to better understand the broad applicability of adenovirus (Ad) as a vector for human vaccine studies, we compared four adenovirus (Ad) vectors from families C (Ad human serotype 5 [HAdV-5; here referred to as AdHu5]), D (HAdV-26; here referred to as AdHu26), and E (simian serotypes SAdV-23 and SAdV-24; here referred to as chimpanzee serotypes 6 and 7 [AdC6 and AdC7, respectively]) of the Adenoviridae. Seroprevalence rates and titers of neutralizing antibodies to the two human-origin Ads were found to be higher than those reported previously, especially in countries of sub-Saharan Africa. Conversely, prevalence rates and titers to AdC6 and AdC7 were markedly lower. Healthy human adults from the United States had readily detectable circulating T cells recognizing Ad viruses, the levels of which in some individuals were unexpectedly high in response to AdHu26. The magnitude of T-cell responses to AdHu5 correlated with those to AdHu26, suggesting T-cell recognition of conserved epitopes. In mice, all of the different Ad vectors induced CD8(+) T-cell responses that were comparable in their magnitudes and cytokine production profiles. Prime-boost regimens comparing different combinations of Ad vectors failed to indicate that the sequential use of Ad vectors from distinct families resulted in higher immune responses than the use of serologically distinct Ad vectors from the same family. Moreover, the transgene product-specific antibody responses induced by the AdHu26 and AdC vectors were markedly lower than those induced by the AdHu5 vector. AdHu26 vectors and, to a lesser extent, AdC vectors induced more potent Ad-neutralizing antibody responses. These results suggest that the potential of AdHu26 as a vaccine vector may suffer from limitations similar to those found for vectors based on other prevalent human Ads.


[Disaster psychiatry in late life].
Disaster preparedness in geriatric psychiatry was proposed on the basis of experience of the Great East Japan Earthquake. 1) Frail or demented elderly should be considered as a special population at risk for disaster victims and addressed in local disaster prevention programs. 2) To response to various psychiatric symptoms(delirium, BPSD, depression, anxiety, insomnia, and posttraumatic stress disorder) caused by medical conditions and rapid environmental changes due to disaster, linkage and coordination systems between psychiatric and medical sections should be established. 3) As a medium- and long-term support for the elderly who lost the community familiar to them, creation of a new community should be promoted in order to prevent depression, alcohol dependence, BPSD, and suicide.


Fluid therapy in children.
Fluid therapy in children is based on biochemical and physiologic principles qualitatively and quantitiatively different from adults. The limitations imposed by body size requires greater precision in calculating fluid therapy for children. General methods of computing maintenance and deficit pediatric fluid therapy, and specific fluid therapy involved in treating acute problems associated with genitourinary disorders with be discussed.


Male breast cancer: 22 case reports at the National Hospital of Niamey-Niger (West Africa).
Male breast cancer (MBC) is rare. The objective of the study is to report clinicopathological characteristics, treatment patterns, and outcomes of MBC. This study, which includes two parts (retrospective and prospective), focused on all hospitalized male patients with breast cancer during 17 years (1992-2008) with histological confirmation. The series included 22 patients. The mean age was 52.8 years (range: 28-80 years). MBC represented 5.7% of all breast cancers. Most patients had an advanced disease with skin ulceration and inflammation T3 (31.9%) and T4 (59.1%). The majority of patients came from rural areas (63.6%). The duration of signs ranged from 1 to 7 years. Histology found infiltrating ductal carcinoma in 14 cases (63.6%), sarcoma in 3 cases (13.6%), papillary carcinoma in 2 cases (9%), and lobular carcinoma, medullar carcinoma, and mucinous carcinoma in 4.6% each of the others cases. The treatment had consisted of a radical mastectomy (Halsted or Patey) in 19 cases (86.4%) with axillary clearance and incomplete resection in 3 cases (13.6%). In the retrospective study follow-up of 14 patients, we lost sight of 13 patients 6 months after surgery. In the prospective study of 8 patients 10 to 36 months after mastectomy, 4 patients were deceased (50%), 4 were alive with 1 case having a local recurrence and pulmonary metastasis. The advanced clinical forms of MBC are most frequent with skin ulceration and nodal enlargement. The absence of radiotherapy and the low access of chemotherapy limited the treatment to radical mastectomy (Halsted) in the majority of cases.


Myomesin and M-protein: expression of two M-band proteins in pectoral muscle and heart during development.
The expression of the myofibrillar M-band proteins myomesin and M-protein was studied in chicken pectoral muscle and heart during differentiation using monoclonal antibodies in a double-antibody sandwich enzyme-linked immunosorbent assay, immunoblotting, and immunocytochemistry. In presumptive pectoral muscle, myomesin accumulated first, increasing from 2% of the adult concentration at day 7 to 70% by day 16 in ovo. M-protein accumulation lagged 6-7 d behind that of myomesin attaining only 40% of the adult concentration in ovo. The molecular masses of myomesin (185 kD) and M-protein (165 kD) remained constant during embryogenesis. In cultured myogenic cells the accumulation and M-band localization of myomesin preceded that of M-protein by 1.5 d. Chicken heart was shown, in addition to M-protein, to contain unique isoforms of myomesin. In hearts of 6 d embryos, a 195-kD myomesin isoform was the major species; throughout development, however, a transition to a mixture of 195 and 190 kD was observed, the latter being the major species in the adult tissue. During heart differentiation the initial accumulation of myomesin again preceded that of M-protein, albeit on an earlier time scale than in pectoral muscle with M-protein reaching adult proportions first.


The effects of perioperative fluorouracil administration on convalescence and wound healing.
Administration of chemotherapy is delayed by most clinicians until complete recovery from surgery because it is generally feared that cytotoxic drugs impair wound healing, reduce resistance against infection, and may hinder the recovery process. However, clinical experience is lacking. This clinical study examines the effect of perioperative administration of fluorouracil on the healing of wounds and intestinal anastomoses and the recovery process in general. Forty patients with advanced gastrointestinal tract cancers entered the study. Intravenous bolus administration of 0.5 g of fluorouracil was started during surgery. The patients underwent a variety of abdominal operations for palliation or cure. A total of 22 gastric and enteric anastomoses were performed. One half gram of fluorouracil diluted in 150 mL of 5% glucose solution was given intravenously over one hour daily for ten days postoperatively. The patients were carefully evaluated for any alteration in the postoperative recovery. Thirty-eight of the 40 patients received the full course of fluorouracil. Twenty-one patients had an uneventful postoperative course. Eighteen had mild to moderate respiratory and cardiovascular complications unrelated to fluorouracil administration. One patient died of pulmonary emboli 16 days after abdominoperineal resection. Surgical wounds healed without complications in 37 patients. One case of wound disruption occurred after sigmoidectomy. Two patients developed wound infections that healed secondarily. All 22 patients with anastomoses recovered without any evidence of leakage. Colostomies and gastrostomies functioned as anticipated. Side effects attributed to fluorouracil appeared in seven of the patients; in only two of the patients were complications life-threatening, involving bone marrow depression. All patients recovered after discontinuation of fluorouracil therapy and with supportive treatment. On the whole, the course of recovery of this group was no different than expected from patients with advanced malignant neoplasms who were undergoing extensive surgery. Based on this study, it seems that fluorouracil administration during and immediately after surgery has no deleterious effect on wound healing and recovery.


Fabrication of thermally conductive and electrically insulating polymer composites with isotropic thermal conductivity by constructing a three-dimensional interconnected network.
Efficient heat removal via thermal management materials has become one of the most critical challenges in the development of modern microelectronic devices. However, the conventional polymer-based thermally conductive composites with randomly distributed filler particles usually yield an undesired value because of the lack of efficient heat transfer pathways. Therefore, constructing a three-dimensional interconnected filler structure is greatly desirable for realizing high thermal conductivity enhancement in composites. Herein, graphene oxide (GO) was used as a thermally conductive filler due to its excellent thermal conductivity and coated with polydopamine (PDA) to enhance its electric insulation performance. A unique "particle-constructing" method was adopted for fabricating highly ordered three-dimensional GO-based polymer composites, throughout which the GO-PDA formed an intact, uniform and well-defined network structure. The composite, even with a very low GO-PDA loading of 0.96 vol%, exhibited both high in-plane (4.13 W m-1 K-1) and through-plane (4.56 W m-1 K-1) thermal conductivities and also presented excellent electrically insulating properties (>1014Ω cm). These composites have promising applications in heat dissipation of next-generation portable and collapsible electronic devices.


Percentile ranking and citation impact of a large cohort of National Heart, Lung, and Blood Institute-funded cardiovascular R01 grants.
Funding decisions for cardiovascular R01 grant applications at the National Heart, Lung, and Blood Institute (NHLBI) largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science. Our aim was to conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants. We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008 and followed their progress for linked publications and citations to those publications. Our coprimary end points were citations received per million dollars of funding, citations obtained <2 years of publication, and 2-year citations for each grant's maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total National Institutes of Health awards, the portfolio yielded 16 793 publications that appeared between 2001 and 2012 (median per grant, 8; 25th and 75th percentiles, 4 and 14; range, 0-123), which received 2 224 255 citations (median per grant, 1048; 25th and 75th percentiles, 492 and 1932; range, 0-16 295). We found no association between percentile rankings and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus nonhuman focus, and institutional funding. An exploratory machine learning analysis suggested that grants with the best percentile rankings did yield more maximally cited papers. In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics.


Ethical issues in infant feeding after disasters.
In the aftermath of many disasters the silence is punctuated by the crying of infants, hungry infants. The aim of this paper is to discuss ethical issues in feeding infants after disasters. The Asia Pacific region generates 25% of the world's GDP, but experiences 45% of natural disasters and 42% of the economic losses due to disasters. The region has 61% of the world's population, but 86% of the population affected by disasters. Breastfeeding, exclusive to six months and continuing thereafter, is important for growth and the health of the infant in the short term and later in life. In most natural disasters, mothers and infants will both suffer, but in some disasters, such as earthquakes and building collapses, infants can survive in small spaces. Infants separated from mothers require a wet nurse (rarely available) or feeding with infant formula and sterile water. Formula companies often donate supplies of infant formula but distribution should follow ethical principles. Mothers who are injured or short of food can still continue breastfeeding and don't need formula. Where formula must be used, health workers need to follow the highest ethical standards to avoid promoting infant formula to vulnerable communities in the post recovery phase.


Inactivation of muscle insulin and IGF-I receptors and insulin responsiveness.
This review will outline the recent advances in the area of insulin-stimulated skeletal muscle glucose uptake and its effect on whole body glucose homeostasis, using gene-deletion and transgenic mouse models. Insulin resistance is often the first abnormality detected in cases of type 2 diabetes, and is seen at the level of the peripheral tissues especially muscle. Both the insulin receptor and the insulin-like growth factor I receptor are capable of stimulating glucose uptake into skeletal muscle. One model involves the gene deletion of muscle glucose transport protein 4, which leads to severe insulin resistance and hyperglycemia, and a second model using a transgenic approach abrogates the function of the insulin-like growth factor I receptor and the insulin receptor resulting in severe insulin resistance and progression to diabetes. Both models demonstrate that abrogation of the insulin-like growth factor I receptor and the insulin receptor or a common signalling pathway must be inhibited to cause sufficient insulin resistance to lead to type 2 diabetes; with either glucotoxicity or lipotoxicity being involved in the progression from severe to resistance to full-blown type 2 diabetes. Thus, abrogation of insulin-stimulated glucose uptake in skeletal muscle, at least in mice, may lead to severe insulin resistance and diabetes.


Bacterial cell wall compounds as promising targets of antimicrobial agents I. Antimicrobial peptides and lipopolyamines.
The first barrier that an antimicrobial agent must overcome when interacting with its target is the microbial cell wall. In the case of Gram-negative bacteria, additional to the cytoplasmic membrane and the peptidoglycan layer, an outer membrane (OM) is the outermost barrier. The OM has an asymmetric distribution of the lipids with phospholipids and lipopolysaccharide (LPS) located in the inner and outer leaflets, respectively. In contrast, Gram-positive bacteria lack OM and possess a much thicker peptidoglycan layer compared to their Gram-negative counterparts. An additional class of amphiphiles exists in Gram-positives, the lipoteichoic acids (LTA), which may represent important structural components. These long molecules cross-bridge the entire cell envelope with their lipid component inserting into the outer leaflet of the cytoplasmic membrane and the teichoic acid portion penetrating into the peptidoglycan layer. Furthermore, both classes of bacteria have other important amphiphiles, such as lipoproteins, whose importance has become evident only recently. It is not known yet whether any of these amphiphilic components are able to stimulate the immune system under physiological conditions as constituents of intact bacteria. However, all of them have a very high pro-inflammatory activity when released from the cell. Such a release may take place through the interaction with the immune system, or with antibiotics (particularly with those targeting cell wall components), or simply by the bacterial division. Therefore, a given antimicrobial agent must ideally have a double character, namely, it must overcome the bacterial cell wall barrier, without inducing the liberation of the pro-inflammatory amphiphiles. Here, new data are presented which describe the development and use of membrane-active antimicrobial agents, in particular antimicrobial peptides (AMPs) and lipopolyamines. In this way, essential progress was achieved, in particular with respect to the inhibition of deleterious consequences of bacterial infections such as severe sepsis and septic shock.


Automated chest X-ray reading for tuberculosis in the Philippines to improve case detection: a cohort study.
BACKGROUND: DetecTB (Diagnostic Enhanced Tools for Extra Cases of TB), an intensified tuberculosis (TB) case-finding programme targeting prisons and high-risk communities was implemented on Palawan Island, the Philippines.OBJECTIVE: To evaluate the performance of TB detection based on computerised chest radiography (CXR) readings.DESIGN: Data from 14 094 subjects were analysed from September 2012 to June 2014. All CXRs were read by a physician and by software. Individuals with TB symptoms or CXR abnormalities according to the physician underwent Xpert® MTB/RIF testing, the remaining persons were considered TB-negative (screening reference). A subset of 200 CXRs was read by an independent human reader (radiological reference). This reader also re-read a subset of the most abnormal cases as identified using the software but read as normal by the physician (discordant cases).RESULTS: A total of 10 755 individuals were included in the analysis, 2534 of whom had a positively assessed CXR; 298 cases were Xpert-positive. Using the screening reference, the area under the receiver operating characteristic curve for software readings was 0.93 (95%CI 0.92-0.94), with a sensitivity of 0.98 (95%CI 0.97-0.99) and a specificity of 0.69 (95%CI 0.40-0.98). Based on the radiological reference, the physician performed slightly worse than the software (sensitivity, 0.82, 95%CI 0.74-0.89 and specificity, 0.87, 95%CI 0.81-0.96 vs. sensitivity, 0.83, 95%CI 0.71-0.93 and specificity, 0.87, 95%CI 0.75-0.95), although this was not statistically significant. Of the 291 discordant cases, 70% were assessed as positive, resulting in a 22% increase in TB detection when extrapolated to the full cohort.CONCLUSION: The performance of automated CXR reading is comparable to that of the attending physicians in DetecTB, and its use as a second reader could increase TB detection.


Mechanism of tachyphylaxis associated with neurogenic plasma extravasation in the rat trachea.
Electrical stimulation of the vagus nerve of rats is known to produce plasma extravasation in the trachea, presumably by releasing substance P or other tachykinins from sensory nerves. We sought to determine whether the tachyphylaxis that develops after prolonged vagal stimulation results from an inability of sensory nerves to release tachykinins or from an inability of tracheal blood vessels to respond to tachykinins. To induce tachyphylaxis, we electrically stimulated the right vagus nerve of Long-Evans rats for 5 min (5 V, 1 ms, 20 Hz). Then, 10 min later, we gave intravenous injections of capsaicin (0.3 mumol/kg), histamine (18 mumols/kg), or substance P (2.2 nmol/kg), which produce equivalent amounts of plasma extravasation as assessed by the extravasation of Evans blue dye. We found that vagal stimulation reduced the amount of dye extravasation produced by capsaicin but not the amount produced by either histamine or substance P. We also found that pretreating neonatal rats with capsaicin, which destroys tachykinin-containing sensory nerves, reduced the amount of dye extravasation produced by capsaicin but not the amount produced by either histamine or substance P. This finding suggests that capsaicin produces plasma extravasation in the trachea by releasing tachykinins from sensory nerves, whereas histamine and substance P do so by acting directly on tracheal blood vessels. Taken together, our results indicate that prolonged vagal stimulation reduces the ability of sensory nerves to release tachykinins but that tracheal blood vessels remain fully responsive to both histamine and substance P.


Characterization of drug resistance associated genetic polymorphisms among Plasmodium falciparum field isolates in Ujjain, Madhya Pradesh, India.
Since 2011, artesunate + sulphadoxine-pyrimethamine (ASP), instead of chloroquine, has been recommended for treatment of uncomplicated malaria in India. In Ujjain, central India, with an annual parasite index <0.1, the prevalence of drug-resistant Plasmodium falciparum is unknown. In other parts of India chloroquine and sulphadoxine-pyrimethamine-resistant P. falciparum is prevalent. The aim of this study was to determine the prevalence of anti-malarial drug resistance-associated genetic polymorphisms in P. falciparum collected in Ujjain in 2009 and 2010, prior to the introduction of ASP. Blood samples from 87 patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons Pfcrt 72-76, pfmdr1 1034-1246, pfdhfr 16-185, pfdhps 436-632 and pfnhe1 ms4760 haplotypes were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism, and pfmdr1 gene copy number by real-time PCR. Sulphadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 75/78 (96%) and 70/78 (90%) samples, respectively, and pfdhps 437G was found in 7/77 (9%) samples. Double mutant pfdhfr 59R + 108 N were found in 62/76 (82%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/76 (8%) samples. Chloroquine-resistance-associated pfcrt 76 T was found in 82/87 (94%). The pfcrt 72-76 haplotypes found were: 80/84 (95%) SVMNT, 3/84 (4%) CVMNK and 1/84 (1%) CVMNT. Pfmdr1 N86 and 86Y were identified in 70/83 (84%) and 13/83 (16%) samples, respectively. Pfmdr1 S1034 + N1042 + D1246 were identified together in 70/72 (97%) of successfully sequenced samples. One pfmdr1 gene copy was found in 74/75 (99%) successfully amplified samples. This is the first characterization of key anti-malarial drug resistance-associated genetic markers among P. falciparum collected in Ujjain, Madhya Pradesh, India. The results indicate that the efficacy of standard dose chloroquine at the time of the study was likely to be poor, whereas ASP was likely to be efficacious, supporting the changed drug treatment policy. However, P. falciparum with reduced susceptibility to sulphadoxine-pyrimethamine is highly prevalent, highlighting the need for continuous surveillance of ASP efficacy in the study area.


The nature of high frequency sister chromatid exchange cells (HFCs).
We employed the three-way differential staining technique (TWD), which allows SCEs to be distinguished on a per generation basis by scoring third metaphases (M3), in order to study the spontaneous levels of SCEs in normal and high frequency cells (HFCs) that occurred in the first (S1), second (S2) and third (S3) S phases. Fifty one of 900 lymphocytes from 37 healthy donors were defined as HFCs by calculating the 95th percentile of the distribution of SCEs in S1 + S2. 'Normal' cells presented almost the same number of SCEs after the first, second and third cell cycles (SCE averages of 2.43, 2.04 and 3.53 respectively). In contrast, HFCs showed a higher SCE count in S1, which decreased rapidly through the cycles and reached baseline level at S3 (SCE averages of 7.18, 4.29 and 3.45 respectively). This would suggest that the lesions responsible for the higher SCE frequency in HFCs were effectively removed after two cell cycles and strongly support the hypothesis that HFCs are lymphocytes which accumulate higher levels of DNA lesions through time.


A new seasonal-deciduous spring phenology submodel in the Community Land Model 4.5: impacts on carbon and water cycling under future climate scenarios.
A spring phenology model that combines photoperiod with accumulated heating and chilling to predict spring leaf-out dates is optimized using PhenoCam observations and coupled into the Community Land Model (CLM) 4.5. In head-to-head comparison (using satellite data from 2003 to 2013 for validation) for model grid cells over the Northern Hemisphere deciduous broadleaf forests (5.5 million km2 ), we found that the revised model substantially outperformed the standard CLM seasonal-deciduous spring phenology submodel at both coarse (0.9 × 1.25°) and fine (1 km) scales. The revised model also does a better job of representing recent (decadal) phenological trends observed globally by MODIS, as well as long-term trends (1950-2014) in the PEP725 European phenology dataset. Moreover, forward model runs suggested a stronger advancement (up to 11 days) of spring leaf-out by the end of the 21st century for the revised model. Trends toward earlier advancement are predicted for deciduous forests across the whole Northern Hemisphere boreal and temperate deciduous forest region for the revised model, whereas the standard model predicts earlier leaf-out in colder regions, but later leaf-out in warmer regions, and no trend globally. The earlier spring leaf-out predicted by the revised model resulted in enhanced gross primary production (up to 0.6 Pg C yr-1 ) and evapotranspiration (up to 24 mm yr-1 ) when results were integrated across the study region. These results suggest that the standard seasonal-deciduous submodel in CLM should be reconsidered, otherwise substantial errors in predictions of key land-atmosphere interactions and feedbacks may result.


[Problems of oculomotor and binocular pathology].
The paper discusses the problems of abnormalities of the oculomotor apparatus and binocular vision, considers the topical aspects of the pathogenesis and treatment of amblyopia, gives data on the new methods of recording the binocular movements of the eye, and provides evidence for the tactics and stage sequence of surgical treatment for concomitant oculomotor disturbances.


[Ginger-separated Snake Moxibustion Improves Yang Deficiency Constitution by Up-regulating Serum Adrenocorticotropic Hormone and Cortisol Levels in Yang Deficiency Constitution Volunteers].
Yang deficiency constitution may bring with different types of illnesses in many people. The present study was designed to observe the effect of ginger-separated snake moxibustion on yang deficiency symptom, and serum adrenocorticotropic hormone (ACTH) and cortisol (CORT) contents in yang deficiency constitution subjects, so as to explore its mechanism underlying improvement of yang deficiency constitution. Ninety subjects with yang deficiency type constitution were equally and randomly assigned to control A group (19 men and 26 women, 18-60 years in age) and moxibustion group (16 men and 29 women, 18-60 years in age) and 45 normal subjects with mild constitution (18 men and 27 women, 18-60 years in age) were assigned to control B group. An snake-like moxa-cone was placed at a moxa-holder covering the middle back of human body from Dazhui (GV 14) to Yaoshu (GV 2) after paving a layer (about 1 cm thick) of fresh ginger in the holder, and then ignited, followed by the next moxa-cone, 3 cones altogether every time for each participant. The treatment was conducted once a week, 12 times in total. The subjects' constitution was scored according to the "Classification and Evaluation of Constitution of Traditional Chinese Medicine" formulated by China Association of Chinese Medicine. The serum ACTH and CORT contents were measured by radioimmunoassay before and at the end of the treatment and 6 months after the treatment. The constitation scores of the moxibustion group and control A group were significantly higher than that of the control B group before treatment (P<0.01). At the end of the treatment, the constitution score was significantly decreased in the moxibustion group (P<0.01) rather than in the control A group relevant to its own pre-treatment (P>0.05). The serum CORT and ACTH contents were significantly decreased in both the moxibustion and control A groups in comparison to the control B group before treatment (P<0.01), and obviously increased at the end of treatment in the moxibustion group compared with its own pre-treatment (P<0.01). No significant differences were found among the three groups in the constitution score, and serum CORT and ACTH levels at the 6th month after the treatment compared with their own post-treatment (P>0.05).. The ginger-separated snake moxibustion treatment may improve the constitution of yang deficiency participants by increasing the levels of serum ACTH and CORT, which may be helpful in resisting diseases.


[Caregiving in an exceptional environment: the military operating theater nurse in a tropical zone].
The profession of operating theater nurse in the French Armed Forces Medical Corps is often little-known. Called upon to serve in mainland France, but also deployed on overseas operations, they provide medical and surgical support to the French armed forces. Personal qualities - human, physical and technical - are essential to adapt to the environmental constraints of this isolated post.


[Preparation and identification of anti-human polyclonal antibody against xylosyltransferase-I].
To prepare the rabbit polyclonal antibody against human xylosyltransferase-I (XT-I) protein and to identify its specificity. The predominant epitope of XT-I gene was predicted by the DNAssist software. The DNA fragment of this epitope region was synthesized by PCR and cloned into the pGEX-4T-2 vector. The recombinant plasmid was transformed into E.coli ER2566 and the fusion protein GST-XT was induced and isolated. The purified fusion protein was used to immunize New Zealand rabbits. The antibody titer was determined by ELISA. Purified polyclonal antibody was obtained through affinity chromatography column and the specificity of the purified antibody was characterized by Western blot. The amino acid 175-205 of XT-I (QKHQPELAKKPPSRQK-ELLKRKLEQQEKGKG) was selected as an antigen epitope. The synthesized DNA fragment of XT-I was successfully inserted into pGEX-4T-2 vector and the protein GST-XT was expressed. The purified fusion protein GST-XT was used as the immunogen to immunize rabbits and the polyclonal antibody against XT-I protein was obtained. The result of ELISA showed that the antibody titer was 1:640 000. Western blot analysis showed that the antibody had a good specificity. The rabbit polyclonal antibody against human XT-I protein has been successfully prepared, which lays the foundation for further study on the biosynthesis of PG by neoplastic myoepithelial cells in salivary tumors.


The consistency of panelists' appropriateness ratings: do experts produce clinically logical scores for rectal cancer treatment?
To quantify the clinical consistency of expert panelists' ratings of appropriateness of pre-operative and post-operative chemotherapy plus radiation for rectal cancer. A panel of nine physicians (two surgeons, four medical oncologists, three radiation oncologists) rated the appropriateness of providing pre-operative and post-operative treatments for rectal cancer, utilizing a modified-Delphi (RAND/UCLA) approach. Clinical scenarios were paired so that each component of a pair differed by only one clinical feature (e.g. tumor stage). A pair of appropriateness ratings was defined as inconsistent when the clinical scenario that should have had the higher (or at least equal) appropriateness rating was given a lower rating. The rate of inconsistency was analyzed for panelists' ratings of pre- and post-operative chemotherapy plus radiation. The final panel rating was inconsistent for 1.19% of pre-operative scenario pairs, and 0.77% of post-operative scenario pairs. Using the conventional RAND/UCLA definition of appropriateness, the magnitude of the inconsistency would produce inconsistent appropriateness ratings in 0.43% of pre-operative and 0.11% of post-operative scenario pairs. There was significant variation in the rate of inconsistency among individual panelists' final ratings of both pre-operative (range: 0.43-5.17%, P < 0.001) and post-operative (range: 0.51-2.34%, P < 0.001) scenarios. Panelists' overall average rate of inconsistency improved significantly after the panel meeting and discussion (from 5.62 to 2.25% for pre-operative scenarios, and from 1.47 to 1.24% for post-operative scenarios, both P < 0.05). There was no clear difference between specialty groups. Inconsistency was related to the structure of the rating manual: in the second round there were no inconsistent ratings when scenario pairs occurred on the same page of the manual. The RAND/UCLA appropriateness method can produce ratings for cancer treatment that are highly clinically consistent. Modifications to the structure of rating manuals to facilitate direct assessment of consistency at the time of rating may reduce inconsistency further.


Akt, IL-4, and STAT Proteins Play Distinct Roles in Prostaglandin Production in Human Follicular Dendritic Cell-like Cells.
This study aimed to explore the role of Akt protein in the induction and inhibition of prostaglandin (PG) in human follicular dendritic cell (FDC)-like cells. FDC-like cells and B cells were isolated from human tonsils. PG production was assessed using enzyme immunoassay, while the upstream cyclooxygenase-2 (COX-2) protein levels were measured using immunoblotting with FDC-like cells transfected with Akt siRNA to analyze the impact of Akt knockdown. The COX-2 expression and PG production induced with IL-1β were significantly increased by Akt knockdown. However, IL-1β did not significantly alter either total or phosphorylated Akt protein levels. Akt knockdown resulted in the augmentation of COX-2 expression induced by B cells, although the addition of B cells did not significantly modulate both total and phosphorylated Akt proteins. In contrast, IL-4 specifically exhibited a potent inhibitory effect on COX-2 protein induction and PG production via STAT6. The inhibitory activity of IL-4 was not hampered by Akt knockdown. Interestingly, COX-2 expression levels induced with IL-1β were markedly modulated with STAT1 and STAT3 knockdown. STAT1 silencing resulted in further augmentation of COX-2, whereas STAT3 silencing prohibited IL-1β from stimulating COX-2 expression. The current results suggest that Akt, IL-4, and STAT1 play inhibitory roles in PG production in FDC-like cells and expand our knowledge of the immune inflammatory milieu.


Moxibustion down-regulates colonic epithelial cell apoptosis and repairs tight junctions in rats with Crohn's disease.
To investigate the effects of moxibustion on down-regulation of the colonic epithelial cell apoptosis and repair of the tight junctions in rats with Crohn's disease (CD). Sixty male Sprague-Dawley rats were randomly divided into a normal control (NC) group, a model control (MC) group, an herbs-partitioned moxibustion (HPM) group, a mild-warm moxibustion (MWM) group and a salicylazosulphapyridine (SASP) group, with 12 rats in each group. The CD model rats were treated with trinitrobenzene sulphonic acid to induce intestinal inflammation. The rats in the HPM and MWM groups were treated at the Tianshu (ST25) and Qihai (CV6) acupoints once daily for 14 d, and the SASP group was fed SASP twice daily for 14 d. No additional treatment was given to the MC and NC groups. The microstructure of the colonic epithelium was observed under a transmission electron microscope, the transepithelial resistance was measured using a short-circuit current, colonic epithelial cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay, and the expression of occludin, claudin-1 and zonula occludens-l (ZO-1) in the colonic epithelial junction was determined by Western blotting and immunofluorescence staining. Compared with the MC group, the microstructure of the colonic epithelial barrier was significantly improved in rats treated with HPM, MWM or SASP, meanwhile, the current flow was reduced significantly, with values of 168.20 ± 6.14 vs 99.70 ± 3.13, 99.10 ± 4.28 and 120.30 ± 3.65 mA, respectively (P = 0.001). However, the HPM and MWM groups had higher current flow rates than the SASP group (99.70 ± 3.13, 99.10 ± 4.28 vs 120.30 ± 3.65 mA, P = 0.001). The number of the apoptotic colonic epithelial cells in HPM, MWM and SASP groups was largely reduced (61.5 ± 16.91 vs 15.5 ± 8.89, 14.8 ± 6.27 and 24.7 ± 9.68, respectively (P = 0.001); and the expression of occludin, claudin-1 and ZO-1 in the MWM and HPM groups was significantly enhanced (0.48 ± 0.10, 0.64 ± 0.09 vs 0.18 ± 0.05 for occludin, 0.12 ± 0.02, 0.17 ± 0.03 vs 0.05 ± 0.01 for claudin-1, and 0.08 ± 0.01, 0.11 ± 0.01 vs 0.02 ± 0.01 for ZO-1). And in SASP group, the expression of occludin and ZO-1 was also significantly increased (0.27 ± 0.04 vs 0.18 ± 0.05 for occludin and 0.05 ± 0.01 vs 0.02 ± 0.01 for ZO-1), but there was no significant difference for claudin-1. The HPM and MWM groups had higher expression of occludin, claudin-1 and ZO-1 than the SASP group. HPM and MWM treatment can down-regulate apoptosis of colonic epithelial cells, repair tight junctions and enhance colonic epithelial barrier function in rats with CD.


A flagging system for multichannel hematology analyzers.
A flagging system to identify blood specimens requiring a blood film review and/or differential leukocyte count is described. Its utility in avoiding unnecessary differential counts particularly in outpatients is given. Significant reductions in workload can be anticipated without deterioration of patient care.


Recovery of Hip and Back Muscle Fatigue Following a Back Extension Endurance Test.
Literature has not shown the minimum time required to recover from muscle fatigue after a prolonged trunk isometric contraction. The purpose of this study was to determine if the lumbar multifidus (LM) and gluteus maximus (GM) muscles would recover from fatigue after three different rest periods following performance of a back extension endurance test. Endurance time and electromyographic (EMG) activity of bilateral LM and GM muscles were collected from 12 healthy adults during a modified Biering-Sørensen test. On three separate visits, each participant performed two modified Biering-Sørensen tests, one before and one after a rest period (3, 6 or 9 min). For each endurance test, endurance time was measured and both mean and median EMG frequency fatigue rates were calculated. The results showed a significantly reduced endurance time and normalized mean frequency fatigue rates on the second modified Biering-Sørensen endurance test regardless of the rest periods (3, 6, and 9 min). This suggests that adequate rest should be considered for fatigue recovery when designing a back and hip endurance exercise program, and that future studies should investigate a rest time longer than 9 minutes for fatigue recovery following a modified Biering-Sørensen endurance test.


Effects of fenofibrate on inflammatory cytokines in diabetic retinopathy patients.
The role of cytokines in diabetic retinopathy (DR) and effects of fenofibrate on cytokines were explored by observing changes in serum IL-1β, TNF-α, VEGF, and Lp-PLA2 in different stages of DR and the intervention effect of oral fenofibrate on cytokines.In total, 190 patients with type 2 DR were enrolled and divided into 3 groups: diabetic without retinopathy (NDR) group (n = 30), nonproliferative diabetic retinopathy (NPDR) group (n = 80), and proliferative diabetic retinopathy (PDR) group (n = 80). According to whether or not to accept fenofibrate treatment, NPDR and PDR groups were further divided into the NPDR control (NPDR1) group (n = 40) and the NPDR treatment (NPDR2) group (n = 40), and the proliferative diabetic retinopathy control (PDR1, n = 40) group and the proliferative diabetic retinopathy treatment (PDR2) group (n = 40). At 12 weeks after fenofibrate treatment, serum IL-1β, TNF-α, VEGF, and Lp-PLA2 levels were detected.In PDR and NPDR patients, levels of serum cytokines such as IL-1β (120.56 ± 27.32 pg/mL vs 112.34 ± 19.45 pg/mL vs 82.9 ± 13.8 pg/mL), TNF-α (125.86 ± 25.57 pg/mL vs 109.48 ± 20.15 pg/mL vs 80.7 ± 12.8 pg/mL), VEGF (166.65 ± 37.74 pg/mL vs 148.54 ± 36.27 pg/mL vs 88.97 ± 24.86 pg/mL), and Lp-PLA2 (172.34 ± 45.22 μg/L vs 154.66 ± 40.98 μg/L vs 125.88 ± 38.87 μg/L) were significantly higher than in diabetes patients without retinopathy. After fenofibrate treatment, serum IL-1β, TNF-α, VEGF, and Lp-PLA2 significantly decreased in NPDR and PDR patients.Serum IL-1β, TNF-α, VEGF, and Lp-PLA2 play an important role in occurrence and development of diabetic retinopathy. Fenofibrate can reduce cytokine levels in DR patients and improve inflammatory response.


The Differentiation of Skin Mesenchymal Stem Cells Towards a Schwann Cell Phenotype: Impact of Sigma-1 Receptor Activation.
Neural crest stem cells (NCSCs) are the source of mature Schwann cells in the peripheral nervous system (PNS). The NCSC population resides in the bulge of hair follicles and in the dermis. Recently, it was shown that 2-3% of the human dermis mesenchymal stem cell (MSC) population expresses the NCSC marker CD271, thus enabling the use of skin MSCs for studying Schwann cell differentiation in vitro. The aims of this study were to establish a protocol for human skin MSC differentiation towards Schwann cell-like cells (SC-lcs) and to analyse the expression of sigma-1 receptor (S1R) in SC-lcs. The impact of S1R ligands, namely the selective agonist PRE-084, the positive allosteric modulator E1R and the selective antagonist NE-100, on Schwann cell differentiation was assessed. The expression of the neuron-specific genes Tubulin-βIII and Integrin-6α, the Schwann cell-specific gene S100b, MBP and the NCSC-specific genes p75NTR, Sox10, Notch1, Integrin-4α, Ap2α and Pax6 was analysed in MSCs and SC-lcs by real-time RT-PCR. BDNF secretion was evaluated by ELISA. The effect of S1R ligands on SC-lc differentiation was measured using BDNF ELISA and MBP flow cytometry. After MSC differentiation, NCSC markers p75NTR and Integrin-4α were downregulated 3.5-fold and 2-fold, respectively. To the contrary, MBP and S100b were significantly upregulated in SC-lcs. S1R ligands showed a tendency to increase the secretion of BDNF by the SC-lc population. PRE-084 and E1R increased MBP expression in the SC-lc population, whereas 3 μM NE-100 inhibited MBP expression in SC-lcs. In conclusion, our data demonstrate that S1R plays an important role in skin MSC differentiation towards myelinating Schwann cells.


Characterization of MRI techniques to assess neonatal brain oxygenation and blood flow.
There is increasing interest in applying physiological MRI in neonates, based on the premise that physiological parameters may provide an early biomarker of neonatal brain health and injury. Two commonly used techniques are oxygen extraction fraction (OEF) measurement using T2 -relaxation-under-spin-tagging (TRUST) MRI and cerebral blood flow measurement using phase-contrast (PC) quantitative flow MRI, which collectively provide an assessment of the brain's oxygen consumption. However, prior research has only demonstrated proof of principle of these methods in neonates, without characterization or benchmarking of the techniques. This is because available time is limited in neonatal subjects, especially when scans are performed as add-ons to clinical scans (typically less than 5 min). The work presented aims to examine the TRUST and PC MRI sequences systematically in normal neonates, through research-dedicated scan sessions. A series of characterization and optimization studies were conducted in a total of 26 radiographically normal neonates on 3 T systems. Our results show that TRUST MRI at the superior sagittal sinus (SSS) provides an OEF measurement equivalent to that at the internal jugular vein (r = 0.80, n = 10), yet with shorter scan time. Lower resolution provided better precision in the TRUST measurement (p = 0.001, n = 9). Therefore, the preferred OEF measurement is to apply TRUST MRI at the SSS using a spatial resolution of 2.5 mm. For PC MRI, our results showed that non-gated PC MRI yielded blood flow measurements comparable to those from the more time-consuming gated approach in neonates (r = 0.89, n = 7). It was also found that blood flow could be overestimated by 18% when imaging resolution is larger than 0.3 mm (n = 7). Therefore, non-gated PC MRI with a spatial resolution of 0.3 mm is recommended for neonatal applications. In conclusion, this study verifies consistency of neonatal brain oxygenation and flow measurements across acquisition schemes and points to optimal strategies in parameter selection when using these sequences.


Timely Monitoring of Inflammation by Fecal Lactoferrin Rapidly Predicts Therapeutic Response in Inflammatory Bowel Disease.
Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics. This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR. For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R2 = 0.769; P < 0.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.58 ± 0.21 vs 0.13 ± 0.09; P < 0.001) and nonresponders (0.81 ± 0.17 vs 0.12 ± 0.08; P < 0.001), and FL levels dropped by up to 99%. Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice.


Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning.
Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.


The reliability of workplace-based assessment in postgraduate medical education and training: a national evaluation in general practice in the United Kingdom.
To investigate the reliability and feasibility of six potential workplace-based assessment methods in general practice training: criterion audit, multi-source feedback from clinical and non-clinical colleagues, patient feedback (the CARE Measure), referral letters, significant event analysis, and video analysis of consultations. Performance of GP registrars (trainees) was evaluated with each tool to assess the reliabilities of the tools and feasibility, given raters and number of assessments needed. Participant experience of process determined by questionnaire. 171 GP registrars and their trainers, drawn from nine deaneries (representing all four countries in the UK), participated. The ability of each tool to differentiate between doctors (reliability) was assessed using generalisability theory. Decision studies were then conducted to determine the number of observations required to achieve an acceptably high reliability for "high-stakes assessment" using each instrument. Finally, descriptive statistics were used to summarise participants' ratings of their experience using these tools. Multi-source feedback from colleagues and patient feedback on consultations emerged as the two methods most likely to offer a reliable and feasible opinion of workplace performance. Reliability co-efficients of 0.8 were attainable with 41 CARE Measure patient questionnaires and six clinical and/or five non-clinical colleagues per doctor when assessed on two occasions. For the other four methods tested, 10 or more assessors were required per doctor in order to achieve a reliable assessment, making the feasibility of their use in high-stakes assessment extremely low. Participant feedback did not raise any major concerns regarding the acceptability, feasibility, or educational impact of the tools. The combination of patient and colleague views of doctors' performance, coupled with reliable competence measures, may offer a suitable evidence-base on which to monitor progress and completion of doctors' training in general practice.


Shaping outcomes of Reciproc Blue and Rotate in roots canals with band-shaped isthmuses: micro-CT study.
This study assessed the outcome of shaping the mesial roots of mandibular first molars containing band-shaped isthmuses with an isthmus floor located at the apical third with Reciproc Blue and Rotate instruments in terms of canal transportation, canal aberrations and unprepared apical canals. Pair-matched mesial roots of mandibular first molars according to their isthmus location (distance from apical foramina) and size were constructed based on quantitative measurements (length, major and minor diameter at isthmus roof and floor) on preoperative micro-CT scanning (n = 10). The pair-matched specimens were prepared either using Reciproc Blue R25 (25.08v) or Rotate (15.04, 20.05, 25.06) instruments and then subjected to a second micro-CT scanning. Micro-CT scans were analysed to evaluate the canal transportation at the apical foramen and isthmus floor levels and the frequency of procedural errors (separated instruments, artificial canal preparation, cross shaping and unprepared apical canals). Canal transportation values were compared using Mann-Whitney U, and the distribution of procedural errors was compared with chi-square tests with a 5% significance threshold. Greater transportation values were detected in the apical foramen level compared to the isthmus floor in both groups. No significant difference was detected between Rotate and Reciproc Blue groups in terms of absolute transportation values and the incidence of procedural errors (p > .05). Preparation of mesial root canals containing a band-shaped isthmus at the apical portion with Reciproc Blue and Rotate instruments caused transportation of the original canal position at the isthmus floor and the apical foramen levels and resulted in procedural errors. This ex vivo micro-CT study using controlled pair-matched specimens showed that presence of a band-shaped isthmus complicates canal preparation procedure irrespective of the preparation systems.


The synthesis of a series of adenosine A3 receptor agonists.
A series of 1'-(6-aminopurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamides that were characterised by 2-dialkylamino-7-methyloxazolo[4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised. This work involved the synthesis of 2-dialkylamino-5-aminomethyl-7-methyloxazolo[4,5-b]pyridines and analogues that were coupled with the known 1'-(6-chloropurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamide. The oxazolo[4,5-b]pyridines were synthesized by regioselective functionalisation of 2,4-dimethylpyridine N-oxides. The regioselectivities of these reactions were found to depend upon the nature of the heterocycle with 2-dimethylamino-5,7-dimethyloxazolo[4,5-b]pyridine-N-oxide undergoing regioselective functionalisation at the 7-methyl group on reaction with trifluoroacetic anhydride in contrast to the reaction of 4,6-dimethyl-3-hydroxypyridine-N-oxide with acetic anhydride that resulted in functionalisation of the 6-methyl group. To optimise selectivity for the A3 receptor, 5-aminomethyl-7-bromo-2-dimethylamino-4-[(3-methylisoxazol-5-yl)methoxy]benzo[d]oxazole was synthesised and coupled with the 1'-(6-chloropurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamide. The products were active as selective adenosine A3 agonists.


Use of medications and resources for treatment of nausea, vomiting, or constipation in hospitalized patients treated with analgesics.
Hospitalized patients often experience adverse events of the gastrointestinal tract due to analgesic treatment. The objectives of this study were to estimate use of medications for treatment of nausea, vomiting, or constipation (NVC medications) after initiation of analgesic treatment, and to compare differences in length of stay and treatment costs between patients who received NVC medications and those who did not. This retrospective cohort study used the Premier Perspective data from January 1, 2005 to December 31, 2007 and stratified inpatients into 4 groups based on the first analgesic agent they were given. Patients were observed for 14 days after the first analgesic use until a regimen change, first use of NVC medication, or hospital discharge, whichever occurred first. Data were analyzed using a Cox proportional hazards model and a generalized linear model. This study found that 239,183 (55.1%) of 434,304 patients received NVC medications after analgesic administration. Compared with oral nonopioid analgesics, the risk of using NVC medication was 4.8 times higher for injectable opioid analgesics after controlling for confounders. Patients who received NVC medications were hospitalized 0.26 days longer (P < 0.0001) at an additional cost of $756 per patient compared with patients who did not receive NVC medications (P < 0.0001). Use of an analgesic with improved gastrointestinal tolerability may potentially reduce use of NVC medications and hospital resources.


Safety of Curcuma aromatica oil gelatin microspheres administered via hepatic artery.
To evaluate the safety of Curcuma aromatica oil gelatin microspheres (CAO-GMS) infused via hepatic artery against primary liver cancer. The safety of CAO-GMS was evaluated in view of its acute toxicity in rats, long-term toxicity in Beagle dogs and general pharmacology in rats and mongrel dogs. The 50% lethal dose (LD50) of CAO-GMS infused via the hepatic artery was 17.19 mg/kg, and the serum biochemical indices of dying rats after the administration changed markedly while those of survived rats did not. Subsequent pathological examination of the tissues from the dead rats indicated improper embolism. Similar edema and small necrotic foci in the hepatic lobule were found in the hepatic tissue of rats receiving 10 and 5 mg/kg CAO-GMS and GMS 60 d after the last administration, while not in the rats of the blank control group, indicating that microspheres infused via the hepatic artery may induce irreversible liver damage dose-dependently. General pharmacological study showed that the activities (posture and gait), respiration frequency, blood pressure or heart rate of the dogs were not affected by CAO-GMS, nor were salivation, tremor or pupil changes of the rats observed or their balancing ability compromised, suggesting CAO-GMS infused via the hepatic artery did not significantly affect the nervous, respiratory and cardiovascular systems. CAO-GMS embolization administered via the hepatic artery is safe but undesired embolization induced by vascular variation should be given due attention in its clinical application. Individualized embolization dosage and super-selective catheterization technique are recommended to avoid undesired embolism and reduce complications.


[Spontaneous activity in the single auditory nerve fiber in the pigeon].
Microelectrode study of spontaneous activity of the pigeon's single auditory nerve fibers and their interval histograms shows in some of them rhythmic oscillations of excitability with characteristic frequency. The existence of these oscillations is supported by the analysis of interval histograms and autocorrelation functions of spontaneous discharges. Stimulation of these fibers with white noise caused no changes of the periodicity of interval histograms and had no effect on their periods. These characteristics of single fibers could be attributed to rhythmic oscillations of the MP of hair cells arising as a result of the mechanical narrow-band filtration of ambient noises at the basilar membrane.