Training-free measures based on algorithmic probability identify high nucleosome occupancy in DNA sequences.
We introduce and study a set of training-free methods of an information-theoretic and algorithmic complexity nature that we apply to DNA sequences to identify their potential to identify nucleosomal binding sites. We test the measures on well-studied genomic sequences of different sizes drawn from different sources. The measures reveal the known in vivo versus in vitro predictive discrepancies and uncover their potential to pinpoint high and low nucleosome occupancy. We explore different possible signals within and beyond the nucleosome length and find that the complexity indices are informative of nucleosome occupancy. We found that, while it is clear that the gold standard Kaplan model is driven by GC content (by design) and by k-mer training; for high occupancy, entropy and complexity-based scores are also informative and can complement the Kaplan model.


Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue.
The obese (ob) gene, the mutation of which results in severe hereditary obesity and diabetes in mice, has recently been isolated through positional cloning. In this study, we isolated a full-length human ob complementary DNA (cDNA) clone and examined the tissue distribution of ob gene expression in humans. The nucleotide sequences of the human ob cDNA coding region were 83% identical to those of the mouse and rat ob cDNA coding regions. Analysis of the deduced amino acid sequences revealed that the human ob protein is a 166-amino acid polypeptide with a putative signal sequence and is 84 and 83% homologous to the mouse and rat ob proteins, respectively. Northern blot analysis using the cloned human ob cDNA fragment as a probe identified a single messenger RNA (mRNA) species 4.5 kb in size found abundantly in the adipose tissues obtained from the subcutaneous, omental, retroperitoneal, perilymphatic, and mesenteric fat pads. However, no significant amount of ob mRNA was present in the brain, heart, lung, liver, stomach, pancreas, spleen, small intestine, kidney, prostate, testis, colon, or skeletal muscle. The ob mRNA level in the adipose tissue varied from region to region even in the same individual. Furthermore, in the human adipose tissue, ob gene expression occurred in mature adipocytes rather than in stromal-vascular cells. This study is the first report of the elucidation of ob gene expression in human tissues, thereby leading to better understanding of the physiological and clinical implications of the ob gene.


Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and recruitment.
Here we investigated the role of murine mast cell protease 4 (MCPT4), the functional counterpart of human mast cell chymase, in an experimental model of renal ischemia reperfusion injury, a major cause of acute kidney injury. MCPT4-deficient mice had worsened kidney function compared to wildtype mice. MCPT4 absence exacerbated pathologic neutrophil infiltration in the kidney and increased kidney myeloperoxidase expression, cell death and necrosis. In kidneys with ischemia reperfusion injury, when compared to wildtype mice, MCPT4-deficient mice showed increased surface expression of adhesion molecules necessary for leukocyte extravasation including neutrophil CD162 and endothelial cell CD54. In vitro, human chymase mediated the cleavage of neutrophil expressed CD162 and also CD54, P- and E-Selectin expressed on human glomerular endothelial cells. MCPT4 also dampened systemic neutrophil activation after renal ischemia reperfusion injury as neutrophils expressed more CD11b integrin and produced more reactive oxygen species in MCPT4-deficient mice. Accordingly, after renal injury, neutrophil migration to an inflammatory site distal from the kidney was increased in MCPT4-deficient versus wildtype mice. Thus, contrary to the described overall aggravating role of mast cells, one granule-released mediator, the MCPT4 chymase, exhibits a potent anti-inflammatory function in renal ischemia reperfusion injury by controlling neutrophil extravasation and activation thereby limiting associated damage.


Controversies in fumonisin mycotoxicology and risk assessment.
Fusarium verticillioides causes several animal diseases and the contamination maize suggests that it could adversely affect human health. The fumonisin B mycotoxins were characterized from the fungal culture material and shown to be the causative principle responsible for the major mycotoxicological effects of the fungus in experimental and farm animals. The main focus was on the toxicological effects in rats and mice, the outcome of which played an important role in setting risk assessment parameters for exposure of the fumonisins to humans. The International Agency for Research on Cancer characterized the fumonisins as Group 2B carcinogens. Several controversial findings regarding the toxicological effects of the culture material of the fungus, the genotoxicity and carcinogenicity of pure fumonisin B(1) (FB(1)) in rats have been reported that should be clarified prior to assessing the risk in humans. The underlying differences between the diets with the high protein levels are likely to sensitize the kidneys to FB(1)-induced toxic and carcinogenic effects. Several other dietary factors, such as plant extracts (antioxidants) and dietary Fe, could either stimulate or inhibit cancer induction of FB(1), which complicates the comparison of toxicological effects in experimental animals. Cognisance should be taken of the modulating role of dietary constituents as it will determine the outcome of toxicological assays and determine the threshold of an adverse effect in a specific target organ to be used in determining risk assessment parameters.


Novel anti-infective potential of salvianolic acid B against human serious pathogen Neisseria meningitidis.
Epidemics of meningococcal meningitis cause significant health problems especially in Sub-Saharan Africa. Novel anti-infective candidates are needed. In modern anti-adhesion therapy initial attachment of bacteria to host cells is prevented. Our unique studies have revealed anti-adhesive candidates from natural products, namely milk and berries, against Neisseria meningitidis adhesion. In the present study against N. meningitidis adhesion, a novel binding inhibitor was found; salvianolic acid B (SA-B), a polyphenol from the radix Salviae miltiorrhizae, an important part of Chinese folk medicine. In order to test inhibition of meningococcal pili binding and anti-adhesion activity of SA-B, bovine thyroglobulin, a reference glycoprotein for meningococcal receptor was used in a microtiter plate assay. Inhibitory activity was tested by using serial dilutions of SA-B extracts of 98 and 70% purity. Results were confirmed in a HEC-1B cell dot assay and antimicrobial activity was measured by using a microbroth dilution assay. Almost total (93%) inhibition of pili binding, anti-adhesion, was achieved with the 70% extract of SA-B at the concentration of 0.3 mg/mL in the bovine thyroglobulin reference model. 50% binding inhibition activity was achieved with 0.6 µg/mL of the SA-B extract. Total inhibition of the pili binding to HEC-1B cells was found at the tested concentration of 0.5 mg/mL. The 98% pure SA-B resulted in weaker inhibition. At the concentration of 0.3 mg/mL 78% inhibition was achieved in the thyroglobulin model. For 50% inhibition 2.4 μg/mL of pure SA-B was needed. The difference between the binding inhibition activities (70 and 98% pure SA-B) was statistically significant (P = 0.03). Antimicrobial activity of 70% SA-B, when investigated against N. meningitidis, was detected only in relatively high concentrations. Our results indicate that plant SA-B may prevent meningococcal infections by inhibiting meningococcal binding and may thus have an impact on the amount of nasopharyngeal carriers of N. meningitidis. This may prevent the spreading of meningococcal infections between humans. One could conclude that SA-B and its source dried radix S. miltiorrhizae, which is an important part of Chinese folk medicine, could be valuable candidates for further research in meningococcal disease prevention.


Prospective comparison of panoramic tomography (zonography) and helical computed tomography in the diagnosis and operative management of mandibular fractures.
This prospective study compared the sensitivity of panoramic tomography (zonography) and helical computed tomography (CT) in diagnosing 73 mandibular fractures in 42 consecutive patients and correlated the results with known surgical findings. The purpose of the study was to determine the optimal radiologic examination for the diagnosis and operative management of mandibular fractures. The attending surgeons' interpretations of panoramic tomograms and helical CT images in the axial plane were compared with the patients' known surgical findings. A series of questions assessed the relative contribution of these two radiologic examinations in formulating an optimal operative plan for each patient. In the 42 patients studied, the sensitivity of helical CT was 100 percent in diagnosing mandibular fractures; this compared with 86 percent (36 of 42) for panoramic tomography, in which significantly more fractures were missed (p = 0.0412). In the six patients with fractures not visualized, the operative management was altered because of the new fracture visualized on helical CT. Of the seven missed fractures, six were in the posterior portion of the mandible. Comparing fracture detection by region, seven fractures found on helical CT were not visualized on panoramic tomography. Helical CT improved the understanding of the nature of mandibular fractures by providing additional information regarding fracture displacement and comminution and by locating injuries missed using panoramic tomography. This study suggests that helical CT alone may be more diagnostic than panoramic tomography alone in evaluating mandibular fractures. Helical CT sufficiently demonstrated details of fractures in 41 of 42 patients; in one patient, the nature of a dental root fracture was better delineated by panoramic tomography.


Radiotherapy beyond cancer: target localization in real-time MRI and treatment planning for cardiac radiosurgery.
Atrial fibrillation (AFib) is the most common cardiac arrhythmia that affects millions of patients world-wide. AFib is usually treated with minimally invasive, time consuming catheter ablation techniques. While recently noninvasive radiosurgery to the pulmonary vein antrum (PVA) in the left atrium has been proposed for AFib treatment, precise target location during treatment is challenging due to complex respiratory and cardiac motion. A MRI linear accelerator (MRI-Linac) could solve the problems of motion tracking and compensation using real-time image guidance. In this study, the authors quantified target motion ranges on cardiac magnetic resonance imaging (MRI) and analyzed the dosimetric benefits of margin reduction assuming real-time motion compensation was applied. For the imaging study, six human subjects underwent real-time cardiac MRI under free breathing. The target motion was analyzed retrospectively using a template matching algorithm. The planning study was conducted on a CT of an AFib patient with a centrally located esophagus undergoing catheter ablation, representing an ideal case for cardiac radiosurgery. The target definition was similar to the ablation lesions at the PVA created during catheter treatment. Safety margins of 0 mm (perfect tracking) to 8 mm (untracked respiratory motion) were added to the target, defining the planning target volume (PTV). For each margin, a 30 Gy single fraction IMRT plan was generated. Additionally, the influence of 1 and 3 T magnetic fields on the treatment beam delivery was simulated using Monte Carlo calculations to determine the dosimetric impact of MRI guidance for two different Linac positions. Real-time cardiac MRI showed mean respiratory target motion of 10.2 mm (superior-inferior), 2.4 mm (anterior-posterior), and 2 mm (left-right). The planning study showed that increasing safety margins to encompass untracked respiratory motion leads to overlapping structures even in the ideal scenario, compromising either normal tissue dose constraints or PTV coverage. The magnetic field caused a slight increase in the PTV dose with the in-line MRI-Linac configuration. The authors' results indicate that real-time tracking and motion compensation are mandatory for cardiac radiosurgery and MRI-guidance is feasible, opening the possibility of treating cardiac arrhythmia patients completely noninvasively.


Epigenetics, heritability and longitudinal analysis.
Longitudinal data and repeated measurements in epigenome-wide association studies (EWAS) provide a rich resource for understanding epigenetics. We summarize 7 analytical approaches to the GAW20 data sets that addressed challenges and potential applications of phenotypic and epigenetic data. All contributions used the GAW20 real data set and employed either linear mixed effect (LME) models or marginal models through generalized estimating equations (GEE). These contributions were subdivided into 3 categories: (a) quality control (QC) methods for DNA methylation data; (b) heritability estimates pretreatment and posttreatment with fenofibrate; and (c) impact of drug response pretreatment and posttreatment with fenofibrate on DNA methylation and blood lipids. Two contributions addressed QC and identified large statistical differences with pretreatment and posttreatment DNA methylation, possibly a result of batch effects. Two contributions compared epigenome-wide heritability estimates pretreatment and posttreatment, with one employing a Bayesian LME and the other using a variance-component LME. Density curves comparing these studies indicated these heritability estimates were similar. Another contribution used a variance-component LME to depict the proportion of heritability resulting from a genetic and shared environment. By including environmental exposures as random effects, the authors found heritability estimates became more stable but not significantly different. Two contributions investigated treatment response. One estimated drug-associated methylation effects on triglyceride levels as the response, and identified 11 significant cytosine-phosphate-guanine (CpG) sites with or without adjusting for high-density lipoprotein. The second contribution performed weighted gene coexpression network analysis and identified 6 significant modules of at least 30 CpG sites, including 3 modules with topological differences pretreatment and posttreatment. Four conclusions from this GAW20 working group are: (a) QC measures are an important consideration for EWAS studies that are investigating multiple time points or repeated measurements; (b) application of heritability estimates between time points for individual CpG sites is a useful QC measure for DNA methylation studies; (c) drug intervention demonstrated strong epigenome-wide DNA methylation patterns across the 2 time points; and (d) new statistical methods are required to account for the environmental contributions of DNA methylation across time. These contributions demonstrate numerous opportunities exist for the analysis of longitudinal data in future epigenetic studies.


Mathematical refocusing of images in electronic holography.
This paper presents an illustration of mathematical refocusing of images obtained by the HoloFringe300K electronic holography program. The purpose is to demonstrate that this form of electronic holography is equivalent to image-plane, phase-stepped digital holography. The mathematical refocusing method used here differs from those in common use and may have some advantages.


Gene regulation by the lysine demethylase KDM4A in Drosophila.
Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. We therefore generated KDM4A mutant Drosophila, and identified 99 mis-regulated genes in first instar larvae. Around half of these genes were down-regulated and the other half up-regulated in dKDM4A mutants. Although heterochromatin protein 1a (HP1a) can stimulate dKDM4A demethylase activity in vitro, we find that they antagonize each other in control of dKDM4A-regulated genes. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Surprisingly, although highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae, suggesting that some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation. By contrast, dKDM4A over-expression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation. Our results show that a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males.


Enzyme-linked immunoassay for dengue virus IgM and IgG antibodies in serum and filter paper blood.
The reproducibilty of dengue IgM and IgG ELISA was studied in serum and filter paper blood spots from Vietnamese febrile patients. 781 pairs of acute (t0) and convalescent sera, obtained after three weeks (t3) and 161 corresponding pairs of filter paper blood spots were tested with ELISA for dengue IgG and IgM. 74 serum pairs were tested again in another laboratory with similar methods, after a mean of 252 days. Cases were classified as no dengue (10 %), past dengue (55%) acute primary (7%) or secondary (28%) dengue. Significant differences between the two laboratories' results were found leading to different diagnostic classification (kappa 0.46, p < 0.001). Filter paper results correlated poorly to serum values, being more variable and lower with a mean (95% CI) difference of 0.82 (0.36 to 1.28) for IgMt3, 0.94 (0.51 to 1.37) for IgGt0 and 0.26 (-0.20 to 0.71) for IgGt3. This also led to differences in diagnostic classification (kappa value 0.44, p < 0.001) The duration of storage of frozen serum and dried filter papers, sealed in nylon bags in an air-conditioned room, had no significant effect on the ELISA results. Dengue virus IgG antibodies in serum and filter papers was not affected by duration of storage, but was subject to inter-laboratory variability. Dengue virus IgM antibodies measured in serum reconstituted from blood spots on filter papers were lower than in serum, in particular in the acute phase of disease. Therefore this method limits its value for diagnostic confirmation of individual patients with dengue virus infections. However the detection of dengue virus IgG antibodies eluted from filter paper can be used for sero-prevalence cross sectional studies.


Novel MRI method to detect altered left ventricular ejection and filling patterns in rodent models of disease.
The aim of this study was to determine whether high-temporal-resolution (HTR) cardiac cine-MRI could be used to identify subtle alterations in contractility and diastolic function in rodent models of disease. Following standard 45-min in vivo MRI measurements of left ventricular (LV) volumes, a single mid-ventricular slice was selected for 3-min HTR imaging. Cavity volume was measured every 2.4 ms, yielding approximately 60 images through the cardiac cycle. From these images, peak ejection and filling rates were calculated and two separate filling phases (comparable with the early (E) and late (A) phases of a Doppler echocardiogram) were identified during diastole. Repeated HTR imaging of the same animals on sequential days indicated reproducibility of E'/A' ratios of 11%. In chronically infarcted rat hearts, HTR imaging revealed lower peak ejection rates (PERs), peak early filling rates (E') and E'/A' ratios, and higher peak late filling rates (A') than in sham-operated rats. Diabetic db/db mouse hearts had the same function as controls when using standard cine-MRI, yet HTR imaging identified significantly lower PERs, early filling rates and E'/A' ratios in diabetic mouse hearts. In conclusion, the HTR MRI technique revealed changes in function that were below the limits of detection of standard cine-MRI.


Radiative heating and cooling with spectrally selective surfaces.
Matter continuously exchanges energy with its surroundings. This exchange can be dominated by radiation, conduction, or convection. In this brief review we discuss how proper design of radiative surface properties can be used for heating and cooling purposes. The desired properties can be understood once it is realized that solar and terrestrial radiation take place in different wavelength ranges and that only part of the solar spectrum is useful for vision and for photosynthesis in plants. These facts allow the possibility of tailoring the spectral absorptance, emittance, reflectance, and transmittance of a surface to meet different demands in different wavelength intervals, i.e., to take advantage of spectral selectivity. One example is the selective surface for efficient photothermal conversion of solar energy, which has high absorptance over the solar spectrum but low emittance for the longer wavelengths relevant to thermal reradiation. Below we discuss the pertinent spectral radiative properties of our ambience. These data are then used as background to the subsequent sections treating four examples of spectrally selective surfaces. The first example is the previously mentioned selective surface for converting solar radiation to useful heat. The second example considers surfaces capable of reaching low temperatures by benefiting from the spectral emittance of the clear night sky. The third example concerns two related types of transparent heat mirror. The fourth example, finally, treats radiative cooling of green leaves; this part is included since it gives a nice example of how nature solves a difficult problem in an elegant and efficient way. This example hence provides an interesting background to the other cruder types of artificial selective surfaces. Throughout our discussion we treat the ideal spectral properties, give an illustrative experimental example of how well this goal can be realized, and-where this is possible-show a corresponding theoretical curve indicating to what extent the measured results can be theoretically understood.


Patellar instability: CT and MRI measurements and their correlation with internal derangement findings.
To test the inter-observer and inter-method reliability among the measures suggesting patellofemoral joint disorder on both CT and MRI in the same subject and find possible association with internal derangements of the patellofemoral joint on MRI. Institutional review board approval was obtained with waiver of the informed consent in this HIPPA-compliant study. CT and MRI were evaluated in 32 knees in 32 respective subjects (10 men/22 women, mean age 38 ± 19 years). Three trained observers assessed tibial tuberosity-trochlear groove (TT-TG) distance, trochlear angle and trochlear depth on both CT and MRI. Intra-class correlation coefficient (ICC) was used to evaluate inter-observer and inter-method reliability. Two radiologists' consensus reading was used to evaluate their association with soft tissue abnormalities of the patellofemoral joint. Chi-square test was used to assess the statistical significance of the qualitative variables. There was an excellent inter-observer reliability (ICC for CT >0.89 and for MRI >0.90) and inter-method reliability (ICC >0.86) for all the quantitative measurements. There was a significant association between increased TT-TG distance value on MR imaging and lateral facet patellar cartilage abnormality and joint effusion (p < 0.05). Quantitative trochlear parameters can be reliably calculated on MRI, and an abnormal TT-TG distance is the most useful measurement among various static MR imaging parameters to correlate with patellar chondrosis and joint effusion. TT-TG distance should be reported in patellofemoral pain syndrome patients. IV.


Anticipating hyperthermic efficiency of magnetic colloids using a semi-empirical model: a tool to help medical decisions.
Magnetic hyperthermia, a modality that uses radio frequency heating assisted with single-domain magnetic nanoparticles, is becoming established as a powerful oncological therapy. Much improvement in nanomaterials development, to enhance their heating efficiency by tuning the magnetic colloidal properties, has been achieved. However, methodological standardization to accurately and univocally determine the colloidal properties required to numerically reproduce a specific heating efficiency using analytical expressions still holds. Thus, anticipating the hyperthermic performances of magnetic colloids entails high complexity due to polydispersity, aggregation and dipolar interactions always present in real materials to a greater or lesser degree. Here, by numerically simulating the experimental results and using real biomedical aqueous colloids, we analyse and compare several approaches to reproduce experimental specific absorption rate values. Then, we show that the relaxation time, determined using a representative mean activation energy consistently derived from four independent experiments accurately reproduces experimental heating efficiencies. Moreover, the so-derived relaxation time can be used to extrapolate the heating performance of the magnetic nanoparticles to the other field conditions within the framework of the linear response theory. We thus present a practical tool that may truly aid the design of medical decisions.


Recent expansion of Toxoplasma through enhanced oral transmission.
The global predominance of three clonal Toxoplasma gondii lineages suggests that they are endowed with an exceptional trait responsible for their current parasitism of nearly all warm-blooded vertebrates. Genetic polymorphism analyses indicate that these clonal lineages emerged within the last 10,000 years after a single genetic cross. Comparison with ancient strains (approximately 1 million years) suggests that the success of the clonal lineages resulted from the concurrent acquisition of direct oral infectivity. This key adaptation circumvented sexual recombination, simultaneously promoting transmission through successive hosts, hence leading to clonal expansion. Thus, changes in complex life cycles can occur rapidly and can profoundly influence pathogenicity.


Recent advances in the pathogenesis of lupus nephritis: autoantibodies and B cells.
Although many factors contribute to the clinical presentation and subsequent course of individuals with lupus nephritis, the formation of glomerular immune deposits is typically one of the initial events. In general, breakdown in immunologic tolerance leads to the production of autoreactive B and T cells that, either through direct infiltration and/or their secretory products, initiate inflammation. Immune deposition within glomeruli results in complement activation and recruitment of inflammatory cells, along with activation of endogenous renal cells. This inflammatory cascade leads to secretion of cytokines and chemokines, which in turn attract more infiltrating cells. Up-regulation of lymphoid-derived chemokines further enhance the cellular influx, augmenting inflammation and resulting in further tissue damage. The degree of inflammation is determined by the extent of this invasion along with both the systemic and local responses to the assault. This review focuses mainly on the contributions of pathogenic autoantibodies, autoreactive B cells to lupus nephritis, and potential immunologic therapies for lupus nephritis. Manipulation of both the cells and soluble mediators that initiate and perpetuate the disease are essential to suppressing autoreactivity and inflammation and preventing disease progression.


Incomplete EHR adoption: late uptake of patient safety and cost control functions.
Many functions important to realizing the full potential from electronic health records (EHRs) may not be selected by all physicians using EHRs in the ambulatory setting. This article examines the extent to which EHR systems used by Florida physicians include functionalities that the Institute of Medicine has designated as being critical for optimal performance. Results indicate that EHR systems used by recent adopters, when compared with early adopters, appear to be missing key patient safety and cost control functions. Overall, many physicians are only partially adopting EHR technologies, suggesting that published adoption rates may be exaggerating the true rate of diffusion.


Adenovirus infection inhibits the phosphorylation of major histocompatibility complex class I proteins.
Major histocompatibility complex (MHC) class I molecules act as peptide receptors to direct the recognition of foreign antigens by cytolytic T cells. The cell surface expression and trafficking of these peptide receptors is thought to be controlled by the conformation of the MHC molecule and possibly by the phosphorylation of the cytoplasmic portion of the heavy chain protein. It is of some interest that adenoviruses (Ads) have evolved proteins that interfere with the expression of MHC molecules. One of these proteins, called E3/19k, binds to newly synthesized MHC molecules in the rough endoplasmic reticulum (RER) and inhibits their trafficking to the cell surface. Here we show that during the infection of a human cell line with Ad2, the phosphorylation of the endogenous MHC molecules is inhibited. We also observe that the phosphorylation of the endogenous HLA molecules is grossly impaired in a human cell line transfected with the Ad2 EcoRI D fragment containing the E3/19k gene. We conclude that the E3/19k protein inhibits the phosphorylation of the MHC heavy chains and that this may be one of the important functions of this protein in infected cells. In addition, we show that a mutant of the E3/19k protein, which lacks an RER retention signal but which retains its ability to bind to HLA molecules, does not inhibit the phosphorylation of HLA molecules and that phosphorylated molecules are not Endo H sensitive. This suggests that HLA molecules are phosphorylated after leaving the medial-Golgi compartment, thus providing the most compelling evidence yet that HLA molecules are phosphorylated at or near the cell surface. Finally, to our knowledge, this is the first study under which the phosphorylation of MHC molecules is shown to be altered and may have some relevance for other pathogenic conditions.


Beyond the tip of the iceberg; a new view of the diversity of sulfite- and sulfate-reducing microorganisms.
Sulfite-reducing and sulfate-reducing microorganisms (SRM) play important roles in anoxic environments, linking the sulfur and carbon cycles. With climate warming, the distribution of anoxic habitats conductive to dissimilatory SRM is expanding. Consequently, we hypothesize that novel SRM are likely to emerge from the rare biosphere triggered by environmental changes. Using the dsrB gene as a molecular marker of sulfite-reducers and sulfate-reducers, we analyzed the diversity, community composition, and abundance of SRM in 200 samples representing 14 different ecosystems, including marine and freshwater environments, oil reservoirs, and engineered infrastructure. Up to 167,397 species-level OTUs affiliated with 47 different families were identified. Up to 96% of these can be considered as "rare biosphere SRM". One third of the dsrB genes identified belonged to uncharacterized lineages. The dsrB sequences exhibited a strong pattern of selection in different ecosystems. These results expand our knowledge of the biodiversity and distribution of SRM, with implications for carbon and sulfur cycling in anoxic ecosystems.


Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus.
Obesity is closely related to type 2 diabetes and long-term weight reduction is an important part of the care delivered to obese persons with diabetes. To assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. Computerized searches were performed of MEDLINE (January 1966 to May 2004), EMBASE (January 1974 to May 2004, Web of Science (January 1981 to May 2004, and other electronic bibliographic databases, supplemented with hand searches of reference lists and selected journals. Randomized, controlled trials were included where pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished literature in any language and with any study design was included. Two reviewers abstracted data and the quality of included studies was evaluated by assessing potential attrition, as well as selection and measurement bias, and a Jadad score was obtained. Effects were combined using a random effects model. A sufficient number of studies were available for a quantitative synthesis for fluoxetine, orlistat, and sibutramine. Twenty two randomized controlled trials were included in the review, with a total of 296 participants for fluoxitine, 2036 for orlistat, and 1047 for sibutramine. Pharmacotherapy produced modest reductions in weight for fluoxetine (5.1 kg (95% confidence interval [CI], 3.3 - 6.9) at 24 to 26 weeks follow up; orlistat 2.0 kg (CI, 1.3 - 2.8) at 12 to 57 weeks follow-up, and sibutramine 5.1 kg (CI, 3.2 - 7.0) at 12 to 52 weeks follow-up. Glycated hemoglobin also modestly and significantly reduced for fluoxetine and orlistat. Gastrointestinal side effects were common with orlistat; tremor, somnolence and sweating with fluoxetine; and palpitations with sibutramine. Some studies, using a variety of study designs, were available on other drugs and a significant decrease in weight was noted in three studies of mazindol, one of phenmetrazine, two of phentermine. No studies were identified that fit inclusion criteria for pseudophedrine, ephedra, sertraline, yohimbine, amphetamine or its derivatives, bupropion, topiramate, benzocaine, threachlorocitric acid, sertraline, and bromocriptine. Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes.


Calcification Characteristics of Low-Flow Low-Gradient Severe Aortic Stenosis in Patients Undergoing Transcatheter Aortic Valve Replacement.
Low-flow low-gradient severe aortic stenosis (LFLGAS) is associated with worse outcomes. Aortic valve calcification patterns of LFLGAS as compared to non-LFLGAS have not yet been thoroughly assessed. 137 patients undergoing transcatheter aortic valve replacement (TAVR) with preprocedural multidetector computed tomography (MDCT) and postprocedural transthoracic echocardiography were enrolled. Calcification characteristics were assessed by MDCT both for the total aortic valve and separately for each leaflet. 34 patients had LFLGAS and 103 non-LFLGAS. Total aortic valve calcification volume (p < 0.001), mass (p < 0.001), and density (p = 0.004) were lower in LFLGAS as compared to non-LFLGAS patients. At 30-day follow-up, mean transaortic pressure gradients and more than mild paravalvular regurgitation did not differ between groups. In conclusion, LFLGAS and non-LFLGAS express different calcification patterns which, however, did not impact on device success after TAVR.


Effect of Roundup® (glyphosate formulation) in the energy metabolism and reproductive traits of Hyalella castroi (Crustacea, Amphipoda, Dogielinotidae).
Roundup(®) (glyphosate formulation) is a nonselective and posts emergent herbicide used for controlling aquatic weeds and different concentrations are used in cultures around the world. The objective of this investigation was to examine the effects of Roundup(®) (glyphosate formulation) on the biochemical composition, levels of lipoperoxidation, Na(+)/K(+)ATPase activity and reproductive traits in the Hyalella castroi. Amphipods were collected in summer 2009, in the southern Brazilian highlands. In the laboratory, the animals were kept in aquariums under controlled conditions for 7 days, and after this period they were exposed to 0.36, 0.52, 1.08 and 2.16 mg/l of glyphosate for 7 days. After the period of exposure, the animals were immediately frozen for determination of glycogen, proteins, lipids, triglycerides, cholesterol, levels of lipoperoxidation, and Na(+)/K(+)ATPase activity. During each day of the cultivation reproductive traits (number of reproductive pairs, ovigerous females and eggs in the marsupium) were observed. All concentrations of Roundup(®) induced significant decreases in all biochemical parameters and Na(+)/K(+)ATPase activity, and significant increase in lipoperoxidation levels. Showing this form a potentially toxic effect at very low concentrations, this pattern of results can lead to significant changes in trophic structure of limnic environments because these amphipods are important links in food chain in these habitats.


Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate epithelial cells.
We studied the effect of prolonged activation of mitogen-activated protein kinase (MAPK) signaling on 1,25 dihydroxyvitamin D (1,25(OH)(2)D(3)) action in the immortalized human prostate epithelial cell line RWPE1 and its Ki-Ras transformed clone RWPE2. 1,25(OH)(2)D(3)-treatment caused growth arrest and induced gene expression in both cell lines but the response was blunted in RWPE2 cells. Vitamin D receptor (VDR) levels were lower in RWPE2 cells but VDR over-expression did not increase vitamin-D-mediated gene transcription in either cell line. In contrast, MAPK inhibition restored normal vitamin D transcriptional responses in RWPE2 cells and MAPK activation with constitutively active MEK1R4F reduced vitamin-D-regulated transcription in RWPE1 cells. 1,25(OH)(2)D(3)-mediated transcription depends upon the VDR and its heterodimeric partner the retinoid X receptor (RXR) so we studied whether changes in the VDR-RXR transcription complex occur in response to MAPK activation. Mutation of putative phosphorylation sites in the activation function 1 (AF-1) domain (S32A, T82A) of RXRalpha restored 1,25(OH)(2)D(3)-mediated transactivation in RWPE2 cells. Mammalian two-hybrid and co-immunoprecipitation assays revealed a vitamin-D-independent interaction between steroid receptor co-activator-1 (SRC-1) and RXRalpha that was reduced by MAPK activation and was restored in RWPE2 cells by mutating S32 and T82 in the RXRalpha AF-1 domain. Our data show that a common contributor to cancer development, prolonged activation of MAPK signaling, impairs 1,25(OH)(2)D(3)-mediated transcription in prostate epithelial cells. This is due in part to the phosphorylation of critical amino acids in the RXRalpha AF-1 domain and impaired co-activator recruitment.


Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance.
The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver. To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals. The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver. These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.


Soil and surface temperatures at the viking landing sites.
The annual temperature range for the martian surface at the Viking lander sites is computed on the basis of thermal parameters derived from observations made with the infrared thermal mappers. The Viking lander 1 (VL1) site has small annual variations in temperature, whereas the Viking lander 2 (VL2) site has large annual changes. With the Viking lander images used to estimate the rock component of the thermal emission, the daily temperature behavior of the soil alone is computed over the range of depths accessible to the lander; when the VL1 and VL2 sites were sampled, the daily temperature ranges at the top of the soil were 183 to 263 K and 183 to 268 K, respectively. The diurnal variation decreases with depth with an exponential scale of about 5 centimeters. The maximum temperature of the soil sampled from beneath rocks at the VL2 site is calculated to be 230 K. These temperature calculations should provide a reference for study of the active chemistry reported for the martian soil.


Antenatal cardiotocography for fetal assessment.
Cardiotocography (CTG) is a continuous recording of the fetal heart rate obtained via an ultrasound transducer placed on the mother's abdomen. CTG is widely used in pregnancy as a method of assessing fetal well-being, predominantly in pregnancies with increased risk of complications. To assess the effectiveness of antenatal CTG (both traditional and computerised assessments) in improving outcomes for mothers and babies during and after pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2009). Randomised and quasi-randomised trials that compared traditional antenatal CTG with no CTG or CTG results concealed; computerised CTG with no CTG or CTG results concealed; and computerised CTG with traditional CTG. Two authors independently assessed eligibility, quality and extracted data. Six studies (involving 2105 women) are included. Overall, the included studies were not of high quality, and only two had both adequate randomisation sequence generation and allocation concealment. All studies that were able to be included enrolled only women at increased risk of complications.Comparison of traditional CTG versus no CTG showed no significant difference identified in perinatal mortality (risk ratio (RR) 2.05, 95% confidence interval (CI) 0.95 to 4.42, 2.3% versus 1.1%, four studies, N = 1627) or potentially preventable deaths (RR 2.46, 95% CI 0.96 to 6.30, four studies, N = 1627, though the meta-analysis was underpowered to assess this outcome. Similarly, there was no significant difference identified in caesarean sections (RR 1.06, 95% CI 0.88 to 1.28, 19.7% versus 18.5%, three trials, N = 1279) nor in the secondary outcomes that were assessed.There were no eligible studies that compared computerised CTG with no CTG.Comparison of computerised CTG versus traditional CTG showed a significant reduction in perinatal mortality with computerised CTG (RR 0.20, 95% CI 0.04 to 0.88, two studies, 0.9% versus 4.2%, 469 women, graph 3.1.1). However, there was no significant difference identified in potentially preventable deaths (RR 0.23, 95% CI 0.04 to 1.29, two studies, N = 469), though the meta-analysis was underpowered to assess this outcome. There was no significant difference identified in caesarean sections (RR 0.87, 95% CI 0.61 to 1.24, 63% versus 72%, one study, N = 59) or in secondary outcomes. There is no clear evidence that antenatal CTG improves perinatal outcome, but further studies focusing on the use of computerised CTG in specific populations of women with increased risk of complications are warranted.


Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.


Compliance leadership: the 17th century model that doesn't work.
The world of health care has changed. We can't operate on 17th century models and be successful. We don't have to argue for the movement to committed, inspired leadership models, and the death of compliance leadership. There is abundant research to document this is the way we must go. In reality, we have a moral obligation to provide the kind of work environment that provides the meaningful work that Maslow (1998) tells us makes life meaningful. No one has the right to make people miserable at work because we have failed to create the cultures that create commitment, inspiration, and transformation for our patients, their families, and our staff. It is unfortunate that in times of staff shortages, this message is heard louder. We should be equally committed no matter what the situation, because it is the right thing to do. We do not have the right to be abusive to others in any context.


The March Against Onychomycosis: A Systematic Review of the Sanitization Methods for Shoes, Socks, and Textiles.
Drug-based treatment of superficial fungal infections, such as onychomycosis, is not the only defense. Sanitization of footwear such as shoes, socks/stockings, and other textiles is integral to the prevention of recurrence and reduction of spread for superficial fungal mycoses. The goal of this review was to examine the available methods of sanitization for footwear and textiles against superficial fungal infections. A systematic literature search of various sanitization devices and methods that could be applied to footwear and textiles using PubMed, Scopus, and MEDLINE was performed. Fifty-four studies were found relevant to the different methodologies, devices, and techniques of sanitization as they pertain to superficial fungal infections of the feet. These included topics of basic sanitization, antifungal and antimicrobial materials, sanitization chemicals and powder, laundering, ultraviolet, ozone, nonthermal plasma, microwave radiation, essential oils, and natural plant extracts. In the management of onychomycosis, it is necessary to think beyond treatment of the nail, as infections enter through the skin. Those prone to onychomycosis should examine their environment, including surfaces, shoes, and socks, and ensure that proper sanitization is implemented.


Yields of SSB and DSB induced in DNA by Al(K) ultrasoft X-rays and alpha-particles: comparison of experimental and simulated yields.
To compare experimental yields of single strand breaks (SSB) and double strand breaks (DSB) induced in plasmid DNA in aqueous solution by alpha-particles and Al(K) ultrasoft X-rays (USX) with the corresponding yields, generated via computer simulations, for a range of mean diffusion distances of the hydroxyl radical (*OH). Aerobic, aqueous solutions of plasmid DNA were irradiated at 277K with 238Pu alpha-particles or USX in the presence of 10(-4) to 0.33 mol dm(-3) Tris and the yields of SSB and DSB determined by gel electrophoresis. Computer simulations, using Monte Carlo track-structure codes for 1.5keV electrons (CPA100) and 3.2MeV alpha-particle track segments (PITS), were used to obtain yields of DNA SSB and DSB at different *OH scavenger conditions. The experimental yield of SSB and DSB induced by AlK USX and SSB induced by alpha-particles and the dependences on the mean diffusion distance of the *OH are in reasonable agreement with the corresponding simulated yields and their corresponding dependences. However, for DSB induced by alpha-particles, a significant systematic difference exists between the simulated and experimental yields over the full *OH scavenging range, with the simulated yields being a factor of two to three greater than the experimental values. That the simulated yields of strand breaks are generally in reasonable agreement with those determined experimentally over a wide range of *OH scavenging capacities, increases confidence in the use of these simulations as a valuable source of quantitative, mechanistic information on DNA damage induced at very low radiation doses.


Analysis of National Trends in Admissions for Pulmonary Embolism.
Pulmonary embolism (PE) remains a significant cause of hospital admission and health-care costs. Estimates of PE incidence came from the 1990s, and data are limited to describe trends in hospital admissions for PE over the past decade. We analyzed Nationwide Inpatient Sample data from 1993 to 2012 to identify patients admitted with PE. We included admissions with International Classification of Diseases, 9th revision, codes listing PE as the principal diagnosis as well as admissions with PE listed secondary to principal diagnoses of respiratory failure or DVT. Massive PE was defined by mechanical ventilation, vasopressors, or nonseptic shock. Outcomes included hospital lengths of stay, adjusted charges, and all-cause hospital mortality. Linear regression was used to analyze changes over time. Admissions for PE increased from 23 per 100,000 in 1993 to 65 per 100,000 in 2012 (P < .001). The percent of admissions meeting criteria for massive PE decreased (5.3% to 4.4%, P = .002), but the absolute number of admissions for massive PE increased (from 1.5 to 2.8 per 100,000, P < .001). Median length of stay decreased from 8 (interquartile range [IQR], 6-11) to 4 (IQR, 3-6) days (P < .001). Adjusted hospital charges increased from $16,475 (IQR, $10,748-$26,211) in 1993 to $25,728 (IQR, $15,505-$44,493) in 2012 (P < .001). All-cause hospital mortality decreased from 7.1% to 3.2% (P < .001), but population-adjusted deaths during admission for PE increased from 1.6 to 2.1 per 100,000 (P < .001). Total admissions and hospital charges for PE have increased over the past two decades. However, the population-adjusted admission rate has increased disproportionately to the incidence of patients with severe PE. We hypothesize that these findings reflect a concerning national movement toward more admissions of less severe PE.


East meets West: Shadow coaching to support online reflective practice.
A structured, reflection-based electronic portfolio program (ePortfolio), with novel faculty development initiative, involving 'shadow coaches', was shared with the newly formed Ottawa-Shanghai Joint School of Medicine (OSJSM). OSJSM is a partnership between Shanghai Jiao Tong University and the University of Ottawa. As the world's first Sino-Canadian Joint Medical School, OSJSM introduced North American undergraduate medical curriculum to China. 'Shadow coaching' involved trans-Pacific pairing of coaches, supplemented by local faculty development. (a) Pre-implementation: The well-established online ePortfolio platform at the University of Ottawa was mirrored at OSJSM. University of Ottawa ePortfolio coaches were recruited to serve as shadow coaches to their OSJSM counterparts. Shadow coaches provided mentoring and resources while maintaining awareness of cross-cultural issues. Faculty development consisted of face-to-face faculty development in Shanghai, several online synchronous sessions, and familiarization of University of Ottawa coaches with the Chinese medical education system. (b) Description/Components: This intervention, introduced in 2016-2017, involved five University of Ottawa shadow coaches paired with five OSJSM ePortfolio coaches. Student reflection encourages open frank discussion which is a new paradigm for Chinese students and faculty. Shadow coaches were encouraged to challenge new OSJSM coaches to widely explore physician roles and competencies. Initial results indicate that the experience served to effectively develop OSJSM coaches' skills as evidenced by shadow coaches' review of anonymized OSJSM student reflective writing. Our project describes a novel tool using shadow coaching for faculty development for a cross-cultural partnership. Similar approaches can be utilized for culturally-sensitive long-distance faculty development.


Entamoeba histolytica. Phagocytosis as a virulence factor.
In this paper, we attempted to define the role of phagocytosis in the virulence of Entamoeba histolytica. We have isolated, from a highly phagocytic and virulent strain, a clone deficient in phagocytosis. Trophozoites of wild-type strain HM1:IMSS were fed with Escherichia coli strain CR34-Thy- grown on 5-bromo,2'-deoxyuridine. The trophozoites that had incorporated the base analog through phagocytosis of the bacteria were killed by irradiation with 310 nm light. The survivors, presumably trophozoites defective in phagocytosis, were grown until log phase and submitted two more times to the selection procedure. Clone L-6, isolated from a subpopulation resulting from this selection procedure, showed 75-85% less erythrophagocytic activity than the wild-type strain. The virulence of clone L-6 and strain HM1:IMSS was measured. The inoculum required to induce liver abscesses in 50% of the newborn hamsters inoculated (AD50) of HM1:IMSS was 1.5 X 10(4) trophozoites. Clone L-6 trophozoites failed to induce liver abscesses in newborn hamsters even with inocula of 5 X 10(5) trophozoites. Virulence revertants were obtained by successive passage of L-6 trophozoites through the liver of young hamsters. The trophozoites that recovered the ability to produce liver abscesses simultaneously recuperate high erythrophagocytic rates. These results show that phagocytosis is involved in the aggressive mechanisms of E. histolytica.


Proteomics. Tissue-based map of the human proteome.
Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.


The influence of manganese concentration on the sensitivity of bandshape and lifetime luminescent thermometers based on Y3Al5O12:Mn3+,Mn4+,Nd3+ nanocrystals.
Luminescent thermometers based on transition metal and lanthanide ion codoped nanocrystals have become a group of non-contact thermometers which are gaining importance due to their high sensitivity upon temperature changes. Here we present two types of luminescent thermometers, namely, bandshape and lifetime temperature sensors based on Y3Al5O12:Mn3+,Mn4+,Nd3+ nanocrystals. Their ability for temperature sensing was investigated as a function of Mn concentration. It was found that both sensitivity and usable temperature range depend on the Mn concentration. The highest sensitivity (S = 2.69%/K) was found for the lifetime luminescent thermometer with 0.01%Mn concentration and its value is gradually reduced with Mn content. Similarly, in the case of the bandshape luminescent thermometer, the sensitivity decreases from 1.69%/K for 0.01%Mn to 0.54%/K for 1%Mn. On the other hand the usable temperature range extends with dopant concentration. The concentration effect on the temperature dependent optical parameters is discussed in terms of interionic interactions facilitated for shorter Mn-Mn distances.


Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia.
With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as "Clinical Global Impression responders" (defined as Clinical Global Impression Severity of Illness score of < or = 3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P = 0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment.


Framing, truth telling and the problem with non-directive counselling.
In this paper several reasons as to why framing issues should be of greater interest to both medical ethicists and healthcare professionals are suggested: firstly, framing can help in explaining health behaviours that can, from the medical perspective, appear perverse; secondly, framing provides a way of describing the internal structure of ethical arguments; and thirdly, an understanding of framing issues can help in identifying clinical practices, such as non-directive counselling, which may, inadvertently, be failing to meet their own stated ethical aims. The effect of framing on how individuals interpret information and how healthcare choices are influenced by framing are described. Next, the role of framing in ethical discourse is discussed with specific reference to Judith Jarvis Thomson's philosophical mind experiment about abortion and the violinist. Finally, the implications of this analysis are examined for the practice of non-directive counselling, which aims at communicating information in a neutral, value-free way and thereby protecting patient autonomy.


Nursing home nurses conceptualize how to care for residents with cardiac vulnerability.
With ageing, older people face cardiovascular problems as the major cause of disability and death. Although immediate medical attention is a major factor in determining outcomes of cardiac problems, lack of personnel (i.e. registered nurse, certified nursing assistant and home care aide) in nursing homes without residing doctor limits the awareness of such problems, thus making it difficult to initiate timely and appropriate intervention. The aim of this study was to conceptualize critical care for nursing home residents with cardiac vulnerability and develop practical knowledge in nursing practice. Conventional content analysis was performed on date from interviews with 30 nurses from 10 nursing homes in South Korea between July and November 2010. The analysis revealed three major cardiac problems resulting from residents' cardiac vulnerability: angina, myocardial infarction (MI) and cardiogenic shock. Through content analysis, we extracted 6 themes and 21 subthemes for nurses' conceptualization of critical care for nursing home residents with cardiac vulnerability. In nursing homes without a residing doctor, nurses assessed the physical, functional and cognitive conditions along with the responses and symptoms of residents when emergency situations related to the cardiac problems occurred. Moreover, with a lack of infrastructures of a hospital, nurses provided critical care to the elderly by using personal practice strategies based on their personal experience in facilities along with practical knowledge of nurses while following the management principles of emergencies. We found that nurses conceptualized critical nursing care for cardiac problems at nursing homes, which are different from those of general hospitals. The results of this study will provide basis for the development of care guidelines and educational materials that can be used by novice nurses or nursing students.


Deciphering and prediction of transcriptome dynamics under fluctuating field conditions.
Determining the drivers of gene expression patterns is more straightforward in laboratory conditions than in the complex fluctuating environments where organisms typically live. We gathered transcriptome data from the leaves of rice plants in a paddy field along with the corresponding meteorological data and used them to develop statistical models for the endogenous and external influences on gene expression. Our results indicate that the transcriptome dynamics are predominantly governed by endogenous diurnal rhythms, ambient temperature, plant age, and solar radiation. The data revealed diurnal gates for environmental stimuli to influence transcription and pointed to relative influences exerted by circadian and environmental factors on different metabolic genes. The model also generated predictions for the influence of changing temperatures on transcriptome dynamics. We anticipate that our models will help translate the knowledge amassed in laboratories to problems in agriculture and that our approach to deciphering the transcriptome fluctuations in complex environments will be applicable to other organisms.


Prognostic factors for persistent pain after a first episode of nonspecific idiopathic, non-traumatic neck pain: A systematic review.
Prognosis of acute idiopathic neck pain is poor. An overview of modifiable and non-modifiable prognostic factors for the development of chronic musculoskeletal neck pain after an episode of idiopathic, non-traumatic neck pain is needed. Identify prognostic factors for pain intensity and perceived non-recovery at three, six and 12 months after a first episode of idiopathic, non-traumatic neck pain. Systematic review METHODS: Systematic literature search up to October 21, 2017 for prospective prognostic studies with main outcomes perceived non-recovery and pain intensity. The QUIPS was used for quality assessment. Out of 2737 screened articles six prospective studies with high-risk-of-bias were identified, analyzing 47 and 43 factors for the outcome variables 'pain intensity' and 'perceived non-recovery', respectively. Based on univariate- and multivariate analyses we found moderate evidence for 'age> 40 years' and 'concomitant back pain' to be prognostic for 'pain intensity'. For the outcome 'perceived non-recovery' at 12 months, we found moderate evidence for both 'a previous period of neck pain' and 'accompanying headache' as prognostic variables for persistent pain, based on univariate analysis. No prognostic factor was found which was retained in more than one multivariate analysis for the outcome variable 'perceived non-recovery'. However, the quality of the evidence for these prognostic factors was low to very low. This review identifies prognostic factors for neck pain, of which only a few are modifiable. Further research is needed before drawing definite conclusions about the prognostic value of these factors.


A neural model of the scintillating grid illusion: disinhibition and self-inhibition in early vision.
A stationary display of white discs positioned on intersecting gray bars on a dark background gives rise to a striking scintillating effect--the scintillating grid illusion. The spatial and temporal properties of the illusion are well known, but a neuronal-level explanation of the mechanism has not been fully investigated. Motivated by the neurophysiology of the Limulus retina, we propose disinhibition and self-inhibition as possible neural mechanisms that may give rise to the illusion. In this letter, a spatiotemporal model of the early visual pathway is derived that explicitly accounts for these two mechanisms. The model successfully predicted the change of strength in the illusion under various stimulus conditions, indicating that low-level mechanisms may well explain the scintillating effect in the illusion.


Optical encryption using multiple intensity samplings in the axial domain.
Image encryption with optical means has attracted attention due to its inherent multidimensionality and degrees of freedom, including phase, amplitude, polarization, and wavelength. In this paper, we propose an optical encoding system based on multiple intensity samplings of the complex-amplitude wavefront with axial translation of the image sensor. The optical encoding system is developed based on a single optical path, where multiple diffraction patterns, i.e., ciphertexts, are sequentially recorded through the axial translation of a CCD camera. During image decryption, an iterative phase retrieval algorithm is proposed for extracting the plaintext from ciphertexts. The results demonstrate that the proposed phase retrieval algorithm possesses a rapid convergence rate during image decryption, and high security can be achieved in the proposed optical cryptosystem. In addition, other advantages of the proposed method, such as high robustness against ciphertext contaminations, are also analyzed.


Axonal neuregulin 1 type III activates NF-kappaB in Schwann cells during myelin formation.
The formation of myelin requires a series of complex signaling events initiated by the axon to surrounding glial cells, which ultimately respond by tightly wrapping the axon with layers of specialized plasma membrane thereby allowing for saltatory conduction. Activation of the transcription factor NF-kappaB in Schwann cells has been suggested to be critical for these cells to differentiate into a myelinating phenotype; however, the mechanisms by which it is activated have yet to be elucidated. Here, we demonstrate that axonal membranes are sufficient to promote NF-kappaB activation in cultured Schwann cells and identify neuregulin 1 (NRG1), specifically the membrane-bound type III isoform, as the signal responsible for activating this transcription factor. Surprisingly, neither membrane-bound type I nor the soluble NRG1 EGF domain could activate NF-kappaB, indicating that type III induces a qualitatively unique signal. The transcriptional activity of NF-kappaB was significantly enhanced by treatment with forskolin, indicating these two signals converge for maximal activation. Both ErbB2 and -3 receptors were required for transducing the NRG1 signal, because gene deletion of ErbB3 in Schwann cells or treatment with the ErbB2 selective inhibitor, PKI-166, prevented the stimulation of NF-kappaB by axonal membranes. Finally, PKI-166 blocked the activation of the transcription factor in myelinating neuron/Schwann cell co-cultures and in vivo, in developing sciatic nerves. Taken together, these data establish NRG1 type III as the activator of NF-kappaB during myelin formation.


Toward point-of-care ultrasound estimation of fetal gestational age from the trans-cerebellar diameter using CNN-based ultrasound image analysis.
Obstetric ultrasound is a fundamental ingredient of modern prenatal care with many applications including accurate dating of a pregnancy, identifying pregnancy-related complications, and diagnosis of fetal abnormalities. However, despite its many benefits, two factors currently prevent wide-scale uptake of this technology for point-of-care clinical decision-making in low- and middle-income country (LMIC) settings. First, there is a steep learning curve for scan proficiency, and second, there has been a lack of easy-to-use, affordable, and portable ultrasound devices. We introduce a framework toward addressing these barriers, enabled by recent advances in machine learning applied to medical imaging. The framework is designed to be realizable as a point-of-care ultrasound (POCUS) solution with an affordable wireless ultrasound probe, a smartphone or tablet, and automated machine-learning-based image processing. Specifically, we propose a machine-learning-based algorithm pipeline designed to automatically estimate the gestational age of a fetus from a short fetal ultrasound scan. We present proof-of-concept evaluation of accuracy of the key image analysis algorithms for automatic head transcerebellar plane detection, automatic transcerebellar diameter measurement, and estimation of gestational age on conventional ultrasound data simulating the POCUS task and discuss next steps toward translation via a first application on clinical ultrasound video from a low-cost ultrasound probe.


Comparison of genomic DNAs of different enterococcal isolates using restriction endonucleases with infrequent recognition sites.
Epidemiologic evaluation of enterococci has been limited by the lack of a simple and effective method for comparing strains. In this study, we have compared chromosomal restriction endonuclease digestion patterns of 27 isolates of Enterococcus faecalis from three different locations by using pulsed-field electrophoresis of large chromosomal fragments (14 to 1,000 kilobases). All but two isolates generated a clear, evaluable pattern with a single lysis and digestion, and the remaining two were visualized when a larger quantity of bacteria was used. All isolates from different locations generated different restriction patterns, as did most isolates within a single location; there was also evidence of spread of strains between individuals in each location. The ease with which this analysis can be performed, together with the clarity and polymorphism seen in the patterns, suggests that this technique will be very useful for epidemiological evaluations of nosocomial enterococcal infections.


A computerized technique for the display and comparison of regional cerebral blood flow data.
A technique is described by which the sizes, shape and orientation of the brain with respect to detector positioning can be reproduced by computerized simulation. Head size is estimated from the distance between the external acoustic meatus (EAM) and the outer canthus and head shape is determined from the length and height of the skull. These values are used to magnify and alter the shape of a standard brain outline to comply with individual patient measurements. The location of the EAM and nasion are used to establish the displacement and rotation of the orbito-meatal base line with respect to the detector holding assembly. The corrected brain outline is then rotated, centered and displayed superimposed on the regional flow data. Comparison of flow data from 2 studies is accomplished by mapping each probe location onto the standard brain and projecting these brain coordinates onto the second study. Flow data from the nearest detectors are averaged to obtain the interpolated flow value for that brain region. This method corrects for differences in head size and shape between patients and for changes in head positioning and rotation between studies. Computer simulation studies demonstrated that this correction procedure can significantly reduce the variance of flow measurements for expected ranges of head size and orientation.


[A case of a univentricular heart developed subaortic stenosis after fontan operation].
The patient was a seven-old-boy with univentricular heart of left ventricular morphology with transposition of the great arteries and coarctation of the Aorta. Pulmonary artery banding and coarctactomy (subclavian flap method) were performed as prior surgery during infancy and significant subaortic stenosis (SAS) was not identified before or immediately after Fontan operation. SAS was suspected in an ejection murmur that developed without symptoms two years and five months after Fontan operation. It became clear that the SAS was caused by both restrictive ventricular septal defect and narrowing of outlet chamber (right ventricle). Surgery was performed with myectomy in the outlet chamber, enlargement of ventricular septal defect and a patch enlargement of the right ventricle outflow tract for relief of the SAS. Postoperative pressure gradient across the subaortic component was decreased, however, valve regurgitation remained grade I to II. The mechanisms of SAS after Fontan operation are related to hypertrophy of the subaortic component that incorporates the infundibulum and trabeculae. Careful morphological investigation is essential in patients with risk factors for SAS Mild deterioration of the ventricular compliance due to progressive SAS may result in reduction of the cardiac function and patient's quality of life. Adequate surgical treatment to relieve the SAS is considered essential before and after Fontan operation.


Mechanism of action of a human interleukin 1 inhibitor.
The urine of febrile humans contains a 30- to 35-Kda glycoprotein (febrile inhibitor) that inhibits interleukin 1 (IL-1)-induced proliferation of murine thymocytes. In the present investigation, the mechanism of action of this febrile inhibitor was analyzed. The inhibitor was not cytotoxic for thymocytes and it did not act by inhibiting the uptake or incorporation of [3H]TdR. The effects of the inhibitor were not blocked by indomethacin, suggesting that it was not acting by a prostaglandin-mediated pathway. The inhibitor appeared to be acting at a later stage of the cell activation sequence, since it was still effective when added as late as 48 hr after the addition of IL-1. However, it did not block the ability IL-1 to bind and activate thymocytes but did block the proliferation of IL-1-primed cells. The inhibitor did not suppress the activation of thymocytes induced by concanavalin A, but did block the augmentation of this response by IL-1. These results suggest that the target of the febrile inhibitor is on IL-1-primed thymocytes, and that it acts at a stage after the initial activation of the cell by IL-1.


Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.
Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.


Finite bandwidth and scattered light effects on the radiometric determination of atmospheric turbidity and the solar constant.
Multispectral solar radiometric measurements are routinely performed at a large number of sites, using equipment of varying degrees of sophistication. From the standard Langley plot technique, one may extract the total optical thickness of the atmosphere (and hence the aerosol component) plus the extraterrestrial solar flux. With increasing concern about possible climatic effects of increased turbidity, or changes in the solar constant, it is becoming more important to know the expected accuracy of these results. In this paper, we analytically examine the effects of finite filter bandwidth (in the absence of spectral lines) and find them to be less than one part in a thousand. This is compared with our earlier results on the effects of scattered light, which turns out to be typically an order of magnitude larger.


Pharmacological characterization of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel transient receptor potential vanilloid 1 antagonist.
Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [(3)H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA(2) values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC(50) values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC(50) values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.


Reverse transcription polymerase chain reaction-based method for selectively detecting vegetative cells of toxigenic Clostridium difficile.
The laboratory diagnostic methods for Clostridium difficile infection (CDI) include toxigenic culture, enzyme immunoassays (EIAs) to detect the toxins of C. difficile, and nucleic acid amplification tests (NAATs) to detect C. difficile toxin genes, but each of these methods has disadvantages; toxigenic cultures require a long time to produce results, EIAs have low sensitivity, and NAATs that target DNA cannot distinguish vegetative cells from spores and dead cells. Here we report a new detection method that uses reverse transcription polymerase chain reaction to target the toxin-gene transcripts. This method was able to specifically detect the vegetative cells of toxigenic C. difficile in fecal samples in spike tests, with a minimum detection limit of 5 × 10(2) colony-forming units per 100 mg of stool specimen. The performance of this method was also demonstrated in a pilot scale evaluation using clinical fecal specimens, which showed that this method may be more sensitive than EIA and requires a shorter time than toxigenic culture. This method could potentially be applied in the clinical laboratory to detect C. difficile in fecal specimens. The ability of this method to discriminate the presence of vegetative cells from spores and dead cells could help to further the understanding of CDI.


Lipidomic analysis of plasma samples from women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common disorder affecting between 5 and 18 % of females of reproductive age and can be diagnosed based on a combination of clinical, ultrasound and biochemical features, none of which on its own is diagnostic. A lipidomic approach using liquid chromatography coupled with accurate mass high-resolution mass-spectrometry (LC-HRMS) was used to investigate if there were any differences in plasma lipidomic profiles in women with PCOS compared with control women at different stages of menstrual cycle. Plasma samples from 40 women with PCOS and 40 controls aged between 18 and 40 years were analysed in combination with multivariate statistical analyses. Multivariate data analysis (LASSO regression and OPLS-DA) of the sample lipidomics datasets showed a weak prediction model for PCOS versus control samples from the follicular and mid-cycle phases of the menstrual cycle, but a stronger model (specificity 85 % and sensitivity 95 %) for PCOS versus the luteal phase menstrual cycle controls. The PCOS vs luteal phase model showed increased levels of plasma triglycerides and sphingomyelins and decreased levels of lysophosphatidylcholines and phosphatidylethanolamines in PCOS women compared with controls. Lipid biomarkers of PCOS were tentatively identified which may be useful in distinguishing PCOS from controls especially when performed during the menstrual cycle luteal phase.


Approaches, Progress, and Challenges to Hepatitis C Vaccine Development.
Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.


Vitamin D and COVID-19: evidence and recommendations for supplementation.
Vitamin D is a hormone that acts on many genes expressed by immune cells. Evidence linking vitamin D deficiency with COVID-19 severity is circumstantial but considerable-links with ethnicity, obesity, institutionalization; latitude and ultraviolet exposure; increased lung damage in experimental models; associations with COVID-19 severity in hospitalized patients. Vitamin D deficiency is common but readily preventable by supplementation that is very safe and cheap. A target blood level of at least 50 nmol l-1, as indicated by the US National Academy of Medicine and by the European Food Safety Authority, is supported by evidence. This would require supplementation with 800 IU/day (not 400 IU/day as currently recommended in UK) to bring most people up to target. Randomized placebo-controlled trials of vitamin D in the community are unlikely to complete until spring 2021-although we note the positive results from Spain of a randomized trial of 25-hydroxyvitamin D3 (25(OH)D3 or calcifediol) in hospitalized patients. We urge UK and other governments to recommend vitamin D supplementation at 800-1000 IU/day for all, making it clear that this is to help optimize immune health and not solely for bone and muscle health. This should be mandated for prescription in care homes, prisons and other institutions where people are likely to have been indoors for much of the summer. Adults likely to be deficient should consider taking a higher dose, e.g. 4000 IU/day for the first four weeks before reducing to 800 IU-1000 IU/day. People admitted to the hospital with COVID-19 should have their vitamin D status checked and/or supplemented and consideration should be given to testing high-dose calcifediol in the RECOVERY trial. We feel this should be pursued with great urgency. Vitamin D levels in the UK will be falling from October onwards as we head into winter. There seems nothing to lose and potentially much to gain.


Growth and total body water in premature infants fed "in-utero" or "ex-utero".
Total body water and anthropometric measurements were compared in two groups of premature infants. The first group included infants with birthweights less than 1,501 g who were fed under usual clinical circumstances and studied at a bodyweight of 1,800-2,100 g ("Ex-utero"); the second group of infants had a birthweight of 1,800 to 2,100 g and were studied within the first week of life ("In-utero"). Triceps and subscapular skinfold thicknesses were significantly greater in "Ex-utero" infants than in "In-utero" infants, whereas body length was significantly greater in the latter group compared to the former. There were no difference in total body water, abdominal skinfold thickness, or midarm circumference between the two groups. These data suggest that feeding premature infants a standard premature infant formula under established guidelines leads to differences in body and fat distribution but not total body water compared to infants nourished "in utero".


The relation of the conceptual self to recent and distant autobiographical memories.
Based on the self-memory system model (SMS; Conway, Singer, & Tagini, 2004) of autobiographical memory, this study uses a large sample of young and middle-aged adults to investigate the relation between individuals' current self-characteristics and the content of both their earliest childhood memory and a recent memory. In the first session, participants' current self-characteristics were assessed. In the second session, individuals provided a written narrative of their earliest childhood memory and a more recent memory (within-participants design) and rated the self themes present in each memory. In keeping with the SMS model, findings show that current self-characteristics were reflected in individuals' memories. As predicted, however, recent memories were more frequently linked to current self-characteristics than were earliest memories. All six current self-characteristics predicted the inclusion of these themes in recent memories, but only four self-characteristics were associated with memory themes in earliest memories. The relation between current self-characteristics and memory themes did not differ across young and middle-aged adults, suggesting developmental stability in these relations. Findings provide general support for the SMS model but also suggest possibilities for its extension and refinement.


Local anesthetic wound infiltration for pain management after periacetabular osteotomy. A randomized, placebo-controlled, double-blind clinical trial with 53 patients.
To our knowledge, there is no evidence to support the use of local infiltration analgesia (LIA) for postoperative pain relief after periacetabular osteotomy (PAO). We investigated the effect of wound infiltration with a long-acting local anesthetic (ropivacaine) for postoperative analgesia after PAO. We performed a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov: NCT00815503) in 53 patients undergoing PAO to evaluate the effect of local anesthetic infiltration on postoperative pain and on postoperative opioid consumption. All subjects received intraoperative infiltration followed by 5 postoperative injections in 10-hour intervals through a multi-holed catheter placed at the surgical site. 26 patients received ropivacaine and 27 received saline. The intervention period was 2 days and the observational period was 4 days. All subjects received patient-controlled opioid analgesia without any restrictions on the total daily dose. Pain was assessed at specific postoperative time points and the daily opioid usage was registered. Infiltration with 75 mL (150 mg) of ropivacaine did not reduce postoperative pain or opioid requirements during the first 4 days. The clinical importance of ropivacaine as single component in postoperative treatment of pain is questionable, and we are planning further studies to explore the potential of LIA in larger volume-and also a multimodal regimen-to treat pain in this category of patients.


Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes.
Increased plasma concentrations of circulating adhesion molecules in patients with Type II (non-insulin-dependent) diabetes mellitus could be associated with the increased cardiovascular risk in these patients. However, it is controversial whether increased adhesion molecule plasma concentrations are primarily related to hyperglycaemia or to hyperinsulinaemia. We evaluated the plasma concentrations of soluble E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) at baseline and during euglycaemic hyperinsulinaemic clamp in three different groups without additional cardiovascular risk factors: group A (control group), 28 healthy volunteers with normal glucose tolerance; group B, 24 subjects with fasting hyperinsulinaemia, normal fasting glucose but impaired glucose tolerance; group C, 32 patients with Type II diabetes, fasting hyperinsulinaemia and chronic hyperglycaemia. Plasma soluble E-selectin, ICAM-1, and VCAM-1 concentrations were higher ( p < 0.05) in patients with Type II diabetes (group C) compared with the other groups. The adhesion molecule concentrations correlate with the fasting plasma glucose ( r = 0.59, p < 0.001), the 2-h OGTT plasma glucose ( r = 0.70, p < 0.01), and the HbA(1 c) value ( r = 0.61, p < 0.05). The E-selectin but not the ICAM-1 and VCAM-1 plasma concentrations correlated with the fasting insulin concentrations ( r = 0.62, p < 0.05) or the whole body glucose uptake ( r = 0.59, p < 0.05) in the clamp. The hyperinsulinaemia during the euglycaemic hyperinsulinaemic clamp had no significant effect on the plasma concentrations of E-selectin, ICAM-1, and VCAM-1 in all three groups. Our results suggest that increased E-selectin concentrations are related to hyperglycaemia, hyperinsulinaemia and insulin resistance, whereas increased ICAM-1 and VCAM-1 plasma concentrations in patients with Type II diabetes are rather related to hyperglycaemia than to hyperinsulinaemia or insulin resistance.


3D printed quantum dot light-emitting diodes.
Developing the ability to 3D print various classes of materials possessing distinct properties could enable the freeform generation of active electronics in unique functional, interwoven architectures. Achieving seamless integration of diverse materials with 3D printing is a significant challenge that requires overcoming discrepancies in material properties in addition to ensuring that all the materials are compatible with the 3D printing process. To date, 3D printing has been limited to specific plastics, passive conductors, and a few biological materials. Here, we show that diverse classes of materials can be 3D printed and fully integrated into device components with active properties. Specifically, we demonstrate the seamless interweaving of five different materials, including (1) emissive semiconducting inorganic nanoparticles, (2) an elastomeric matrix, (3) organic polymers as charge transport layers, (4) solid and liquid metal leads, and (5) a UV-adhesive transparent substrate layer. As a proof of concept for demonstrating the integrated functionality of these materials, we 3D printed quantum dot-based light-emitting diodes (QD-LEDs) that exhibit pure and tunable color emission properties. By further incorporating the 3D scanning of surface topologies, we demonstrate the ability to conformally print devices onto curvilinear surfaces, such as contact lenses. Finally, we show that novel architectures that are not easily accessed using standard microfabrication techniques can be constructed, by 3D printing a 2 × 2 × 2 cube of encapsulated LEDs, in which every component of the cube and electronics are 3D printed. Overall, these results suggest that 3D printing is more versatile than has been demonstrated to date and is capable of integrating many distinct classes of materials.


National approaches to managing cancer care: responses of countries in the MENA region to the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic presents serious challenges to cancer care because of the associated risks from the infection itself and the disruption of care delivery. Therefore, many professional societies have published recommendations to help manage patients with cancer during the current pandemic. The objective of our study is to assess the national responses of Middle East North Africa (MENA) countries in terms of publishing relevant guidelines and analyse various components of these guidelines. A survey based on the preliminary review of the literature regarding cancer care adaptations has been developed and then completed by a group of oncologists from the following Arab countries affected by the pandemic: Algeria, Egypt, Iraq, Jordan, Kuwait, Lebanon, Morocco, Oman, Saudi Arabia, Syria, Tunisia, United Arab Emirates and Yemen. The survey inquired about COVID-19 cases, national recommendations regarding general measures of COVID-19 prevention and patient care in oncology as well as their implementation about cancer care adaptations during the pandemic. Analysis of the COVID-19 pandemic-related guidelines revealed at least 30 specific recommendations that we categorised into seven essential components. All included countries had national guidelines except one country. Estimated full compliances with all specific category recommendations ranged from 30% to 69% and partial compliance ranged from 23% to 61%. There is a very good response and preparedness in the Arab Middle East and North Africa region surveyed. However, there are inconsistencies in the various components of the guidelines across the region, which reflects the evolving status of the pandemic in each country as well as the lack of clear evidence-based guidelines for many of the issues in question. There is a need for a clear framework on essential components that should be included in these guidelines to assure providing the best guidance to the oncology community.


Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study.
The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.