Combined Effect of Number of Players and Dribbling on Game-Based-Drill Demands in Basketball.
To examine the physiological, physical, and technical demands of game-based drills (GBDs) with regular dribble (RD) or no dribble (ND) involving a different number of players (3 vs 3, 4 vs 4, and 5 vs 5). Ten regional-level male basketball players performed 6 full-court GBD formats (each consisting of 3 bouts of 4 min and 2 min rest) on multiple occasions. The physiological and perceptual responses were measured through heart rate and rating of perceived exertion. Video-based time-motion analysis was performed to assess the GBD physical demands. The frequencies of occurrence and the duration were calculated for high-intensity, moderate-intensity, low-intensity, and recovery activities. Technical demands were assessed with a notional-analysis technique. A 2-way repeated-measures analysis of variance was used to assess statistical differences between GBD formats. A greater perceptual response (rating of perceived exertion) was recorded during 3 versus 3 than 5 versus 5 formats (P = .005). Significant interactions were observed for the number of recovery (P = .021), low-intensity activity (P = .007), and all movements (P = .001) completed. Greater time was spent performing low-intensity and high-intensity activities during RD than ND format. Greater technical demands were observed for several variables during 3 versus 3 than 4 versus 4 or 5 versus 5. A greater number of turnovers (P = .027), total (P ≤ .001), and correct passes (P ≤ .001) were recorded during ND than RD format. The number of players predominantly affected the perceptual response to GBD, while both the number of players and rule modification (RD vs ND) affected activities performed during GBD. Reducing the number of players increases the GBD technical elements, while ND format promotes a greater number of turnovers and passes.


Evaluation of different analytical methods to assess failure of passive transfer in neonatal calves.
The objective of this study was to evaluate different analytical methods of assessing failure of passive transfer (FPT) in neonatal calves. We hypothesized that 3 different media (i.e., centrifuged serum, centrifuged plasma, filtered plasma) and different analytical methods [i.e., ELISA, capillary electrophoresis (CE), Brix refractometer, and handheld optical refractometer] would be highly correlated with the gold standard radial immunodiffusion (RID) and would generate comparable results. Serum and plasma blood samples were collected from Holstein Friesian calves (n = 216) aged 1 to 7 d, from 2 commercial dairy herds in northeast Germany. The RID analysis showed that 59 of 216 calves (27%) had serum IgG concentrations of <10 mg/mL and 157 calves (73%) had serum concentrations of ≥10 mg/mL. The mean IgG concentration (± standard deviation) was 17.1 ± 9.8 mg/mL, and the range was 0.8 to 47.8 mg/mL. In serum, the correlation between RID and CE was r = 0.97, and between RID and ELISA was r = 0.90; CE and ELISA were also highly correlated (r = 0.89). Both refractometry methods were highly correlated with RID using centrifuged serum, centrifuged plasma, or filtered plasma (Brix refractometer: r = 0.84, 0.80, and 0.78, respectively; handheld optical refractometer: r = 0.83, 0.81, and 0.80, respectively). We determined test characteristics (optimum thresholds, sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve) for CE, ELISA, and the handheld optical and digital refractometers using receiver operating characteristic curve analyses with RID as the reference value. Optimal thresholds for assessing FPT using plasma were higher than for serum, regardless of the method of plasma harvesting. The 4 different devices had comparable areas under the curve, irrespective of the medium used. All analytical methods can be used to assess FPT.


Cyclin D2 Overexpression Enhances the Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Myocardial Repair in a Swine Model of Myocardial Infarction.
Human induced pluripotent stem cells with normal (wild-type) or upregulated (overexpressed) levels of CCND2 (cyclin D2) expression were differentiated into cardiomyocytes (CCND2WTCMs or CCND2OECMs, respectively) and injected into infarcted pig hearts. Acute myocardial infarction was induced by a 60-minute occlusion of the left anterior descending coronary artery. Immediately after reperfusion, CCND2WTCMs or CCND2OECMs (3×107 cells each) or an equivalent volume of the delivery vehicle was injected around the infarct border zone area. The number of the engrafted CCND2OECMs exceeded that of the engrafted CCND2WTCMs from 6- to 8-fold, rising from 1 week to 4 weeks after implantation. In contrast to the treatment with the CCND2WTCMs or the delivery vehicle, the administration of CCND2OECM was associated with significantly improved left ventricular function, as revealed by magnetic resonance imaging. This correlated with reduction of infarct size, fibrosis, ventricular hypertrophy, and cardiomyocyte apoptosis, and increase of vascular density and arterial density, as per histologic analysis of the treated hearts. Expression of cell proliferation markers (eg, Ki67, phosphorylated histone 3, and Aurora B kinase) was also significantly upregulated in the recipient cardiomyocytes from the CCND2OECM-treated than from the CCND2WTCM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured human induced pluripotent stem cell cardiomyocytes were significantly greater after treatment with exosomes isolated from the CCND2OECMs (CCND2OEExos) than from the CCND2WTCMs (CCND2WTExos). As demonstrated by our study, CCND2OEExos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2OEExos versus CCND2WTExos identified 206 and 91 miRNAs that were significantly upregulated and downregulated, respectively. Gene ontology enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis. We demonstrated that enhanced potency of CCND2OECMs promoted myocyte proliferation in both grafts and recipient tissue in a large mammal acute myocardial infarction model. These results suggest that CCND2OECMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.


[Transmissibility and severity of the pandemic influenza A (H1N1) 2009 virus in Spain].
To estimate the value of the basic reproduction number for the pandemic wave of influenza A (H1N1) 2009 in Spain and to assess its impact on morbidity and mortality in the Spanish population compared with those in the previous influenza season. Data on the incidence of influenza and viral detections were obtained from the Spanish Influenza Surveillance System. Deaths from pandemic influenza were obtained from the Coordinating Center for Health Alerts and Emergencies of the Spanish Ministry of Health and Social Policy, and deaths from seasonal influenza during the period 2003-2008 were obtained from the National Statistics Institute. The reproduction number was estimated by two methods: firstly, by using the growth rate of the cumulative incidence of influenza during the exponential growth phase of the pandemic wave, and secondly (maximum likelihood estimation), through analysis the dates of onset of symptoms observed in pairs of cases based on generation time distribution. We calculated the fatality rate and mortality from influenza by comparing potential years of life lost in the pandemic season with those in previous interpandemic seasons. The start of the pandemic wave occurred in Spain earlier in week 40/2009 (from 4 to 10 October), with an absolute predominance of the new strain in the pattern of circulating viruses. The value of R(0) in the growth phase of the wave was 1.29 (95% CI: 1.25-1.33), estimated with the first method, and was 1.01 (95% CI: 0.99-1.03) with the second method. During the pandemic season, there were 318 deaths from pandemic influenza, affecting younger age groups than in previous interpandemic seasons. Consequently, the number of potential years of life lost in the pandemic season (11,612) was estimated at six times the adjusted annual average of the interpandemic influenza seasons for comparison (1,802). The estimates of R(0) for the growth phase of the pandemic wave were in the lower range of estimates of this parameter in previous pandemics. Mortality indicators calculated in the pandemic period showed an increase in deaths compared with previous interpandemic seasons, which was most pronounced in young patients.


Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.
Renal transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (-XM) transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and -XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of -XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates.


Severe Molecular Defects Exhibited by the R179H Mutation in Human Vascular Smooth Muscle α-Actin.
Mutations in vascular smooth muscle α-actin (SM α-actin), encoded by ACTA2, are the most common cause of familial thoracic aortic aneurysms that lead to dissection (TAAD). The R179H mutation has a poor patient prognosis and is unique in causing multisystemic smooth muscle dysfunction (Milewicz, D. M., Østergaard, J. R., Ala-Kokko, L. M., Khan, N., Grange, D. K., Mendoza-Londono, R., Bradley, T. J., Olney, A. H., Ades, L., Maher, J. F., Guo, D., Buja, L. M., Kim, D., Hyland, J. C., and Regalado, E. S. (2010) Am. J. Med. Genet. A 152A, 2437-2443). Here, we characterize this mutation in expressed human SM α-actin. R179H actin shows severe polymerization defects, with a 40-fold higher critical concentration for assembly than WT SM α-actin, driven by a high disassembly rate. The mutant filaments are more readily severed by cofilin. Both defects are attenuated by copolymerization with WT. The R179H monomer binds more tightly to profilin, and formin binding suppresses nucleation and slows polymerization rates. Linear filaments will thus not be readily formed, and cells expressing R179H actin will likely have increased levels of monomeric G-actin. The cotranscription factor myocardin-related transcription factor-A, which affects cellular phenotype, binds R179H actin with less cooperativity than WT actin. Smooth muscle myosin moves R179H filaments more slowly than WT, even when copolymerized with equimolar amounts of WT. The marked decrease in the ability to form filaments may contribute to the poor patient prognosis and explain why R179H disrupts even visceral smooth muscle cell function where the SM α-actin isoform is present in low amounts. The R179H mutation has the potential to affect actin structure and function in both the contractile domain of the cell and the more dynamic cytoskeletal pool of actin, both of which are required for contraction.


When deaf signers read English: do written words activate their sign translations?
Deaf bilinguals for whom American Sign Language (ASL) is the first language and English is the second language judged the semantic relatedness of word pairs in English. Critically, a subset of both the semantically related and unrelated word pairs were selected such that the translations of the two English words also had related forms in ASL. Word pairs that were semantically related were judged more quickly when the form of the ASL translation was also similar whereas word pairs that were semantically unrelated were judged more slowly when the form of the ASL translation was similar. A control group of hearing bilinguals without any knowledge of ASL produced an entirely different pattern of results. Taken together, these results constitute the first demonstration that deaf readers activate the ASL translations of written words under conditions in which the translation is neither present perceptually nor required to perform the task.


Experimental and mathematical evidence that thrombin-binding aptamers form a 1 aptamer:2 protein complex.
The thrombin-binding 15mer and 29mer ssDNA aptamers are a widely used model system. Despite their ubiquity, controversies persist regarding the nature of the aptamer-protein interactions. Reported affinities vary widely; the role of metal ions in binding is unclear; the structure of the complex is contested. We interrogated the effects of instrument, buffer, and mathematical model on apparent affinities of thrombin aptamers for their target. Instrumental method had a pronounced effect on affinity constants for the 15mer and marginal effect the apparent affinity of the 29mer. Buffer composition and ionic environment did not have significant effects. Affinity probe capillary electrophoresis experiments revealed distinct peaks from samples of 29mer aptamer and thrombin, supporting the model of a 1 aptamer:2 protein complex. Fits to high quality data with five mathematical models further support this stoichiometry, as the binding of both aptamers was best described by the Hill equation with Hill coefficients > 1. Our results indicate that the instrumental method and mathematical model influence apparent affinity of thrombin aptamers and that both aptamers bind thrombin in a 1 aptamer: 2 protein stoichiometry through an induced fit mechanism.


The clinical features of bipolar depression: a comparison with matched major depressive disorder patients.
Despite a resurgence of interest in the treatment of bipolar depression, there have been few controlled studies of the clinical characteristics of this condition. Identification of any distinctive clinical "signatures" of bipolar depression would be helpful in determining treatment options in the clinical setting. From a cohort of 270 inpatients and outpatients assessed in detail during a DSM-IV major depressive episode, 39 bipolar I disorder patients were identified and closely matched with 39 major depressive disorder patients for gender, age, and the presence or absence of DSM-IV melancholic subtype. Patients were compared on a broad range of parameters including the Hamilton Rating Scale for Depression (depression severity), 54 depressive symptoms, the Newcastle Endogenous Depression Diagnostic Index, 3 family history items, 2 physical health items, the CORE scale (psychomotor disturbance), and 5 history items. Although the bipolar patients were no more severely depressed than the major depressive disorder controls, they were more likely to demonstrate psychomotor-retarded melancholic and atypical depressive features and to have had previous episodes of psychotic depression. These findings were largely duplicated even when the population was confined to those with DSM-IV melancholia. The clinical admixture of psychomotor-retarded melancholic signs and symptoms, "atypical" features, and (less frequently) psychosis may provide a "bipolar signature" in clinical scenarios when there is uncertainty concerning the polarity of a depressive presentation.


Trypanosomatids in honey bee colonies in Spain: A new specific qPCR method for specific quantification of Lotmaria passim, Crithidia mellificae and Crithidia bombi.
Bee trypanosomatids have not been widely studied due to the original belief that these organisms were not pathogenic to honey bees. However, trypanosomatids have been linked to increased winter mortality in honey bee colonies in recent years and it has been shown that these pathogens can shorten a honey bee worker's lifespan in laboratory conditions. These studies found that this mortality corresponded to dose-dependent infection. Although Lotmaria passim is the most prevalent species worldwide, the natural load in colonies remains poorly investigated. Here we describe a new highly specific and sensitive qPCR method that allows the differentiation and quantification of the parasitic load of each of the three most common trypanosomatid species described to date in honey bee colonies: L. passim, Crithidia mellificae, and Crithidia bombi. We have used this new method to analyze honey bee colonies in central Spain and confirm that L. passim is the most common species and the one with higher parasitic loads in the colonies, which increased over the years, being higher in spring than in autumn. Crithidia mellificae was present along the study, with the highest prevalence in autumn 2019 and lately it was only found in non-quantifiable loads. Crithidia bombi was not detected in any of the colonies analyzed.


Comparison of porcine brain mechanical properties to potential tissue simulant materials in quasi-static and sinusoidal compression.
In both finite element and physical surrogate models of head blast injury, accurate material properties of the brain and/or tissue simulants are necessary to ensure biofidelity in predicted response. Thus, there is a need for experimental comparisons between tissue and simulant materials under the same experimental conditions. This study compares the response of porcine brain tissue and a variety of brain tissue simulants in quasi-static and sinusoidal compression tests. Fresh porcine brain tissue was obtained from a local abattoir and tested within 4 h post mortem. Additionally, the effect of post mortem time was investigated by comparing samples stored at room temperature and stored frozen (-18 °C), at various time intervals. The brain tissue simulants tested were bovine gelatin (3%, 5%, and 10% concentration), agarose gelatin (e0.4%, 0.6%, 0.8% concentration), and Sylgard 527. The experiments were performed using a DMA apparatus (TA Instruments Q800). The quasi-static compression data were fit to Ogden hyperelastic functions so that parameters could be compared. It was found that bovine gelatin at 3% and 5% concentration demonstrated the closest response to brain tissue in quasi-static compression. Conversely, in sinusoidal compression, the agarose gel and Sylgard 527 were found to be in closer agreement with the tissue, than bovine gel. In terms of post mortem time and storage, there was no statistically significant difference detected in the response of tissue samples after 48 h, regardless of storage method. However, samples stored at room temperature after 48 h appeared to demonstrate a reduction in stiffness.


A novel approach to expedite wound healing with plasma brush of cold flame.
Excessive or persistent infection is a major contributing factor in impeding chronic wound healing. Wound bed preparations using antiseptics do not necessarily target the entire bacterial spectrum, and the highly proliferating granulation tissue may be sensitive to the cytotoxic effects, impairing tissue repair. Non-thermal gas atmospheric pressure plasmas are partially ionized gases that contain highly reactive particles while the gas phase remains near room temperature, thus having the capability of accessing small irregular cavities and fissures and killing bacteria because of the diffusive nature of gas phase plasma species that are chemically reactive, providing an ideal approach to topical wound disinfection. A non-thermal plasma brush device of novel design has been developed that is suitable for clinical application in the disinfection of oral and wound bacteria. In vivo studies have indicated that the plasma brush treatment rendered no harmful effect on healthy skin or tissues, while it could improve wound healing in Pseudomonas aeruginosa biofilm infected wounds exposed to an optimized treatment with argon plus 1% nitrogen (Ar + N2) plasma.


The aryl hydrocarbon receptor promotes IL-10 production by NK cells.
The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In the present studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but NK cells were a major early source of this cytokine. These IL-10 reporter(+) NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-γ, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10, and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator, which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and AHR nuclear translocator were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr(-/-) mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Taken together, these data identify the AHR as a critical cofactor involved in NK cell production of IL-10.


Dose integration characteristics in normoxic polymer gel dosimetry investigated using sequential beam irradiation.
Dose integration properties were investigated for normoxic polymer gels based on methacrylic acid (nMAG) and acrylamide/N, N'-methylenebisacrylamide (nPAG). The effect of sequential irradiation was studied for different fractionation schemes and varying amounts of methacrylic acid for the nMAG gels. Magnetic resonance imaging (MRI) was used for read out of the absorbed dose response. The investigated gels exhibited a dependence on the fractionation scheme. The response when the total dose was divided into fractions of 0.5 Gy was compared with the response when the total dose was delivered in a single fraction. The slope of the R2 versus the absorbed dose response decreased when the absorbed dose per fraction was increased. Also, for higher amounts of methacrylic acid in the nMAG system the difference in the response increased. For gels containing 2, 4, 6 and 8% methacrylic acid, the R2 versus the absorbed dose response increased by 35, 37, 63 and 93%, respectively. Furthermore, the effect of the fractionation was larger when a higher total absorbed dose was given. The effect was less pronounced for the investigated nPAG, containing 3% acrylamide and 3% N, N'-methylenebisacrylamide, than for the nMAG systems. Consequently, this study indicates that the nPAG system has preferable beam integration characteristics compared with the nMAG system.


MALDI Mass Spectrometry Imaging Linked with Top-Down Proteomics as a Tool to Study the Non-Small-Cell Lung Cancer Tumor Microenvironment.
Advanced non-small-cell lung cancer (NSCLC) is generally linked with a poor prognosis and is one of the leading causes of cancer-related deaths worldwide. Since only a minority of the patients respond well to chemotherapy and/or targeted therapies, immunotherapy might be a valid alternative in the lung cancer treatment field, as immunotherapy attempts to strengthen the body's own immune response to recognize and eliminate malignant tumor cells. However, positive response patterns to immunotherapy remain unclear. In this study, we demonstrate how immune-related factors could be visualized from single NSCLC tissue sections (Biobank@UZA) while retaining their spatial information by using matrix assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI), in order to unravel the molecular profile of NSCLC patients. In this way, different regions in lung cancerous tissues could be discriminated based on the molecular composition. In addition, we linked visualization (MALDI MSI) and identification (based on liquid chromatography higher resolution mass spectrometry) of the molecules of interest for the correct biological interpretation of the observed molecular differences within the area in which these molecules are detected. This is of major importance to fully understand the underlying molecular profile of the NSCLC tumor microenvironment.


Computed Tomographic Tenography of Normal Equine Digital Flexor Tendon Sheath: An Ex Vivo Study.
Aim of this study was to document the normal computed tomographic tenography findings of digital flexor tendon sheath. Six ex vivo normal equine forelimbs were used. An axial approach was used to inject 185 mg/mL of iopamidol in a total volume of 60 mL into the digital flexor tendon sheaths. Single-slice helical scans, with 5 mm thickness, spaced every 3 mm, for a pitch of 0.6, and with bone algorithm reconstruction, were performed before and after injections of contrast medium. To obtain better image quality for multiplanar reconstruction and 3D reformatting, postprocessing retroreconstruction was performed to reduce the images to submillimetre thickness. Computed tomographic tenography of digital flexor tendon sheaths could visualize the following main tendon structures for every forelimb in contrast-enhanced images as low densities surrounded by high densities: superficial digital flexor tendon, deep digital flexor tendon, manica flexoria, mesotendons, and synovial recess. Results of this study suggest that computed tomographic tenography can be used with accuracy and sensitivity to evaluate the common disorders of the equine digital flexor tendon sheath and the intrathecal structures.


Non-nutrient causes of low-grade, systemic inflammation: support for a 'canary in the mineshaft' view of obesity in chronic disease.
A form of low-grade, systemic inflammation ('metaflammation') is linked to many types of chronic disease. Initially, this was thought to be causally related to weight gain and obesity and a possible explanation of the link between obesity and disease. However, several lifestyle-related inducers of such inflammation, some of which are associated with obesity, but some of which are not, have now been identified. The most common of these have been nutritive related, suggesting that there could still be a relationship, either directly or indirectly, with obesity. Here we provide evidence for non-nutritive inflammatory inducers, providing further support for an earlier suggestion that while obesity, beyond a point, may have a direct link with disease, this may be neither necessary nor sufficient to explain the current epidemic of chronic disease. A more ubiquitous cause encompassing all inflammatory inducers is the modern, post-industrial environment and lifestyles emanating from this. Obesity may thus be more of 'a canary in the mineshaft', warning of bigger global problems, than just a single pathway to modern environmentally driven disease.


Two Dictyostelium orthologs of the prokaryotic cell division protein FtsZ localize to mitochondria and are required for the maintenance of normal mitochondrial morphology.
In bacteria, the protein FtsZ is the principal component of a ring that constricts the cell at division. Though all mitochondria probably arose through a single, ancient bacterial endosymbiosis, the mitochondria of only certain protists appear to have retained FtsZ, and the protein is absent from the mitochondria of fungi, animals, and higher plants. We have investigated the role that FtsZ plays in mitochondrial division in the genetically tractable protist Dictyostelium discoideum, which has two nuclearly encoded FtsZs, FszA and FszB, that are targeted to the inside of mitochondria. In most wild-type amoebae, the mitochondria are spherical or rod-shaped, but in fsz-null mutants they become elongated into tubules, indicating that a decrease in mitochondrial division has occurred. In support of this role in organelle division, antibodies to FszA and FszA-green fluorescent protein (GFP) show belts and puncta at multiple places along the mitochondria, which may define future or recent sites of division. FszB-GFP, in contrast, locates to an electron-dense, submitochondrial body usually located at one end of the organelle, but how it functions during division is unclear. This is the first demonstration of two differentially localized FtsZs within the one organelle, and it points to a divergence in the roles of these two proteins.


Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders.
Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment. A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35-40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P < 0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P < 0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups (P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF (P < 0.05). For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant. Chinese Clinical Trial Registry Center ( ChiCTR1800016107 ). Registered on 11 May 2018.


Developmental abnormalities in striatum in young bipolar patients: a preliminary study.
Anatomical abnormalities in the basal ganglia of adult mood disorder patients have been reported. To investigate whether these abnormalities are present early in illness course, we compared the volume of striatal structures in young bipolar patients and healthy controls. Brain magnetic resonance images of 15 children and adolescents who met DSM-IV criteria for bipolar disorders and 21 healthy controls were obtained. Measurements were performed manually, by trained evaluators, who were blind to subjects' diagnosis. The volumes of caudate and putamen were compared in patients and controls. The volumes of striatal structures were not significantly different in patients and controls (ANCOVA, p > 0.05). However, we found a significant inverse relationship between age and the volumes of left caudate (r = -0.72, p < 0.01), right caudate (r = -0.66, p = 0.02) and left putamen (r = -0.71, p = 0.01) in bipolar patients, not present in healthy controls. Abnormalities in striatal development may be involved in the pathophysiology of bipolar disorder.


A modified single-prolonged stress model for post-traumatic stress disorder.
In the rat, single-prolonged stress (SPS) model produces a core symptom of post-traumatic stress disorder (PTSD), the enhanced fear response to the traumatic cue (conditioned fear response). This investigative tool is typically used for PTSD studies. However, whether SPS can produce another core symptom of PTSD, hyperarousal (the sensitized fear response in animal models), has not been evaluated. It is also not clear whether SPS can enhance both conditioned and sensitized fear responses after different incubation times. In this study, a single inescapable electric foot shock was given to rats immediately after SPS procedures (SPS&S). After different incubation times (1, 7 or 14 days), the conditioned or sensitized fear response was measured by re-exposing the stressed rats to the shock context or a neutral tone in a novel environment. Additionally, paroxetine, a selective serotonin reuptake inhibitor (SSRI) was administered after SPS&S for 14 days to test its potential preventive effect on PTSD-like symptoms. We observed that conditioned fear persisted and sensitized fear increased with ongoing incubation times after SPS&S. Early rapid intervention with paroxetine after SPS&S ameliorated PTSD-like symptoms in both fear responses and anxiety behaviors. Our data suggests that this modified SPS&S model may be both novel and predictably mimic the clinical characteristics of PTSD better than other investigative paradigms.


Aquatic suction feeding dynamics: insights from computational modelling.
Aquatic suction feeding in vertebrates involves extremely unsteady flow, externally as well as internally of the expanding mouth cavity. Consequently, studying the hydrodynamics involved in this process is a challenging research area, where experimental studies and mathematical models gradually aid our understanding of how suction feeding works mechanically. Especially for flow patterns inside the mouth cavity, our current knowledge is almost entirely based on modelling studies. In the present paper, we critically discuss some of the assumptions and limitations of previous analytical models of suction feeding using computational fluid dynamics.


Neuromonitoring in thyroid surgery: prospective evaluation of intraoperative electrophysiological responses for the prediction of recurrent laryngeal nerve injury.
We evaluated the ability of neuromonitoring to predict postoperative outcome in patients undergoing thyroid surgery for different indications. Neuromonitoring has been advocated to reduce the risk of vocal cord palsy and to predict postoperative vocal cord function. Three hundred twenty-eight patients (502 nerves at risk) were studied prospectively at a single center. Neuromonitoring was performed with the Neurosign 100 device by transligamental placement of the recording electrode into the vocalis muscles. Cumulative distribution of stimulation thresholds was determined by stepwise decreases in current (1 mA to 0.05 mA) for both the vagus and the recurrent nerve. Patients were grouped according to surgical risk (benign and malignant disease, reoperation for benign and for malignant disease). If the electrophysiological response was correlated to postoperative vocal cord function, the sensitivity of neuromonitoring was modest (86% in surgery for benign disease) to low (25% in reoperation for malignant disease); the positive predictive value was modest (overall rate 62%) but acceptable (87%) if corrected for technical problems. Specificity and negative predictive values were high (ie, overall >95%). Stimulation thresholds were not augmented in 11 patients, in whom postoperative palsy developed despite normal intraoperative recordings. Similarly, an electrical field response was elicited in 14 of 21 patients with preoperative vocal cord palsy. Electromyographic recordings did not reveal an abnormal amplitude or a decline in nerve conduction velocity. Neuromonitoring is useful for identifying the recurrent laryngeal nerve, in particular if the anatomic situation is complicated by prior surgery, large tissue masses, aberrant nerve course. However, neuromonitoring does not reliably predict postoperative outcome.


Dimensions over categories: a meta-analysis of taxometric research.
Taxometric procedures have been used extensively to investigate whether individual differences in personality and psychopathology are latently dimensional or categorical ('taxonic'). We report the first meta-analysis of taxometric research, examining 317 findings drawn from 183 articles that employed an index of the comparative fit of observed data to dimensional and taxonic data simulations. Findings supporting dimensional models outnumbered those supporting taxonic models five to one. There were systematic differences among 17 construct domains in support for the two models, but psychopathology was no more likely to generate taxonic findings than normal variation (i.e. individual differences in personality, response styles, gender, and sexuality). No content domain showed aggregate support for the taxonic model. Six variables - alcohol use disorder, intermittent explosive disorder, problem gambling, autism, suicide risk, and pedophilia - emerged as the most plausible taxon candidates based on a preponderance of independently replicated findings. We also compared the 317 meta-analyzed findings to 185 additional taxometric findings from 96 articles that did not employ the comparative fit index. Studies that used the index were 4.88 times more likely to generate dimensional findings than those that did not after controlling for construct domain, implying that many taxonic findings obtained before the popularization of simulation-based techniques are spurious. The meta-analytic findings support the conclusion that the great majority of psychological differences between people are latently continuous, and that psychopathology is no exception.


Evaluating the environmental impacts of stabilization and solidification technologies for managing hazardous wastes through life cycle assessment: A case study of Hong Kong.
Proper management of hazardous materials arouses widespread environmental concerns due to its enormous ecological and health impacts. The development of green stabilization/solidification (S/S) technology for resourceful utilization of hazardous materials, as well as the immobilization of potentially toxic elements is of great scientific interests. Cement-based S/S is often considered a low-cost and highly efficient technology, but the environmental sustainability of a broad spectrum of S/S technologies has yet to be evaluated. Therefore, this study assessed the environmental sustainability of S/S technologies for managing two common types of hazardous wastes, i.e., contaminated marine sediment and municipal solid waste incineration fly ash (MIFA) by using life cycle assessment (LCA). A total of 17 scenarios under three strategies for sediment and two strategies for MIFA S/S technologies were comprehensively evaluated. The LCA results identified the most preferable S/S technology in each strategy. In particular, Scenario 1 (mixture of sediment with a small percentage of ordinary Portland cement and incinerated sewage sludge ash) of Strategy 1 (use as fill materials) would be the preferred option, as it reduces about 54% and 70% global warming potential compared to those of Scenarios 2 and 3, respectively. This is the first initiative for evaluating the environmental impacts of a wide range of recently developed S/S technologies using green/alternative binders for diverting hazardous wastes from disposal. The results can serve as a decision support for the practical application of the environmentally friendly S/S technology for sustainable remediation.


Either bacteriophage T4 RNase H or Escherichia coli DNA polymerase I is essential for phage replication.
Bacteriophage T4 rnh encodes an RNase H that removes ribopentamer primers from nascent DNA chains during synthesis by the T4 multienzyme replication system in vitro (H. C. Hollingsworth and N. G. Nossal, J. Biol. Chem. 266:1888-1897, 1991). This paper demonstrates that either T4 RNase HI or Escherichia coli DNA polymerase I (Pol I) is essential for phage replication. Wild-type T4 phage production was not diminished by the polA12 mutation, which disrupts coordination between the polymerase and the 5'-to-3' nuclease activities of E. coli DNA Pol I, or by an interruption in the gene for E. coli RNase HI. Deleting the C-terminal amino acids 118 to 305 from T4 RNase H reduced phage production to 47% of that of wild-type T4 on a wild-type E. coli host, 10% on an isogenic host defective in RNase H, and less than 0.1% on a polA12 host. The T4 rnh(delta118-305) mutant synthesized DNA at about half the rate of wild-type T4 in the polA12 host. More than 50% of pulse-labelled mutant DNA was in short chains characteristic of Okazaki fragments. Phage production was restored in the nonpermissive host by providing the T4 rnh gene on a plasmid. Thus, T4 RNase H was sufficient to sustain the high rate of T4 DNA synthesis, but E. coli RNase HI and the 5'-to-3' exonuclease of Pol I could substitute to some extent for the T4 enzyme. However, replication was less accurate in the absence of the T4 RNase H, as judged by the increased frequency of acriflavine-resistant mutations after infection of a wild-type host with the T4 rnh (delta118-305) mutant.


Biotransformation of 13(Z)-retinoic acid in mouse skin and human keratinocyte cultures.
The metabolism of 13-(CIS) in mouse skin in vivo which was treated with TPA (or vehicle) typically showed that the retinoid was oxidized to 4-hydroxy, 5,6-epoxy-13-CIS, 5,8-oxy-13-CIS and undergoes geometric isomerization to RA. Applied 13-(CIS) in human keratinocyte cultures showed that the retinoid was oxidized to 5,6-epoxy-13-CIS, 5,8-oxy-13-CIS, and isomers. Pretreatment with the antioxidant butylated hydroxyanisole(BHA) resulted in a large decrease in formation of the oxirane and increased formation of the alcohol in mouse skin. Proposed mechanisms suggested the involvement of peroxyl radicals and prostaglandin H synthase for the biotransformation of retinoids.


Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate.
Autotaxin (ATX) or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2) is an NPP family member that promotes tumor cell motility, experimental metastasis, and angiogenesis. ATX primarily functions as a lysophospholipase D, generating the lipid mediator lysophosphatidic acid (LPA) from lysophosphatidylcholine. ATX uses a single catalytic site for the hydrolysis of both lipid and non-lipid phosphodiesters, but its regulation is not well understood. Using a new fluorescence resonance energy transfer-based phosphodiesterase sensor that reports ATX activity with high sensitivity, we show here that ATX is potently and specifically inhibited by LPA and sphingosine 1-phosphate (S1P) in a mixed-type manner (Ki approximately 10(-7) M). The homologous ecto-phosphodiesterase NPP1, which lacks lysophospholipase D activity, is insensitive to LPA and S1P. Our results suggest that, by repressing ATX activity, LPA can regulate its own biosynthesis in the extracellular environment, and they reveal a novel role for S1P as an inhibitor of ATX, in addition to its well established role as a receptor ligand.


E-cigarette use is differentially related to smoking onset among lower risk adolescents.
E-cigarette use has been linked to onset of cigarette smoking among adolescents, but some commentators have suggested that this simply reflects high-risk adolescents being more likely to use e-cigarettes and to smoke. We tested whether the effect of e-cigarette use for smoking onset differs for youth who are lower versus higher on propensity to smoke. School-based survey with a longitudinal sample of 1136 students (9th-11th graders, mean age 14.7 years) in Hawaii, initially surveyed in 2013 (T1) and followed up 1 year later (T2). We assessed e-cigarette use, propensity to smoke based on 3 psychosocial factors known to predict smoking (rebelliousness, parental support and willingness to smoke), and cigarette smoking status. Analyses based on T1 never-smokers tested the relation of T1 e-cigarette use to T2 smoking status for participants lower versus higher on T1 propensity to smoke. The relation between T1 e-cigarette use and T2 smoking onset was stronger among participants with lower levels of rebelliousness and willingness and higher levels of parental support. A multiple logistic regression analysis with T2 smoking as the criterion tested the cross-product of T1 e-cigarette use and T1 smoking propensity score; the interaction (OR=0.88, p=0.01) indicated a significantly larger effect for smoking onset among lower risk youth. The results indicate e-cigarette use is a risk factor for smoking onset, not just a marker of high risk for smoking. This study provides evidence that e-cigarettes are recruiting lower risk adolescents to smoking, which has public health implications.


Changing trends of acute otitis media bacteriology in central Israel in the pneumococcal conjugate vaccines era.
The widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has changed acute otitis media (AOM) bacteriology. Only scattered data with regard to this effect of PCV13 have been published so far. We retrospectively identified children <6 years of age who presented to our hospital with AOM, and had middle ear fluid (MEF) cultures obtained during tympanocentesis or from spontaneous otorrhea during 2008-2013, when PCV7 (2009) and PCV13 (2010) were gradually introduced in the Israeli National Immunization Program. Data were extracted for demographics, clinical and microbiologic parameters, according to vaccination status. Of the 295 eligible AOM episodes reported in 279 children, 224 (76%) had MEF cultures from tympanocentesis and 71 (24%) from spontaneous otorrhea. Boys and children <2 years of age contributed 178 (60%) and 219 (74%) AOM episodes, respectively. Acute mastoiditis complicated 58 (20%) of these episodes. None of the children were PCV immunized in 2008, but >90% had received ≥1 PCV dose(s) by 2011 or later. Of the 106 (36%) MEF cultures which tested positive for otopathogens, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and multiple bacteria grew in 60 (57%), 39 (37%), 2 (2%) and 5 (5%) episodes, respectively. S. pneumonia-positive MEF culture rate in unimmunized children (31, 69%) was significantly higher than in PCV7-immunized children (22, 59%) or PCV13-immunized children (12, 50%), P = 0.04 and P = 0.02, respectively. PCV7 and PCV13 implementations in the Israeli National Immunization Program were associated with a rapid reduction of "severe" pneumococcal AOM episodes.


Nucleophosmin/B23 activates Aurora A at the centrosome through phosphorylation of serine 89.
Aurora A (AurA) is a major mitotic protein kinase involved in centrosome maturation and spindle assembly. Nucleophosmin/B23 (NPM) is a pleiotropic nucleolar protein involved in a variety of cellular processes including centrosome maturation. In the present study, we report that NPM is a strong activator of AurA kinase activity. NPM and AurA coimmunoprecipitate and colocalize to centrosomes in G2 phase, where AurA becomes active. In contrast with previously characterized AurA activators, NPM does not trigger autophosphorylation of AurA on threonine 288. NPM induces phosphorylation of AurA on serine 89, and this phosphorylation is necessary for activation of AurA. These data were confirmed in vivo, as depletion of NPM by ribonucleic acid interference eliminated phosphorylation of CDC25B on S353 at the centrosome, indicating a local loss of AurA activity. Our data demonstrate that NPM is a strong activator of AurA kinase activity at the centrosome and support a novel mechanism of activation for AurA.


"I Can Remember Sort of Vivid People…but to Me They Were Plasticine." Delusions on the Intensive Care Unit: What Do Patients Think Is Going On?
Patients who develop intensive care unit (ICU) acquired delirium stay longer in the ICU, and hospital, and are at risk of long-term mental and physical health problems. Despite guidelines for patient assessment, risk limitation, and treatment in the ICU population, delirium and associated delusions remain a relatively common occurrence on the ICU. There is considerable information in the literature describing the incidence, suspected causes of, and discussion of the benefits and side-effects of the various treatments for delirium in the ICU. But peer-reviewed patient-focused research is almost non-existent. There is therefore a very limited understanding of the reality of delusions in the intensive care unit from the patient's point of view. A secondary analysis of the original interviews conducted by the University of Oxford Health Experiences Research Group was undertaken to explore themes relating specifically to sleep and delirium. Patients describe a liminal existence on the ICU. On the threshold of consciousness their reality is uncertain and their sense of self is exposed. Lack of autonomy in an unfamiliar environment prompts patients to develop explanations and understandings for themselves with no foothold in fact. Patients on the ICU are perhaps more disoriented than they appear and early psychological intervention in the form of repeated orientation whilst in the ICU might improve the patient experience and defend against development of side-effects.


Fbxo45 inhibits calcium-sensitive proteolysis of N-cadherin and promotes neuronal differentiation.
Fbxo45 is an atypical E3 ubiquitin ligase, which specifically targets proteins for ubiquitin-mediated degradation. Fbxo45 ablation results in defective neuronal differentiation and abnormal formation of neural connections; however, the mechanisms underlying these defects are poorly understood. Using an unbiased mass spectrometry-based proteomic screen, we show here that N-cadherin is a novel interactor of Fbxo45. N-cadherin specifically interacts with Fbxo45 through two consensus motifs overlapping the site of calcium-binding and dimerization of the cadherin molecule. N-cadherin interaction with Fbxo45 is significantly abrogated by calcium treatment. Surprisingly, Fbxo45 depletion by RNAi-mediated silencing results in enhanced proteolysis of N-cadherin. Conversely, ectopic expression of Fbxo45 results in decreased proteolysis of N-cadherin. Fbxo45 depletion results in dramatic reduction in N-cadherin expression, impaired neuronal differentiation, and diminished formation of neuronal processes. Our studies reveal an unanticipated role for an F-box protein that inhibits proteolysis in the regulation of a critical biological process.


Use of behavioral economics and social psychology to improve treatment of acute respiratory infections (BEARI): rationale and design of a cluster randomized controlled trial [1RC4AG039115-01]--study protocol and baseline practice and provider characteristics.
Inappropriate antibiotic prescribing for nonbacterial infections leads to increases in the costs of care, antibiotic resistance among bacteria, and adverse drug events. Acute respiratory infections (ARIs) are the most common reason for inappropriate antibiotic use. Most prior efforts to decrease inappropriate antibiotic prescribing for ARIs (e.g., educational or informational interventions) have relied on the implicit assumption that clinicians inappropriately prescribe antibiotics because they are unaware of guideline recommendations for ARIs. If lack of guideline awareness is not the reason for inappropriate prescribing, educational interventions may have limited impact on prescribing rates. Instead, interventions that apply social psychological and behavioral economic principles may be more effective in deterring inappropriate antibiotic prescribing for ARIs by well-informed clinicians. The Application of Behavioral Economics to Improve the Treatment of Acute Respiratory Infections (BEARI) Trial is a multisite, cluster-randomized controlled trial with practice as the unit of randomization. The primary aim is to test the ability of three interventions based on behavioral economic principles to reduce the rate of inappropriate antibiotic prescribing for ARIs. We randomized practices in a 2 × 2 × 2 factorial design to receive up to three interventions for non-antibiotic-appropriate diagnoses: 1) Accountable Justifications: When prescribing an antibiotic for an ARI, clinicians are prompted to record an explicit justification that appears in the patient electronic health record; 2) Suggested Alternatives: Through computerized clinical decision support, clinicians prescribing an antibiotic for an ARI receive a list of non-antibiotic treatment choices (including prescription options) prior to completing the antibiotic prescription; and 3) Peer Comparison: Each provider's rate of inappropriate antibiotic prescribing relative to top-performing peers is reported back to the provider periodically by email. We enrolled 269 clinicians (practicing attending physicians or advanced practice nurses) in 49 participating clinic sites and collected baseline data. The primary outcome is the antibiotic prescribing rate for office visits with non-antibiotic-appropriate ARI diagnoses. Secondary outcomes will examine antibiotic prescribing more broadly. The 18-month intervention period will be followed by a one year follow-up period to measure persistence of effects after interventions cease. The ongoing BEARI Trial will evaluate the effectiveness of behavioral economic strategies in reducing inappropriate prescribing of antibiotics. ClinicalTrials.gov: NCT01454947.


[A conceptual framework for the evaluation of health programs].
Evaluation can have three distinct goals: to help plan and develop programs, to provide information which will improve programs and to determine the outcomes and impact of programs. Evaluation questions flow from each of these goals. Described in this paper are different types of evaluation useful in answering these questions. Whatever type of evaluation is chosen, the evaluator must attempt to assess its validity. This validity concerns the equivalence between answers to evaluation questions and the "true value" of the program. It is just as concerned with measurement strategy and instruments as it is with the designs and techniques of analysis used, and the population studied.


Genetic architecture of grain yield in bread wheat based on genome-wide association studies.
Identification of loci for grain yield (GY) and related traits, and dissection of the genetic architecture are important for yield improvement through marker-assisted selection (MAS). Two genome-wide association study (GWAS) methods were used on a diverse panel of 166 elite wheat varieties from the Yellow and Huai River Valleys Wheat Zone (YHRVWD) of China to detect stable loci and analyze relationships among GY and related traits. A total of 326,570 single nucleotide polymorphism (SNP) markers from the wheat 90 K and 660 K SNP arrays were chosen for GWAS of GY and related traits, generating a physical distance of 14,064.8 Mb. One hundred and twenty common loci were detected using SNP-GWAS and Haplotype-GWAS, among which two were potentially functional genes underpinning kernel weight and plant height (PH), eight were at similar locations to the quantitative trait loci (QTL) identified in recombinant inbred line (RIL) populations in a previous study, and 78 were potentially new. Twelve pleiotropic loci were detected on eight chromosomes; among these the interval 714.4-725.8 Mb on chromosome 3A was significantly associated with GY, kernel number per spike (KNS), kernel width (KW), spike dry weight (SDW), PH, uppermost internode length (UIL), and flag leaf length (FLL). GY shared five loci with thousand kernel weight (TKW) and PH, indicating significantly affected by two traits. Compared with the total number of loci for each trait in the diverse panel, the average number of alleles for increasing phenotypic values of GY, TKW, kernel length (KL), KW, and flag leaf width (FLW) were higher, whereas the numbers for PH, UIL and FLL were lower. There were significant additive effects for each trait when favorable alleles were combined. UIL and FLL can be directly used for selecting high-yielding varieties, whereas FLW can be used to select spike number per unit area (SN) and KNS. The loci and significant SNP markers identified in the present study can be used for pyramiding favorable alleles in developing high-yielding varieties. Our study proved that both GWAS methods and high-density genetic markers are reliable means of identifying loci for GY and related traits, and provided new insight to the genetic architecture of GY.


Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice.
For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions.


Treatment of corneal neovascularization in ocular chemical injury with an off-label use of subconjunctival bevacizumab: a case report.
In this report, we describe the case of a patient with ocular chemical injury, symblepharon, and corneal neovascularization in whom subconjunctival injection of bevacizumab caused regression of corneal opacification and neovascularization, which led to visual improvement. A 54-year-old Caucasian woman presented at our eye emergency department following a splash injury of the left eye with sodium hydroxide. At presentation, her visual acuity was light perception. Slit-lamp examination showed diffuse corneal epithelial defects, stromal edema, and localized Descemet's folds. Despite administration of topical and systemic steroids, she developed symblepharon after 3 months as well as superficial and deep corneal neovascularization with visual acuity 0.5 logarithm of the minimum angle of resolution. A subconjunctival bevacizumab injection (dose 1.25mg/0.05ml) was administered. After 1 week, the vessels appeared thinner and corneal opacity was clearer. Her visual acuity improved to 0.3 logarithm of the minimum angle of resolution. Three weeks later her visual acuity had not changed, and the vessels had started to perfuse again. A second subconjunctival bevacizumab injection was given. After 2 weeks, her vision had improved to 0.1 logarithm of the minimum angle of resolution, vessel regression was observed, and corneal opacity was significantly reduced. Three months after the second injection her vision was unchanged, and the neovascularization remained stable. During the next months, the patient's condition was well-controlled, and, at the end of follow-up 24 months later, her visual acuity and clinical condition were unaltered. Subconjunctival bevacizumab injection may be considered as a second-line treatment of corneal neovascularization caused by chemical injury that is unresponsive to conventional steroid therapy.


Distinct Patterns of Everyday Executive Function Problems Distinguish Children With Tourette Syndrome From Children With ADHD or Autism Spectrum Disorders.
The aim is to investigate the everyday executive function (EF) in children with Tourette syndrome (TS), Inattentive or Combined presentations of ADHD (ADHD-I/ADHD-C), autism spectrum disorders (ASD), and typically developing children (TDC). Nineteen TS, 33 ADHD-C, 43 ADHD-I, 34 ASD, and 50 TDC participated (8-17 years). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). TS, ADHD-C, ADHD-I, or ASD were rated with significantly more regulation problems on all scales compared with TDC. Considerable overlap of symptoms between clinical groups made differentiation difficult on individual scales. Scale configurations showed children with TS to have more problems with emotional control (EC) than cognitive flexibility in relation to children with ASD, more problems with EC than inhibitory control in relation to ADHD-C, and more problems with EC than planning/organizing in relation to ADHD-I. Paired BRIEF scales dissociated EF problems in children with TS from children with ADHD-C, ADHD-I, or ASD. Clinical relevance is discussed.


Non-Fusion Versus Fusion Surgery in Pediatric Idiopathic Scoliosis: What Trade-Offs in Outcomes Are Acceptable for the Patient and Family?
Vertebral body tethering and other non-fusion techniques for the treatment of pediatric idiopathic scoliosis are increasing in popularity. There is limited physician consensus on this topic as the result of a paucity of published data regarding which patients most benefit from non-fusion strategies. Thus, much of the decision-making is left to patients and parents, who must select a treatment based on their goals and values and the information available from health-care providers, the internet, and social media. We sought to understand patient and family preferences regarding the attributes of fusion versus non-fusion surgery that drive these choices. Patients and families were recruited from 7 pediatric spine centers and were asked to complete a survey-based choice experiment that had been jointly developed with the U.S. Food and Drug Administration (FDA) to evaluate patient preferences. Choices between experimentally designed alternatives were analyzed to estimate the relative importance of outcomes and requirements associated with the choice options (attributes). The attributes included appearance, confidence in the planned correction, spinal motion, device failure, reoperation, and recovery period. The inclusion criteria were (1) an age of 10 to 21 years and (2) a diagnosis of adolescent idiopathic scoliosis in patients who were considering, or who had already undergone, treatment with fusion or non-fusion surgery. Preference weights were estimated from the expected changes in choice given changes in the attributes. A total of 344 respondents (124 patients, 92 parents, and 128 parent/patient dyads) completed the survey. One hundred and seventy-three patients were enrolled prior to surgery, and 171 were enrolled after surgery. Appearance and motion were found to be the most important drivers of choice. For the entire cohort, fusion was preferred over non-fusion. For patients who were considering surgery, the most important attributes were preservation of spinal motion and appearance. Patients and families seeking treatment for idiopathic scoliosis value appearance and preservation of spinal motion and, to a lesser extent, reoperation rates when considering fusion versus non-fusion surgery.


The impact of Lee Silverman Voice Treatment (LSVT LOUD®) on voice, communication, and participation: Findings from a prospective, longitudinal study.
Lee Silverman Voice Treatment (LSVT LOUD®), an intensive 4-week program of voice therapy, is regarded as the most well-researched, efficacious treatment for hypokinetic dysarthria in individuals with Parkinson's disease (PD). Although numerous studies have published acoustic and perceptual findings, there is comparatively little information about the impact of LSVT LOUD® on functional communication outcomes. This prospective, longitudinal study investigated the impact of treatment on daily communication in 25 individuals with PD. Three validated communication measures (the Voice Handicap Index, the Communicative Effectiveness Scale, and the Communicative Participation Item Bank) were given before and after treatment and again 4-8 weeks and 3-6 months following treatment. Communication partners were also asked to rate communication effectiveness at all four timepoints. Significant improvements were found for all three self-reported scales which remained above baseline across all post-treatment timepoints. In addition, self-reported communicative effectiveness was significantly correlated with the assessments of communication partners. Particular benefits were reported for more complex communicative activities such as asking questions, giving detailed information, communicating in noisy situations, and speaking in groups. Overall, the findings suggested that LSVT LOUD® promotes an increased sense of personal control over the communication difficulties resulting from PD by decreasing voice handicap and improving communication effectiveness and communicative participation. For individuals with PD, LSVT LOUD® may reduce the risk of social isolation by improving communication and facilitating social participation. As a result of this activity, the participant will be able to (1) describe the impact of PD on voice and communication, (2) discuss how these characteristics may be associated with more global measures of functional communication and particularly communicative participation, (3) explain which aspects of functional communication were affected by LSVT LOUD® as assessed by study participants and their communication partners.


[Technique and results of lung transplantation in rats].
Lung transplantation has recently emerged as an efficient therapy for a variety of endstage pulmonary diseases. Nevertheless, many problems remain unsolved. A simple and reproducible experimental model allows examination of some of the problems encountered. We report here our experience of lung transplantation in the rat. One hundred and thirty six lung transplantations have been performed. After the initial phase necessary to master the technique, an overall survival rate of 86% was achieved. Graft function, as assessed by chest X-rays and lung isotope scans, was satisfactory up to 4 months after transplantation. Lung transplantation in the rat is a reliable and reproductible experimental model allowing the development of research projects in this field.


Cancer patients' needs for support in expressing instrumental concerns and emotions.
The aim of our study was to provide an overview of intervention guidelines on how to address patients' practical needs for support in expressing instrumental concerns and emotions regarding medical, psychosocial and practical topics. Six focus groups of cancer patients and survivors (N = 39) were organised. An interview guide was created that consisted of three topics: (a) concerns, (b) needs for support, and (c) a Concern Prompt List. Using the framework method, the transcripts were coded and analysed in Atlas T.I. Patients prefer to receive practical and emotional support, help with preparation, prompts/cues, instructions on how to perform the behaviour (i.e., express their concerns or emotions), feedback, a different structure for the consultation and tailoring. Most of these techniques should preferably be delivered via interpersonal communication. Needs sometimes differ for instrumental concerns and emotions. Only some needs for support were exclusively related to instrumental concerns or emotions. The typical needs for support were not solely linked to the medical, psychosocial and practical topics. Different needs to express instrumental concerns and emotions throughout the disease trajectory are categorised. These needs provide input for developing interventions to support concern expression.


The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.
Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.


Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma.
Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.


Evolution of the regulatory control of vertebrate striated muscle: the roles of troponin I and myosin binding protein-C.
Troponin I (TnI) and myosin binding protein-C (MyBP-C) are key regulatory proteins of contractile function in vertebrate muscle. TnI modulates the Ca(2+) activation signal, while MyBP-C regulates cross-bridge cycling kinetics. In vertebrates, each protein is distributed as tissue-specific paralogs in fast skeletal (fs), slow skeletal (ss), and cardiac (c) muscles. The purpose of this study is to characterize how TnI and MyBP-C have changed during the evolution of vertebrate striated muscle and how tissue-specific paralogs have adapted to different physiological conditions. To accomplish this we have completed phylogenetic analyses using the amino acid sequences of all known TnI and MyBP-C isoforms. This includes 99 TnI sequences (fs, ss, and c) from 51 different species and 62 MyBP-C sequences from 26 species, with representatives from each vertebrate group. Results indicate that the role of protein kinase A (PKA) and protein kinase C (PKC) in regulating contractile function has changed during the evolution of vertebrate striated muscle. This is reflected in an increased number of phosphorylatable sites in cTnI and cMyBP-C in endothermic vertebrates and the loss of two PKC sites in fsTnI in a common ancestor of mammals, birds, and reptiles. In addition, we find that His(132), Val(134), and Asn(141) in human ssTnI, previously identified as enabling contractile function during cellular acidosis, are present in all vertebrate cTnI isoforms except those from monotremes, marsupials, and eutherian mammals. This suggests that the replacement of these residues with alternative residues coincides with the evolution of endothermy in the mammalian lineage.


Play and video effects on mood and procedure behaviors in school-aged children visiting the pediatrician.
This study examines how different types of activities, including medical play, typical play, and videos, affect the mood and behaviors of children visiting a pediatric office. Seventy-two school-aged children visiting a pediatrician's office were randomly assigned to 1 of 4 groups: medical play, medical information video, typical play, and nonmedical information video control. Children completed a mood self-report measure and their behaviors were recorded during triage by nurses. The medical information video improved the school-aged children's mood. Children in the medical information video displayed less difficult behaviors during procedures than the medical play group. The findings suggest that providing information about medical equipment through a video of a child engaging in medical play may benefit children visiting the pediatrician.


Adverse Placental Perfusion and Pregnancy Outcomes in a New Nonhuman Primate Model of Gestational Protein Restriction.
Maternal malnutrition during pregnancy impacts fetal growth, with developmental consequences that extend to later life outcomes. In underdeveloped countries, this malnutrition typically takes the form of poor dietary protein content and quality, even if adequate calories are consumed. Here, we report the establishment of a nonhuman primate model of gestational protein restriction (PR) in order to understand how placental function and pregnancy outcomes are affected by protein deficiency. Rhesus macaques were assigned to either a control diet containing 26% protein or switched to a 13% PR diet prior to conception and maintained on this PR diet throughout pregnancy. Standard fetal biometry, Doppler ultrasound of uteroplacental blood flow, ultrasound-guided amniocentesis, and contrast-enhanced ultrasound (CE-US) to assess placental perfusion were performed mid-gestation (gestational day 85 [G85] where term is G168) and in the early third trimester (G135). Our data demonstrate that a 50% reduction in dietary protein throughout gestation results in reduced placental perfusion, fetal growth restriction, and a 50% rate of pregnancy loss. In addition, we demonstrate reduced total protein content and evidence of fetal hypoxia in the amniotic fluid. This report highlights the use of CE-US for in vivo assessment of placental vascular function. The ability to detect placental dysfunction, and thus a compromised pregnancy, early in gestation, may facilitate the development of interventional strategies to optimize clinical care and improve long-term offspring outcomes, which are future areas of study in this new model.


Repurposing anthelmintic agents to eradicate resistant leukemia.
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.


Size-dependent passivation shell and magnetic properties in antiferromagnetic/ferrimagnetic core/shell MnO nanoparticles.
The magnetic properties of bimagnetic core/shell nanoparticles consisting of an antiferromagnetic MnO core and a ferrimagnetic passivation shell have been investigated. It is found that the phase of the passivation shell (gamma-Mn(2)O(3) or Mn(3)O(4)) depends on the size of the nanoparticles. Structural and magnetic characterizations concur that while the smallest nanoparticles have a predominantly gamma-Mn(2)O(3) shell, larger ones have increasing amounts of Mn(3)O(4). A considerable enhancement of the Néel temperature, T(N), and the magnetic anisotropy of the MnO core for decreasing core sizes has been observed. The size reduction also leads to other phenomena such as persistent magnetic moment in MnO up to high temperatures and an unusual temperature behavior of the magnetic domains.


Application of monoclonal antibodies as cancer therapy in solid tumors.
Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.


[Globule--substrate complex: several effects caused by the polymeric nature of the globule].
To anaylse possible role of globule polymeric nature in enzyme functioning, an equilibrium complex of homopolymeric liquidlike globule with a hard ball which models the substrate is considered. It is shown that the presence of linear memory in the globule may lead to an increase of the braking moment of forces affecting the substrate, to additional phase transitions concerned with a transition of the substrate of the globule centram to the perifery and vice versa etc. The shape of the globule surface adsorbed on the substrate is calculated.


Understanding loss to follow-up in a longitudinal study of people with traumatic brain injury.
To examine factors related to attrition in a traumatic brain injury (TBI) study sample assessed up to 15 years after injury. One thousand twenty-eight participants with TBI who completed the year 1 follow-up assessment at a TBI Model Systems Center between 1992 and 2018. Secondary analysis of data from a prospective longitudinal cohort study considering follow-up data collection completion status at years 1, 2, 5, 10, and 15. In univariable analyses, multiple factors were associated with loss to follow-up (LOFU) including being a member of a socially disadvantaged group, substance use history, residence, payor, cause of injury, and results of earlier follow-up attempts. In a multiple logistic regression analysis examining the prediction of follow-up condition at 10 or 15 years post-injury, only payor and race/ethnicity were significant predictors. Hispanic ethnicity was associated with higher odds of LOFU, and these participants often spoke Spanish and were born outside of the United States. The findings suggest a need to understand sociodemographic variables and their influence on participant attrition in longitudinal TBI research. With a better understanding of these predictors, procedures can be developed to address retention of participants who are identified as being at increased risk for study drop out.


Nucleotide sequence and restriction fragment-length polymorphism analysis of human T-cell lymphotropic virus type II (HTLV-II) in southern Europe: evidence for the HTLV-IIa and HTLV-IIb subtypes.
Human T-cell lymphotropic virus type II (HTLV-II) has been subtyped into two major groups, IIa and IIb, according to molecular studies involving env gene sequencing. Subsequently, this retrovirus was further subclassified by examining the long terminal repeat (LTR), the most divergent genomic region. Sequence analysis and restriction fragment-length polymorphism (RFLP) applied to the LTR region identified either four or five groups within the IIa subtype (depending on the restriction enzyme sets used) and six within the IIb subtype. In this study, we analyzed the LTR sequences of 29 samples obtained from HTLV-II-infected individuals living in Spain and Italy, which included 24 injecting drug users (IDUs), three blood donors, and two subjects at risk for HIV/HTLV infection. Sequence analysis and phylogenetic analysis of 720 base pairs of the LTR performed in 10 Spanish samples showed that all of these samples belonged to IIb subtype, with a divergence of 7.5% and 1.66% compared with MoT (IIa) and NRA/G12 (IIb) isolates, respectively. RFLP analysis demonstrated the presence of the IIb 4-subtype restriction pattern in 26 samples, a IIb5-subtype pattern in one Italian IDU, and a IIa0-subtype pattern in two Italian samples (blood donors), according to W.M. Switzer's nomenclature. This is the first report of the presence of IIb5 in Southern Europe and IIa0 among Italian blood donors. RFLP correlated with nucleotide sequence and phylogenetic data obtained in this study, demonstrating the ability of the RFLP method to predict the phylogroup of HTLV-II-infected samples.


The dynamic link between the integrity of the immune system and zinc status.
The results of more than three decades of work indicate that zinc deficiency rapidly diminishes antibody- and cell-mediated responses in both humans and animals. The moderate deficiencies in zinc noted in sickle cell anemia, renal disease, chronic gastrointestinal disorders and acrodermatitis enteropathica; subjects with human immunodeficiency virus; children with diarrhea; and elderly persons can greatly alter host defense systems, leading to increases in opportunistic infections and mortality rates. Conversely, short periods of zinc supplementation substantially improve immune defense in individuals with these diseases. Mouse models demonstrate that 30 d of suboptimal intake of zinc can lead to 30-80% losses in defense capacity. Collectively, the data clearly demonstrate that immune integrity is tightly linked to zinc status. Lymphopenia and thymic atrophy, which were the early hallmarks of zinc deficiency, are now known to be due to high losses of precursor T and B cells in the bone marrow. This ultimately leads to lymphopenia or a failure to replenish the lymphocytic system. Glucocorticoid-mediated apoptosis induced by zinc deficiency causes down-regulation of lymphopoiesis. Indeed, zinc itself can modulate death processes in precursor lymphocytes. Finally, there is substantial evidence that zinc supplementation may well reduce the impact of many of the aforementioned diseases by preventing the dismantling of the immune system. The latter represents an important area for research.


Cloning and characterization of cDNA clones corresponding to transcripts from the BamHI G region of the Epstein-Barr virus genome and expression of BGLF2.
A cDNA library was constructed from poly(A)+ RNA isolated from the iododeoxyuridine-treated P3HR1 cell line. Five cDNA clones, which hybridized with the BamHI G fragment of Epstein-Barr virus (EBV) DNA, were subcloned and sequenced. Clones G2, G3 and G4 corresponded to the BGLF2 open reading frame (ORF) of EBV (B95-8, nucleotides 126,837 to 125,866); G3 was found to contain the entire BGLF2 ORF. The predicted Mr of the putative protein product of the EBV B95-8 BGLF2 ORF is 36K. Complete nucleotide sequencing of G3 revealed that there were two nucleotide changes from the reported sequence of the EBV B95-8 BGLF2 gene, but these did not alter the predicted amino acid sequence of the products. Clone G3 and a cDNA derived from it by N-terminal deletion were expressed in Escherichia coli, producing fusion proteins. Rabbit antisera against these proteins were shown to react with viral capsid antigen-expressing HR1 cells in an indirect immunofluorescence assay. In vitro transcription/translation products and fusion proteins expressed in E. coli were used to determine the presence of antibodies in sera from EBV-infected individuals. The results of immunoprecipitation and immunoblotting studies showed that the majority of EBV-seropositive individuals mount a serum antibody response to the BGLF2 ORF-encoded protein.


The molecular genetics of medulloblastoma: an assessment of new therapeutic targets.
Medulloblastoma is the most common pediatric primary malignant intracranial neoplasm. The 5-year survival rates vary from 40% to 70% depending on clinical prognostic criteria, and many of the patients who survive exhibit long-term neurocognitive and/or neuroendocrine sequelae. Because of these results, research is required to increase our understanding of the basic biology of medulloblastoma, helping to refine patient stratification, decrease side effects of treatments, identify novel prognostic markers, and discover new less toxic therapies. The recognition that some medulloblastomas occur in familial cancer syndromes has led to some important discoveries in the molecular pathogenesis of medulloblastoma. These syndromes provide us with clues regarding alterations in key signaling or growth factor activation pathways that contribute to medulloblastoma formation. A better understanding of the molecular pathways involved in medulloblastoma formation may allow the discovery of new drugs that act on specific targets, yet many steps must still be taken before clinical use of new drugs. In addition, the identification of a novel signaling pathways in medulloblastoma is often accompanied by the quest for novel pharmacotherapeutics that have the potential to act favorably on this disease.


Fuzzy clustering-based segmented attenuation correction in whole-body PET imaging.
Segmented attenuation correction is now a widely accepted technique to reduce noise propagation from transmission scanning in positron emission tomography (PET). In this paper, we present a new method for segmenting transmission images in whole-body scanning. This reduces the noise in the correction maps while still correcting for differing attenuation coefficients of specific tissues. Based on the fuzzy C-means (FCM) algorithm, the method segments the PET transmission images into a given number of clusters to extract specific areas of differing attenuation such as air, the lungs and soft tissue, preceded by a median filtering procedure. The reconstructed transmission image voxels are, therefore, segmented into populations of uniform attenuation based on knowledge of the human anatomy. The clustering procedure starts with an overspecified number of clusters followed by a merging process to group clusters with similar properties (redundant clusters) and removal of some undesired substructures using anatomical knowledge. The method is unsupervised, adaptive and allows the classification of both pre- or post-injection transmission images obtained using either coincident 68Ge or single-photon 137Cs sources into main tissue components in terms of attenuation coefficients. A high-quality transmission image of the scanner bed is obtained from a high statistics scan and added to the transmission image. The segmented transmission images are then forward projected to generate attenuation correction factors to be used for the reconstruction of the corresponding emission scan. The technique has been tested on a chest phantom simulating the lungs, heart cavity and the spine, the Rando-Alderson phantom, and whole-body clinical PET studies showing a remarkable improvement in image quality, a clear reduction of noise propagation from transmission into emission data allowing for reduction of transmission scan duration. There was very good correlation (R2 = 0.96) between maximum standardized uptake values (SUVs) in lung nodules measured on images reconstructed with measured and segmented attenuation correction with a statistically significant decrease in SUV (17.03% +/- 8.4%, P < 0.01) on the latter images, whereas no proof of statistically significant differences on the average SUVs was observed. Finally, the potential of the FCM algorithm as a segmentation method and its limitations as well as other prospective applications of the technique are discussed.


Body composition changes during interventions to treat overweight and obesity in children and adolescents; a descriptive review.
Nutrition, physical activity and behavior-modifying techniques are widely applied components of interventions treating obesity. Our aim was to review available information on the short and long term effects of intervention treatment on body fat composition of overweight and obese children and adolescents and, to obtain a further understanding on how different body composition techniques detect longitudinal changes. In total, thirteen papers were included; seven included a multidisciplinary intervention component, five applied a combined dietary and physical activity intervention and one a physical activity intervention. Body composition techniques used included anthropometric indices, bioelectrical impedance analysis, and dual energy X-ray absorptiometry. Percentage of fat mass change was calculated in when possible. Findings suggested, no changes were observed in fat free mass after 16 weeks of nutritional intervention and the lowest decrease on fat mass percentage was obtained. However, the highest fat mass percentage with parallel increase in fat free mass, both assess by DXA was observed in a multi-component intervention applied for 20 weeks. In conclusion, more studies are needed to determine the best field body composition method to monitor changes during overweight treatment in children and adolescents.


The causes and profile of visual loss in an onchocerciasis-endemic forest-savanna zone in Nigeria.
In an onchocerciasis-endemic forest-savanna mosaic zone of southeastern Nigeria, blindness was found in 5.4% of 1,217 people who voluntarily attended for examination from a population of 14,000. Apart from cataract, the most important causes of blindness in the area were eye diseases that are known to be associated with onchocerciasis. Refractive error, although a non-onchocerciasis-related eye defect, was the number one cause of visual loss found in the study. The causes of blindness in our examined population are similar to what is found in onchocerciasis-endemic areas of the savanna zone and dissimilar from those found in the forest zone. In this forest-savanna mosaic zone, the prevalence of onchocerciasis was higher in the respondents with poor vision than in those with adequate vision. Similarly, low vision was found to be more common in people with high microfilarial loads, but people with high loads also tended to be older than those with moderate or low microfilarial loads, which might suggest that low vision was only a function of age. Nonetheless, analysis of our data shows evidence of an association between low vision and microfilarial load in adults aged 60 years and above. It is concluded that onchocerciasis in the forest-savanna mosaic zone of Nigeria has the features until recently associated only with savanna onchocerciasis, and that this should be taken into consideration in planning and executing onchocerciasis control programs in the area.


Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis.
Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOACs, outside that recommended, is unlikely to improve the outcomes. Click to hear Dr Braunwald's perspective on antithrombotic therapy in cardiovascular disease SUMMARY: Background Concerns have arisen in direct oral anticoagulant (DOAC)-treated patients about safety and efficacy in extremes of body weight. The aims of this systematic review were to investigate the association of body weight and patient-important outcomes in patients treated with DOACs or warfarin, and to demonstrate the fixed-dose effect of DOACs. Methods MEDLINE and EMBASE were searched until November 2016. Phase III randomized controlled trials (RCTs) using DOACs in atrial fibrillation (AF) and acute venous thromboembolism (VTE) were included. Relative risk and 95% confidence interval were calculated. The pooled estimates were performed using a Mantel-Haenszel random effects model. Results A total of 11 phase III RCTs were included. Low body weight was associated with increased risk of thromboembolism compared with non-low body weight (relative risk [RR], 1.57; 95% confidence interval [CI], 1.34-1.85). High body weight was not associated with risk of thromboembolism compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). Bleeding outcomes were comparable for all body weight comparisons. There were no clear interactions between types of anticoagulant in all outcomes. Conclusion The pooled effect of both the DOAC and comparison arms was likely to be attributable to differences in baseline thrombotic risk in each body weight category, rather than an effect of the type or dose of DOAC used for each indication. Dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.