Cysteine scanning of the surroundings of an alkali-ion binding site of the glutamate transporter GLT-1 reveals a conformationally sensitive residue.
Glutamate transporters remove this transmitter from the extracellular space by cotransport with three sodium ions and a proton. The cycle is completed by translocation of a potassium ion in the opposite direction. Recently we have identified two adjacent amino acid residues of the glutamate transporter GLT-1 that influence potassium coupling. Using the scanning cysteine accessibility method we have now explored the highly conserved region surrounding them. Replacement of each of the five consecutive residues 396-400 by cysteine abolished transport activity but at several other positions the substitution is tolerated. One residue, tyrosine 403, was identified where cysteine substitution renders the transporter sensitive to modification by positively charged methanethiosulfonate derivates in a sodium-protectable fashion. In the presence of sodium, the nontransported glutamate analogue dihydrokainate potentiated the covalent modification, presumably by binding to the glutamate site and locking the protein in a conformation in which tyrosine 403 is accessible from the external bulk medium. In contrast, transported substrates significantly slowed the reaction, suggesting that during the transport cycle residue 403 becomes occluded. On the other hand, transportable substrates are not able to protect Y403C transporters against N-ethylmaleimide, which is highly permeant but unable to modify cysteine residues buried within membrane proteins. These results indicate that tyrosine 403 is alternately accessible from either side of the membrane, consistent with its role as structural determinant of the potassium binding site.


Business analysis in occupational health and safety consultations.
We present a method for incorporating business analysis into comprehensive health and safety consultations using as an example a plant with an elevated incidence of cumulative trauma disorders. Business information, including product and management history, short- and long-term corporate goals, functional analysis, profit history, organizational structure with respect to health and safety, and personnel and labor-management relationships are evaluated simultaneously with traditional ergonomic factors. The additional business data allow consultants to identify the full scope of etiologies and make practical, credible recommendations that are more likely to be adopted by management and labor. We propose that techniques of "business analysis" be routinely incorporated into occupational health and safety consultations. However, because collection and interpretation of these data require business skills outside the occupational safety and health expert's usual repertoire, the consulting team must include participants with business expertise. We have found that occupational health medical personnel with an understanding of business analysis concepts can be very effective advocates for changes in health and safety practices. We strongly recommend incorporating methods of business analysis into the occupational health and safety curriculum.


[Maternal deaths due to infectious cause, results from the French confidential enquiry into maternal deaths, 2010-2012].
Over the period 2010-2012, maternal mortality from infectious causes accounted for 5% of maternal deaths by direct causes and 16% of maternal deaths by indirect causes. Among the 22 deaths caused by infection occurred during this period, 6 deaths were attributed to direct causes from genital tract origin, confirming thus the decrease in direct maternal deaths by infection during the last ten years. On the contrary, indirect maternal deaths by infection, from extragenital origin, doubled during the same period, with 16 deaths in the last triennium, dominated by winter respiratory infections, particularly influenza: the 2009-2010 influenza A (H1N1) virus pandemic was the leading cause of indirect maternal mortality by infection during the studied period. The main infectious agents involved in maternal deaths from direct causes were Streptococcus A, Escherichia Coli and Clostridium perfringens: these bacterias were responsible for toxic shock syndrome, severe sepsis, secondary in some cases to cellulitis or necrotizing fasciitis. Of the 6 deaths due to direct infection, 4 were considered avoidable because of inadequate management: delayed or missed diagnosis, delayed or inadequate initiation of a specific medical and/or surgical treatment. Of the 16 indirect maternal deaths due to infection causes, the most often involved infectious agents were influenza A (H1N1) virus and Streptococcus pneumonia with induced purpura fulminans: the absence of influenza vaccination during pregnancy, delayed diagnosis and emergency initiation of a specific treatment, were the main contributory factors to these deaths and their avoidability in 70% of the cases analyzed.


Recent advances in surface chemistry strategies for the fabrication of functional iron oxide based magnetic nanoparticles.
The synthesis of superparamagnetic nanostructures, especially iron-oxide based nanoparticles (IONPs), with appropriate surface functional groups has been intensively researched for many high-technological applications, including high density data storage, biosensing and biomedicine. In medicine, IONPs are nowadays widely used as contrast agents for magnetic resonance imaging (MRI), in hyperthermia therapy, but are also exploited for drug and gene delivery, detoxification of biological fluids or immunoassays, as they are relatively non-toxic. The use of magnetic particles in vivo requires IONPs to have high magnetization values, diameters below 100 nm with overall narrow size distribution and long time stability in biological fluids. Due to the high surface energies of IONPs agglomeration over time is often encountered. It is thus of prime importance to modify their surface to prevent aggregation and to limit non-specific adsorption of biomolecules onto their surface. Such chemical modifications result in IONPs being well-dispersed and biocompatible, and allow for targeted delivery and specific interactions. The chemical nature of IONPs thus determines not only the overall size of the colloid, but also plays a significant role for in vivo and in vitro applications. This review discusses the different concepts currently used for the surface functionalization and coating of iron oxide nanoparticles. The diverse strategies for the covalent linking of drugs, proteins, enzymes, antibodies, and nucleotides will be discussed and the chemically relevant steps will be explained in detail.


The chemical synthesis of 1-O-(indol-3'-ylacetyl)-beta-D-glucopyranose. The higher activity of the glucoside in comparison with exogenous indol-3-ylacetic acid in plant-section elongation tests.
1. The synthesis of 1-O-(indol-3'-ylacetyl)-beta-d-glucopyranose via the fully benzylated 1-O-(indol-3'-ylacetyl)-d-glucopyranose is described. The configuration of the free ester glucoside was confirmed by complete hydrolysis with beta-glucosidase and by the n.m.r. spectrum of the tetra-acetyl derivative. 2. The growth-promoting effect of the glucoside in Avena coleoptile- and pea stem-section tests distinctly exceeds the responses stimulated by equimolar amounts of indol-3-ylacetic acid or equimolar mixtures of indol-3-ylacetic acid and glucose at all concentrations investigated. Time-sequence experiments revealed that the sections stimulated by the glucoside exhibit a markedly greater rate of elongation than those promoted by indol-3-ylacetic acid. 3. 1-O-(Indol-3'-ylacetyl)-beta-d-glucopyranose was isolated from intact Avena coleoptiles. 4. According to the results, the conjugation of indol-3-ylacetic acid with glucose could not be considered merely as a detoxication mechanism for indol-3-ylacetic acid in plant tissues.


Socio-Cognitive Engineering of a Robotic Partner for Child's Diabetes Self-Management.
Social or humanoid robots do hardly show up in "the wild," aiming at pervasive and enduring human benefits such as child health. This paper presents a socio-cognitive engineering (SCE) methodology that guides the ongoing research & development for an evolving, longer-lasting human-robot partnership in practice. The SCE methodology has been applied in a large European project to develop a robotic partner that supports the daily diabetes management processes of children, aged between 7 and 14 years (i.e., Personal Assistant for a healthy Lifestyle, PAL). Four partnership functions were identified and worked out (joint objectives, agreements, experience sharing, and feedback & explanation) together with a common knowledge-base and interaction design for child's prolonged disease self-management. In an iterative refinement process of three cycles, these functions, knowledge base and interactions were built, integrated, tested, refined, and extended so that the PAL robot could more and more act as an effective partner for diabetes management. The SCE methodology helped to integrate into the human-agent/robot system: (a) theories, models, and methods from different scientific disciplines, (b) technologies from different fields, (c) varying diabetes management practices, and (d) last but not least, the diverse individual and context-dependent needs of the patients and caregivers. The resulting robotic partner proved to support the children on the three basic needs of the Self-Determination Theory: autonomy, competence, and relatedness. This paper presents the R&D methodology and the human-robot partnership framework for prolonged "blended" care of children with a chronic disease (children could use it up to 6 months; the robot in the hospitals and diabetes camps, and its avatar at home). It represents a new type of human-agent/robot systems with an evolving collective intelligence. The underlying ontology and design rationale can be used as foundation for further developments of long-duration human-robot partnerships "in the wild."


Regulation of Aurora-A kinase gene expression via GABP recruitment of TRAP220/MED1.
The TRAP/Mediator coactivator complex serves as a functional interface between DNA-bound transactivators and the RNA polymerase II-associated basal transcription apparatus. TRAP220/MED1 is a variably associated subunit of the complex that plays a specialized role in selectively targeting TRAP/Mediator to specific genes. Ablation of the Trap220/Med1 gene in mice impairs embryonic cell growth, yet the underlying mechanism is unknown. In this report, we identified distinct cell growth regulatory genes whose expression is affected by the loss of TRAP220/MED1 by RNA interference. Among the down-regulated genes revealed by cDNA microarray analyses, we identified Aurora-A, a centrosome kinase that plays a critical role in regulating M phase events and is frequently amplified in several types of cancer. In general, we found that TRAP220/MED1 expression is required for high basal levels of Aurora-A gene expression and that ectopic overexpression of TRAP220/MED1 coactivates transcription from the Aurora-A gene promoter. Furthermore, chromatin immunoprecipitation assays show that TRAP220/MED1-containing TRAP/Mediator complexes directly bind to the Aurora-A promoter in vivo. Finally, we present evidence suggesting that TRAP/Mediator is recruited to the Aurora-A gene via direct interactions between TRAP220/MED1 and the Ets-related transcription factor GABP. Taken together, these findings suggest that TRAP220/MED1 plays a novel coregulatory role in facilitating the recruitment of TRAP/Mediator to specific target genes involved in growth and cell cycle progression.


The most abundant protein in bovine herpes 1 virions is a homologue of herpes simplex virus type 1 UL47.
The bovine herpesvirus type 1 (BHV-1) protein VP8 is present, in large amounts, in the tegument of virions. As a preliminary step towards determining the function of VP8 and the biological relevance for its abundant presence, we describe the mapping of the location of its gene and determination of its nucleotide sequence. The gene for VP8 was located between 0.088 and 0.108 map units on the BHV-1 genome and contained a 2226 bp reading frame encoding a 742 amino acid protein. The protein, produced in vitro by transcribing and translating the reading frame, was precipitated by monoclonal antibodies and polyclonal serum directed against VP8. The primary structure of VP8 showed considerable homology with the product of the UL47 reading frame of herpes simplex virus type 1.


[Meningeal myelomatosis as an exclusive form of recurrence in a case of IgA-lambda myeloma in complete systemic remission].
Meningeal myelomatosis is an extremely rare clinical presentation generally associated to terminal states of the disease and is more frequent in the presence of peripheric plasmocytosis or leukemia of the plasmatic cells. Diagnosis requires its demonstration in the cephalorhachidian liquid and its monoclonal secretion. A case of relapse of meningeal myelomatosis in a patient with multiple IgA-lambda myeloma is presented in which the systemic disease fulfilled the criteria for complete remission.


Early detection of breast cancer in the emerging world.
Breast cancer is the number one cancer of women in the world. In middle income countries, and in many low income countries, breast cancer has become the most frequent cancer in women, supplanting cancer of the cervix. In such countries, breast cancer is usually diagnosed at an advanced stage, the majority in stage III and IV, indicating substantial delay in diagnosis. Further, because of the age distribution of the population pyramid, the majority of breast cancers are diagnosed in women under the age of 50. However, that age distribution does not mean that breast cancer is a different disease than in the West. Where population-based cancer registry data are available, it becomes clear that the individual risk for women at every age is no greater than in the West, and in many countries much less.


Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland.
As the juvenile mouse mammary gland matures, it undergoes extensive epithelial proliferation, leading to a network of ductal branching that transverses the organ. Recent evidence suggests that the epidermal growth factor-related peptide amphiregulin (AR) may play multiple roles in the proliferation, differentiation, and neoplastic conversion of the mouse mammary gland. Using a dual approach of recombinant AR in slow-release pellets and retroviral expression of AR, we explored the roles of this growth factor in the mouse mammary gland in vivo. We first noted that recombinant AR can reestablish longitudinal ductal proliferation in growth quiescent mammary glands of ovariectomized mice. Furthermore, retrovirally transduced mammary transplants overexpressing AR developed into hyperplastic tertiary ducts and hyperplastic lobules with increased lateral branching, apparent 9 weeks after transplantation into cleared mammary fat pads. This is the first study to demonstrate that AR can reestablish the early developmental activity of ductal mammary epithelium and induce hyperplasia in vivo. These data, coupled with previous findings that demonstrated nearly universal overexpression of AR in human breast cancer and rodent mammary tumorigenesis, suggest that AR may be an important intermediary in glandular maturation and early malignant progression.


Live Ultrasound Color-Encoded Speckle Imaging Platform for Real-Time Complex Flow Visualization In Vivo.
Complex flow patterns are prevalent in the vasculature, but they are difficult to image noninvasively in real time. This paper presents the first real-time scanning platform for a high-frame-rate ultrasound technique called color-encoded speckle imaging (CESI) and its use in visualizing arterial flow dynamics in vivo. CESI works by simultaneously rendering flow speckles and color-coded flow velocity estimates on a time-resolved basis. Its live implementation was achieved by integrating a 192-channel programmable ultrasound front-end module, a 4.8-GB/s capacity data streaming link, and a series of computing kernels implemented on the graphical processing unit (GPU) for beamforming and Doppler processing. A slow-motion replay mode was also included to offer coherent visualization of CESI frames acquired at high frame rate [3000 frames per second (fps) in our experiments]. The live CESI scanning platform was found to be effective in facilitating real-time image guidance (at least 20 fps for live video display with 55-fps GPU processing throughout). In vivo pilot trials also showed that live CESI, when running in replay mode, can temporally resolve triphasic flow at the brachial bifurcation and can reveal flow dynamics in the brachial vein during a fist-clenching maneuver. Overall, live CESI has potential for use in routine investigations in vivo that seek to identify complex flow dynamics in real time and relate these dynamics to vascular physiology.


Influence of Estimated Fetal Weight on Labor Management.
Prior studies suggest knowledge of estimated fetal weight (EFW), particularly by ultrasound (US), increases the risk for cesarean delivery. These same studies suggest that concern for macrosomia potentially alters labor management leading to increased rates of cesarean delivery. We aimed to assess if shortened labor management, as a result of suspected macrosomia (≥4,000 g), leads to an increased rate of cesarean delivery. This is a secondary analysis of a retrospective cohort study at a single tertiary center in 2015 of women with singleton pregnancies ≥36 weeks with documented EFW by US within 3 weeks or physical exam on admission. Women were excluded if an initial cervical exam was ≥6 cm or no attempt was made to labor. In addition, patients were excluded for the diagnosis of hypertension, diabetes, or prior cesarean delivery, as these comorbidities influence the use of US, labor management, and cesarean delivery independent of fetal weight. Patients were classified as EFW of ≥4,000 and <4,000 g. Secondary analysis examined the impact of US within 3 weeks of admission when compared with physical exam at the time of admission. The primary maternal outcomes were duration of labor and cesarean delivery. Duration of labor was evaluated as total time from 4 cm to delivery (with 4-cm dilation being a surrogate marker for active labor), length of time allowed from 4 cm until the first documented cervical change (or delivery), and time in second stage of labor (complete dilation to delivery). Cesarean delivery for arrest of labor was a secondary outcome. Student's t-test, Mann-Whitney U-test, chi-squared test, and Fisher's exact test were used for univariate data analysis as appropriate. Of 1,506 patients included, 54 (3.5%) had EFW of ≥4,000 g. Women with EFW of ≥4,000 g had a larger body mass index, higher fetal birth weight, were more likely to be undergoing induction of labor, had a more advanced gestational age, and were more likely to have had an US within 3 weeks of delivery. They were more likely to undergo cesarean delivery (29.6 vs. 9.3%, adjusted odds ratio [AOR]: 2.7, 95% confidence interval [CI]: 1.3-5.5) despite not having shortened labor times. When analyzing this population by method of obtaining EFW, those with EFW based on US rather than external palpation were more likely to undergo cesarean delivery (13.1 vs. 7.9%, AOR: 1.5, 95% CI: 1.01-2.12), again without having shortened labor times. EFW of ≥4,000 g and use of US to estimate fetal weight do not appear to shorten labor management despite being associated with an increased risk of cesarean delivery.


Neuroprotection of completely lacerated spinal cord of adult rats by homotopic and heterotopic transplantation.
To evaluate the neuroprotective effect of transplants placed in the lesion zone after a complete spinal cord (SC) laceration, two independent series of experiments were carried out. In the first, allogeneic or xenogeneic fetal SC was transplanted into the gaps of the damaged lower thoracic SC of adult rats. In the transplanted rats the incidence of life-threatening complications was reduced, and the survival rate was increased compared with the control group (lesion, without implant). Histological examination showed less damage to the neighboring SC parenchyma in the transplanted rats. The measurement of this neuroprotective effect was made in a second series of experiments. Using the same model of SC injury, allogeneic fetal SC, autologous peripheral nerve and/or adipose tissue were implanted. Rats with implants of Gelfoam and damaged rats without implants were the controls. The implanted rats of all groups, including the Gelfoam group, showed a better survival rate than the nonimplanted rats. Significantly less damage to the neighboring SC parenchyma was measured in implanted rats with any of the live tissues tested compared with non-implanted rats, although no significant differences were observed between the Gelfoam group and the nonimplanted rats. Histological evidence of tissue implant survival was observed in all corresponding groups. It is concluded that the transplanted tissues tested here have a neuroprotective effect, possibly by acting as a buffer to neurotoxic substance(s) released by the stumps, and/or by exerting trophic effect(s) on the host.


SuperSAGE analysis of the Nicotiana attenuata transcriptome after fatty acid-amino acid elicitation (FAC): identification of early mediators of insect responses.
Plants trigger and tailor defense responses after perception of the oral secretions (OS) of attacking specialist lepidopteran larvae. Fatty acid-amino acid conjugates (FACs) in the OS of the Manduca sexta larvae are necessary and sufficient to elicit the herbivory-specific responses in Nicotiana attenuata, an annual wild tobacco species. How FACs are perceived and activate signal transduction mechanisms is unknown. We used SuperSAGE combined with 454 sequencing to quantify the early transcriptional changes elicited by the FAC N-linolenoyl-glutamic acid (18:3-Glu) and virus induced gene silencing (VIGS) to examine the function of candidate genes in the M. sexta-N. attenuata interaction. The analysis targeted mRNAs encoding regulatory components: rare transcripts with very rapid FAC-elicited kinetics (increases within 60 and declines within 120 min). From 12,744 unique Tag sequences identified (UniTags), 430 and 117 were significantly up- and down-regulated >or= 2.5-fold, respectively, after 18:3-Glu elicitation compared to wounding. Based on gene ontology classification, more than 25% of the annotated UniTags corresponded to putative regulatory components, including 30 transcriptional regulators and 22 protein kinases. Quantitative PCR analysis was used to analyze the FAC-dependent regulation of a subset of 27 of these UniTags and for most of them a rapid and transient induction was confirmed. Six FAC-regulated genes were functionally characterized by VIGS and two, a putative lipid phosphate phosphatase (LPP) and a protein of unknown function, were identified as important mediators of the M. sexta-N. attenuata interaction. The analysis of the early changes in the transcriptome of N. attenuata after FAC elicitation using SuperSAGE/454 has identified regulatory genes involved in insect-specific mediated responses in plants. Moreover, it has provided a foundation for the identification of additional novel regulators associated with this process.


The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors.
Circulating eosinophils, basophils and eosinophil/basophil (Eo/B) progenitors were examined in 12 patients at the time of an exacerbation of asthma accompanied by sputum eosinophilia and after resolution of the exacerbation with inhaled corticosteroid treatment. Differential counts were performed and peripheral blood non-adherent mononuclear cells were cultured for 14 days in methyl-cellulose to determine the number of Eo/B and granulocyte-macrophage (GM) colonies without knowledge of the clinical conditions or findings. With resolution of the asthma exacerbation on beclomethasone therapy, there were significant falls in circulating eosinophils, basophils and Eo/B colonies whereas GM colonies were unchanged. To elucidate whether the observed changes could be due to systemic absorption or local action of inhaled corticosteroid, seven subjects with allergic rhinitis and no current evidence of lower airway inflammation (no symptoms of asthma and normal methacholine airway responsiveness) received 14 days' treatment with the same dose of inhaled beclomethasone or of placebo in a double-blind randomized cross-over study. No significant changes in airway function or in circulating cell counts were observed. The results suggest reduced production of eosinophils and basophils after the resolution of an exacerbation of asthma. This effect may be due to reduced levels of airway-derived eosinophil-basophil growth and differentiation factors.


Including non-concurrent control patients in the analysis of platform trials: is it worth it?
Platform trials allow adding new experimental treatments to an on-going trial. This feature is attractive to practitioners due to improved efficiency. Nevertheless, the operating characteristics of a trial that adds arms have not been well-studied. One controversy is whether just the concurrent control data (i.e. of patients who are recruited after a new arm is added) should be used in the analysis of the newly added treatment(s), or all control data (i.e. non-concurrent and concurrent). We investigate the benefits and drawbacks of using non-concurrent control data within a two-stage setting. We perform simulation studies to explore the impact of a linear and a step trend on the inference of the trial. We compare several analysis approaches when one includes all the control data or only concurrent control data in the analysis of the newly added treatment. When there is a positive trend and all the control data are used, the marginal power of rejecting the corresponding hypothesis and the type one error rate can be higher than the nominal value. A model-based approach adjusting for a stage effect is equivalent to using concurrent control data; an adjustment with a linear term may not guarantee valid inference when there is a non-linear trend. If strict error rate control is required then non-concurrent control data should not be used; otherwise it may be beneficial if the trend is sufficiently small. On the other hand, the root mean squared error of the estimated treatment effect can be improved through using non-concurrent control data.


Patient requirements for nursing care: the development of an instrument.
The determination of nursing staff mix is a challenge for many health care agencies. Staff mix decisions have historically been based on workload measurement information, the type of patient care unit and on a subjective or intuitive basis. Weighted task lists (workload measurement systems) do not comprehensively consider the skill and knowledge level required to meet patient care needs. This project describes the development of an instrument that considers patient's nursing care needs as a determinant of nursing staff mix. Recommendations for the use of the tool are identified.


Laparoscopic cholecystectomy assisted by combined intravenous and intracholecystic fluorescent cholangiography: a case report.
This case report describes a laparoscopic approach using fluorescence imaging guidance to treat gangrenous cholecystitis with perforation (GCP). A male patient in his early 60s presented with 3 days of right upper abdominal pain. Computed tomography and ultrasonography findings were consistent with a stone incarcerated in the gallbladder neck, GCP, and localized peritonitis. Percutaneous gallbladder drainage was initially performed, followed by laparoscopic cholecystectomy 7 days later, using combined intravenous and intracholecystic fluorescent cholangiography. This technique allowed visualization of the cystic and common bile ducts during surgery and enabled safe removal of the diseased gallbladder. The patient recovered well without complications, and reported no pain or discomfort at a 2-month follow-up.


The effects of temperature on the kinetics and stability of mesophilic and thermophilic 3-phosphoglycerate kinases.
The effects of temperature on the kinetic parameters kcat and Km, for three isolates of the highly conserved monomeric enzyme 3-phosphoglycerate kinase (PGK), were investigated in detail using a rapid automated kinetics apparatus. PGK was purified from the thermophilic bacterium Thermoanaerobacter sp. Rt8.G4 (optimum growth temperature 68 degrees C), the mesophile Zymomonas mobilis (optimum growth temperature 32 degrees C) and a second, unidentified, soil mesophile designated unid A (optimum growth temperature 27 degrees C). The kinetic behaviour with temperature of each PGK preparation was distinct, despite the conserved nature of the enzyme. The kcat values increased with temperature, but not as rapidly exponentially, as might be expected from the Arrhenius equation. Maximum kcat values were at much higher temperatures than the optimum growth temperatures for the mesophiles, but for the thermophile the temperature of maximum kcat was close to its optimum growth temperature. Km values were in general nearly constant through the lower temperature ranges, but increased substantially as the optimum temperature (highest kcat) was passed. Thermal irreversible denaturation of the PGK proteins was also investigated by measuring loss of activity over time. In a dilute buffer, Arrhenius plots for denaturation were linear, and the calculated apparent energy of activation (Eact) for denaturation for the thermophilic PGK was 600 kJ.mol-1, whereas for the mesophilic enzymes the values were 200-250 kJ.mol-1. In the presence of substrates, a considerable stabilization occurred, and in the case of the Z. mobilis enzyme, the apparent Eact was increased to 480 kJ.mol-1. A theoretical explanation for these observations is presented. Comparing the kinetics data with irreversible denaturation rates determined at relevant temperatures, it was clear that kcat values reached a maximum, and then decreased with higher temperature before irreversible denaturation had any significant influence.


Quantification of quercetin glycosides in 6 onion cultivars and comparisons of hydrolysis-HPLC and spectrophotometric methods in measuring total quercetin concentrations.
This study was performed to purify and quantify quercetin glycosides (QG) and aglycone (free) quercetin (Q) in 6 selected onion cultivars and to compare analytical approaches based on high-performance liquid chromatography (HPLC) and spectrophotometry for the quantification of total quercetin (TQ) concentrations. Individual mono- and di-glycoside Q compounds were purified using a semipreparative HPLC and identified by comparing spectral data and by confirming corresponding peaks of QG and Q after incomplete enzyme-hydrolysis. Purified QG were quantified as Q by enzyme-hydrolysis/HPLC. TQ concentrations obtained from 20 onion bulbs with enzyme-hydrolysis/HPLC, no-hydrolysis/HPLC, and a spectrophotometric method without prior hydrolysis were significantly correlated (r(2)= 0.99) and were about 15% higher, identical, or 10% less than those concentrations by a standard acid-hydrolysis/HPLC method, respectively. During enzyme-hydrolysis of onion extracts, progressive reduction of the QG and formation of the corresponding mono-glycosides and Q were monitored using an analytical HPLC. TQ ranged from 83 to 330 microg/g F.W. in 6 selected cultivars of long-day or short-day onions. Q3,4'G and Q4'G were the 2 major compounds and comprised approximately between 94% and 97% of TQ in onions.


Framework for assessing stewardship of the oral health system in Islamic Republic of Iran.
This study designed a framework for assessing the stewardship function of the oral health system in Islamic Republic of Iran. The modified RAND Corporation/University of California Los Angeles (RAND-UCLA) Appropriateness Method was used in a 2-step process that combined literature evidence and the collective judgement of experts. After a comprehensive literature review, policy instruments related to stewardship components were extracted as candidate standards and categorized according to the 6 sub-functions of stewardship (accountability; defining strategic direction; alignment of policy objectives and organizational structure; regulation; intersectoral leadership; and generation of intelligence). Five key informants then rated the appropriateness of the 85 standards on a 5-point Likert scale. The 38 highest ranked standards, including at least 2 standards in each of the 6 sub-functions, formed a set of proposed standards for evaluating the current stewardship of oral health system. Piloting of the instrument will be reported separately.


Identification and functional characterization of circRNA-0008717 as an oncogene in osteosarcoma through sponging miR-203.
Circular RNA (circRNA) is a key regulator in the development and progression of human cancers, however its role in osteosarcoma tumorigenesis is not well understood. The present study aims to investigate the expression profiles and potential modulation of circRNA on osteosarcoma carcinogenesis. Human circRNA microarray was performed to screen for abnormally expressed circRNA in osteosarcoma tissue and circRNA-0008717 was identified as one circRNA significantly upregulated in osteosarcoma tissue. Osteosarcoma patients with high circRNA-0008717 expression had shortened survival. Gain and loss functional assays suggested that knockdown of circRNA-0008717 suppressed cell proliferation, migration and invasion, but promoted cell apoptosis. By using biotin-labeled circRNA-0008717 probe to perform RNA precipitation in osteosarcoma cells, we identified miR-203 as the circ0008717-associated microRNA. Subsequently, Bmi-1 was identified as the functional target of miR-203. In addition, overexpression of circRNA-0008717 in osteosarcoma could elevate Bmi-1 expression, resulting in the promotion of osteosarcoma cell proliferation and invasion. Furthermore, the tumor promoting effect of circRNA-0008717 was abolished by miR-203 mimics or Bmi-1 silencing vector. In conclusion, circRNA-0008717 plays an oncogenic role in osteosarcoma and may serve as a promising prognostic biomarker for osteosarcoma patients. Therefore, silence of circRNA-0008717 could be a future direction to develop a novel treatment strategy.


Metabolic effects of hypocaloric diets in management of gestational diabetes.
Although hypocaloric diets have been advocated for the management of the obese gravida and the obese mother with gestational diabetes, there is no general agreement on how severely calories should be restricted or on how this therapeutic approach compares with insulin therapy. The lack of consensus is in part because of the lack of studies comparing insulin management with the effects of different degrees of hypocaloric feeding and its effects on metabolism and glycemic status. We review the effects of 50 and 33% calorie restriction on glycemic status and intermediary fuel status in obese gestational diabetic subjects and compare the results with the administration of 20 U NPH and 10 U regular insulin every morning, a therapy of proven value in reducing macrosomia in gestational diabetes. When the two calorie-restriction regimens were compared after a 9-h overnight fast, glycemic status improved 10-20% on both. Ketonuria increased about twofold with 50% calorie restriction, but on average no increase in ketonuria was seen on the 33% calorie-restriction regimen. Both calorie-restriction programs led to a reduction in levels of plasma triglyceride, a correlate of infant birth weight. In contrast, the insulin regimen diminished ketonuria, but glycemic status improved little, and plasma triglyceride concentrations did not decline. Although more studies are needed to confirm these trends, the beneficial effect of 33% calorie restriction, which occurred without marked ketonuria, is consistent with previous studies in gestational diabetes. In addition, the simultaneous improvements observed in plasma glucose and triglyceride concentrations suggest that moderate calorie restriction may be valuable in preventing macrosomia in the offspring of the obese subject with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)


The increasing significance of impact within the Research Excellence Framework (REF).
The UK's Research Excellence Framework (REF) is a performance-based research funding system that was introduced in 2014. REF is a process of expert review in universities which assesses the quality and reach of research across higher education. It highlights areas of excellence, benchmarks the quality of previously funded research and provides accountability for ongoing public investment in research. In addition to assessing the quality of research outputs and the environment in which research is undertaken, the REF became the first exercise to evaluate the impact of research outside of academia. This article specifically addresses the impact component of the REF, explaining what is understood by the term 'impact' and considering how impact is gaining significance within the REF framework as a measure of research excellence. It also reflects on the complexities of measuring impact and ongoing resistance from academics to the impact agenda, which they believe threatens academic freedom and appears only to value research that generates specific outcomes. In order to address these and other issues arising from the first-ever assessment of impact in REF 2014, institutions were consulted on the proposed guidance for the REF 2021 submission. The final REF 2021 guidance has sought to provide clearer detail on interpretations of impact and its underpinning research in order to reassure researchers that their academic freedom will not come under threat. However, this process still fails to capture other impactful research being undertaken across institutions, which falls outside of the strict REF criteria.


[Clinico-endoscopic peculiarities of gastric ulcer of type I and II].
A detailed analysis of clinico-endoscopic peculiarities of gastric ulcer type I and II was presented. The peculiarities of a clinical course and the complications character of differently localized gastric ulcers were determined. There was shown the connection between concomitant disorders of esophagogastroduodenal motor-evacuation function and gastric ulcer localization and type. While tactics of treatment and operative procedure choosing it is mandatory to take into account the clinical course peculiarities and the results of endoscopic investigation.


Phenotypic and genotypic characterization of some lactic Acid bacteria isolated from bee pollen: a preliminary study.
In the present work, five hundred and sixty-seven isolates of lactic acid bacteria were recovered from raw bee pollen grains. All isolates were screened for their antagonistic activity against both Gram-positive and Gram-negative pathogenic bacteria. Neutralized supernatants of 54 lactic acid bacteria (LAB) cultures from 216 active isolates inhibited the growth of indicator bacteria. They were phenotypically characterized, based on the fermentation of 39 carbohydrates. Using the simple matching coefficient and unweighted pair group algorithm with arithmetic averages (UPGMA), seven clusters with other two members were defined at the 79% similarity level. The following species were characterized: Lactobacillus plantarum, Lactobacillus fermentum, Lactococcus lactis, Pediococcus acidilactici, Pediococcus pentosaceus, and unidentified lactobacilli. Phenotypic characteristics of major and minor clusters were also identified. Partial sequencing of the 16S rRNA gene of representative isolates from each cluster was performed, and ten strains were assigned to seven species: Lactobacillus plantarum, Lactobacillus fermentum, Lactococcus lactis, Lactobacillus ingluviei, Pediococcus pentosaceus, Lactobacillus acidipiscis and Weissella cibaria. The molecular method used failed to determine the exact taxonomic status of BH0900 and AH3133.


Technetium 99m sulfur colloid spleen/liver ratio and other liver tests in the diagnosis of cirrhosis.
The results of seven laboratory tests of liver function, including spleen/liver activity ratios obtained by densitometric analysis of scans, are analyzed in 50 patients with proven Laennec's cirrhosis. In this series, the liver scan not only disclosed the liver gross anatomy and structural abnormality and established the best possible site for biopsy examination, but also, the increased splenic activity served as a useful diagnostic indication of Laennec's cirrhosis. Of 50 proven cases of Laennec's cirrhosis, 41 (82%) had abnormal spleen/liver ratios. An abnormal spleen/liver ratio in combination with abnormal results from any one or two other tests was relatively effective in the detection of cirrhosis. The accuracy is improved if the other laboratory tests are chosen from among tests for serum albumin, serum bilirubin, and SGOT. (Liver abnormalities other than cirrhosis can also present an abnormal spleen/liver ratio.) This simple determination extends the value of the liver scan commonly requested in search of metastases, primary lesions, or inflammatory processes, or in preparation for needle biopsy examination.


Crystal structures of CusC review conformational changes accompanying folding and transmembrane channel formation.
Gram-negative bacteria, such as Escherichia coli, frequently utilize tripartite efflux complexes in the RND (resistance-nodulation-cell division) family to expel diverse toxic compounds from the cell. These complexes span both the inner and outer membranes of the bacterium via an α-helical, inner membrane transporter; a periplasmic membrane fusion protein; and a β-barrel, outer membrane channel. One such efflux system, CusCBA, is responsible for extruding biocidal Cu(I) and Ag(I) ions. To remove these toxic ions, the CusC outer membrane channel must form a β-barrel structural domain, which creates a pore and spans the entire outer membrane. We here report the crystal structures of wild-type CusC, as well as two CusC mutants, suggesting that the first N-terminal cysteine residue plays an important role in protein-membrane interactions and is critical for the insertion of this channel protein into the outer membrane. These structures provide insight into the mechanisms on CusC folding and transmembrane channel formation. It is found that the interactions between CusC and membrane may be crucial for controlling the opening and closing of this β-barrel, outer membrane channel.


Photophysical Tuning of N-Oxide-Based Probes Enables Ratiometric Photoacoustic Imaging of Tumor Hypoxia.
Hypoxia results when the oxygen supply to rapidly growing tumors becomes inadequate to support various physiological processes. This plays a role in tumor metastasis and treatment resistance. Therefore, identifying tumor hypoxia can guide treatment planning and predict patient responses. However, hypoxic volumes are heterogeneously dispersed throughout a tumor, making it a challenge to pinpoint them with any degree of accuracy. Herein, we report the development of ratiometric hypoxia probe 1 (rHyP-1), which is a hypoxia-responsive small-molecule probe designed for reliable hypoxia detection using photoacoustic imaging. Photoacoustic imaging utilizes near-infrared (NIR) light to induce the production of ultrasound signals, enabling high-resolution image acquisition at centimeter depths. Together with the ratiometric capability of rHyP-1, reliable hypoxia detection with unprecedented spatial resolution is possible while minimizing error associated with concentration dependence and tissue heterogeneity.


Factors influencing patient satisfaction with the first diagnostic consultation in multiple sclerosis: a Swiss Multiple Sclerosis Registry (SMSR) study.
Patient satisfaction is predictive of adherence, malpractice litigation and doctor-switching. To investigate which factors of the first diagnostic consultation (FDC) influence patient satisfaction and which topics persons with multiple sclerosis (PwMS) thought were missing. Using retrospective patient-reported data of the Swiss Multiple Sclerosis Registry from PwMS with relapsing disease onset, we fitted ordered logistic regression models on satisfaction with FDC, with socio-demographic and FDC features as explanatory factors. 386 PwMS diagnosed after 1995 were included. Good satisfaction with the FDC was associated with a conversation more than 20 min [multivariable odds ratio, 95% confidence interval 3.9 (2.42; 6.27)], covering many topics [1.35 (1.19; 1.54) per additional topic], the presence of a significant others [1.74 (1.03; 2.94) ], and shared decision making [3.39 (1.74; 6.59)]. Not receiving a specific diagnosis was main driver for low satisfaction [0.29 (0.15; 0.55)]. Main missing topics concerned long-term consequences (reported by 6.7%), psychological aspects (6.2%) and how to obtain support and further information (5.2%). A conversation of more than 20 min covering many MS relevant topics, a clear communication of the diagnosis, the presence of a close relative or significant other, as well as shared decision making enhanced patient satisfaction with the FDC. ClinicalTrials.gov Identifier: NCT02980640.


Decolonising medical curricula through diversity education: lessons from students.
The General Medical Council (GMC) expects that medical students graduate with an awareness of how the diversity of the patient population may affect health outcomes and behaviours. However, little guidance has been provided on how to incorporate diversity teaching into medical school curricula. Research highlights the existence of two different models within medical education: cultural competency and cultural humility. The Southampton medical curriculum includes both models in its diversity teaching, but little was known about which model was dominant or about the students' experience. Fifteen semi-structured, in-depth interviews were carried out with medical students at the University of Southampton. Data were analysed thematically using elements of grounded theory and constant comparison. Students identified early examples of diversity teaching consistent with a cultural humility approach. In later years, the limited diversity teaching recognised by students generally adopted a cultural competency approach. Students tended to perceive diversity as something that creates problems for healthcare professionals due to patients' perceived differences. They also reported witnessing a number of questionable practices related to diversity issues that they felt unable to challenge. The dissonance created by differences in the largely lecture based and the clinical environments left students confused and doubting the value of cultural humility in a clinical context. Staff training on diversity issues is required to encourage institutional buy-in and establish consistent educational and clinical environments. By tackling cultural diversity within the context of patient-centred care, cultural humility, the approach students valued most, would become the default model. Reflective practice and the development of a critical consciousness are crucial in the improvement of cultural diversity training and thus should be facilitated and encouraged. Educators can adopt a bidirectional mode of teaching and work with students to decolonise medical curricula and improve medical practice.


Domestic radon and childhood cancer in Denmark.
Higher incidence rates of childhood cancer and particularly leukemia have been observed in regions with higher radon levels, but case-control studies have given inconsistent results. We tested the hypothesis that domestic radon exposure increases the risk for childhood cancer. We identified 2400 incident cases of leukemia, central nervous system tumor, and malignant lymphoma diagnosed in children between 1968 and 1994 in the Danish Cancer Registry. Control children (n = 6697) were selected from the Danish Central Population Registry. Radon levels in residences of children and the cumulated exposure of each child were calculated as the product of exposure level and time, for each address occupied during childhood. Cumulative radon exposure was associated with risk for acute lymphoblastic leukemia (ALL), with rate ratios of 1.21 (95% confidence interval = 0.98-1.49) for levels of 0.26 to 0.89 x 10(3) Bq/m3-years and 1.63 (1.05-2.53) for exposure to >0.89 x 10(3) Bq/m3-years, when compared with <0.26 x 10(3) Bq/m3-years. A linear dose-response analysis showed a 56% increase in the rate of ALL per 10(3) Bq/m3-years increase in exposure. The association with ALL persisted in sensitivity analyses and after adjustment for potential confounders. No association was found with the other types of childhood cancer. This study suggests that domestic radon exposure increases the risk for ALL during childhood but not for other childhood cancers.


A Chromosome Segment Substitution Library of Weedy Rice for Genetic Dissection of Complex Agronomic and Domestication Traits.
Chromosome segment substitution lines (CSSLs) are a powerful alternative for locating quantitative trait loci (QTL), analyzing gene interactions, and providing starting materials for map-based cloning projects. We report the development and characterization of a CSSL library of a U.S. weedy rice accession 'PSRR-1' with genome-wide coverage in an adapted rice cultivar 'Bengal' background. The majority of the CSSLs carried a single defined weedy rice segment with an average introgression segment of 2.8 % of the donor genome. QTL mapping results for several agronomic and domestication traits from the CSSL population were compared with those obtained from two recombinant inbred line (RIL) populations involving the same weedy rice accession. There was congruence of major effect QTLs between both types of populations, but new and additional QTLs were detected in the CSSL population. Although, three major effect QTLs for plant height were detected on chromosomes 1, 4, and 8 in the CSSL population, the latter two escaped detection in both RIL populations. Since this was observed for many traits, epistasis may play a major role for the phenotypic variation observed in weedy rice. High levels of shattering and seed dormancy in weedy rice might result from an accumulation of many small effect QTLs. Several CSSLs with desirable agronomic traits (e.g. longer panicles, longer grains, and higher seed weight) identified in this study could be useful for rice breeding. Since weedy rice is a reservoir of genes for many weedy and agronomic attributes, the CSSL library will serve as a valuable resource to discover latent genetic diversity for improving crop productivity and understanding the plant domestication process through cloning and characterization of the underlying genes.


Development of a bioengineered tissue model and its application in the investigation of the depth selectivity of polarization gating.
Understanding the propagation of polarized light in tissue is crucial for a number of biomedical optics applications. Here we report the development of a bioengineered connective tissue model fabricated by the combination of scaffolding and cross-linking techniques to study light transport in biological tissue. It demonstrates great similarity to real connective tissue in its optical properties as well as microarchitecture. Moreover, the optical properties of the model can be reproducibly controlled. As an example, we report the utilization of this model to study the effect of epithelium and the underlying connective tissue on the depth selectivity of polarization gating.


Migration health research and policy in south and south-east Asia: mapping the gaps and advancing a collaborative agenda.
Migrant health has been the subject of various international agreements in recent years. In parallel, there has been a growth in academic research in this area. However, this increase in focus at international level has not necessarily strengthened the capacity to drive evidence-informed national policy and action in many low- and middle-income countries. The Migration Health South Asia (MiHSA) network aims to challenge some of the barriers to progress in the region. Examples include the bias towards institutions in high-income countries for research funding and agenda-setting and the overall lack of policy-focused research in the region. MiHSA will engage researchers, funders and policy-makers in collectively identifying the most pressing, yet feasible, research questions that could help strengthen migrant and refugee health relevant to the region's national contexts. In addition, policies and provisions for different migrant populations in the region will be reviewed from the health and rights perspectives, to identify opportunities to strategically align research agendas with the questions being asked by policy-makers. The convergence of migration policy with other areas such as health and labour at global level has created a growing imperative for policy-makers in the region to engage in cross-sector dialogue to align priorities and coordinate responses. Such responses must go beyond narrow public health interventions and embrace rights-based approaches to address the complex patterns of migration in the region, as well as migrants' precarity, vulnerabilities and agency.


ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis.
Inappropriate CD4+ T helper (Th) differentiation can compromise host immunity or promote autoimmune disease. To identify disease-relevant regulators of T cell fate, we examined mutations that modify risk for multiple sclerosis (MS), a canonical organ-specific autoimmune disease. This analysis identified a role for Zinc finger E-box-binding homeobox (ZEB1). Deletion of ZEB1 protects against experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Mechanistically, ZEB1 in CD4+ T cells is required for pathogenic Th1 and Th17 differentiation. Genomic analyses of paired human and mouse expression data elucidated an unexpected role for ZEB1 in JAK-STAT signaling. ZEB1 inhibits miR-101-3p that represses JAK2 expression, STAT3/STAT4 phosphorylation, and subsequent expression of interleukin-17 (IL-17) and interferon gamma (IFN-γ). Underscoring its clinical relevance, ZEB1 and JAK2 downregulation decreases pathogenic cytokines expression in T cells from MS patients. Moreover, a Food and Drug Administration (FDA)-approved JAK2 inhibitor is effective in EAE. Collectively, these findings identify a conserved, potentially targetable mechanism regulating disease-relevant inflammation.


Non-EPI DW MRI in planning the surgical approach to primary and recurrent cholesteatoma.
To investigate a correlation between preoperative non-echo planar diffusion-weighted magnetic resonance imaging (non-EPI DW MRI) with surgical findings of localization and extension of cholesteatoma and to develop criteria for surgical planning. Preoperative non-EPI DWMRI was available and positive for cholesteatoma in 27 patients with primary and 23 with residual/recurrent lesions. Patients with cholesteatoma limited to the middle ear and its extensions were managed with a transcanal endoscopic approach. Patients with extension of the cholesteatoma posteriorly to the lateral semicircular canal underwent retroauricular mastoidectomy combined with an endoscopic approach. Comparison of preoperative radiologic to surgical findings. DWI showed isolated tympanic and attic extension in 33 cases and attico-antral and mastoid extension in 17 cases. MRI findings correlated with surgical findings in all patients with primary cholesteatoma, 19 of whom were managed with a transcanal endoscopic approach and 8 with endoscope-assisted ear surgery. The transcanal endoscopic approach was applied in 14 of the patients with residual/recurrent cholesteatoma, and the other 9 residual/recurrent lesions were eradicated using endoscope-assisted mastoidectomy. DWI overestimated cholesteatoma sites in 1 patient with residual lesion. The smallest cholesteatoma detected on DWI was a 3-mm lesion in the middle ear over the facial nerve. Primary and residual/recurrent cholesteatoma was accurately detected on non-EPI DWI with 98% clinical and radiologic concordance. Lesions less than 8 mm confined to the middle ear and its extensions can be eradicated with a minimally invasive endoscopic transcanal technique, whereas endoscope-assisted retroauricular mastoidectomy is preferred for larger lesions.


The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.
Estrogen-related receptor alpha (ERRalpha) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERRalpha is an effector of the transcriptional coactivator PGC-1alpha [peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERRalpha compromises the ability of PGC-1alpha to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERRalpha is sufficient to elicit both responses. ERRalpha binding sites are present in the transcriptional control regions of ERRalpha/PGC-1alpha-induced genes and contribute to the transcriptional response to PGC-1alpha. The ERRalpha-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERRalpha activity could be linked to pathological changes in metabolic disease, such as diabetes.


Quantum effect enhanced magnetism of C-doped phosphorene nanoribbons: first-principles calculations.
Manipulating magnetism of low-dimensional materials is of great importance for their practical applications. Here, using first-principles calculations, we report a systematic investigation of the magnetic properties of C-doped H saturated zigzag phosphorene nanoribbons (H-ZPNRs), which are rather different from those of 2D periodic systems due to the quantum size effect. First of all, we observed a greatly enhanced magnetic moment locating mainly on the C atom and also slightly on its surrounding P atoms. Our results also indicated a strong dependence of the magnetic moment of the C atom on its location, which decays from the edge to the center site of the nanoribbons with an odd-even oscillating behavior originating from Friedel oscillation in low-dimensional materials. As for the C atom on a specific location, its magnetic moment decreases gradually with increasing width of H-ZPNRs, degenerating to the 2D case. What is more, we found that both the magnitude and the oscillating behavior of the magnetic moment on the C atom can be tuned by the edge saturation atoms. In addition, the case of two C atoms co-doping H-ZPNRs was also studied, showing non-magnetic (NM), ferromagnetic (FM) and antiferromagnetic (AFM) states depending on the locations of the two C atoms. Our findings suggest a plausible route for manipulating magnetism of the sp element doped H-ZPNRs, which are expected to have potential applications in spintronics.


Why are phenotypic mutation rates much higher than genotypic mutation rates?
The evolution of genotypic mutation rates has been investigated in numerous theoretical and experimental studies. Mutations, however, occur not only when copying DNA, but also when building the phenotype, especially when translating and transcribing DNA to RNA and protein. Here we study the effect of such phenotypic mutations. We find a maximum phenotypic mutation rate, umax, that is compatible with maintaining a certain function of the organism. This may be called a phenotypic error threshold. In particular, we find a minimum phenotypic mutation rate, umin, with the property that there is (nearly) no selection pressure to reduce the rate of phenotypic mutations below this value. If there is a cost for lowering the phenotypic mutation rate, then umin is close to the optimum phenotypic mutation rate that maximizes the fitness of the organism. In our model, there is selective pressure to decrease the rate of genotypic mutations to zero, but to decrease the rate of phenotypic mutations only to a positive value. Despite its simplicity, our model can explain part of the huge difference between genotypic and phenotypic mutation rates that is observed in nature. The relevant data are summarized.


GABA transporters and GABA-transaminase as drug targets.
The fine-tuning and homeostatic balance of the GABAergic inhibitory tone in the central nervous system (CNS) is a prerequisite for controlling the excitatory neurotransmission. This principal mechanism for controlling excitation is inhibition which has been the topic of intensive research covering all known functional entities of the GABAergic synapse. The therapeutical scope for targeting the GABA system covers a large number of neurological and psychiatric disorders. This review focuses on the major inactivation systems for GABAergic neurotransmission, the GABA transporters (GATs) and the GABA catabolic enzyme GABA -transaminase (GABA-T) as drug targets. Tiagabin and Vigabatrin, two anti-epileptic drugs on the market today, specifically inhibit GABA transport and metabolism, respectively. However, previous and recent evidence has clearly demonstrated the importance and differential functional roles of glial and neuronal GABA uptake and the metabolic fate of the sequestered neurotransmitter GABA in these cells. Moreover, the diverse expression patterns of the GABA transporters, in combination with development of GAT inhibitors with novel pharmacological profiles may initiate a renaissance for these inactivation systems as drugs targets. In particular, further research to elucidate the specialized physiological function of the GATs combined with their differential spatial expression could be of fundamental importance for the understanding of concerted action with regard to the fine-tuning of the GABAergic inhibitory tone. As such, selective targeting and modulation of GABA transporter subtypes and cell-specific GABA uptake and metabolism is of therapeutical interest in GABA-related CNS disorders, including epilepsy.


PCSK9 inhibitor use during pregnancy in a case of familial hypercholesterolemia complicated with coronary artery disease.
Limited data have been reported on the use of proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors during pregnancy in women with familial hypercholesterolemia (FH). Here, we present the first case of initiating evolocumab (PCSK9 inhibitor) in a compound heterozygous FH mother. The patient was a 34-year-old primipara with severe dyslipidemia and a history of coronary artery bypass surgery. An elevated low-density lipoprotein cholesterol (LDL-C) level of 420 mg/dL was detected in the first trimester and persistently increased throughout pregnancy. Evolocumab was administered at 31 and 35 weeks of gestation, showing a positive effect on stabilizing LDL-C levels. Planned delivery with labor analgesia was performed at 38 + 4 weeks. Both the mother and infant were discharged without any notable complications. Hence, evolocumab, an IgG2 monochromatic antibody with little placental permeability, may be an alternative medication with limited influence on infants. Further studies are needed to assess the safety of evolocumab administration during pregnancy.


Telomerase inhibitors from cyanobacteria: isolation and synthesis of sulfoquinovosyl diacylglycerols from Microcystis aeruguinosa PCC 7806.
By using the Telospot assay, 27 different extracts of cyanobacteria were evaluated for telomerase inhibition. All extracts showed varying, but significant activity. We selected Microcystis aeruguinosa PCC 7806 to identify the active compound and a bioassay guided fractionation led us to isolate mixtures of sulfoquinovosyl diacylglycerols (SQDGs), which were identified by 2D NMR and MS/MS experiments. Pure SQDG derivatives were then synthesized. The IC(50) values of pure synthetic sulfoquinovosyl dipalmitoylglycerol and the monopalmitoylated derivative against telomerase were determined to be 17 and 40 μM, respectively. A structure-activity relationship study allowed the identification of compounds with modified lipophilic acyl groups that display improved activity.


Energetic hot electrons from exciton-to-hot electron upconversion in Mn-doped semiconductor nanocrystals.
Generation of hot electrons and their utilization in photoinduced chemical processes have been the subjects of intense research in recent years mostly exploring hot electrons in plasmonic metal nanostructures created via decay of optically excited plasmon. Here, we present recent progress made in generation and utilization of a different type of hot electrons produced via biphotonic exciton-to-hot electron "upconversion" in Mn-doped semiconductor nanocrystals. Compared to the plasmonic hot electrons, those produced via biphotonic upconversion in Mn-doped semiconductor nanocrystals possess much higher energy, enabling more efficient long-range electron transfer across the high energy barrier. They can even be ejected above the vacuum level creating photoelectrons, which can possibly produce solvated electrons. Despite the biphotonic nature of the upconversion process, hot electrons can be generated with weak cw excitation equivalent to the concentrated solar radiation without requiring intense or high-energy photons. This perspective reviews recent work elucidating the mechanism of generating energetic hot electrons in Mn-doped semiconductor nanocrystals, detection of these hot electrons as photocurrent or photoelectron emission, and their utilization in chemical processes such as photocatalysis. New opportunities that the energetic hot electrons can open by creating solvated electrons, which can be viewed as the longer-lived and mobile version of hot electrons more useful for chemical processes, and the challenges in practical utilization of energetic hot electrons are also discussed.


Neutralization of bovine herpesvirus type 4 by pairs of monoclonal antibodies raised against two glycoproteins and identification of antigenic determinants involved in neutralization.
In infected cattle, bovine herpesvirus type 4 (BHV-4) induces an immune response with low neutralizing antibody levels or in the absence of such antibodies. For the study of this phenomenon, monoclonal antibodies (MAbs) raised against two BHV-4 glycoproteins identified previously (150K/120K/51K and 120K/16.5K) were used in neutralization tests. None of the MAbs except for MAb 16 could neutralize alone; pairs of MAbs against the 150K/120K/51K and 120K/16.5K glycoproteins were able to neutralize BHV-4 infectivity. MAbs involved in neutralization were used in competitive binding assays to identify epitopes relevant for BHV-4 neutralization. These MAbs showed a low avidity and a weak neutralizing activity, and they partially decreased BHV-4 attachment to cells. These results suggest that the BHV-4 glycoprotein domains involved in viral infectivity are poorly exposed to the immune system.


Excision of the donor cornea instead of enucleation.
Shortage of corneal grafts is common in many countries. The method presented here has been developed to relieve this situation and make it easier, especially from the psychological point of view, to obtain a license for excising corneas from cadavers. An 11 mm. corneal button is excised from the donor eye in situ with a Draeger electric rotor trephine and the donor eyes remain apparently normal looking. These excised corneas without sclerocorneal rims are placed in adequate without sclerocorneal rims are placed in adequate storage media for long-term cryopreservation according to Capella, Kaufman, and Robbins or for short-term storage according to McCarey and Kaufman. The preliminary results are promising and the technique seems not to be too delicate or complicated to be carried out by an experienced eye bank technician. It has improved our possibilities for storing donor corneas and for collecting many tissue-typed corneas in our eye bank.


Ecological constraints on breeding system evolution: the influence of habitat on brood desertion in Kentish plover.
1. One of the fundamental insights of behavioural ecology is that resources influence breeding systems. For instance, when food resources are plenty, one parent is able to care for the young on its own, so that the other parent can desert and became polygamous. We investigated this hypothesis in the context of classical polyandry when females may have several mates within a single breeding season, and parental duties are carried out largely by the male. 2. We studied a precocial wader, the Kentish plover Charadrius alexandrinus, that exhibits variable brood care such that the chicks may be raised by both parents, only by the female or, more often, only by the male. The timing of female desertion varies: some females desert their brood at hatching of the eggs and lay a clutch for a new mate, whereas other females stay with their brood until the chicks fledge. Kentish plovers are excellent organisms with which to study breeding system evolution, as some of their close relatives exhibit classical polyandry (Eurasian dotterel Eudromias morinellus, mountain plover Charadrius montanus), whereas others are polygynous (northern lapwing Vanellus vanellus). 3. Kentish plovers raised their broods in two habitats in our study site in southern Turkey: saltmarsh and lakeshore. Food intake was higher on the lakeshore than in the saltmarsh as judged from feeding behaviour of chicks and adults. As the season proceeded and the saltmarsh dried out, the broods moved toward the lakeshore. 4. As the density of plovers increased on lakeshore, the parents spent more time defending their young, and female parents stayed with their brood longer on the lakeshore. 5. We conclude that the influence of food abundance on breeding systems is more complex than currently anticipated. Abundant food resources appear to have profound implications on spatial distribution of broods, and the social interactions between broods constrain female desertion and polyandry.


OsSHOC1 and OsPTD1 are essential for crossover formation during rice meiosis.
Meiosis is essential for eukaryotic sexual reproduction and plant fertility, and crossovers (COs) are essential for meiosis and the formation of new allelic combinations in gametes. In this study, we report the isolation of a meiotic gene, OsSHOC1, and the identification of its partner, OsPTD1. Osshoc1 was sterile both in male and female gametophytes, and it showed a striking reduction in the number of meiotic COs, indicating that OsSHOC1 was required for normal CO formation. Further investigations showed that OsSHOC1 physically interacted with OsPTD1 and that the latter was also required for normal CO formation and plant fertility. Additionally, the expression profiles of both genes were consistent with their functions. Our results suggest that OsSHOC1 and OsPTD1 are essential for rice fertility and CO formation, possibly by stabilizing the recombinant intermediates during meiosis.


The GUIDES checklist: development of a tool to improve the successful use of guideline-based computerised clinical decision support.
Computerised decision support (CDS) based on trustworthy clinical guidelines is a key component of a learning healthcare system. Research shows that the effectiveness of CDS is mixed. Multifaceted context, system, recommendation and implementation factors may potentially affect the success of CDS interventions. This paper describes the development of a checklist that is intended to support professionals to implement CDS successfully. We developed the checklist through an iterative process that involved a systematic review of evidence and frameworks, a synthesis of the success factors identified in the review, feedback from an international expert panel that evaluated the checklist in relation to a list of desirable framework attributes, consultations with patients and healthcare consumers and pilot testing of the checklist. We screened 5347 papers and selected 71 papers with relevant information on success factors for guideline-based CDS. From the selected papers, we developed a 16-factor checklist that is divided in four domains, i.e. the CDS context, content, system and implementation domains. The panel of experts evaluated the checklist positively as an instrument that could support people implementing guideline-based CDS across a wide range of settings globally. Patients and healthcare consumers identified guideline-based CDS as an important quality improvement intervention and perceived the GUIDES checklist as a suitable and useful strategy. The GUIDES checklist can support professionals in considering the factors that affect the success of CDS interventions. It may facilitate a deeper and more accurate understanding of the factors shaping CDS effectiveness. Relying on a structured approach may prevent that important factors are missed.


Cerebral specialization in individuals with Down syndrome.
Recent research in which investigators examined cerebral specialization in individuals with Down syndrome was reviewed. Although dichotic listening studies seem to indicate that individuals with Down syndrome are more likely than those without Down syndrome to display a left ear/right hemisphere advantage for speech sounds, evidence from other experimental paradigms makes a simple model of reversed cerebral specialization for individuals with Down syndrome untenable. We proposed a model of cerebral specialization that has as its main feature the biological dissociation between speech perception and the production of speech and other complex movements. In light of this feature, possible directions for future research were discussed.


The razor curl: a functional approach to hamstring training.
This study examined the effectiveness of a functional hamstring training exercise, the razor curl on conditioning the hamstring and gluteal musculature. Eight healthy, female intercollegiate athletes participated (mean age 20.8 +/- 3.9 years; mean height, 177.8 +/- 10.9 cm; mean weight, 67.3 +/- 9.9 kg). Electromyographic (EMG) data were collected on the following muscles: medial hamstring (semimembranosus and semitendinosus), biceps femoris, gluteus medius, and gluteus maximus while participants performed the razor curl. The functional positioning of the razor curl showed maximum activation of the medial hamstring muscle group of up to 220% of its maximum voluntary isometric contraction (MVIC), just as the biceps femoris displayed a max of up to 140% of MVIC. Maximum activation of the hamstrings and gluteals were observed from the point of 90 degrees of hip flexion to the point of knee flexion beyond 90 degrees . These data reveal that the razor curl does indeed activate the hamstring musculature and based on the mechanics of the razor curl one can train in a more functional position. It is known biomechanically that flexing the hip allows for a lengthening contraction of the hamstring at the hip, thus allowing for a more optimal forceful contraction of the hamstrings at the knee. In conclusion, the razor curl hamstring exercise is designed to increase hamstring contractibility by placing the hip into flexion. By including strengthening the hamstring in a functional position one accentuates other land based training methods such as jump landing training in efforts to ultimately decrease the susceptibility of anterior cruciate ligament injury.


Thioester-containing proteins in the tsetse fly (Glossina) and their response to trypanosome infection.
Thioester-containing proteins (TEPs) are conserved proteins with a role in innate immune immunity. In the current study, we characterized the TEP family in the genome of six tsetse fly species (Glossina spp.). Tsetse flies are the biological vectors of several African trypanosomes, which cause sleeping sickness in humans or nagana in livestock. The analysis of the tsetse TEP sequences revealed information about their structure, evolutionary relationships and expression profiles under both normal and trypanosome infection conditions. Phylogenetic analysis of the family showed that tsetse flies harbour a genomic expansion of specific TEPs that are not found in other dipterans. We found a general expression of all TEP genes in the alimentary tract, mouthparts and salivary glands. Glossina morsitans and Glossina palpalis TEP genes display a tissue-specific expression pattern with some that are markedly up-regulated when the fly is infected with the trypanosome parasite. A different TEP response was observed to infection with Trypanosoma brucei compared to Trypanosoma congolense, indicating that the tsetse TEP response is trypanosome-specific. These findings are suggestive for the involvement of the TEP family in tsetse innate immunity, with a possible role in the control of the trypanosome parasite.


Canadian ground ambulance services: provincial funding and standards for equipment and training.
There is an increasing demand for improved, up-to-date training and equipment for ground ambulance services across Canada. This paper presents the results of a survey of ambulance operations and their funding by the provinces, as well as a comparison of provincial legislation and recommendations on standards for equipment and the training of ambulance personnel. The training standards were found to be very diverse, and the legislated or recommended equipment standards did not meet those of the American College of Surgeons committee on trauma (ACSCT). The cost of ambulance services per capita and the cost to the user of an average 43-km run varied widely between the provinces. There was no correlation between the second cost and how well the province met the ACSCT's equipment standards.


Thirty-Day Outcomes following Pediatric Bone and Soft Tissue Sarcoma Surgery: A NSQIP Pediatrics Analysis.
Pediatric bone and soft tissue sarcomas are rare; therefore, national registries are essential tools for orthopedic oncology research. Past studies provide excellent data on long-term prognosis and survival trends but fail to examine treatment-specific morbidity. The aim of this study is to use a national registry to describe patient demographics, comorbidities, and adverse events in the first thirty days following surgical management of pediatric bone and soft tissue sarcomas. A retrospective review of patients in the American College of Surgeons National Surgical Quality Improvement Program-Pediatrics database (NSQIP-P) was performed. The cohort was partitioned by tumor origin (bone versus soft tissue) and tumor location (axial versus appendicular). One-hundred ninety-two patients were identified. Bone sarcomas were more common (71.9%) and predominately appendicular (62.3%), while soft tissue sarcomas were predominately axial (77.8%). The overall complication rate was 8.9%. The most frequent etiologies were wound dehiscence (3.6%) and infectious complications such as surgical site infections (2.6%), pneumonia (1.6%), urinary tract infections (1.6%), and C. diff colitis (1.0%). Twenty-four percent of patients experienced bleeding requiring transfusion. The unplanned readmission rate was 12.5% (3.6% related to principle procedure), and the unplanned reoperation rate was 4.7% (4.2% related to principle procedure). The mortality rate was 1.0%. Neoadjuvant chemotherapy was associated with higher rates of wound dehiscence and infectious complications. There were no differences in adverse events with respect to tumor origin or location. Approximately 1 in 11 pediatric patients will experience a complication in the first thirty days following surgery. However, perioperative mortality remains low. This study represents the first comprehensive review of pediatric bone and soft tissue sarcoma surgery in the NSQIP-P database. As the case volume of NSQIP-P continues to grow, NSQIP-P has the potential to become a powerful tool for pediatric orthopedic oncology research.


Variations of dynamic contrast-enhanced magnetic resonance imaging in evaluation of breast cancer therapy response: a multicenter data analysis challenge.
Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as K (trans) (rate constant for plasma/interstitium contrast agent transfer), v e (extravascular extracellular volume fraction), and v p (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for K (trans) and v p being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the K (trans) intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for K (trans)) to 0.92 (for K (trans) percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor K (trans) and k ep (=K (trans)/v e, intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response.


The effect of body mass index on fasting blood glucose and development of diabetes mellitus after initiation of extended-release niacin.
Niacin increases blood glucose, but whether the degree of increase is associated with increasing body mass index (BMI) is unknown. We evaluated the effect of extended-release niacin initiation on fasting plasma glucose (FPG) and the development of new-onset diabetes mellitus (DM) in relation to body mass index (kg/m(2)) in nondiabetic patients. This retrospective observational study used data from six facilities within a geographical region of the Department of Veterans Affairs (VA). Patients included were 18 years of age or older and on a stable extended-release niacin dose (minimum 100 days) of at least 250 mg/day between January, 2001, and April, 2007. Patients were excluded if they were new to the VA, on corticosteroids or insulin, if medication adherence was <80%, or if they met criteria for DM. A total of 811 nondiabetic patients taking extended-release niacin initiation were studied. FPG after niacin initiation was stastically significantly correlated with increasing BMI (P < 0.001, R = 0.144 Pearson correlation coefficient). Factors independently associated with change in FPG using multiple linear regression were BMI (P = 0.043), baseline average glucose (P < 0.001), and baseline average triglycerides (P = 0.037). Of all patients started on niacin, 220 (27.1%) patients developed DM after niacin initiation. BMI, (P = 0.002) and baseline average glucose (P < 0.001) were independent predictors of the development of new-onset DM (logistic regression analysis). We found an association between increasing BMI and increasing FPG and diagnosis of new-onset DM after initiation of extended-release niacin initiation. This suggests that extended-release niacin may increase FPG into the diabetic range, especially for obese patients.


Oxidative stress and antioxidant activity in orbital fibroadipose tissue in Graves' ophthalmopathy.
To investigate the oxidative stress and antioxidant activity in the orbit in Graves' ophthalmopathy (GO). Orbital fibroadipose tissue samples were obtained from 13 cases during orbital fat decompression surgery. All cases demonstrated features of moderate or severe GO according to the European Group on Graves' Orbitopathy classification. The disease activity was evaluated with the Clinical Activity Score, and the clinical features of GO were evaluated with the Ophthalmopathy Index. Orbital fibroadipose tissue samples of 8 patients without any thyroid or autoimmune disease were studied as controls. In the tissue samples, lipid hydroperoxide level was examined to determine the level of oxidative stress; glutathione level to determine antioxidant level; superoxide dismutase, glutathione reductase, and glutathione peroxidase activities to determine antioxidant activity. Lipid hydroperoxide level and all three antioxidant enzyme activities were found to be significantly elevated, while glutathione level significantly diminished in tissue samples from GO cases compared to controls (p < 0.05). Glutathione levels in tissue samples of GO cases showed negative correlation with Ophthalmopathy Index (r = -0.59, p < 0.05). The antioxidant activity in the orbit is enhanced in GO. However, the oxidative stress appears to be severe enough to deplete the tissue antioxidants and leads to oxidative tissue damage. This study may support the possible value of antioxidant treatment in GO.


Increased survival after EMS witnessed cardiac arrest. Observations from the Resuscitation Outcomes Consortium (ROC) Epistry-Cardiac arrest.
Out of hospital cardiac arrest (OHCA) is common and lethal. It has been suggested that OHCA witnessed by EMS providers is a predictor of survival because advanced help is immediately available. We examined EMS witnessed OHCA from the Resuscitation Outcomes Consortium (ROC) to determine the effect of EMS witnessed vs. bystander witnessed and unwitnessed OHCA. Data were analyzed from a prospective, population-based cohort study in 10 U.S. and Canadian ROC sites. Individuals with non-traumatic OHCA treated 04/01/06-03/31/07 by EMS providers with defibrillation or chest compressions were included. Cases were grouped into EMS-witnessed, bystander witnessed, and unwitnessed and further stratified for bystander CPR. Multiple logistic regressions evaluated the odds ratio (OR) for survival to discharge relative to the EMS-witnessed group after adjusting for age, sex, public/private location of collapse, ROC site, and initial ECG rhythm. Of 9991 OHCA, 1022 (10.2%) of EMS-witnessed, 3369 (33.7%) bystander witnessed, and 5600 (56.1%) unwitnessed. The most common initial rhythm in the EMS-witnessed group was PEA which was higher than in the bystander- and unwitnessed groups (p<0.001). The adjusted OR (95% CI) of survival compared to the EMS-witnessed group was 0.41, (0.36, 0.46) in bystander witnessed with bystander CPR, 0.37 (0.33, 0.43) in bystander witnessed without bystander CPR, 0.17 (0.14, 0.20) in unwitnessed with bystander CPR and 0.21 (0.18, 0.24) in unwitnessed cases without bystander CPR. Immediate application of prehospital care for OHCA may improve survival. Efforts should be made to educate patients to access 9-1-1 for prodromal symptoms.


A placebo-controlled trial of nadolol in the treatment of neuroleptic-induced akathisia.
Although propranolol has been documented to be useful in treatment of neuroleptic-induced akathisia, preliminary anecdotal reports on the efficacy of nadolol in treatment of this condition are contradictory. To evaluate the efficacy of nadolol in treatment of this condition, a double-blind, placebo-controlled trial was conducted in 20 psychiatric inpatients. Patients with akathisia of at least moderate severity were randomly assigned to receive nadolol 40 to 80 mg/day or placebo. Patients were rated daily for 4 days, then every other day for 15 days by means of the Extrapyramidal Symptom Rating Scale. No significant differences were found between or within groups in subjective restlessness scores. In objective akathisia scores, there were no significant differences between groups; however, beginning at Day 9, both groups showed significant improvement compared with Day 1. There was no difference between groups in number of responders. The authors' data do not support the efficacy of nadolol in the treatment of neuroleptic-induced akathisia and do not provide support for a peripheral site of action for beta-blockers in treatment of this condition.


Motor-enriched learning for improving pre-reading and word recognition skills in preschool children aged 5-6 years - study protocol for the PLAYMORE randomized controlled trial.
Results from previous studies suggest that bodily movements, spanning from gestures to whole-body movements, integrated into academic lessons may benefit academic learning. However, only few studies have investigated the effects of movement integrated into reading practice. The PLAYMORE study aims to investigate the effects of two interventions focusing on a close and meaningful coupling between bodily movement and academic content on early pre-reading and word recognition skills in children. Further, the study aims to compare two interventions involving either hand movements (i.e. using arms and hands) or whole-body movements (i.e. using the whole body). Potential mediating factors underlying the link between bodily movement on early pre-reading and word recognition skills will be explored. The PLAYMORE study will be conducted as a three-armed randomized controlled trial including children aged five to six years recruited from four schools in the Copenhagen area, Denmark. Stratified by class, children will be randomly allocated to one of three 8-week intervention/control periods: 1) teaching involving whole-body movements, 2) teaching involving hand movements (i.e. arms and hands) or 3) teaching involving minimal motor movements (i.e. seated on a chair using paper and pencil). Outcome measurements, including pre-reading and word recognition skills, will be collected before and after the intervention period to assess the intervention effects. This study protocol follows the SPIRIT guidelines. The PLAYMORE study will add to the current knowledge concerning the link between bodily movement and academic performance with important details about pre-reading and word recognition skills in preschool children. If effective, evaluation of the implementation of the PLAYMORE program should be conducted in order to investigate whether the effects can be transferred into standard school settings. The PLAYMORE study will lay the foundation for future research that have the potential to inform the political and scientific debate and importantly, to provide teachers with detailed information of how to implement movements effectively during teaching in order to support and motivate children in the process of learning to read. The study was retrospectively registered in ClinicalTrials.gov ( NCT04618822 ) the 5th of November 2020.


Mason-Pfizer monkey virus: analysis and localization of virion proteins and glycoproteins.
The polypeptide composition of Mason-Pfizer monkey virus was determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Six major polypeptides of molecular weights 68,000, 27,000, 20,000, 14,000, 12,000, and 10,000 were resolved regardless of the cell type (i.e., two human and two rhesus) in which the virus was grown. Protein gp68 (68,000) represented the major virus glycoprotein and protein gp20 (20,000) represented a minor glycoprotein of the virion, again regardless of the cell type of origin of the virus. Protein gp68 appears to be located on the outer surface of the viral envelope, as demonstrated by lactoperoxidase catalyzed iodination of intact virions. Additional glycoproteins were shown to be virion associated; their presence depended, however, on the cell type in which the virus was propagated.


Capecitabine-related intracranial hypotension syndrome mimicking dural metastasis in a breast cancer patient: case report and review of the literature.
Spontaneous intracranial hypotension (SICH) is an entity, which is secondary to iatrogenic manipulation and breaching of dura. Postural headache in patients should be suspected, cranial magnetic resonance imaging (MRI) is essential for precise diagnosis. Hallmark of MRI is regular shape of pachymeningeal gadolinium enhancement and subdural effusion. It may mimic central nervous system (CNS) metastasis. Prevention of such cases from receiving cranial radiotherapy by misinterpretation of the gadolinium enhancement as CNS metastasis is an important issue. Capecitabine is an antineoplastic agent, of which metabolites can cross blood-brain barrier in CNS via epithelial tissue. It may cause decrease in CSF production. SICH might be the clinical reflection of this decrease in CSF production. Review of the English literature revealed limited data because of the very little experience with oncologic patients suffering from intracranial hypotension. We report a case of spontaneous intracranial hypotension during capecitabine treatment. Patient was completely well following drug discontinuation and supportive treatment.


Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization.
The Swi6 transcription factor, required for G1/S-specific gene expression in Saccharomyces cerevisiae, is highly phosphorylated in vivo. Within the limits of resolution of the peptide analysis, the synchrony, and the time intervals tested, serine 160 appears to be the only site of phosphorylation in Swi6 that varies during the cell cycle. Serine 160 resides within a Cdc28 consensus phosphorylation site and its phosphorylation occurs at about the time of maximal transcription of Swi6- and Cdc28-dependent genes containing SCB or MCB elements. However, phosphorylation at this site is not Cdc28-dependent, nor does it control G1/S-specific transcription. The role of the cell cycle-regulated phosphorylation is to control the subcellular localization of Swi6. Phosphorylation of serine 160 persists from late G1 until late M phase, and Swi6 is predominantly cytoplasmic during this time. Aspartate substitution for serine 160 inhibits nuclear localization throughout the cycle. Swi6 enters the nucleus late in M phase and throughout G1, when serine 160 is hypophosphorylated. Alanine substitution at position 160 allows nuclear entry of Swi6 throughout the cell cycle. GFP fusions with the N-terminal one-third of Swi6 display the same cell cycle-regulated localization as Swi6.


Trends in Illicit Cannabis Potency based on the Analysis of Law Enforcement Seizures in the Southern Area of Rome.
Cannabis remains the most illicitly produced and consumed substance worldwide, and the average trans-Δ9-tetrahydrocannabinol (THC) content in cannabis products (marijuana, hashish) has increased over time. This paper presents data about THC concentration in cannabis resin samples seized by law enforcement from 2015 to 2022 in the southern area of Rome (Italy). From 2015 to 2022, more than 1000 hashish samples were analyzed; the average THC content was 18.0% and dramatically increased from 13.7% (2015) to 27.1% (2022). The potency of THC in some samples characterized by unusual shape and color was higher than 24% and, in a few cases, higher than 40%. The age group most involved in seizures of cannabis resin concerned males aged between 15 and 36 years old. The spread of this phenomenon increases the risk of adverse health outcomes. Many observational studies compare the increased cannabis potency with the onset of psychosis, depression, anxiety and cannabis use disorders (CUDs), mainly in young adults. THC-potency monitoring provides data that can be helpful to create a network of communication and interaction between universities, and legislative and public health institutions to support education, awareness and surveillance related to cannabis abuse.


Fluorescence modulation with photochromic switches.
Photochromic compounds change their color under illumination. In most instances, a colorless state switches to a colored one upon ultraviolet irradiation. The photogenerated species reverts to the original one either by thermal means or upon visible irradiation. These reversible transformations are accompanied by pronounced structural and electronic modifications, which often alter the ability of the photochromic compound to emit light. Under these conditions, the photoinduced and reversible interconversion of the colorless and colored states results in the modulation of the fluorescence intensity. Alternatively, fluorescence modulation can be implemented by attaching covalently a fluorescent group to a photochromic compound. Photoinduced changes in the dipole moment or conjugation of the photochromic component can then be designed to alter the emissive behavior of the fluorescent appendage. Similarly, photoinduced shifts in the redox potential or absorption wavelength of the photochromic fragment can be engineered to activate electron or energy, respectively, transfer pathways. Both processes can efficiently quench the fluorescence of the emissive component. Furthermore, the reversible absorption changes of a photochromic compound can effectively filter the emission of a compatible, but separate, fluorophore as long as the emission bands of the latter overlap the absorption bands of one of the two states of the former. When this design requirement is satisfied, fluorescence modulation can be achieved even if the two functional components are operated in distinct environments. Thus, either one of these ingenious mechanisms can be exploited to regulate the emissive behavior of collections of molecules in solution or even in rigid matrixes. In fact, the investigation of these fascinating systems can eventually lead to novel photoresponsive materials for photonic applications, while contributing to advance our basic understanding of the photochemical and photophysical properties of organic compounds.