The second life of Kowloon Walled City: Crime, media and cultural memory.
Kowloon Walled City (hereafter KWC or Walled City), Hong Kong has been described as 'one of history's great anomalies'. The territory remained under Chinese rule throughout the period of British colonialism, with neither jurisdiction wishing to take active responsibility for its administration. In the postwar period, the area became notorious for vice, drugs and unsanitary living conditions, yet also attracted the attention of artists, photographers and writers, who viewed it as an instance of anarchic urbanism. Despite its demolition in 1993, KWC has continued to capture the imaginations of successive generations across Asia. Drawing on data from an oral and visual history project on the enclave, alongside images, interviews and observations regarding the 'second life' of KWC, this article will trace the unique flow of meanings and reimaginings that KWC has inspired. The article will locate the peculiar collisions of crime and consumerism prompted by KWC within the broader contexts in which they are embedded, seeking out a new interdisciplinary perspective that attends to the internecine spaces of crime, media and culture in contemporary Asian societies.


Optimizing clinical trials recruitment via deep learning.
Clinical trials, prospective research studies on human participants carried out by a distributed team of clinical investigators, play a crucial role in the development of new treatments in health care. This is a complex and expensive process where investigators aim to enroll volunteers with predetermined characteristics, administer treatment(s), and collect safety and efficacy data. Therefore, choosing top-enrolling investigators is essential for efficient clinical trial execution and is 1 of the primary drivers of drug development cost. To facilitate clinical trials optimization, we propose DeepMatch (DM), a novel approach that builds on top of advances in deep learning. DM is designed to learn from both investigator and trial-related heterogeneous data sources and rank investigators based on their expected enrollment performance on new clinical trials. Large-scale evaluation conducted on 2618 studies provides evidence that the proposed ranking-based framework improves the current state-of-the-art by up to 19% on ranking investigators and up to 10% on detecting top/bottom performers when recruiting investigators for new clinical trials. The extensive experimental section suggests that DM can provide substantial improvement over current industry standards in several regards: (1) the enrollment potential of the investigator list, (2) the time it takes to generate the list, and (3) data-informed decisions about new investigators. Due to the great significance of the problem at hand, related research efforts are set to shift the paradigm of how investigators are chosen for clinical trials, thereby optimizing and automating them and reducing the cost of new therapies.


Glutathione peroxidase 1 deficiency attenuates allergen-induced airway inflammation by suppressing Th2 and Th17 cell development.
Engagement of T cell receptor (TCR) triggers signaling pathways that mediate activation, proliferation, and differentiation of T lymphocytes. Such signaling events are mediated by reactive oxygen species (ROS), including hydrogen peroxide and lipid peroxides, both of which are reduced by glutathione peroxidase 1 (GPx1). We have now examined the role of GPx1 in the activation, differentiation, and functions of CD4(+) T helper (Th) cells. TCR stimulation increased the intracellular ROS concentration in Th cells in a time-dependent manner, and such TCR-induced ROS generation was found to promote cell proliferation. GPx1-deficient Th cells produced higher levels of intracellular ROS and interleukin-2 than wild-type Th cells and proliferated at a faster rate than did wild-type cells. Moreover, differentiation of GPx1-deficient Th cells was biased toward Th1, and Th17 cell development was also impeded by GPx1 depletion. Consistent with these findings, GPx1-null mice were protected from the development of ovalbumin-induced allergic asthma. Eosinophil infiltration, goblet cell hyperplasia, collagen deposition, and airway hyperresponsiveness were thus all attenuated in the lungs of GPx1-null mice. These data indicate that GPx1-dependent control of intracellular ROS accumulation is important not only for regulation of Th cell proliferation but for modulation of differentiation into Th1, Th2, and Th17 cells.


Aortic dissection and renal failure in a patient with severe hypothyroidism.
Acute aortic dissection (AAD) is a life-threatening condition associated with high morbidity and mortality. The most important recognized acquired cause that leads to dissection is chronic arterial hypertension. With respect to the anuria and renal failure, aortic dissection is not something that is always considered and is still not a very common presentation unless both renal arteries come off the false lumen of the dissection. However, when present, preoperative renal failure in patients with acute type B dissection has been noted to be an independent predictor of mortality. Early recognition and diagnosis is the key and as noted by previous studies as well, almost a third of these patients are initially worked up for other causes until later when they are diagnosed with aortic dissection. Here we present a case of a patient presenting with severe hypothyroidism, long-standing hypertension, and anuria. Through the case, we highlight the importance of having aortic dissection as an important differential in patients presenting with anuria who have a long standing history of uncontrolled hypertension. Pathophysiology relating to severe hypothyroidism-induced renal dysfunction is also discussed.


Interweaving Multimodal Interaction With Flexible Unit Visualizations for Data Exploration.
Multimodal interfaces that combine direct manipulation and natural language have shown great promise for data visualization. Such multimodal interfaces allow people to stay in the flow of their visual exploration by leveraging the strengths of one modality to complement the weaknesses of others. In this article, we introduce an approach that interweaves multimodal interaction combining direct manipulation and natural language with flexible unit visualizations. We employ the proposed approach in a proof-of-concept system, DataBreeze. Coupling pen, touch, and speech-based multimodal interaction with flexible unit visualizations, DataBreeze allows people to create and interact with both systematically bound (e.g., scatterplots, unit column charts) and manually customized views, enabling a novel visual data exploration experience. We describe our design process along with DataBreeze's interface and interactions, delineating specific aspects of the design that empower the synergistic use of multiple modalities. We also present a preliminary user study with DataBreeze, highlighting the data exploration patterns that participants employed. Finally, reflecting on our design process and preliminary user study, we discuss future research directions.


Structure of the transforming region of human cytomegalovirus AD169.
The minimum size fragment of human cytomegalovirus AD169 required to initiate transformation was determined by transfection of primary rat embryo cells with deletion fragments constructed by digestion of a cloned fragment containing the transforming region (pCM4000) with exonuclease III and S1 nuclease. The results indicate that the left-hand boundary of the minimum size sequence for transformation must reside between 490 and 318 bases from the HindIII site of pCM4000. The right-hand boundary was defined by the EcoRI site which is 20 bases from the HindIII site. The nucleotide sequence of the transforming fragment of human cytomegalovirus was determined by the chemical degradation technique of Maxam and Gilbert and with the dideoxynucleoside triphosphate chain termination method. The sequence of pCM4000 comprises 2,848 base pairs and has an A X T composition of 59.5%. Reading frame analysis of the sequence indicated the longest open reading frame was 118 amino acids in length. Northern blot analysis of polyadenylated and non-polyadenylated RNA extracted from cells at immediate early and late times after infection with human cytomegalovirus indicate that one 5.0-kilobase RNA species hybridized to pCM4000 (Jahn et al., J. Virol, in press). The direction of transcription was determined by hybridization of this transcript with M13 single-stranded probes, and S1 analysis of this RNA did not detect introns.


Risk factors, hospital management and outcomes after acute myocardial infarction in South Asian Canadians and matched control subjects.
Coronary artery disease affects a significantly larger proportion of Canadians of South Asian origin than Canadians of other ethnic origins. We compared differences in presentation, risk factors and management of myocardial infarction (MI) between South Asian Canadians and matched control subjects. We reviewed the charts of 553 South Asian patients and 553 non-South Asian matched control subjects presenting with acute MI (International Classification of Diseases code 410) to 2 hospitals in Canada from January 1994 to April 1999. We identified South Asian subjects by their surnames and first names, and by using self-reported ethnicity and country of birth when available. Patients of Southeast Asian and Middle Eastern origin were excluded. The remaining patients were classified as non-South Asian. Subjects were matched by age within 5 years, sex, discharge date within 6 months and hospital of admission. Presentation characteristics, risk factors and major complications were compared between the 2 groups. The median time from symptom onset to presentation with acute MI was significantly longer among the South Asian subjects than among the control subjects (3.92 v. 3.08 hours) (p = 0.04). The South Asians were more likely than the control subjects to have diabetes mellitus (43.4% v. 28.2%) (p < 0.001) despite having a significantly lower mean body mass index (25.7 v. 28.0) (p = 0.05) but were less likely to have hyperlipidemia (36.2% v. 42.7%, p = 0.05), to smoke (29.3% v. 67.8%) (p < 0.001) or to have pre-existing vascular disease (49.4% v. 55.0%, p = 0.04). Treatment of acute MI was similar between the South Asian and matched control groups. Also similar were the in-hospital outcomes, including mortality (9.6% and 7.8%, p = 0.27). There are clear differences in the risk factor profile between Canadians of South Asian origin and those of non-South Asian origin who have acute MI. Despite the higher incidence of cardiovascular disease in the South Asian population, our results indicate that the in-hospital case-fatality rate for MI is the same for South Asian and non-South Asian Canadians.


Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study.
Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat®). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 104 (n = 3), 2.4 × 105 (n = 3), or 8.0 × 105 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aqueous humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 weeks after injection of 2.4 × 105 TU or 8.0 × 105 TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent reduction in fluorescein angiographic leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 105 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.


One size does not fit all: Examining heterogeneity and identifying moderators of the alliance-outcome association.
Although the alliance-outcome association is one of the most consistent findings in psychotherapy research, it is also highly heterogeneous. Little is known about the factors explaining this variability, and consequently there is a lack of adequate knowledge about how to utilize this association to improve treatment. The present study had the following objectives: (a) to examine the associations between within- and between-individual variability in alliance and outcome, controlling for previous symptomatic levels; (b) to examine the duration of the alliance-outcome association; and (c) to examine potential moderators of the alliance-outcome association. A total of 547 patients treated in a primary care psychotherapy setting in Chile were randomly assigned to 5 feedback conditions. The alliance-outcome association was analyzed using multilevel models, disentangling changes in alliance within-individuals from alliance between-individuals. Patient and therapist characteristics were examined as potential moderators. Findings suggest that patients who reported a better early alliance also reported a better outcome. Furthermore, patients reporting time-specific improvement in alliance also reported a greater reduction in symptoms. The unique effect of alliance on outcome at one point in time is maintained for a period of 2 weeks. Patients with more severe symptoms and longer treatments benefited more from a good alliance. Therapists identifying themselves as more integrative in their treatment orientation were able to better utilize good alliances for treatment success. Finally, the size of the alliance-outcome association can be manipulated by feedback to therapists.


The management of ankle fractures in patients with diabetes.
Patients with diabetes mellitus have higher complication rates following both open and closed management of ankle fractures. Diabetic patients with neuropathy or vasculopathy have higher complication rates than both diabetic patients without these comorbidities and nondiabetic patients. Unstable ankle fractures in diabetic patients without neuropathy or vasculopathy are best treated with open reduction and internal fixation with use of standard techniques. Patients with neuropathy or vasculopathy are at increased risk for both soft-tissue and osseous complications, including delayed union and nonunion. Careful soft-tissue management as well as stable, rigid internal fixation are crucial to obtaining a good outcome. Prolonged non-weight-bearing and subsequently protected weight-bearing are recommended following both operative and nonoperative management of ankle fractures in patients with diabetes.


Occupational health profile of workers employed in the manufacturing sector of India.
The occupational health scenario of workers engaged in the manufacturing sector in India deserves attention for their safety and increasing productivity. We reviewed the status of the manufacturing sector, identified hazards faced by workers, and assessed the existing legislations and healthcare delivery mechanisms. From October 2014 to March 2015, we did a literature review by manual search of pre-identified journals, general electronic search, electronic search of dedicated websites/databases and personal communication with experts of occupational health. An estimated 115 million workers are engaged in the manufacturing sector, though the Labour Bureau takes into account only one-tenth of them who work in factories registered with the government. Most reports do not mention the human capital employed neither their quality of life, nor occupational health services available. The incidence of accidents were documented till 2011, and industry-wise break up of data is not available. Occupational hazards reported include hypertension, stress, liver disease, diabetes, tuberculosis, eye/ hearing problems, cancers, etc. We found no studies for manufacturing industries in glass, tobacco, computer and allied products, etc. The incidence of accidents is decreasing but the proportion of fatalities is increasing. Multiple legislations exist which cover occupational health, but most of these are old and have not been amended adequately to reflect the present situation. There is a shortage of manpower and occupational health statistics for dealing with surveillance, prevention and regulation in this sector. There is an urgent need of a modern occupational health legislation and an effective machinery to enforce it, preferably through intersectoral coordination between the Employees' State Insurance Corporation, factories and state governments. Occupational health should be integrated with the general health services.


Ex vivo fecal fermentation of human ileal fluid collected after raspberry consumption modifies (poly)phenolics and modulates genoprotective effects in colonic epithelial cells.
Diets rich in fruit and vegetables are associated with a decreased incidence of colorectal cancer (CRC) due, in part, to the bioactive (poly)phenolic components and their microbiota-mediated metabolites. This study investigated how such compounds, derived from ingested raspberries in the gastrointestinal tract, may exert protective effects by reducing DNA damage. Ileal fluids collected pre- and post-consumption of 300 g of raspberries by ileostomists (n = 11) were subjected to 24 h ex vivo fermentation with fecal inoculum to simulate interaction with colonic microbiota. The impact of fermentation on (poly)phenolics in ileal fluid was determined and the bioactivity of ileal fluids pre- and post fermentation investigated. (Poly)phenolic compounds including sanguiin H-6, sanguiin H-10 and cyanidin-3-O-sophoroside decreased significantly during fermentation while, in contrast, microbial catabolites, including 3-(3'-hydroxyphenyl)propanoic acid, 3-hydroxybenzoic acid and benzoic acid increased significantly. The post-raspberry ileal fermentate from 9 of the 11 ileostomates significantly decreased DNA damage (~30%) in the CCD 841 CoN normal cell line using an oxidative challenge COMET assay. The raspberry ileal fermentates also modulated gene expression of the nuclear factor 2-antioxidant responsive element (Nrf2-ARE) pathway involved in oxidative stress cytoprotection, namely Nrf2, NAD(P)H dehydrogenase, quinone-1 and heme oxygenase-1. Four of the phenolic catabolites were assessed individually, each significantly reducing DNA damage from an oxidative challenge over a physiologically relevant 10-100 μM range. They also induced a differential pattern of expression of key genes in the Nrf2-ARE pathway in CCD 841 CoN cells. The study indicates that the colon-available raspberry (poly)phenols and their microbial-derived catabolites may play a role in protection against CRC in vivo.


Clinical judgement, expertise and skilled coping.
Medicine involves specific practical expertise as well as more general context-independent medical knowledge. This raises the question, what is the nature of the expertise involved? Is there a model of clinical judgement or understanding that can accommodate both elements? This paper begins with a summary of a published account of the kinds of situation-specific skill found in anaesthesia. It authors claim that such skills are often neglected because of a prejudice in favour of the 'technical rationality' exemplified in evidence-based medicine but they do not themselves offer a general account of the relation of practical expertise and general medical knowledge. The philosopher Hubert Dreyfus provides one model of the relation of general knowledge to situation-specific skilled coping. He claims that the former logically depends on the latter and provides two arguments, which I articulate in the second section, for this. But he mars those arguments by building in the further assumption that such situation-specific responses must be understood as concept-free and thus mindless. That assumption is held in place by three arguments all of which I criticize in the next section to give a unified account of clinical judgement as both practical and conceptually structured and thus justified in the face of a prejudice in favour of 'technical rationality'.


Efficiency of MR imaging in the detection of malignant liver lesions.
To evaluate the efficacy of preoperative magnetic resonance (MR) imaging in the detection of malignant liver neoplasms. MR images of 23 patients who had undergone hepatic resection or liver transplantation in the last two years were evaluated retrospectively. All MR imaging studies were performed with a 1.5 T magnet using a phased-array multi-coil. The MR imaging protocol was comprised of fat-suppressed T2-weighted TSE imaging, GRE with and without fat-suppressed T1-weighted imaging, and gadolinium-enhanced multiphasic dynamic GRE imaging. Images were reviewed on a PACS workstation by two independent abdominal radiologists. The image review was conducted on a lesion-by-lesion as well as segment-by-segment basis. MR imaging findings were compared with the results of pathology studies and intraoperative ultrasound examinations. Sensitivity, specificity, and positive predictive value (PPV) of MR imaging and interobserver variation were evaluated. A total of 59 malignant liver lesions in 23 patients were identified by pathology studies and intraoperative sonographic examinations. Sensitivity and PPV of MR imaging on a lesion-by-lesion analysis were 68-86% and 85-89%, respectively; kappa=0.175 and agreement was 65.8% in these analyses. Sensitivity of MR images for small ( < 1cm) lesions was 13-67% and for large ( > 3 cm) lesions it was 100%. In segment-by-segment analysis, sensitivity and specificity of MR images were 87-95% and 97-98%, respectively; kappa=0.207 and agreement was 76.1%. Sensitivity and PPV of MR imaging in the detection of hepatocellular carcinoma were 46-85% and 55-73%, respectively. Although MR imaging is generally a highly accurate method for the diagnosis of malignant liver tumors, it has some difficulty in detecting small lesions and hepatocellular carcinoma in cirrhotic livers.


A study of the structure, function and distribution of beta 5 integrins using novel anti-beta 5 monoclonal antibodies.
Here, we have utilized six new anti-human beta 5 monoclonal antibodies to perform a detailed investigation of the structure, function and distribution of beta 5 integrins. Monoclonal anti-beta 5 specificity was confirmed by reactivity with beta 5-transfected CHO cells, by direct binding to the beta 5 subunit (immunoblotting), and by immunodepletion experiments using polyclonal anti-beta 5 serum. The beta 5 subunit was predominantly associated with the alpha v subunit, although on some cell lines, the level of beta 5 exceeded that of alpha v for unknown reasons. Cell adhesion studies showed that the adhesive function of beta 5 could be stimulated, inhibited or unaltered by different anti-beta 5 monoclonal antibodies. The beta 5 subunit was involved in adhesion to both vitronectin and fibronectin and, at least for K562 cells, fibronectin appeared to be the preferred ligand. Flow-cytometry studies showed that the beta 5 subunit was expressed at moderate to high levels on all adherent cell lines examined, was absent from all lymphoid cell lines, and was only weakly expressed on myeloid cell lines. Staining of thymic sections showed the distribution of beta 5 on blood vessels, Hassal's corpuscles, cortical and medullary stromal cells, and basement membranes. Skin sections showed beta 5 on the basal layer of the epidermis and on some dermal blood vessel walls, and kidney sections showed staining of glomerular regions, juxta glomerular apparatus, proximal convoluted tubules and collecting tubules, and at least one anti-beta 5 antibody also stained epithelial cells of proximal tubules.


The roles of want to commitment and have to commitment in explaining physical activity behavior.
Several theories and models have been proposed to explain decisions in changing and adopting behavior but few address the intricacies of behavioral maintenance. The current study assesses the utility of the Investment Model, which identifies satisfaction, investments, and involvement alternatives as predictors of commitment and continued behavior, in predicting physical activity behavior. Participants (N = 267) completed questionnaires about physical activity and commitment. Structural equation modeling assessed relationships among 2 types of exercise commitment (want to or enthusiastic commitment, have to or obligatory commitment), 3 commitment determinants (satisfaction, investments, and alternatives), and physical activity (minutes of physical activity, stage of behavior change). Want to commitment, but not have to commitment, was related to stage of exercise behavior change and time spent in physical activity. Satisfaction and investments were positively related to want to commitment; whereas, satisfaction, investments, and alternatives were positively related to have to commitment. The model explained 68% and 23% of the variance in time spent in physical activity and stage of behavior change, respectively. This study provides support for the application of the Investment Model to physical activity and suggests that want to commitment may be important for explaining and predicting sustained physical activity behavior.


Subfemtosecond Control of Molecular Fragmentation by Hard X-Ray Photons.
Tuning hard x-ray excitation energy along Cl 1s→σ^{*} resonance in gaseous HCl allows manipulating molecular fragmentation in the course of the induced multistep ultrafast dissociation. The observations are supported by theoretical modeling, which shows a strong interplay between the topology of the potential energy curves, involved in the Auger cascades, and the so-called core-hole clock, which determines the time spent by the system in the very first step. The asymmetric profile of the fragmentation ratios reflects different dynamics of nuclear wave packets dependent on the photon energy.


An integrated model of the transcriptome of HER2-positive breast cancer.
Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2-positive breast cancer. We interrogated RNA-Seq data from benign breast lesions, ER+, triple negative, and HER2-positive tumors to identify 685 differentially expressed genes, 102 alternatively spliced genes, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were associated with the HER2-positive tumors in our survey panel. These features were integrated into a transcriptome landscape model that identified 12 highly interconnected genomic modules, each of which represents a cellular processes pathway that appears to define the genomic architecture of the HER2-positive tumors in our test set. The generality of the model was confirmed by the observation that several key pathways were enriched in HER2-positive TCGA breast tumors. The ability of this model to make relevant predictions about the biology of breast cancer cells was established by the observation that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. Additional modules from the HER2 transcriptome model, including ubiquitin-mediated proteolysis, TGF-beta signaling, RHO-family GTPase signaling, and M-phase progression, were linked to response to lapatinib and paclitaxel in vitro and/or risk of relapse in the N9831 dataset. These data indicate that an integrated transcriptome landscape model derived from a test set of HER2-positive breast tumors has potential for predicting outcome and for identifying novel potential therapeutic strategies for this breast cancer subtype.


Comparison of the anthelmintic efficacy of oxfendazole or ivermectin administered orally and ivermectin administered subcutaneously to sheep during the periparturient period.
The suppression of nematode egg output in faeces was measured in ewes treated just before lambing with either oxfendazole or ivermectin by oral drench or with ivermectin by subcutaneous injection. Ivermectin and oxfendazole given orally were similarly effective, whereas ivermectin given by subcutaneous injection extended the period of suppressed egg output by about one week. The more persistent anthelmintic effect of ivermectin given subcutaneously was probably due to its extended half-life in the plasma of treated sheep. Plasma pepsinogen activity was less in the sheep given anthelmintic than in the untreated controls. Ivermectin caused a significantly greater reduction in pepsinogen activity than oxfendazole and was more effective when given subcutaneously than when given orally.


Promethium: To Strive, to Seek, to Find and Not to Yield.
Promethium (Pm), element #61, got its name from the Greek Titan Prometheus, who stole fire from Zeus and passed it to people. The only element in the lanthanide series of the periodic table with no stable isotopes, Pm has found an impressive number of applications since its announcement in 1947 after World War II. Despite promethium having 38 known isotopes, 147Pm is by far the most utilized and useful one. Promethium is used in long-life atomic batteries for satellites or space probes, satellite-to-submarine laser communication systems, "cosmic clocks" for the measurement of cosmic rays lifetime, monitoring of the changes in water content of citrus leaves caused by wetting and drying cycles in the soil, radiotherapy, and even for prevention of dandruff, to name but a few applications. During the Moon expeditions, Pm was used to illuminate instruments in the Apollo landing modules; currently it is used during preparations for long-term interplanetary missions (e.g., Mars) to simulate space conditions on Earth. This mini review offers a comprehensive illustration of promethium's history, synthesis techniques, properties, and its major applications in science, technology, and everyday life.


Optimizing the acquisition and analysis of confocal images for quantitative single-mobile-particle detection.
Quantification of the fluorescence properties of diffusing particles in solution is an invaluable source of information for characterizing the interactions, stoichiometry, or conformation of molecules directly in their native environment. In the case of heterogeneous populations, single-particle detection should be the method of choice and it can, in principle, be achieved by using confocal imaging. However, the detection of single mobile particles in confocal images presents specific challenges. In particular, it requires an adapted set of imaging parameters for capturing the confocal images and an adapted event-detection scheme for analyzing the image. Herein, we report a theoretical framework that allows a prediction of the properties of a homogenous particle population. This model assumes that the particles have linear trajectories with reference to the confocal volume, which holds true for particles with moderate mobility. We compare the predictions of our model to the results as obtained by analyzing the confocal images of solutions of fluorescently labeled liposomes. Based on this comparison, we propose improvements to the simple line-by-line thresholding event-detection scheme, which is commonly used for single-mobile-particle detection. We show that an optimal combination of imaging and analysis parameters allows the reliable detection of fluorescent liposomes for concentrations between 1 and 100 pM. This result confirms the importance of confocal single-particle detection as a complementary technique to ensemble fluorescence-correlation techniques for the studies of mobile particle.


Reduction of lipid accumulation rescues Bietti's crystalline dystrophy phenotypes.
Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.


Prioritization strategies for pandemic influenza vaccine in 27 countries of the European Union and the Global Health Security Action Group: a review.
Although there is rapid progress in vaccine research regarding influenza pandemic vaccines it is expected that pandemic influenza vaccine production can only start once the pandemic virus has been recognized. Therefore, pandemic vaccine capacity will be limited at least during the first phase of an influenza pandemic, requiring vaccine prioritization strategies. WHO recommends developing preliminary priorities for pandemic vaccine use. The goal of this review is to provide a thorough overview of pandemic vaccine prioritization concepts in the 27 European Union (EU) member states and the four non-EU countries of the Global Health Security Action Group. Between September and December 2006 data was collected for each country through two data sources: (i) the national influenza pandemic plan; (ii) contacting key persons involved in pandemic planning by email and/or phone and/or fax. Twenty-six (84%) countries had established at least one vaccine priority group. Most common reported vaccine priority groups were health care workers (HCW) (100%), essential service providers (ESP) (92%) and high risk individuals (HRI) (92%). Ranking of at least one vaccine priority group was done by 17 (65%) of 26 countries. Fifteen (88%) of these 17 countries including a ranking strategy, decided that HCW with close contact to influenza patients should be vaccinated first; in most countries followed and/or ranked equally by ESP and subsequently HRI. Rationales for prioritization were provided by 22 (85%) of 26 countries that established vaccine priority groups. There was large variation in the phrasing and level of detailed specification of rationales. Seven (32%) of 22 countries providing rationales clearly associated each vaccine priority group with the specific rationale. Ten (32% of the 31 countries studied) countries have consulted and involved ethical experts to guide decisions related to vaccine prioritization. In the majority of the countries the establishment of vaccine priority groups, ranking and underlying rationales are in line with WHO recommendations. In most public plans the criteria by which prioritized groups are identified are not easily recognizable. Clarity however, may be necessary to assure public acceptability of the prioritization. Ethical experts, results of modelling exercises could play an increasing role in the future decision making process.


Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures.
The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis.


Photosystem-II shutdown evolved with Nitrogen fixation in the unicellular diazotroph Crocosphaera watsonii.
Protection of nitrogenase from oxygen in unicellular Cyanobacteria is obtained by temporal separation of photosynthesis and diazotrophy through transcriptional and translational regulations of nitrogenase. But diazotrophs can face environmental situations in which N2 fixation occurs significantly in the light, and we believe that another control operates to make it possible. The night-time shutdown of PSII activity is a peculiar behaviour that discriminates Crocosphaera watsonii WH8501 from any other phototroph, whether prokaryote or eukaryote. This phenomenon is not only due to the plastoquinone pool redox status, and suggests that the sentinel D1 protein, expressed in periods of nitrogen fixation, is inactive. Results demonstrate a tight constraint of oxygen evolution in C. watsonii as additional protection of nitrogenase activity and suggest a possible recycling of cellular components.


Effect of mandibular position achieved using an oral appliance on genioglossus activity in healthy adults during sleep.
Oral appliances (OAs) are generally designed to displace the mandible anteriorly and downward, to increase the airway patency. The present study aimed to examine the relationship between genioglossus (GG) muscle activity and mandibular position, considering both anterior and vertical displacements during sleep. Seven healthy male adults aged 29.4 ± 1.99 years were evaluated. Maxillary and mandibular OAs were fabricated from 2-mm-thick resin plates with pressure-welding. The activity of the left GG was recorded using two silver ball electrodes attached to the lingual edge of the mandibular OA. Respiratory status and right masseter muscle activity were measured by an airflow sensor and surface electrodes, respectively. Electroencephalography was used to determine the sleep status. Stage 2 (the second stage of sleep) was defined as the state of sleeping. Four test conditions with different mandibular positions (0 and 50% anterior protrusion) and bite openings (4 mm and 12 mm) were examined. GG activity in SL4A (4 mm bite opening, 50% protrusion during sleep) and SL12 (12 mm bite opening, 0% protrusion during sleep) were significantly higher than that in SL4 (4 mm bite opening, 0% protrusion during sleep). Respiratory volume did not significantly differ between all test conditions. GG activity is influenced not only by anterior protrusion of the mandible but also by vertical displacement during sleep. Thus, when determining the effectiveness of intraoral appliances in the treatment of obstructive sleep apnea, both protrusion and the size of the mandibular opening should be evaluated and taken into account.


Thermal decomposition of 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), a novel brominated flame retardant.
1,2-Bis(2,4,6-tribromophenoxy)ethane (BTBPE) is currently one of the most commonly applied novel brominated flame retardants. In this contribution, we analyze in detail the mechanisms pertinent to its thermal decomposition in view of analogous experimental findings. We demonstrate that a 1,3-hydrogen shift, leading to 2,4,6-tribromophenol (M9) and 1,3,5-tribromo-2-(vinyloxy)benzene (M10) molecules, dominates direct scission of O-CH2 bonds up to a temperature of ∼ 680 K. H atom abstraction from CH2 sites, followed by a fission of a C-C bond, produce a 2,4,6-tribromophenoxy radical (M2) and a M10 molecule. Bimolecular condensation reactions involving M2, M9, and M10 generate several congeners of brominated diphenyl ethers and their OH/OCHCH2 substituents, which serve as direct precursors for the formation of polybrominated dibenzo-p-dioxins. Reaction of M9 with a model compound of a hydrocarbon chain preferentially yields M2. Strong adsorption energy of the latter on a radical site of a hydrocarbon chain suggests that mechanisms such as Langmuir-Hinshelwood, Eley-Rideal, and Diels-Alder might be operating during the formation of PBDD/Fs from brominated flame retardants (BFRs). Reactions of alkyl primary/secondary radicals and diradical with the BTBPE molecule proceed via H abstraction from a -CH2- moiety.


Treatment of African children with severe malaria - towards evidence-informed clinical practice using GRADE.
Severe malaria is a major contributor of deaths in African children up to five years of age. One valuable tool to support health workers in the management of diseases is clinical practice guidelines (CPGs) developed using robust methods. A critical assessment of the World Health Organization (WHO) and Kenyan paediatric malaria treatment guidelines with quinine was undertaken, with a focus on the quality of the evidence and transparency of the shift from evidence to recommendations. Systematic reviews of the literature were conducted using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool to appraise included studies. The findings were used to evaluate the WHO and Kenyan recommendations for the management of severe childhood malaria. The WHO 2010 malaria guidance on severe malaria in children, which informed the Kenyan guidelines, only evaluated the evidence on one topic on paediatric care using the GRADE tool. Using the GRADE tool, this work explicitly demonstrated that despite the established use of quinine in the management of paediatric cases of severe malaria for decades, low or very low quality evidence of important outcomes, but not critical outcomes such as mortality, have informed national and international guidance on the paediatric quinine dosing, route of administration and adverse effects. Despite the foreseeable shift to artesunate as the primary drug for treatment of severe childhood malaria, the findings reported here reflect that the particulars of quinine therapeutics for the management of severe malaria in African children have historically been a neglected research priority. This work supports the application of the GRADE tool to make transparent recommendations and to inform advocacy efforts for a greater research focus in priority areas in paediatric care in Africa and other low-income settings.


In vivo characterization of magnesium alloy biodegradation using electrochemical H2 monitoring, ICP-MS, and XPS.
The effect of widely different corrosion rates of Mg alloys on four parameters of interest for in vivo characterization was evaluated: (1) the effectiveness of transdermal H2 measurements with an electrochemical sensor for noninvasively monitoring biodegradation compared to the standard techniques of in vivo X-ray imaging and weight loss measurement of explanted samples, (2) the chemical compositions of the corrosion layers of the explanted samples by XPS, (3) the effect on animal organs by histology, and (4) the accumulation of corrosion by-products in multiple organs by ICP-MS. The in vivo biodegradation of three magnesium alloys chosen for their widely varying corrosion rates - ZJ41 (fast), WKX41 (intermediate) and AZ31 (slow) - were evaluated in a subcutaneous implant mouse model. Measuring H2 with an electrochemical H2 sensor is a simple and effective method to monitor the biodegradation process in vivo by sensing H2 transdermally above magnesium alloys implanted subcutaneously in mice. The correlation of H2 levels and biodegradation rate measured by weight loss shows that this non-invasive method is fast, reliable and accurate. Analysis of the insoluble biodegradation products on the explanted alloys by XPS showed all of them to consist primarily of Mg(OH)2, MgO, MgCO3 and Mg3(PO4)2 with ZJ41 also having ZnO. The accumulation of magnesium and zinc were measured in 9 different organs by ICP-MS. Histological and ICP-MS studies reveal that there is no significant accumulation of magnesium in these organs for all three alloys; however, zinc accumulation in intestine, kidney and lung for the faster biodegrading alloy ZJ41 was observed. Although zinc accumulates in these three organs, no toxicity response was observed in the histological study. ICP-MS also shows higher levels of magnesium and zinc in the skull than in the other organs. Biodegradable devices based on magnesium and its alloys are promising because they gradually dissolve and thereby avoid the need for subsequent removal by surgery if complications arise. In vivo biodegradation rate is one of the crucial parameters for the development of these alloys. Promising alloys are first evaluated in vivo by being implanted subcutaneously in mice for 1month. Here, we evaluated several magnesium alloys with widely varying corrosion rates in vivo using multiple characterization techniques. Since the alloys biodegrade by reacting with water forming H2 gas, we used a recently demonstrated, simple, fast and noninvasive method to monitor the biodegradation process by just pressing the tip of a H2 sensor against the skin above the implant. The analysis of 9 organs (intestine, kidney, spleen, lung, heart, liver, skin, brain and skull) for accumulation of Mg and Zn revealed no significant accumulation of magnesium in these organs. Zinc accumulation in intestine, kidney and lung was observed for the faster corroding implant ZJ41. The surfaces of explanted alloys were analyzed to determine the composition of the insoluble biodegradation products. The results suggest that these tested alloys are potential candidates for biodegradable implant applications.


Normal vascular development in mice deficient in endothelial NO synthase: possible role of neuronal NO synthase.
Nitric oxide formation by nitric oxide synthase (NOS) has been implicated in vascular injury and retinal neovascularization during oxygen-induced retinopathy. However, the role of NOS in normal retinal vascular development and growth has not been studied. The purpose of these experiments was to characterize the expression of NOS in relation to vascular development and to determine the effect of deleting endothelial NOS (eNOS) on this process. Retinal vascular development was analyzed in 150 eNOS+/+ and eNOS-/- mice ranging from 1 day to 6 months old by using a combination of morphometric and biochemical approaches. The pattern of vascular development was analyzed in retinal tissue sections and whole-mount preparations labeled with fluorescein-conjugated Griffonia simplicifolia lectin. Analysis of vascular density and arterial diameter were performed with the lectin-labeled whole-mounts using computer-assisted morphometry. NO production was quantified by measuring retinal levels of nitrate/nitrite accumulation using the Greiss reaction. Western blotting techniques with isoform-specific NOS antibodies were used to evaluate differences in levels of NOS protein expression. Retinal distribution of nNOS was characterized using nNOS immunocytochemistry and NADPH diaphorase histochemistry. These analyses showed that the rate and pattern of retinal vascular development in eNOS-/- mice were comparable with those in wild-type control mice. Measurement of vascular density showed no significant differences between the two strains. The amount of NO production in the eNOS-/- retina was also equivalent to that in the eNOS+/+ retina. Analysis of nNOS expression within the eNOS+/+ and eNOS-/- mice showed similar levels of total nNOS protein in the two strains. Inducible NOS was not detected in either strain. Studies of nNOS distribution showed intense labeling of the deep capillary plexus in the eNOS-/- retina. This was not seen in the wild-type retinas. The number of neuronal cells showing NADPH-diaphorase activity was also significantly increased in the eNOS-/- mice. Development of the retinal vasculature occurs normally without eNOS. The observations of similar levels of NO production, perivascular redistribution of nNOS and increased numbers of NADPH-diaphorase reactive neurons in the eNOS-/- retinas suggest that increases in vascular-associated nNOS activity compensate for the eNOS deficiency in the developing mutant retina.


The association between adult asthma and superoxide dismutase and catalase gene activity.
Adult asthma is caused by interaction effects of multiple genetic and environmental factors. Some studies have suggested that antioxidant enzyme activity and gene polymorphisms may play important roles in the context of asthma. Therefore, our study objectives were to investigate the association between asthma, antioxidant activities and the polymorphisms of manganese superoxide dismutase (Mn-SOD) or catalase (CAT). A case-control study, for which we recruited 250 asthmatic adults and 250 age- and sex-matched controls. All subjects completed a questionnaire. Waist and hip circumference measurements, a lung function test and DNA genotyping were performed. In total, 50 incident cases and 50 matched controls who were non-smokers or had quit smoking for at least 1 year were selected in order to investigate SOD and CAT activity levels. In our study, we did not find a significant association between Mn-SOD Ala16Val, CAT C-262T and asthma. The level of SOD activity in new-onset asthma patients was significantly lower than in control subjects (p < 0.0005). The level of CAT activity in new-onset asthma patients was significantly higher than in control subjects (p < 0.0005). The levels of SOD and CAT activity were significantly related to adult asthma. SOD and CAT activity may be good tools to differentiate potential asthma sufferers. This would enable us to further investigate the mechanism of defective antioxidant enzymes in the context of asthma pathogenesis.


In vitro and in vivo investigation of PLA/PCL scaffold coated with metformin-loaded gelatin nanocarriers in regeneration of critical-sized bone defects.
Large bone defects constitute a major challenge in bone tissue engineering and usually fail to heal due to the incomplete differentiation of recruited mesenchymal stem cells (MSCs) into osteogenic precursor cells. As previously proposed, metformin (MET) induces differentiation of MSCs into osteoblastic lineages in vitro. We fabricated a Poly (lactic acid) and Polycaprolactone (PLA/PCL) scaffold to deliver metformin loaded gelatin nanocarriers (MET/GNs) to critical-sized calvarial bone defects in a rat model. The scaffolds were evaluated regarding their morphology, porosity, contact angle, degradation rate, blood compatibility, biomechanical, cell viability and their osteogenic differentiation. In animal study, the defects were filled with autograft, scaffolds and a group was left empty. qRT-PCR analyses showed the expression level of osteogenic and angiogenic markers considerably increased in MET/GNs-PLA/PCL. The in vivo results showed that MET/GNs-PLA/PCL improved bone ingrowth, angiogenesis and defect reconstruction. Our results represent the applicability of MET/GNs-PLA/PCL for successful bone regeneration.


Monitoring guanine photo-oxidation by enantiomerically resolved Ru(II) dipyridophenazine complexes using inosine-substituted oligonucleotides.
The intercalating [Ru(TAP)2(dppz)](2+) complex can photo-oxidise guanine in DNA, although in mixed-sequence DNA it can be difficult to understand the precise mechanism due to uncertainties in where and how the complex is bound. Replacement of guanine with the less oxidisable inosine (I) base can be used to understand the mechanism of electron transfer (ET). Here the ET has been compared for both Λ- and Δ-enantiomers of [Ru(TAP)2(dppz)](2+) in a set of sequences where guanines in the readily oxidisable GG step in {TCGGCGCCGA}2 have been replaced with I. The ET has been monitored using picosecond and nanosecond transient absorption and picosecond time-resolved IR spectroscopy. In both cases inosine replacement leads to a diminished yield, but the trends are strikingly different for Λ- and Δ-complexes.


[Genetic and environmental factors of asthma and allergy: Results of the EGEA study].
The EGEA study (epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), which combines a case-control and a family-based study of asthma case (n=2120 subjects) with three surveys over 20 years, aims to identify environmental and genetic factors associated with asthma and asthma-related phenotypes. We summarize the results of the phenotypic characterization and the investigation of environmental and genetic factors of asthma and asthma-related phenotypes obtained since 2007 in the EGEA study (42 articles). Both epidemiological and genetic results confirm the heterogeneity of asthma. These results strengthen the role of the age of disease onset, the allergic status and the level of disease activity in the identification of the different phenotypes of asthma. The deleterious role of active smoking, exposure to air pollution, occupational asthmogenic agents and cleaning products on the prevalence and/or activity of asthma has been confirmed. Accounting for gene-environment interactions allowed the identification of new genetic factors underlying asthma and asthma-related traits and better understanding of their mode of action. The EGEA study is contributing to the advances in respiratory research at the international level. The new phenotypic, environmental and biological data available in EGEA study will help characterizing the long-term evolution of asthma and the factors associated to this evolution.


[Disappointing response of chronic C hepatitis to interferon].
From February 1990 to August 1995 we treated 58 patients with chronic hepatitis C alfa-interferon, 3 million units 3 times weekly for 6 months. Of the 48 patients with adequate follow-up, 34 did not respond to treatment at all. 10 patients responded, but within a few months hepatic enzymes again increased. These 2 groups can be considered failures of interferon treatment. In 4 patients enzymes remained normal for the duration of follow-up, (10-34 months). Even in this small group, 1 patient had a positive test for HCV RNA after completion of treatment. A partial explanation of our disappointing results may be the high prevalence of a subtype of C hepatitis-subtype 1b, which has recently been reported in Israel. This strain is particularly resistant to interferon. The means to define subtypes were not, and as far as we know are not yet available in Israel. Various groups have attempted to improve the outcome of treatment of hepatitis C, which in other hands too was still far from satisfactory. Thus, regimens of interferon utilizing higher doses and longer periods of treatment are being evaluated, as well as the addition of Ribavirin, which hopefully will improve results.


Bifurcation study of phase oscillator systems with attractive and repulsive interaction.
We study a model of globally coupled phase oscillators that contains two groups of oscillators with positive (synchronizing) and negative (desynchronizing) incoming connections for the first and second groups, respectively. This model was previously studied by Hong and Strogatz (the Hong-Strogatz model) in the case of a large number of oscillators. We consider a generalized Hong-Strogatz model with a constant phase shift in coupling. Our approach is based on the study of invariant manifolds and bifurcation analysis of the system. In the case of zero phase shift, various invariant manifolds are analytically described and a new dynamical mode is found. In the case of a nonzero phase shift we obtained a set of bifurcation diagrams for various systems with three or four oscillators. It is shown that in these cases system dynamics can be complex enough and include multistability and chaotic oscillations.


Unraveling the Hierarchy of cis and trans Factors That Determine the DNA Binding by Peroxisome Proliferator-Activated Receptor γ.
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor essential for adipocyte development and the maintenance of the alternatively polarized macrophage phenotype. Biochemical studies have established that as an obligate heterodimer with retinoid X receptor (RXR), PPARγ binds directly repeated nuclear receptor half sites spaced by one nucleotide (direct repeat 1 [DR1]). However, it has not been analyzed systematically and genome-wide how cis factors such as the sequences of DR1s and adjacent sequences and trans factors such as cobinding lineage-determining transcription factors (LDTFs) contribute to the direct binding of PPARγ in different cellular contexts. We developed a novel motif optimization approach using sequence composition and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) densities from macrophages and adipocytes to complement de novo motif enrichment analysis and to define and classify high-affinity binding sites. We found that approximately half of the PPARγ cistrome represents direct DNA binding; both half sites can be extended upstream, and these are typically not of equal strength within a DR1. Strategically positioned LDTFs have greater impact on PPARγ binding than the quality of DR1, and the presence of the extension of DR1 provides a remarkable synergy with LDTFs. This approach of considering not only nucleotide frequencies but also their contribution to protein binding in a cellular context is applicable to other transcription factors.


Fibrosarcoma of the nose and the paranasal sinuses.
We report a case of fibrosarcoma of the nose and paranasal sinuses and give a brief review of the literature. Fibrosarcoma of the nose and paranasal sinuses is uncommon, and few cases have been reported to date. Previously these tumors may have been overdiagnosed secondary to inadequate diagnostic procedures. Because histologic diagnosis is difficult, these tumors have been confused with other lesions of the head and neck. Thus, the improvement in diagnostic procedures has significantly reduced the reported incidence of fibrosarcoma. Because histologic diagnosis is difficult, this tumor has often been confused with other lesions of the head and neck. To ensure proper handling of the tissue, the pathologist should be informed if fibrosarcoma is suspected. It may be necessary to use electron microscopy or staining techniques such as immunoperoxidase stains to distinguish fibrosarcoma from other lesions. Unfortunately, the early signs and symptoms of the tumor are vague and sometimes misleading. Thus, at the patient's initial visit, it is important that the physician consider the possibility of fibrosarcoma.


Treatment Guidelines for Rheumatologic Manifestations of Sjögren's Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain.
The Sjögren's Syndrome Foundation clinical practice guidelines (CPGs) are designed to improve quality and consistency of care in Sjögren's syndrome by offering recommendations for management. Management questions for the systemic manifestations of Sjögren's syndrome were posed by the CPG committee with input from patients and rheumatologists. Clinical questions were assigned to a topic review group that performed systematic reviews and data extraction and drafted guidelines. Quality of evidence and strength of recommendation were rated using the American Society of Clinical Oncology's modification of the Grading of Recommendations Assessment, Development, and Evaluation. Guideline recommendations were reviewed by a consensus expert panel (CEP) composed of 30-40 clinicians from academia and community practices, as well as registered nurses and patients, using a modified Delphi process. A CEP agreement level of 75% was set as a minimum for adoption of a guideline recommendation. Consensus was achieved for 19 recommendations; for 11 additional modules, available data were insufficient to allow a recommendation to be formulated. Of the 19 recommendations, 15 required 1 Delphi round, 2 required 2 rounds, and 2 required 3 rounds. Key recommendations include a decision tree for the use of oral disease-modifying antirheumatic drugs for inflammatory musculoskeletal pain, use of self-care measures and advice regarding exercise to reduce fatigue, and the use of rituximab in selected clinical settings for oral and ocular dryness and for certain extraglandular manifestations, including vasculitis, severe parotid swelling, inflammatory arthritis, pulmonary disease, and mononeuritis multiplex. The CPG committee strongly discouraged the use of tumor necrosis factor inhibitors for sicca symptoms and for the majority of clinical contexts in primary Sjögren's syndrome.


The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.
Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.


The influence of forward head posture on dental occlusion.
A well established premise in the field of craniomandibular and cervical spine orthopedics is that forward head posture (FHP) adversely affects mandibular position and therefore dental occlusion. The purpose of this study was to investigate the influence of FHP on the initial occlusal contact pattern (IOCP) in order to provide further clarification on this important topic. Thirty-nine healthy subjects, 10-74 years old, underwent a series of tests in which the IOCP was recorded in four different head positions using the T-Scan Occlusal Diagnostic System. Three tests each were performed in military posture (MP), natural sitting posture (NP), FHP, and maximal forward head posture (MFHP) for a total of twelve trials. A repeated measures analysis of variance failed to demonstrate a correlation between FHP and IOCP; however, a multiple linear regression analysis revealed a relationship between age and the IOCP. This study raises questions about the relationship between FHP and occlusion.


Visualization of changes in ciliary tip configuration caused by sliding displacement of microtubules in macrocilia of the ctenophore Beroë.
Macrocilia from the lips of the ctenophore Beroë consist of multiple rows of ciliary axonemes surrounded by a common membrane, with a giant capping structure at the tip. The cap is formed by extensions of the A and central-pair microtubules, which are bound together by electron-dense material into a pointed projection about 1.5 micron long. The tip undergoes visible changes in configuration during the beat cycle of macrocilia. In the rest position at the end of the effective stroke (+30 degrees total bend angle), there is no displacement between the tips of the axonemes, and the capping structure points straight into the stomach cavity. In the sigmoid arrest position at the end of the recovery stroke (-60 degrees total bend angle), the tip of the macrocilium is hook-shaped and points toward the stomach in the direction of the subsequent effective stroke. This change in tip configuration is caused by sliding displacement of microtubules that are bound together at their distal ends. Electron microscopy and two-dimensional models show that the singlet microtubule cap acts as if it were hinged to the ends of the axonemes and tilted to absorb the microtubule displacement that occurs during the recovery stroke. The straight and hooked shapes of the tip are thought to help the ctenophore ingest prey.


Review of diagnostic uses of shunt fraction quantification with technetium-99m macroaggregated albumin perfusion scan as illustrated by a case of Osler-Weber-Rendu syndrome.
Bilateral pulmonary arteriovenous malformations (AVMs) are rare and are often associated with the hereditary hemorrhagic telangiectasia (HHT/Osler-Weber-Rendu) syndrome. We present a woman who presented with neurological symptoms due to a cerebral abscess. On further evaluation, bilateral pulmonary AVMs were identified. The patient was diagnosed with HHT, based on positive family history and multiple cerebral AVMs recognized on subsequent catheter angiogram, in addition to the presence of bilateral pulmonary AVMs. Craniotomy with drainage of the brain abscess and endovascular embolization of the pulmonary AVMs was offered to the patient. As a preembolization work-up, the patient underwent nuclear lung perfusion scan with technetium-99m macroaggregated albumin (Tc-99m MAA) to assess the right-to-left shunt secondary to the pulmonary AVMs. Postembolization follow-up perfusion scan was also obtained to estimate the hemodynamic response. The case is presented to describe the role of Tc-99m MAA perfusion lung scan in preoperatively evaluating patients with pulmonary AVMs and to emphasize on the scan's utility in posttreatment follow-up. Various present day usages of the Tc-99m MAA lung perfusion scan, other than diagnosing pulmonary thromboembolism, are discussed. Providing background knowledge on the physiological and hemodynamic aspects of the Tc-99m MAA lung perfusion scan is also attempted. Various imaging pitfalls and necessary precautions while performing Tc-99m MAA lung perfusion scan are highlighted.


Legionella pneumophila down-regulates MHC class I expression of human monocytic host cells and thereby inhibits T cell activation.
Legionella (L.) pneumophila, the causative agent of Legionnaires' disease, is an intracellular pathogen of alveolar macrophages that resides in a compartment displaying features of endoplasmatic reticulum (ER). In this study, we show that intracellular multiplication of L. pneumophila results in a remarkable decrease in MHC class I expression by the infected monocytes. During intracellular multiplication, L. pneumophila absorbs ER-resident chaperons such as calnexin and BiP, molecules that are required for the correct formation of the MHC class I complex. Due to reduced MHC class I expression, stimulation of allogeneic blood mononuclear cells was severely inhibited by infected host cells but cytotoxicity of autologous natural killer cells against Legionella-infected monocytes was not enhanced. Thus, reduced expression of MHC class I in infected monocytes may resemble a new immune escape mechanism induced by L. pneumophila.


Neuroanatomical tract-tracing techniques that did go viral.
Neuroanatomical tracing methods remain fundamental for elucidating the complexity of brain circuits. During the past decades, the technical arsenal at our disposal has been greatly enriched, with a steady supply of fresh arrivals. This paper provides a landscape view of classical and modern tools for tract-tracing purposes. Focus is placed on methods that have gone viral, i.e., became most widespread used and fully reliable. To keep an historical perspective, we start by reviewing one-dimensional, standalone transport-tracing tools; these including today's two most favorite anterograde neuroanatomical tracers such as Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine. Next, emphasis is placed on several classical tools widely used for retrograde neuroanatomical tracing purposes, where Fluoro-Gold in our opinion represents the best example. Furthermore, it is worth noting that multi-dimensional paradigms can be designed by combining different tracers or by applying a given tracer together with detecting one or more neurochemical substances, as illustrated here with several examples. Finally, it is without any doubt that we are currently witnessing the unstoppable and spectacular rise of modern molecular-genetic techniques based on the use of modified viruses as delivery vehicles for genetic material, therefore, pushing the tract-tracing field forward into a new era. In summary, here, we aim to provide neuroscientists with the advice and background required when facing a choice on which neuroanatomical tracer-or combination thereof-might be best suited for addressing a given experimental design.


Human preferences for sexually dimorphic faces may be evolutionarily novel.
A large literature proposes that preferences for exaggerated sex typicality in human faces (masculinity/femininity) reflect a long evolutionary history of sexual and social selection. This proposal implies that dimorphism was important to judgments of attractiveness and personality in ancestral environments. It is difficult to evaluate, however, because most available data come from large-scale, industrialized, urban populations. Here, we report the results for 12 populations with very diverse levels of economic development. Surprisingly, preferences for exaggerated sex-specific traits are only found in the novel, highly developed environments. Similarly, perceptions that masculine males look aggressive increase strongly with development and, specifically, urbanization. These data challenge the hypothesis that facial dimorphism was an important ancestral signal of heritable mate value. One possibility is that highly developed environments provide novel opportunities to discern relationships between facial traits and behavior by exposing individuals to large numbers of unfamiliar faces, revealing patterns too subtle to detect with smaller samples.


Mechanism of inhibition of herpes simplex virus and vaccinia virus DNA polymerases by aphidicolin, a highly specific inhibitor of DNA replication in eucaryotes.
The inhibition in vitro of herpes simplex virus 1 and vaccinia virus DNA polymerases by aphidicolin is primarily noncompetitive with dGTP, dATP, dTTP, DNA, and Mg2+ and competitive with dCTP in analogy with the mode of inhibition of cellular alpha-polymerase. The degree of inhibition of viral or cellular growth in vivo can be quantitatively predicted by the degree of inhibition of the isolated replicative DNA polymerases at the same concentration of aphidicolin in suitable conditions (limiting dCTP concentration). Thus, the only in vivo target for aphidicolin is probably the replicative DNA polymerase, and aphidicolin is a highly specific inhibitor of replicative nuclear DNA synthesis in eucaryotes. This, coupled with the lack of mutagenic effect, represents a valuable property for an anticancer drug. The specificity of inhibition (contrary to the aspecific effect on almost all DNA polymerases by a true competitive inhibitor, such as 1-beta-D-arabinofuranosylcytidine 5'-triphosphate) and the structure of the drug, which does not resemble that of the triphosphates, suggest that aphidicolin must recognize a site common only to the replicative DNA polymerases of eucaryotes and different from the binding site for deoxyribonucleic triphosphates and DNA, which should be similar in reparative and procaryote-type DNA polymerase; the aphidicolin binding site is probably very near to, or even overlaping with, the binding site for dCTP so that the drug mimics a competitive effect with this nucleotide.


Low levels of bile acids increase bacterial uptake in colonic biopsies from patients with collagenous colitis in remission.
Patients with collagenous colitis have an impaired mucosal barrier. Moreover, collagenous colitis is associated with bile acid malabsorption. Bile acids can increase bacterial mucosal uptake in humans. Mucosal barrier function was investigated by exposing colonic biopsies to chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) in Ussing chamber experiments. To find if low levels of bile acids increase bacterial uptake in colonic biopsies from collagenous colitis patients. The study comprised 33 individuals; 25 with collagenous colitis (14 in clinical remission without treatment, 11 with active disease and 10 examined in clinical remission resulting from treatment with 6 mg budesonide); eight healthy individuals undergoing screening colonoscopy served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (Isc), potential difference, trans-epithelial resistance and transmucosal passage of Escherichia coli K12 after adding 100 μmol/L CDCA or DCA. When adding 100 μmol/L CDCA or DCA, bacterial uptake increased fourfold in biopsies of patients in remission; CDCA 6.5 units [2.5-9.8] and DCA 6.2 units [2.1-22] (median [IQR]), compared with uptake in biopsies without added bile acids 1.6 units [1.1-3] (P=0.004 and P=0.01 respectively). In active disease and in patients in remission due to budesonide treatment, bile acids did not affect bacterial uptake. Confocal microscopy revealed trans-epithelial passage of E. coli K12 within 30 min. Low concentrations of dihydroxy-bile acids exacerbate mucosal barrier dysfunction in colonic biopsies of patients with collagenous colitis in remission. This allows a substantially increased bacterial uptake, which may contribute to recurrence of inflammation.


Heat shock protein 27 R127W mutation: evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy.
Heat shock protein 27 (HSP27) mutations have been reported to cause both Charcot-Marie-Tooth disease (CMT) type 2F and distal hereditary motor neuropathy (dHMN) although never previously in a single family. To analyse clinical and electrophysiological findings obtained in a single large Sardinian family bearing the HSP27 R127W mutation. Twenty-one members of a five generation Sardinian family have been studied, including thirteen members affected by peroneal muscular atrophy and proved heterozygous for the known HSP27 R127W mutation. Twelve patients and eight unaffected relatives were subjected to clinical examination. A standardised electrophysiological study was performed in eleven patients and six unaffected relatives. Mean age at onset (+/-SD) was 31.2+/-7.2 years. Mean age at investigation was 45.2+/-12.9 years and mean disease duration at the time of investigation was 14+/-12.9 years. According to current criteria for CMT2 and dHMN, of the 10 patients who had undergone both clinical and neurophysiological examination, five were diagnosed as CMT2, two as dHMN and a further two patients were labelled as an intermediate type. Finally, due to the presence of spastic paraplegia, the index patient did not meet established criteria for the diagnosis of CMT or dHMN. Findings obtained in the present study, broadening the spectrum of clinical manifestations of disorders associated with HSP27 mutations, support the hypothesis of a continuum between CMT2 and dHMN forms and suggest a possible common spectrum between these entities and several forms of CMT plus pyramidal features (HMSN V), providing important implications for molecular genetic testing.


Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies.
Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.


Prognostic Value of Stimulated Thyroglobulin Levels at the Time of Radioiodine Administration in Differentiated Thyroid Cancer.
The prognostic value of stimulated thyroglobulin (sTg) and Tg-related parameters prior to and immediately after radioactive iodine (RAI) administration was assessed in a cohort of patients presenting with differentiated thyroid cancer (DTC) as a predictor of recurrent or progressive structural disease. Clinical records of 180 DTC patients were retrospectively reviewed, and serum TSH, Tg, and Tg antibodies were recorded just before RAI administration (pre-) and at the time of whole body scanning (post-). Based on the results of initial staging and RAI scintigraphy, patients were divided into two groups: those who were considered to be structurally disease-free after thyroidectomy and RAI (group 1) and those who were not (group 2). Univariate analyses were performed for pre-Tg, ratioTg (post-Tg/pre-Tg), and other clinical and pathological markers for long-term outcome, as well as separate bivariate analyses focusing on pre-Tg to correct for possible confounders. Different pre-Tg cut-off values for predicting structural disease recurrence were assessed in a subgroup of patients in group 1 prepared with thyroid hormone withdrawal. In group 1, (n = 166) male gender, higher T-stage and both Tg-related parameters proved to be significant risk factors for structural disease relapse. Of all candidate variables, only higher T-stage served to predict progressive structural disease in group 2 (n = 14). Subgroup analysis showed a negative predictive value of 91.67$ for pre-Tg < 10 µg/L. The sTg value at the time of RAI administration may be helpful in predicting structural disease recurrence in patients with DTC.


Characteristics and Consequences of Family Support in Latino Dementia Care.
The purpose of this study is to explore variations in family support for Latino dementia caregivers and describe the role of the family in dementia caregiver stress processes. Content analysis is utilized with themes derived inductively from 16 in-depth interviews with Latino caregivers recruited in California from 2002 to 2004. Three types of family support are described: extensive (instrumental and emotional support from family, n = 3), limited (instrumental support from one family member, n = 7), and lacking (no support from family, n = 6). Most caregivers report limited support, high risk for burnout and distress, and that dementia-related neuropsychiatric symptoms are obstacles to family unity. Caregivers with extensive support report a larger family size, adaptable family members, help outside of the family, and formalized processes for spreading caregiving duties across multiple persons. Culturally competent interventions should take into consideration diversity in Latino dementia care by (a) providing psychoeducation on problem solving and communication skills to multiple family members, particularly with respect to the nature of dementia and neuropsychiatric symptoms, and by (b) assisting caregivers in managing family tensions - including, when appropriate, employing tactics to mobilize family support.


Metallo-β-lactamases among Enterobacteriaceae from routine samples in an Italian tertiary-care hospital and long-term care facilities during 2008.
The emergence of metallo-β-lactamase (MBL)-producing Enterobacteriaceae is a serious public health concern. Producers have been repeatedly isolated from patients and long-term care facility (LTCF) residents around Bolzano, and we sought to assess their prevalence and clinical impact. All routine Enterobacteriaceae isolates from a Bolzano tertiary-care hospital and associated long-term care facilities in 2008 (n = 5500) were screened for MBLs, with case details reviewed for the source patients. In total, 36 producers were obtained from 29 patients, comprising 14 Escherichia coli, six Klebsiella pneumoniae, four Klebsiella oxytoca, four Citrobacter freundii, two Enterobacter cloacae and two Morganella morganii, as well as single Citrobacter amalonaticus, Enterobacter aerogenes, Providencia stuartii and Proteus mirabilis isolates. All were PCR-positive for bla(VIM) and 25 were PCR-positive for qnrS; 19 non-K. pneumoniae had bla(SHV) and one had bla(CTX-M-group1); 13 were from 12 LTCF residents and 23 were from 17 acute-care patients. All these patients had serious underlying diseases with prolonged hospitalization or LTCF stay; only seven had infections due to the MBL producers, comprising four urinary tract infections, two catheter-related bloodstream infections and one patient with both a surgical site infection and pneumonia. Five patients had more than one MBL-producing organism. Pulsed-field gel electrophoresis identified a cluster of six related E. coli, whereas pairs of K. pneumoniae and C. freundii isolates had >85% profile similarity. Transformants prepared from two isolates were shown to be PCR-positive for bla(VIM), qnrS and bla(SHV); their plasmids gave similar restriction fragment length polymorphism patterns, and bla(VIM-1), qnrS1 and bla(SHV-12) were detected by sequencing.


Chlorhexidine is not an essential component in alcohol-based surgical hand preparation: a comparative study of two handrubs based on a modified EN 12791 test protocol.
Surgical hand preparation is an essential part of modern surgery. Both alcohol-based and antiseptic detergent-based hand preparation are recommended practices, with a trend towards use of alcohol based handrubs. However, discussion has arisen whether chlorhexidine is a required ingredient in highly efficacious alcohol-based formulations, in view of providing sustained antimicrobial efficacy. One alcohol-only formulation (product A), containing ethanol and n-propanol, and one formulation containing a chlorhexidine-ethanol combination (product B) were directly compared with each other using a modified test protocol based on European standard EN 12791 (2016) with 25 volunteers. The alcohol-only formulation (product A) was applied for only 90 s, the chlorhexidine-alcohol formulation (product B) for 180 s. Microbial log reduction factors were determined and statistically compared immediately after application and at 6 h under surgical gloves. The alcohol-only formulation (product A) achieved mean log reduction factors of 1.96 ± 1.06 immediately after application and 1.67 ± 0.71 after 6 h. The chlorhexidine-alcohol combination (product B) achieved mean log reduction factors of 1.42 ± 0.79 and 1.24 ± 0.90 immediately and after 6 h, respectively. The values for product A were significantly greater than those for product B at both measured time points (p ≤ 0.025 immediately after application and p ≤ 0.01 after 6 h). An optimized alcohol-only formulation tested according to a modified EN 12791 protocol in 25 healthy volunteers outperformed a chlorhexidine-alcohol formulation both immediately after application and at 6 h under surgical gloves, despite a much shorter application time. Thus, optimized alcohol-only formulations do not require chlorhexidine to achieve potent immediate and sustained efficacy. In conclusion, chlorhexidine is not an essential component for alcohol-based surgical hand preparation.


Firing back: how great leaders rebound after career disasters.
Among the tests of a leader, few are more challenging-and more painful-than recovering from a career catastrophe. Most fallen leaders, in fact, don't recover. Still, two decades of consulting experience, scholarly research, and their own personal experiences have convinced the authors that leaders can triumph over tragedy--if they do so deliberately. Great business leaders have much in common with the great heroes of universal myth, and they can learn to overcome profound setbacks by thinking in heroic terms. First, they must decide whether or not to fight back. Either way, they must recruit others into their battle. They must then take steps to recover their heroic status, in the process proving, both to others and to themselves, that they have the mettle necessary to recover their heroic mission. Bernie Marcus exemplifies this process. Devastated after Sandy Sigoloff ired him from Handy Dan, Marcus decided to forgo the distraction of litigation and instead make the marketplace his batttleground. Drawing from his network of carefully nurtured relationships with both close and more distant acquaintances, Marcus was able to get funding for a new venture. He proved that he had the mettle, and recovered his heroic status, by building Home Depot, whose entrepreneurial spirit embodied his heroic mission. As Bank One's Jamie Dimon, J.Crew's Mickey Drexler, and even Jimmy Carter, Martha Stewart, and Michael Milken have shown, stunning comebacks are possible in all industries and walks of life. Whatever the cause of your predicament, it makes sense to get your story out. The alternative is likely to be long-lasting unemployment. If the facts of your dismissal cannot be made public because they are damning, then show authentic remorse. The public is often enormously forgiving when it sees genuine contrition and atonement.


Assembling a library of typical surgery video clips to construct a system for assessing the surgical difficulty of laparoscopic cholecystectomy.
To explore best practices for acute cholecystitis, it is necessary to construct a system to assess the difficulty of laparoscopic cholecystectomy (LC) based on intraoperative findings. In this study, multiple evaluators assessed videos of LC to assemble a library of typical video clips for 25 intraoperative findings. We have previously identified 25 items that contribute to surgical difficulty in LC. For each item, roughly 30-second video clips were submitted from videos of LC performed at member institutions. We then selected one typical video from the collected clips based on simple tabulation of the instances of agreement. Inter-rater agreement was assessed with Fleiss's κ and Gwet's agreement coefficient (AC). Except in the case of two assessment items ("edematous change" and "easy bleeding"), κ or AC significantly exceeded 0.5 and the typical videos were judged to be applicable. For the two remaining items, the evaluation was repeated after clarifying the definitions of positive and negative findings. Eventually, they were recognized as typical. The completed video clip library contains 31 clips and is divided into five categories (http://www.jshbps.jp/modules/project/index.php?content_id=13). This clip library may be highly useful in clinical settings as a more objective standard for assessing surgical difficulty in LC.


Cyclin G and the Polycomb Repressive complexes PRC1 and PR-DUB cooperate for developmental stability.
In Drosophila, ubiquitous expression of a short Cyclin G isoform generates extreme developmental noise estimated by fluctuating asymmetry (FA), providing a model to tackle developmental stability. This transcriptional cyclin interacts with chromatin regulators of the Enhancer of Trithorax and Polycomb (ETP) and Polycomb families. This led us to investigate the importance of these interactions in developmental stability. Deregulation of Cyclin G highlights an organ intrinsic control of developmental noise, linked to the ETP-interacting domain, and enhanced by mutations in genes encoding members of the Polycomb Repressive complexes PRC1 and PR-DUB. Deep-sequencing of wing imaginal discs deregulating CycG reveals that high developmental noise correlates with up-regulation of genes involved in translation and down-regulation of genes involved in energy production. Most Cyclin G direct transcriptional targets are also direct targets of PRC1 and RNAPolII in the developing wing. Altogether, our results suggest that Cyclin G, PRC1 and PR-DUB cooperate for developmental stability.


Streptococcus bovis Endocarditis after Colonic Polypectomy.
We describe a case of Streptococcus lutetiensis infective endocarditis occurring in a patient following colonic polypectomy. The patient had multiple risk factors for infective endocarditis including pre-existing mitral valve prolapse and regurgitation. Transoesophageal echocardiography revealed a friable mass on the posterior mitral valve leaflet, confirming the diagnosis. The patient was treated with intravenous antibiotics, successfully underwent mitral valve surgery and was discharged home for outpatient follow-up. This report details an uncommon case presentation, highlights areas for improvement in clinical practice, and summarises the current knowledge available in the literature regarding Streptococcus bovis infective endocarditis. Infective endocarditis occurring in association with gastrointestinal endoscopy is rare.Clinical suspicion of infective endocarditis after colonic polypectomy or biopsy should be maintained, especially in those with risk factors for infective endocarditis.Antibiotic prophylaxis against infective endocarditis is not recommended for routine gastrointestinal endoscopic procedures.


Acousto-optic low-frequency shifter.
Here a large deflection angle, low optical frequency-shift acousto-optic device is presented. This is realized by two successive acousto-optic interactions in the same cell. The relevant parameters of operation are analyzed in detail. A practical case with paratellurite material is then considered. Results from numerical computations leading to practical design parameters are given and compared with experimental ones.


Identification of the miRNA targetome in hippocampal neurons using RIP-seq.
MicroRNAs (miRNAs) are key players in the regulation of neuronal processes by targeting a large network of target messenger RNAs (mRNAs). However, the identity and function of mRNAs targeted by miRNAs in specific cells of the brain are largely unknown. Here, we established an adeno-associated viral vector (AAV)-based neuron-specific Argonaute2:GFP-RNA immunoprecipitation followed by high-throughput sequencing to analyse the regulatory role of miRNAs in mouse hippocampal neurons. Using this approach, we identified more than two thousand miRNA targets in hippocampal neurons, regulating essential neuronal features such as cell signalling, transcription and axon guidance. Furthermore, we found that stable inhibition of the highly expressed miR-124 and miR-125 in hippocampal neurons led to significant but distinct changes in the AGO2 binding of target mRNAs, resulting in subsequent upregulation of numerous miRNA target genes. These findings greatly enhance our understanding of the miRNA targetome in hippocampal neurons.


Discovery and validation of graft-versus-host disease biomarkers.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective tumor immunotherapy available. Although allo-HSCT provides beneficial graft-versus-tumor effects, acute GVHD (aGVHD) is the primary source of morbidity and mortality after HSCT. Diagnosis of aGVHD is typically based on clinical symptoms in one or more of the main target organs (skin, liver, gastrointestinal tract) and confirmed by biopsy. However, currently available diagnostic and staging tools often fail to identify patients at higher risk of GVHD progression, unresponsiveness to therapy, or death. In addition, there are shortcomings in the prediction of GVHD before clinical signs develop, indicating the urgent need for noninvasive and reliable laboratory tests. Through the continuing evolution of proteomics technologies seen in recent years, plasma biomarkers have been identified and validated as promising diagnostic tools for GVHD and prognostic tools for nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention but should be more widely validated and incorporated into a new grading system for risk stratification of patients and better-customized treatment. This review identifies biomarkers for detecting GVHD, summarizes current information on aGVHD biomarkers, proposes future prospects for the blinded evaluation of these biomarkers, and discusses the need for biomarkers of chronic GVHD.


Intermittent pneumatic compression for prevention of pulmonary thromboembolism after gynecologic surgery.
To investigate the incidence of pulmonary embolism and risk factors for this condition after obstetric and gynecologic surgery, as well as the efficacy of intermittent pneumatic compression. A total of 6,218 patients operated at Keio University Hospital excluding obstetric or infertility-related surgery and uterine cervical conization were evaluated retrospectively to determine the preventive effect of intermittent pneumatic compression on postoperative pulmonary embolism. Pulmonary embolism occurred in 42 patients (0.68%). Multivariate analysis showed that malignancy, blood transfusion, and a body mass index > or =25 kg/m2 or > or =28 kg/m2 were independent risk factors for postoperative pulmonary embolism. A significantly lower incidence of pulmonary embolism occurred in patients receiving pneumatic compression postoperatively versus those without it. Among gynecologic malignancies, endometrial cancer was a significant risk factor for pulmonary embolism. Preventive measures, including intermittent pneumatic compression, should be taken to avoid postoperative pulmonary thromboembolism in the gynecology field.


Expression of two soybean vegetative storage protein genes during development and in response to water deficit, wounding, and jasmonic acid.
The expression of vspA and vspB genes encoding soybean vegetative storage proteins was studied during seedling development and in response to water deficit, tissue wounding, and jasmonic acid treatment. vspA and vspB encode VSP-alpha and VSP-beta, 28-kilodalton and 31-kilodalton vacuole-localized polypeptides that are 80% homologous. vspA and vspB mRNAs could be distinguished on RNA blots using 3'-end probes. vspA mRNA was threefold to sevenfold more abundant than vspB mRNA in leaves, about equal expression was observed in stems, and vspB mRNA exceeded vspA in roots. Transcripts were not detected in dry seeds but appeared in intact or excised seedling axes between 12 hr and 24 hr after initiation of imbibition. Both transcripts were highly abundant in the meristematic region of seedling stems and in developing leaves but were rare in mature stems, leaves, and roots. In situ localization showed that vsp transcripts were found throughout the hypocotyl hook but were concentrated in cells associated with the epidermis and vascular bundles. Water deficit caused increased vsp mRNA levels in leaves and stems, which suggests that inhibition of growth necessitates temporary storage of amino acids. Wounding induced primarily vspB mRNA in etiolated seedlings, whereas both vspA and vspB mRNA levels increased in wounded leaves. Jasmonic acid and methyl jasmonate were potent inducers of vsp gene expression in cell cultures, developing axes, leaves, and roots. We hypothesize that jasmonic acid levels modulate vsp mRNA abundance in vivo.