Composition, source, and influencing factors of white spots formation in soybean paste.
White spots are commonly found in bean-based fermented food, which will significantly lower the product quality. This study aimed to analyze the composition of white spots and further reveal the source and influencing factors of white spots in bean-based fermented food using soybean paste as study model. The results showed that white spots were mainly composed of 40.96% free tyrosine and 37.94% tyrosine in combination form. During soybean paste fermentation, tyrosine was found to be produced by the actions of proteolytic enzymes secreted by Aspergillus oryzae 3.042 instead of the microbial metabolism and the excessive accumulation of tyrosine in soybean paste led to the formation of white spots. Among all influencing factors, high temperature treatment favored the formation of white spots. The existence of soy peptone and phenylalanine would postpone the precipitation of tyrosine while promoting the aggregation of the tyrosine precipitation. Field emission scanning electron microscope analysis showed that tyrosine would accumulate around the soybean protein particles and treatment at 120 °C would disrupt the structure of tyrosine-protein complex. Based on the above results, we proposed that treatment of soybean paste at temperature lower than 80 °C was the current practically applicable method to control the formation of white spots in soybean paste. PRACTICAL APPLICATION: This study developed a new idea to understand the composition and formation of white spots in soybean paste, which would provide guidance for prevention and control of white spots during the production of soybean paste for manufacturers and researchers.


Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies.
PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-κB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-κB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKγ, NF-κB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies.


Development of modelling method selection tool for health services management: from problem structuring methods to modelling and simulation methods.
There is an increasing recognition that modelling and simulation can assist in the process of designing health care policies, strategies and operations. However, the current use is limited and answers to questions such as what methods to use and when remain somewhat underdeveloped. The aim of this study is to provide a mechanism for decision makers in health services planning and management to compare a broad range of modelling and simulation methods so that they can better select and use them or better commission relevant modelling and simulation work. This paper proposes a modelling and simulation method comparison and selection tool developed from a comprehensive literature review, the research team's extensive expertise and inputs from potential users. Twenty-eight different methods were identified, characterised by their relevance to different application areas, project life cycle stages, types of output and levels of insight, and four input resources required (time, money, knowledge and data). The characterisation is presented in matrix forms to allow quick comparison and selection. This paper also highlights significant knowledge gaps in the existing literature when assessing the applicability of particular approaches to health services management, where modelling and simulation skills are scarce let alone money and time. A modelling and simulation method comparison and selection tool is developed to assist with the selection of methods appropriate to supporting specific decision making processes. In particular it addresses the issue of which method is most appropriate to which specific health services management problem, what the user might expect to be obtained from the method, and what is required to use the method. In summary, we believe the tool adds value to the scarce existing literature on methods comparison and selection.


Salutogenesis as a framework for child protection: literature review.
The aim of this paper is to demonstrate the usefulness of salutogenesis in work relating to child protection. A systematic review to explore the links between parenting, social factors and failure to thrive was carried out using 17 CD ROM and online databases using keywords in appropriate medical subject headings (MeSH terms) and Boolean operators refined for the studies. The salutogenic framework was then used as a way of clarifying what benefit particular research findings may have in identifying and using factors which can be associated with protection, safety and well being of children. Cross-referencing the evidence from the systematic review against Antonovsky's generalized resistance resources created a salutogenic matrix. Four factors in the systematic review were found crucially important: parent factors; parenting factors; child factors; and social factors. However, it is probable that these are useful within all child protection research and the evidence gathered in particular cases (here failure to thrive) could be plotted against each factor. Application of a salutogenic framework to the results was further illuminating and has utility for both systematic review methodology and other child protection explorations. The matrix created a warp and weft effect that identified gaps in current evidence and practice and was able to disentangle some of the complexities inherent within failure to thrive situations. By beginning to shed understanding on such processes, the concept of salutogenesis added further depth and rigour to the analysis. The concept of salutogenesis is widely used in some areas of nursing practice and research, and can also be regarded as a theoretical tool that has potential in child care and protection research, development and practice. The paper also illustrates the importance of a sound theoretical framework in ensuring depth and rigour in analyses of literature review findings.


Temporary percutaneous T-fastener gastropexy and continuous decompressive gastrostomy in dogs with experimentally induced gastric dilatation.
OBJECTIVE To evaluate a percutaneous, continuous gastric decompression technique for dogs involving a temporary T-fastener gastropexy and self-retaining decompression catheter. ANIMALS 6 healthy male large-breed dogs. PROCEDURES Dogs were anesthetized and positioned in dorsal recumbency with slight left-lateral obliquity. The gastric lumen was insufflated endoscopically until tympany was evident. Three T-fasteners were placed percutaneously into the gastric lumen via the right lateral aspect of the abdomen, caudal to the 13th rib and lateral to the rectus abdominis muscle. Through the center of the T-fasteners, a 5F locking pigtail catheter was inserted into the gastric lumen and attached to a device measuring gas outflow and intragastric pressure. The stomach was insufflated to 23 mm Hg, air was allowed to passively drain from the catheter until intraluminal pressure reached 5 mm Hg for 3 cycles, and the catheter was removed. Dogs were hospitalized and monitored for 72 hours. RESULTS Mean ± SD catheter placement time was 3.3 ± 0.5 minutes. Mean intervals from catheter placement to a ≥ 50% decrease in intragastric pressure and to ≤ 6 mm Hg were 2.1 ± 1.3 minutes and 8.4 ± 5.1 minutes, respectively. After catheter removal, no gas or fluid leakage at the catheter site was visible laparoscopically or endoscopically. All dogs were clinically normal 72 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE The described technique was performed rapidly and provided continuous gastric decompression with no evidence of postoperative leakage in healthy dogs. Investigation is warranted to evaluate its effectiveness in dogs with gastric dilatation-volvulus.


Immunoglobulin g for the treatment of chronic pain: report of an expert workshop.
The treatment of chronic pain is still unsatisfactory. Despite the availability of different drugs, most patients with chronic pain do not receive satisfactory pain relief or report side effects. Converging evidence implicates involvement of the immune system in the pathogenesis of different types of nociceptive and neuropathic chronic pain. At a workshop in Liverpool, UK (October 2012), experts presented evidence suggesting immunological involvement in chronic pain and recent data supporting the concept that the established immune-modulating drug, polyvalent immunoglobulin G (IgG), either given intravenously (IVIg) or subcutaneously (SCIg), may reduce pain in some peripheral neuropathies and a range of other pain disorders. Workshop's attendees discussed the practicalities of using IVIg and SCIg in these disorders, including indications, cost-effectiveness, and side effects. IgG may reduce pain in a range of nociceptive and neuropathic chronic pain conditions, including diabetes mellitus, Sjögren's syndrome, fibromyalgia, complex regional pain syndrome, post-polio syndrome, and pain secondary to pathological autoantibodies. IgG is a promising treatment in several chronic pain conditions. IgG is a relatively safe therapeutic strategy, with uncommon and mild side effects but high costs. Randomized, controlled trials and predictive tests are needed to better support the use of IgG for refractory chronic pain.


IGF-1 and prostate cancer.
By virtue of their potent proliferative and anti-apoptotic effects, the insulin-like growth factors (IGFs) have been the subject of long-term scrutiny for their role in tumorigenesis. With regard to prostate cancer in particular, IGF-1 has been shown to stimulate the proliferation of human prostate epithelial cells in culture and to be necessary for normal growth and development of the rat and mouse prostate. Epidemiological studies have established a link between high circulating serum IGF-1 levels and the risk of later developing advanced prostate cancer, and overexpression of IGF-1 in the prostate basal epithelial layer of transgenic mice results in prostate adenocarcinoma that is similar to human disease. Thus, IGF-1 action appears to be important for prostate cancer initiation. On the other hand, decreased IGF action, subsequent to the down-regulation of IGF-1 receptor expression, is associated with advanced, metastatic disease. This decrease in IGF-1 receptor may confer a survival advantage to prostate cancer cells that have entered the circulation by making them resistant to the differentiative effects of IGF-1 at metastatic sites such as bone. The molecular mechanisms that effect IGF-1 receptor down-regulation appear to involve novel oncogenic functions of the Wilms' tumour suppressor, as well as novel actions of the androgen receptor.


Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations.
Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.


The orientation selectivity of color-responsive neurons in macaque V1.
Form has a strong influence on color perception. We investigated the neural basis of the form-color link in macaque primary visual cortex (V1) by studying orientation selectivity of single V1 cells for pure color patterns. Neurons that responded to color were classified, based on cone inputs and spatial selectivity, into chromatically single-opponent and double-opponent groups. Single-opponent cells responded well to color but weakly to luminance contrast; they were not orientation selective for color patterns. Most double-opponent cells were orientation selective to pure color stimuli as well as to achromatic patterns. We also found non-opponent cells that responded weakly or not at all to pure color; most were orientation selective for luminance patterns. Double-opponent and non-opponent cells' orientation selectivities were not contrast invariant; selectivity usually increased with contrast. Double-opponent cells were approximately equally orientation selective for luminance and equiluminant color stimuli when stimuli were matched in average cone contrast. V1 double-opponent cells could be the neural basis of the influence of form on color perception. The combined activities of single- and double-opponent cells in V1 are needed for the full repertoire of color perception.


Extrauterine Pelvic Serous Carcinomas: Current Update on Pathology and Cross-sectional Imaging Findings.
The spectrum of extrauterine pelvic serous carcinomas includes ovarian serous carcinoma, primary peritoneal serous carcinoma, and primary fallopian tube carcinoma. Ovarian serous carcinoma, the most common ovarian malignant epithelial neoplasm, consists of two distinct entities: high-grade and low-grade serous carcinomas. Primary peritoneal serous carcinoma and primary fallopian tube carcinoma are rare malignancies that share many characteristics of high-grade serous carcinomas. Recent advances in the genetics and molecular biology of gynecologic cancers have suggested a common origin of many extrauterine pelvic serous carcinomas from fallopian tube epithelium. With the exception of low-grade serous carcinomas, which arise from cortical inclusion cysts lined by tubal epithelium, most extrauterine pelvic serous carcinomas are believed to originate from serous tubal intraepithelial carcinomas and show similar clinical-biologic behaviors and natural histories. Indeed, the International Federation of Gynecology and Obstetrics Committee on Gynecologic Oncology recently recognized that these cancers should be considered collectively, with a common system of staging and management strategies for ovarian, primary peritoneal, and fallopian tube cancers. A paradigm shift has occurred in our understanding of the pathogenesis of extrauterine pelvic serous carcinomas that has the potential to change current strategies for screening, prevention, diagnosis, and management. Ultrasonography (US), computed tomography (CT), magnetic resonance imaging, and combined positron emission tomography and CT are pivotal in screening, initial diagnosis, and treatment follow-up; however, because of this paradigm shift, new radiologic techniques, such as contrast material-enhanced US and molecular US imaging, and various optical imaging techniques are being investigated as important screening and diagnostic tools. Because of evolving knowledge of genetic and molecular changes underlying the pathogenesis of extrauterine pelvic serous carcinomas, new targeted therapies are being developed to improve patient prognosis. (©)RSNA, 2016.


Cerebral Organoid Research Ethics and Pinning the Tail on the Donkey.
The risk of creating cerebral organoids/assembloids conscious enough to suffer is a recurrent concern in organoid research ethics. On one hand, we should, apparently, avoid discovering how to distinguish between organoids that it would be permissible (non-conscious) and impermissible (conscious) to use in research, since if successful we would create organoids that suffer. On the other, if we do not, the risk persists that research might inadvertently continue to cause organoids to suffer. Moreover, since modeling some brain disorders may require inducing stress in organoids, it is unclear how to eliminate the risk, if we want to develop effective therapies. We are committed to harm avoidance but hamstrung by a presumption that we should avoid research that might tell us clearly when suffering occurs. How can we negotiate this challenge and maximize the therapeutic benefits of cerebral organoid research? The author interrogates the challenge, suggesting a tentative way forward.


Potential influence of sewer heat recovery on in-sewer processes.
Heat recovery from combined sewers has a significant potential for practical renewable energy provision as sources of heat demand and sewer pipes are spread across urban areas. Sewers are continuously recharged with relatively hot wastewater, as well as interacting with heat sources from surrounding air and soil. However, the potential effects of modifying sewage temperature on in-sewer processes have received little attention. The deposition of fats, oils and greases (FOGs) and hydrogen sulphide formation are biochemical processes and are thus influenced by temperature. This paper utilises a case study approach to simulate anticipated temperature reductions in a sewer network due to heat recovery. A laboratory investigation into the formation of FOG deposits at temperatures varying between 5 °C and 20 °C provided mixed results, with only a weak temperature influence, highlighting the need for more research to fully understand the influence of the wastewater composition as well as temperature on FOG deposit formation. A separate modelling investigation into the formation of hydrogen sulphide when inflow temperature is varied between 5 °C and 20 °C showed considerable reductions in hydrogen sulphide formation. Hence, heat extraction from sewers could be a promising method for managing some in-sewer processes, combined with traditional methods such as chemical dosing.


Advanced radiological work-up as an adjunct to decision in early reconstructive surgery in brachial plexus injuries.
As neurophysiologic tests may not reveal the extent of brachial plexus injury at the early stage, the role of early radiological work-up has become increasingly important. The aim of the study was to evaluate the concordance between the radiological and clinical findings with the intraoperative findings in adult patients with brachial plexus injuries. Seven consecutive male patients (median age 33; range 15-61) with brachial plexus injuries, caused by motor cycle accidents in 5/7 patients, who underwent extensive radiological work-up with magnetic resonance imaging (MRI), computed tomography myelography (CT-M) or both were included in this retrospective study. A total of 34 spinal nerve roots were evaluated by neuroradiologists at two different occasions. The degree of agreement between the radiological findings of every individual nerve root and the intraoperative findings was estimated by calculation of kappa coefficient (capital KA, Cyrillic-value). Using the operative findings as a gold standard, the accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the clinical findings and the radiological findings were estimated. The diagnostic accuracy of radiological findings was 88% compared with 65% for the clinical findings. The concordance between the radiological findings and the intraoperative findings was substantial (capital KA, Cyrillic = 0.76) compared with only fair (capital KA, Cyrillic = 0.34) for the clinical findings. There were two false positive and two false negative radiological findings (sensitivity and PPV of 0.90; specificity and NPV of 0.87). The advanced optimized radiological work-up used showed high reliability and substantial agreement with the intraoperative findings in adult patients with brachial plexus injury.


Functional expression of voltage-gated sodium channels Nav1.5 in human breast cancer cell line MDA-MB-231.
Voltage-gated sodium channels (VGSCs) are known to be involved in the initiation and progression of many malignancies, and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumors. This study investigated the functional expression of Nav1.5 and its effect on invasion behavior of human breast cancer cell line MDA-MB-231. The mRNA and protein expression of Nav1.5 was detected by real time PCR, Western Blot and immunofluorescence. The effects of Nav1.5 on cell proliferation, migration and invasion were respectively assessed by MTT and Transwell. The effects of Nav1.5 on the secretion of matrix metalloproteases (MMPs) by MDA-MB-231 were analyzed by RT-PCR. The over-expressed Nav1.5 was present on the membrane of MDA-MB-231 cells. The invasion ability in vitro and the MMP-9 mRNA expression were respectively decreased to (47.82+/-0.53)% and (43.97+/-0.64)% (P<0.05) respectively in MDA-MB-231 cells treated with VGSCs specific inhibitor tetrodotoxin (TTX) by blocking Nav1.5 activity. It was concluded that Nav1.5 functional expression potentiated the invasive behavior of human breast cancer cell line MDA-MB-231 by increasing the secretion of MMP-9.


Prospective associations between parental feeding practices and children's oral processing behaviours.
Previous research demonstrated that faster eating rates are linked with increased intake of energy during a meal. Here, we examined whether within-meal parental feeding practices show cross-sectional and prospective associations with children's oral processing behaviours and whether the previously demonstrated association between faster eating rates and higher energy intakes varies by parental feeding practices. A subset (n = 155) of children and their mothers from the Growing Up in Singapore Towards healthy Outcomes cohort participated in an ad libitum meal at age 4.5 years. Children's oral processing behaviours (eating rate, bite size, chews per gram, oral exposure time, and meal duration) and parental feeding practices (autonomy-supporting and coercive prompts, restrictions, hurrying, and slowing) were recorded during the meal. Subsequently, 94 of the children participated in a follow-up meal without their mothers at age 6 years. Parental feeding practices were not consistently associated with child oral processing behaviours overall. However, exploratory post hoc analyses revealed some sex differences. The mothers of girls with faster eating rates, larger bite sizes, and fewer chews were more likely to use hurrying, slowing, and restrictions, but similar associations were not observed among boys. Children who had the most problematic eating style and were eating fast and for long experienced more restrictions, instructions to slow down, and prompts. Faster eating rates were linked with the highest energy intakes if children were additionally prompted to eat. Prospective analyses showed that children who were more often prompted using coercive techniques and less frequently hurried at age 4.5 years had faster eating rates at 6 years and a larger increase in eating rates between ages 4.5 and 6 years but did not consume more energy. Although the direction of these associations cannot be assumed, these exploratory analyses suggest sex differences in the associations between feeding practices and oral processing behaviours and highlight the potential role of parents in the development of children's oral processing behaviours.


Key interactions in integrin ectodomain responsible for global conformational change detected by elastic network normal-mode analysis.
Integrin, a membrane protein with a huge extracellular domain, participates in cell-cell and cell-extracellular-matrix interactions for metazoan. A group of integrins is known to perform a large-scale structural change when the protein is activated, but the activation mechanism and generality of the conformational change remain to be elucidated. We performed normal-mode analysis of the elastic network model on integrin alpha(V)beta(3) ectodomain in the bent form and identified key residues that influenced molecular motions. Iterative normal-mode calculations demonstrated that the specific nonbonded interactions involving the key residues work as a snap to keep integrin in the bent form. The importance of the key residues for the conformational change was further verified by mutation experiments, in which integrin alpha(IIb)beta(3) was used. The conservation pattern of amino acid residues among the integrin family showed that the characteristic pattern of residues seen around these key residues is found in the limited groups of integrin beta-chains. This conservation pattern suggests that the molecular mechanism of the conformational change relying on the interactions found in integrin alpha(V)beta(3) is unique to the limited types of integrins.


Identification of an NK/T cell-restricted progenitor in adult bone marrow contributing to bone marrow- and thymic-dependent NK cells.
Although bone marrow (BM) is the main site of natural killer (NK)-cell development in adult mice, recent studies have identified a distinct thymic-dependent NK pathway, implicating a possible close link between NK- and T-cell development in adult hematopoiesis. To investigate whether a potential NK-/T-lineage restriction of multipotent progenitors might take place already in the BM, we tested the full lineage potentials of NK-cell progenitors in adult BM. Notably, although Lin(-)CD122(+)NK1.1(-)DX5(-) NK-cell progenitors failed to commit to the B and myeloid lineages, they sustained a combined NK- and T-cell potential in vivo and in vitro at the single-cell level. Whereas T-cell development from NK/T progenitors is Notch-dependent, their contribution to thymic and BM NK cells remains Notch-independent. These findings demonstrate the existence of bipotent NK-/T-cell progenitors in adult BM.


Young and vulnerable: spatial-temporal trends and risk factors for infant mortality in rural South Africa (Agincourt), 1992-2007.
Infant mortality is an important indicator of population health in a country. It is associated with several health determinants, such as maternal health, access to high-quality health care, socioeconomic conditions, and public health policy and practices. A spatial-temporal analysis was performed to assess changes in infant mortality patterns between 1992-2007 and to identify factors associated with infant mortality risk in the Agincourt sub-district, rural northeast South Africa. Period, sex, refugee status, maternal and fertility-related factors, household mortality experience, distance to nearest primary health care facility, and socio-economic status were examined as possible risk factors. All-cause and cause-specific mortality maps were developed to identify high risk areas within the study site. The analysis was carried out by fitting Bayesian hierarchical geostatistical negative binomial autoregressive models using Markov chain Monte Carlo simulation. Simulation-based Bayesian kriging was used to produce maps of all-cause and cause-specific mortality risk. Infant mortality increased significantly over the study period, largely due to the impact of the HIV epidemic. There was a high burden of neonatal mortality (especially perinatal) with several hot spots observed in close proximity to health facilities. Significant risk factors for all-cause infant mortality were mother's death in first year (most commonly due to HIV), death of previous sibling and increasing number of household deaths. Being born to a Mozambican mother posed a significant risk for infectious and parasitic deaths, particularly acute diarrhoea and malnutrition. This study demonstrates the use of Bayesian geostatistical models in assessing risk factors and producing smooth maps of infant mortality risk in a health and socio-demographic surveillance system. Results showed marked geographical differences in mortality risk across a relatively small area. Prevention of vertical transmission of HIV and survival of mothers during the infants' first year in high prevalence villages needs to be urgently addressed, including expanded antenatal testing, prevention of mother-to-child transmission, and improved access to antiretroviral therapy. There is also need to assess and improve the capacity of district hospitals for emergency obstetric and newborn care. Persisting risk factors, including inadequate provision of clean water and sanitation, are yet to be fully addressed.


Skeletal fluorosis from brewed tea.
High fluoride ion (F(-)) levels are found in many surface and well waters. Drinking F(-)-contaminated water typically explains endemic skeletal fluorosis (SF). In some regions of Asia, however, poor quality "brick tea" also causes this disorder. The plant source of brick, black, green, orange pekoe, and oolong tea, Camellia sinensis, can contain substantial amounts of F(-). Exposure to 20 mg F(-) per day for 20 yr of adult life is expected to cause symptomatic SF. High F(-) levels stimulate osteoblasts and enhance bone apposition but substitute for OH(-) groups in hydroxyapatite crystals and thereby result in skeletal fragility and perhaps lead to secondary hyperparathyroidism. Beginning in 2005, we showed that daily consumption of 1-2 gallons of instant tea made from this plant can lead to SF. We describe a 48-yr-old American woman who developed SF from brewed tea. Our patient had elevated bone mineral density revealed by dual-energy x-ray absorptiometry (spine Z-score, +9.9), severe chronic bone and joint pain, and kyphosis after consuming 1-2 gallons of brewed orange pekoe tea daily for more than three decades. F(-) levels were high in her serum, urine, and clippings of fingernails and toenails, as well as in our reproduction of her beverage. Renal function was normal. She had vitamin D deficiency. Elevated serum PTH levels were unresponsive to adequate vitamin D supplementation. Pain resolved over several months when she stopped drinking tea and continued ergocalciferol. Our patient shows that SF can result from chronic consumption of large volumes of brewed tea.


Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer.
Hypoxia, via the hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2), upregulates many genes involved in cell survival. However, proapoptotic pathways are also induced. BCL-2/adenovirus E1B-19 kDa-interacting protein 3 (BNIP3) represents a paradigm of a cell death protein that is hypoxically upregulated via HIF-1 in most cancers. We found that in contrast to many other cell types, 6/8 colorectal cancer (CRC) cell lines show little hypoxic induction of BNIP3 despite an intact HIF signalling system. Colorectal tumour tissue also loses BNIP3 expression relative to matched normal samples. Downregulation of hypoxic BNIP3 in CRC cells was independent of the expression of other BCL-2 family members, or BNIP3L. That BNIP3 plays a functional role in hypoxic survival in CRC cells was demonstrated by the fact that CRC cell lines that do not upregulate BNIP3 or have been treated with BNIP3 RNA interference were insensitive to hypoxia-induced cell death. Promoter methylation and histone deacetylation were shown to silence BNIP3 in these CRC cell lines. Of significance, hypoxic induction of BNIP3 was restored in 4/6 cell lines by trichostatin-A treatment alone. These data suggest that BNIP3 plays an important role in hypoxic cell death and epigenetic mechanisms selectively silence its expression in CRC.


Investigation of collisional-activation decomposition process and spectra in the transport region of an electrospray single-quadrupole mass spectrometer.
The use of collisional-activation dissociation (CAD) in the electrospray transport region was evaluated for generating structural information on several pesticides and antibiotics. The collision energy used to generate the CAD spectra could be varied easily by changing the capillary/skimmer potential difference, imparting from 0 eV to above 16 eV internal energy to the near thermal ions generated by electrospray. The internal energy distribution for low-energy collisions (capillary/skimmer potential difference of 20 V) closely matches the curves generated by a triple-quadrupole mass spectrometer. Furthermore, the CAD spectra for selected compounds generated by electrospray in the transport region at a capillary/skimmer potential difference of 30-50 V closely resembled those obtained from the [M + H]+ ion by a triple quadrupole using 30 eV collision energy. The CAD of ions in the transport region resulted in 70% to 80% daughter-ion yields and minimal loss in overall ion current compared to the ion current for protonated or cationized parent molecules. The major daughter ions for 10 pg of Aldicarb and penicillin G could be detected (signal-to-noise ratio greater than 5) under full-scan CAD conditions.


Focus cues affect perceived depth.
Depth information from focus cues--accommodation and the gradient of retinal blur--is typically incorrect in three-dimensional (3-D) displays because the light comes from a planar display surface. If the visual system incorporates information from focus cues into its calculation of 3-D scene parameters, this could cause distortions in perceived depth even when the 2-D retinal images are geometrically correct. In Experiment 1 we measured the direct contribution of focus cues to perceived slant by varying independently the physical slant of the display surface and the slant of a simulated surface specified by binocular disparity (binocular viewing) or perspective/texture (monocular viewing). In the binocular condition, slant estimates were unaffected by display slant. In the monocular condition, display slant had a systematic effect on slant estimates. Estimates were consistent with a weighted average of slant from focus cues and slant from disparity/texture, where the cue weights are determined by the reliability of each cue. In Experiment 2, we examined whether focus cues also have an indirect effect on perceived slant via the distance estimate used in disparity scaling. We varied independently the simulated distance and the focal distance to a disparity-defined 3-D stimulus. Perceived slant was systematically affected by changes in focal distance. Accordingly, depth constancy (with respect to simulated distance) was significantly reduced when focal distance was held constant compared to when it varied appropriately with the simulated distance to the stimulus. The results of both experiments show that focus cues can contribute to estimates of 3-D scene parameters. Inappropriate focus cues in typical 3-D displays may therefore contribute to distortions in perceived space.


Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.
Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD). We investigated if nonpsychotropic cannabinoids, such as cannabidiol (CBD), produced similar effects in this experimental model of ACD. HaCaT cells were stimulated with poly-(I:C), and the release of chemokines and cytokines was measured in the presence of CBD or other phytocannabinoids (such as cannabidiol acid, cannabidivarin, cannabidivarinic acid, cannabichromene, cannabigerol, cannabigerolic acid, cannabigevarin, tetrahydrocannabivarin, and tetrahydrocannabivarinic acid) and antagonists of CB1, CB2, or transient receptor potential vanilloid type-1 (TRPV1) receptors. HaCaT cell viability following phytocannabinoid treatment was also measured. The cellular levels of endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol] and related molecules (palmitoylethanolamide, oleoylethanolamide) were quantified in poly-(I:C)-stimulated HaCaT cells treated with CBD. We show that in poly-(I:C)-stimulated HaCaT cells, CBD elevates the levels of AEA and dose-dependently inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α in a manner reversed by CB2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5'-iodio-resiniferatoxin (I-RTX), respectively, with no cytotoxic effect. This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD.


Molecular mechanism of acrylamide neurotoxicity: lessons learned from organic chemistry.
Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function. In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles. In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission. ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress. These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins.


Physiological recordings: basic concepts and implementation during functional magnetic resonance imaging.
Combining human functional neuroimaging with other forms of psychophysiological measurement, including autonomic monitoring, provides an empirical basis for understanding brain-body interactions. This approach can be applied to characterize unwanted physiological noise, examine the neural control and representation of bodily processes relevant to health and morbidity, and index covert expression of affective and cognitive processes to enhance the interpretation of task-evoked regional brain activity. In recent years, human neuroimaging has been dominated by functional magnetic resonance imaging (fMRI) studies. The spatiotemporal information of fMRI regarding central neural activity is valuably complemented by parallel physiological monitoring, yet such studies still remain in the minority. This review article highlights fMRI studies that employed cardiac, vascular, respiratory, electrodermal, gastrointestinal and pupillary psychophysiological indices to address specific questions regarding interaction between brain and bodily state in the context of experience, cognition, emotion and behaviour. Physiological monitoring within the fMRI environment presents specific technical issues, most importantly related to safety. Mechanical and electrical hazards may present dangers to scanned subjects, operator and/or equipment. Furthermore, physiological monitoring may interfere with the quality of neuroimaging data, or itself be compromised by artefacts induced by the operation of the scanner. We review the sources of these potential problems and the current approaches and advice to enable the combination of fMRI and physiological monitoring in a safe and effective manner.


Palliative and end-of-life care in stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
The purpose of this statement is to delineate basic expectations regarding primary palliative care competencies and skills to be considered, learned, and practiced by providers and healthcare services across hospitals and community settings when caring for patients and families with stroke. Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee. Members were chosen to reflect the diversity and expertise of professional roles in delivering optimal palliative care. Writing group members were assigned topics relevant to their areas of expertise, reviewed the appropriate literature, and drafted manuscript content and recommendations in accordance with the American Heart Association's framework for defining classes and level of evidence and recommendations. The palliative care needs of patients with serious or life-threatening stroke and their families are enormous: complex decision making, aligning treatment with goals, and symptom control. Primary palliative care should be available to all patients with serious or life-threatening stroke and their families throughout the entire course of illness. To optimally deliver primary palliative care, stroke systems of care and provider teams should (1) promote and practice patient- and family-centered care; (2) effectively estimate prognosis; (3) develop appropriate goals of care; (4) be familiar with the evidence for common stroke decisions with end-of-life implications; (5) assess and effectively manage emerging stroke symptoms; (6) possess experience with palliative treatments at the end of life; (7) assist with care coordination, including referral to a palliative care specialist or hospice if necessary; (8) provide the patient and family the opportunity for personal growth and make bereavement resources available if death is anticipated; and (9) actively participate in continuous quality improvement and research. Addressing the palliative care needs of patients and families throughout the course of illness can complement existing practices and improve the quality of life of stroke patients, their families, and their care providers. There is an urgent need for further research in this area.


Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease.
The Working Group on research in adult congenital heart disease (ACHD) was convened in September 2004 under the sponsorship of National Heart, Lung, and Blood Institute (NHLBI) and the Office of Rare Diseases, National Institutes of Health, Department of Health and Human Services, to make recommendations on research needs. The purpose of the Working Group was to advise the NHLBI on the current state of the science in ACHD and barriers to optimal clinical care, and to make specific recommendations for overcoming those barriers. The members of the Working Group were chosen to provide expert input on a broad range of research issues from both scientific and lay perspectives. The Working Group reviewed data on the epidemiology of ACHD, long-term outcomes of complex cardiovascular malformations, issues in assessing morphology and function with current imaging techniques, surgical and catheter-based interventions, management of related conditions including pregnancy and arrhythmias, quality of life, and informatics. After research and training barriers were discussed, the Working Group recommended outreach and educational programs for adults with congenital heart disease, a network of specialized adult congenital heart disease regional centers, technology development to support advances in imaging and modeling of abnormal structure and function, and a consensus on appropriate training for physicians to provide care for adults with congenital heart disease.


The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production.
Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-beta (A(beta)) peptides, which are derive from processing of the beta-amyloid precursor protein (APP), better named amyloid-beta precursor protein (A(beta)PP), by secretases. The A(beta)PP intracellular domain (AID), which is released together with A(beta), has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A(beta)PP processing are poorly understood. As cleavage of other gamma-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A(beta)PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A(beta)PP. Interestingly, 17 amino acids corresponding to the NH2-terminal portion of A(beta) are necessary for this interaction. Moreover, BRI2 expression regulates A(beta)PP processing resulting in reduced A(beta) and AID levels. Altogether, these findings characterize the BRI2-A(beta)PP interaction as a regulatory mechanism of A(beta)PP processing that inhibits A(beta) production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A(beta)PP processing would define dysregulation of A(beta)PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD.


Parity, breastfeeding and risk of coronary heart disease: A pan-European case-cohort study.
There is uncertainty about the direction and magnitude of the associations between parity, breastfeeding and the risk of coronary heart disease (CHD). We examined the separate and combined associations of parity and breastfeeding practices with the incidence of CHD later in life among women in a large, pan-European cohort study. Data were used from European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD, a case-cohort study nested within the EPIC prospective study of 520,000 participants from 10 countries. Information on reproductive history was available for 14,917 women, including 5138 incident cases of CHD. Using Prentice-weighted Cox regression separately for each country followed by a random-effects meta-analysis, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CHD, after adjustment for age, study centre and several socioeconomic and biological risk factors. Compared with nulliparous women, the adjusted HR was 1.19 (95% CI: 1.01-1.41) among parous women; HRs were higher among women with more children (e.g., adjusted HR: 1.95 (95% CI: 1.19-3.20) for women with five or more children). Compared with women who did not breastfeed, the adjusted HR was 0.71 (95% CI: 0.52-0.98) among women who breastfed. For childbearing women who never breastfed, the adjusted HR was 1.58 (95% CI: 1.09-2.30) compared with nulliparous women, whereas for childbearing women who breastfed, the adjusted HR was 1.19 (95% CI: 0.99-1.43). Having more children was associated with a higher risk of CHD later in life, whereas breastfeeding was associated with a lower CHD risk. Women who both had children and breastfed did have a non-significantly higher risk of CHD.


Developing constructs for psychopathology research: research domain criteria.
There exists a divide between findings from integrative neuroscience and clinical research focused on mechanisms of psychopathology. Specifically, a clear correspondence does not emerge between clusters of complex clinical symptoms and dysregulated neurobiological systems, with many apparent redundancies. For instance, many mental disorders involve multiple disruptions in putative mechanistic factors (e.g., excessive fear, deficient impulse control), and different disrupted mechanisms appear to play major roles in many disorders. The Research Domain Criteria (RDoC) framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. Such integration might be achieved by shifting the central research focus of the field away from clinical description to more squarely examine aberrant mechanisms. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms. This approach will require new methods to ascertain samples, relying on hypothesized psychopathological mechanisms to define experimental groups instead of traditional diagnostic categories. RDoC, by design, uncouples research efforts from clinically familiar categories to focus directly on fundamental mechanisms of psychopathology. RDoC proposes a matrix of domains and levels of analyses and invites the field to test and refine the framework. If RDoC is successful, the domains will ultimately relate to familiar psychopathologies in ways that promote new knowledge regarding etiology and more efficient development of new preventive and treatment interventions.


Spectral luminous efficiency as a function of age.
Spectral luminous efficiency function for a 2-deg field at a photopic level (100 Td) was measured for 91 observers by flicker photometry (FP) and for 97 observers by direct brightness matching (DBM), to find age-related change in the efficiency function as well as to obtain a reliable data set to be used in photometry. Observers ranged in age from 11 to 78 years. A gradual reduction of luminous efficiency with age was observed for both functions by FP and by DBM in the short-wave region, which was expected because of the age-related increase of optical density of eye lens. A similar age-related reduction of efficiency was observed in the long-wave region for the function obtained by DBM; this reduction was regarded as being due to reduced chromatic contribution to brightness with age. Principal components analysis on the spectral efficiency data and an analysis of the efficiency difference between the data obtained by DBM and FP confirmed this conclusion. Assuming a log-linear change in efficiency with age for any wavelength throughout the life span, spectral luminous efficiency function at any age was derived for photometric use.


Intravoxel Incoherent Motion at 7 Tesla to quantify human spinal cord perfusion: limitations and promises.
To develop a noninvasive technique to map human spinal cord (SC) perfusion in vivo. More specifically, to implement an intravoxel incoherent motion (IVIM) protocol at ultrahigh field for the human SC and assess parameters estimation errors. Monte-Carlo simulations were conducted to assess estimation errors of 2 standard IVIM fitting approaches (two-step versus one-step fit) over the range of IVIM values reported for the human brain and for typical SC diffusivities. Required signal-to-noise ratio (SNR) was inferred for estimation of the parameters product, fIVIM D* (microvascular fraction times pseudo-diffusion coefficient), within 10% error margins. In-vivo IVIM imaging of the SC was performed at 7T in 6 volunteers. An image processing pipeline is proposed to generate IVIM maps and register them for an atlas-based region-wise analysis. Required b = 0 SNRs for 10% error estimation on fIVIM D* with the one-step fit were 159 and 185 for diffusion-encoding perpendicular and parallel to the SC axis, respectively. Average in vivo b = 0 SNR within cord was 141 ± 79, corresponding to estimation errors of 12.7% and 14.7% according to numerical simulations. Slice- and group-averaging reduced noise in IVIM maps, highlighting the difference in perfusion between gray and white matter. Mean ± standard deviation fIVIM and D* values across subjects within gray (respectively white) matter were 16.0 ± 1.7 (15.0 ± 1.6)% and 11.4 ± 2.9 (11.5 ± 2.4) × 10-3 mm2 /s. Single-subject data SNR at 7T was insufficient for reliable perfusion estimation. However, atlas-averaged IVIM maps highlighted the higher microvascular fraction of gray matter compared to white matter, providing first results of healthy human SC perfusion mapping with MRI.


Stripe and ring artifact removal with combined wavelet--Fourier filtering.
A fast, powerful and stable filter based on combined wavelet and Fourier analysis for the elimination of horizontal or vertical stripes in images is presented and compared with other types of destriping filters. Strict separation between artifacts and original features allowing both, suppression of the unwanted structures and high degree of preservation of the original image information is endeavoured. The results are validated by visual assessments, as well as by quantitative estimation of the image energy loss. The capabilities and the performance of the filter are tested on a number of case studies related to applications in tomographic imaging. The case studies include (i) suppression of waterfall artifacts in electron microscopy images based on focussed ion beam nanotomography, (ii) removal of different types of ring artifacts in synchrotron based X-ray microtomography and (iii) suppression of horizontal stripe artifacts from phase projections in grating interferometry.


The effect of a familiarisation period on subsequent strength gain.
Untrained subjects can display diverse strength gain following an identical period of resistance exercise. In this investigation, 28 untrained males completed 16-weeks of resistance exercise, comprising 4-weeks familiarisation, and 12-weeks of heavy-load (80-85%) activity. High and low responders were identified by the Δ1RM (Δ one repetition maximum) observed following familiarisation (25.1 ± 1.4%, 9.5 ± 1.4%, P < 0.0001) and differences in electromyographic root mean square amplitude (ΔEMG(RMS) 29.5 ± 8.3%, 2.4 ± 6.0%, P = 0.0140), and habitual and occupational activity patterns were observed between these respective groups. The strength gain (P < 0.0001) observed within high (29.6 ± 1.7%) and low (31.4 ± 2.7%) responding groups was similar during the heavy-load phase, yet ΔEMG(RMS) increased (P = 0.0048) only in low responders (31.5 ± 9.3%). Retrospectively, differences (P < 0.0001) in baseline 1RM strength of high- (19.7 ± 0.9 kg) and low-responding (15.6 ± 0.7 kg) groups were identified, and a strong negative correlation with Δ1RM after 16-weeks (r (2 )= -0.85) was observed. As such, baseline 1RM strength provided a strong predicative measure of strength adaptation. The ΔEMG(RMS) suggests strength variability within high and low responders may be attributed to neural adaptation. However, differences in habitual endurance and occupational physical activity suggests one should consider screening not only recent resistance training, but also other modes of physical activity during participant recruitment.


Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.
This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.


Comorbidities of obesity in school children: a cross-sectional study in the PIAMA birth cohort.
There is ample evidence that childhood overweight is associated with increased risk of chronic disease in adulthood. The aim of this study was to investigate associations between childhood overweight and common childhood health problems. Data were used from a general population sample of 3960 8-year-old children, participating in the Dutch PIAMA birth cohort study. Weight and height, measured by the investigators, were used to define BMI status (thinness, normal weight, moderate overweight, obesity). BMI status was studied cross-sectionally in relation to the following parental reported outcomes: a general health index, GP visits, school absenteeism due to illness, health-related functional limitations, doctor diagnosed respiratory infections and use of antibiotics. Obesity was significantly associated with a lower general health score, more GP visits, more school absenteeism and more health-related limitations, (adjusted odds ratios around 2.0 for most outcomes). Obesity was also significantly associated with bronchitis (adjusted odds ratio (aOR) and 95% confidence intervals (95%CI): 5.29 (2.58;10.85) and with the use of antibiotics (aOR (95%CI): 1.79 (1.09;2.93)). Associations with flu/serious cold, ear infection and throat infection were positive, but not statistically significant. Moderate overweight was not significantly associated with the health outcomes studied. Childhood obesity is not merely a risk factor for disease in adulthood, but obese children may experience more illness and health related problems already in childhood. The high prevalence of the outcomes studied implies a high burden of disease in terms of absolute numbers of sick children.


The plasma peptides of breast versus ovarian cancer.
There is a need to demonstrate a proof of principle that proteomics has the capacity to analyze plasma from breast cancer versus other diseases and controls in a multisite clinical trial design. The peptides or proteins that show a high observation frequency, and/or precursor intensity, specific to breast cancer plasma might be discovered by comparison to other diseases and matched controls. The endogenous tryptic peptides of breast cancer plasma were compared to ovarian cancer, female normal, sepsis, heart attack, Alzheimer's and multiple sclerosis along with the institution-matched normal and control samples collected directly onto ice. Endogenous tryptic peptides were extracted from individual breast cancer and control EDTA plasma samples in a step gradient of acetonitrile, and collected over preparative C18 for LC-ESI-MS/MS with a set of LTQ XL linear quadrupole ion traps working together in parallel to randomly and independently sample clinical populations. The MS/MS spectra were fit to fully tryptic peptides or phosphopeptides within proteins using the X!TANDEM algorithm. The protein observation frequency was counted using the SEQUEST algorithm after selecting the single best charge state and peptide sequence for each MS/MS spectra. The observation frequency was subsequently tested by Chi Square analysis. The log10 precursor intensity was compared by ANOVA in the R statistical system. Peptides and/or phosphopeptides of common plasma proteins such as APOE, C4A, C4B, C3, APOA1, APOC2, APOC4, ITIH3 and ITIH4 showed increased observation frequency and/or precursor intensity in breast cancer. Many cellular proteins also showed large changes in frequency by Chi Square (χ2 > 100, p < 0.0001) in the breast cancer samples such as CPEB1, LTBP4, HIF-1A, IGHE, RAB44, NEFM, C19orf82, SLC35B1, 1D12A, C8orf34, HIF1A, OCLN, EYA1, HLA-DRB1, LARS, PTPDC1, WWC1, ZNF562, PTMA, MGAT1, NDUFA1, NOGOC, OR1E1, OR1E2, CFI, HSA12, GCSH, ELTD1, TBX15, NR2C2, FLJ00045, PDLIM1, GALNT9, ASH2L, PPFIBP1, LRRC4B, SLCO3A1, BHMT2, CS, FAM188B2, LGALS7, SAT2, SFRS8, SLC22A12, WNT9B, SLC2A4, ZNF101, WT1, CCDC47, ERLIN1, SPFH1, EID2, THOC1, DDX47, MREG, PTPRE, EMILIN1, DKFZp779G1236 and MAP3K8 among others. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. An increase in mean precursor intensity of peptides was observed for QSER1 as well as SLC35B1, IQCJ-SCHIP1, MREG, BHMT2, LGALS7, THOC1, ANXA4, DHDDS, SAT2, PTMA and FYCO1 among others. In contrast, the QSER1 peptide QPKVKAEPPPK was apparently specific to ovarian cancer. There was striking agreement between the breast cancer plasma peptides and proteins discovered by LC-ESI-MS/MS with previous biomarkers from tumors, cells lines or body fluids by genetic or biochemical methods. The results indicate that variation in plasma peptides from breast cancer versus ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research. It may be possible to use a battery of sensitive and robust linear quadrupole ion traps for random and independent sampling of plasma from a multisite clinical trial.


Comparative genomics of enterohemorrhagic Escherichia coli O145:H28 demonstrates a common evolutionary lineage with Escherichia coli O157:H7.
Although serotype O157:H7 is the predominant enterohemorrhagic Escherichia coli (EHEC), outbreaks of non-O157 EHEC that cause severe foodborne illness, including hemolytic uremic syndrome have increased worldwide. In fact, non-O157 serotypes are now estimated to cause over half of all the Shiga toxin-producing Escherichia coli (STEC) cases, and outbreaks of non-O157 EHEC infections are frequently associated with serotypes O26, O45, O103, O111, O121, and O145. Currently, there are no complete genomes for O145 in public databases. We determined the complete genome sequences of two O145 strains (EcO145), one linked to a US lettuce-associated outbreak (RM13514) and one to a Belgium ice-cream-associated outbreak (RM13516). Both strains contain one chromosome and two large plasmids, with genome sizes of 5,737,294 bp for RM13514 and 5,559,008 bp for RM13516. Comparative analysis of the two EcO145 genomes revealed a large core (5,173 genes) and a considerable amount of strain-specific genes. Additionally, the two EcO145 genomes display distinct chromosomal architecture, virulence gene profile, phylogenetic origin of Stx2a prophage, and methylation profile (methylome). Comparative analysis of EcO145 genomes to other completely sequenced STEC and other E. coli and Shigella genomes revealed that, unlike any other known non-O157 EHEC strain, EcO145 ascended from a common lineage with EcO157/EcO55. This evolutionary relationship was further supported by the pangenome analysis of the 10 EHEC str ains. Of the 4,192 EHEC core genes, EcO145 shares more genes with EcO157 than with the any other non-O157 EHEC strains. Our data provide evidence that EcO145 and EcO157 evolved from a common lineage, but ultimately each serotype evolves via a lineage-independent nature to EHEC by acquisition of the core set of EHEC virulence factors, including the genes encoding Shiga toxin and the large virulence plasmid. The large variation between the two EcO145 genomes suggests a distinctive evolutionary path between the two outbreak strains. The distinct methylome between the two EcO145 strains is likely due to the presence of a BsuBI/PstI methyltransferase gene cassette in the Stx2a prophage of the strain RM13514, suggesting a role of horizontal gene transfer-mediated epigenetic alteration in the evolution of individual EHEC strains.


Correspondence mapping induced state and action metrics for robotic imitation.
This paper addresses the problem of body mapping in robotic imitation where the demonstrator and imitator may not share the same embodiment [degrees of freedom (DOFs), body morphology, constraints, affordances, and so on]. Body mappings are formalized using a unified (linear) approach via correspondence matrices, which allow one to capture partial, mirror symmetric, one-to-one, one-to-many, many-to-one, and many-to-many associations between various DOFs across dissimilar embodiments. We show how metrics for matching state and action aspects of behavior can be mathematically determined by such correspondence mappings, which may serve to guide a robotic imitator. The approach is illustrated and validated in a number of simulated 3-D robotic examples, using agents described by simple kinematic models and different types of correspondence mappings.


The association between cigarette smoking and inflammation: The Genetic Epidemiology Network of Arteriopathy (GENOA) study.
To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p<0.003). High sensitivity C-reactive protein was the most elevated biomarker among current smokers when compared to never smokers [GM ratio = 1.39 (95% CI: 1.23, 1.57); p <0.001]. Among former smokers, each pack-year of cigarettes smoked was associated with a 0.4% higher serum level of hsCRP [GM ratio = 1.004 (95% CI: 1.001, 1.006); p = 0.002] and each 5-year lapsed since quitting was associated with a 4% lower serum level of hsCRP [GM ratio = 0.96 (95% CI: 0.93, 0.99); p = 0.006]. However, we found no significant association of smoking intensity or burden with biomarkers of inflammation among current smokers. HsCRP appears to be the most sensitive biomarker of inflammation associated with cigarette smoking of those investigated, and could be a useful biomarker of smoking-related injury for the study and regulation of emerging tobacco products.


The rabbit lacrimal gland in vitamin A deficiency.
To investigate the morphology, ultrastructure, and protein secretion of the vitamin A-deficient rabbit lacrimal gland. The lacrimal glands of vitamin A-deficient rabbits and age-matched controls were fixed, processed by standard methods, and examined by light and transmission electron microscopy. Protein secreted by the lacrimal gland was analyzed using gel filtration chromatography and electrophoresis. By light microscopy, the glands of experimental and control rabbits were indistinguishable. Electron microscopy showed little effect of vitamin A deficiency on the lacrimal acini, although occasional pyknotic nuclei were observed. The intralobular ductal epithelium was unaffected. Protein concentration and composition were essentially unchanged in lacrimal gland fluid of vitamin A-deficient rabbits compared to controls. The rabbit lacrimal gland is minimally affected by vitamin A deficiency, suggesting species differences between rabbits and rats in the vitamin A requirements of the lacrimal gland. Normal lacrimal gland structure and function in vitamin A deficiency allow for the prompt secretion of retinol on the restoration of vitamin A to the diet.


A single LC-tandem mass spectrometry method for the simultaneous determination of 14 antimalarial drugs and their metabolites in human plasma.
Among the various determinants of treatment response, the achievement of sufficient blood levels is essential for curing malaria. For helping us at improving our current understanding of antimalarial drugs pharmacokinetics, efficacy and toxicity, we have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 200mul of plasma for the simultaneous determination of 14 antimalarial drugs and their metabolites which are the components of the current first-line combination treatments for malaria (artemether, artesunate, dihydroartemisinin, amodiaquine, N-desethyl-amodiaquine, lumefantrine, desbutyl-lumefantrine, piperaquine, pyronaridine, mefloquine, chloroquine, quinine, pyrimethamine and sulfadoxine). Plasma is purified by a combination of protein precipitation, evaporation and reconstitution in methanol/ammonium formate 20mM (pH 4.0) 1:1. Reverse-phase chromatographic separation of antimalarial drugs is obtained using a gradient elution of 20mM ammonium formate and acetonitrile both containing 0.5% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 21min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effect variability, overall process efficiency, standard addition experiments as well as antimalarials short- and long-term stability in plasma. The reactivity of endoperoxide-containing antimalarials in the presence of hemolysis was tested both in vitro and on malaria patients samples. With this method, signal intensity of artemisinin decreased by about 20% in the presence of 0.2% hemolysed red-blood cells in plasma, whereas its derivatives were essentially not affected. The method is precise (inter-day CV%: 3.1-12.6%) and sensitive (lower limits of quantification 0.15-3.0 and 0.75-5ng/ml for basic/neutral antimalarials and artemisinin derivatives, respectively). This is the first broad-range LC-MS/MS assay covering the currently in-use antimalarials. It is an improvement over previous methods in terms of convenience (a single extraction procedure for 14 major antimalarials and metabolites reducing significantly the analytical time), sensitivity, selectivity and throughput. While its main limitation is investment costs for the equipment, plasma samples can be collected in the field and kept at 4 degrees C for up to 48h before storage at -80 degrees C. It is suited to detecting the presence of drug in subjects for screening purposes and quantifying drug exposure after treatment. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of antimalarials and better define the therapeutic dose ranges in different patient populations.


A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.
Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data.


Functional lesions in dysphagia due to acute stroke: discordance between abnormal findings of bedside swallowing assessment and aspiration on videofluorography.
Bedside swallowing assessments are often used to assess dysphagia. However, in some patients, aspiration pneumonia occurs without any problems on bedside swallowing assessments and some patients do not suffer aspiration pneumonia despite abnormal results of bedside swallowing assessments in acute stroke. To detect the differences of lesions related to bedside swallowing assessment abnormality and aspiration, we investigated swallowing-related functional lesions in terms of cerebral blood flow in patients with dysphagia after stroke. The study included 50 acute stroke patients who underwent bedside swallowing assessments and videofluorography as well as single-photon emission computed tomography (CT) at approximately the same time. Bedside swallowing assessments included repetitive saliva swallowing test and modified water swallowing test as dry and wet swallowing tasks. The presence or absence of aspiration was assessed using videofluorography. We divided patients into three subgroups based on the outcomes of the bedside swallowing assessments and presence or absence of aspiration. Statistical image analysis was performed using single-photon emission CT to determine their relationship with bedside swallowing assessments and videofluorography results. Twenty-seven (54.0%) and 28 (56.0%) patients had abnormal repetitive saliva swallowing test and modified water swallowing test results. Videofluorography indicated aspiration in 35 (70.0%) patients. In comparing patients with and without abnormal results on each test, the groups with abnormal repetitive saliva swallowing test, abnormal modified water swallowing test, and aspiration demonstrated lower cerebral blood flow in the left precuneus, left insula, and anterior cingulate gyrus, respectively. Based on the analysis of cerebral blood flow, functional lesions differed across abnormal repetitive saliva swallowing test and abnormal modified water swallowing test findings and aspiration on videofluorography, and each test may assess different functions among the many processes involved in swallowing.


Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants : a systematic review and meta-analysis.
Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers. Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged > or =18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities. Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.


Moraxella catarrhalis binding to host cellular receptors is mediated by sequence-specific determinants not conserved among all UspA1 protein variants.
The Moraxella catarrhalis ubiquitous surface proteins (UspAs) are autotransporter molecules reported to interact with a variety of different host proteins and to affect processes ranging from serum resistance to cellular adhesion. The role of UspA1 as an adhesin has been confirmed with a number of different human cell types and is mediated by binding to eukaryotic proteins including carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs), fibronectin, and laminin. A distinct difference in the ability of prototypical M. catarrhalis strains to adhere to CEACAM-expressing cell lines prompted us to perform strain-specific structure-function analyses of UspA1 proteins. In this study, we characterized CEACAM binding by a diverse set of UspA1 proteins and showed that 3 out of 10 UspA1 proteins were incapable of binding CEACAM. This difference resulted from the absence of a distinct CEACAM binding motif in nonadhering strains. Our sequence analysis also revealed a single M. catarrhalis isolate that lacked the fibronectin-binding motif and was defective in adherence to Chang conjunctival epithelial cells. These results clearly demonstrate that UspA1-associated adhesive functions are not universally conserved. Instead, UspA1 proteins must be considered as variants with the potential to confer both different cell tropisms and host cell responses.


Museomics for reconstructing historical floristic exchanges: Divergence of stone oaks across Wallacea.
Natural history collections and tropical tree diversity are both treasure troves of biological and evolutionary information, but their accessibility for scientific study is impeded by a number of properties. DNA in historical specimens is generally highly fragmented, complicating the recovery of high-grade genetic material. Furthermore, our understanding of hyperdiverse, wide-spread tree assemblages is obstructed by extensive species ranges, fragmented knowledge of tropical tree diversity and phenology, and a widespread lack of species-level diagnostic characters, prohibiting the collecting of readily identifiable specimens which can be used to build, revise or strengthen taxonomic frameworks. This, in turn, delays the application of downstream conservation action. A sizable component of botanical collections are sterile-thus eluding identification and are slowing down progress in systematic treatments of tropical biodiversity. With rapid advances in genomics and bioinformatic approaches to biodiversity research, museomics is emerging as a new field breathing life into natural collections that have been built up over centuries. Using MIGseq (multiplexed ISSR genotyping by sequencing), we generated 10,000s of short loci, for both freshly collected materials and museum specimens (aged >100 years) of Lithocarpus-a widespread tropical tree genus endemic to the Asian tropics. Loci recovery from historical and recently collected samples was not affected by sample age and preservation history of the study material, underscoring the reliability and flexibility of the MIGseq approach. Phylogenomic inference and biogeographic reconstruction across insular Asia, highlights repeated migration and diversification patterns between continental regions and islands. Results indicate that co-occurring insular species at the extremity of the distribution range are not monophyletic, raising the possibility of multiple independent dispersals along the outer edge of Wallacea. This suggests that dispersal of large seeded tree genera throughout Malesia and across Wallacea may have been less affected by large geographic distances and the presence of marine barriers than generally assumed. We demonstrate the utility of MIGseq in museomic studies using non-model taxa, presenting the first range-wide genomic assessment of Lithocarpus and tropical Fagaceae as a proof-of-concept. Our study shows the potential for developing innovative genomic approaches to improve the capture of novel evolutionary signals using valuable natural history collections of hyperdiverse taxa.


Pathways towards instability in financial networks.
Following the financial crisis of 2007-2008, a deep analogy between the origins of instability in financial systems and complex ecosystems has been pointed out: in both cases, topological features of network structures influence how easily distress can spread within the system. However, in financial network models, the details of how financial institutions interact typically play a decisive role, and a general understanding of precisely how network topology creates instability remains lacking. Here we show how processes that are widely believed to stabilize the financial system, that is, market integration and diversification, can actually drive it towards instability, as they contribute to create cyclical structures which tend to amplify financial distress, thereby undermining systemic stability and making large crises more likely. This result holds irrespective of the details of how institutions interact, showing that policy-relevant analysis of the factors affecting financial stability can be carried out while abstracting away from such details.


Collaborative deliberation: a model for patient care.
Existing theoretical work in decision making and behavior change has focused on how individuals arrive at decisions or form intentions. Less attention has been given to theorizing the requirements that might be necessary for individuals to work collaboratively to address difficult decisions, consider new alternatives, or change behaviors. The goal of this work was to develop, as a forerunner to a middle range theory, a conceptual model that considers the process of supporting patients to consider alternative health care options, in collaboration with clinicians, and others. Theory building among researchers with experience and expertise in clinician-patient communication, using an iterative cycle of discussions. We developed a model composed of five inter-related propositions that serve as a foundation for clinical communication processes that honor the ethical principles of respecting individual agency, autonomy, and an empathic approach to practice. We named the model 'collaborative deliberation.' The propositions describe: (1) constructive interpersonal engagement, (2) recognition of alternative actions, (3) comparative learning, (4) preference construction and elicitation, and (5) preference integration. We believe the model underpins multiple suggested approaches to clinical practice that take the form of patient centered care, motivational interviewing, goal setting, action planning, and shared decision making.


Comparison of capacitive and radio frequency resonator sensors for monitoring parallelized droplet microfluidic production.
Scaled-up production of microfluidic droplets, through the parallelization of hundreds of droplet generators, has received a lot of attention to bring novel multiphase microfluidics research to industrial applications. However, apart from droplet generation, other significant challenges relevant to this goal have never been discussed. Examples include monitoring systems, high-throughput processing of droplets and quality control procedures among others. In this paper, we present and compare capacitive and radio frequency (RF) resonator sensors as two candidates that can measure the dielectric properties of emulsions in microfluidic channels. By placing several of these sensors in a parallelization device, the stability of the droplet generation at different locations can be compared, and potential malfunctions can be detected. This strategy enables for the first time the monitoring of scaled-up microfluidic droplet production. Both sensors were prototyped and characterized using emulsions with droplets of 100-150 μm in diameter, which were generated in parallelization devices at water-in-oil volume fractions (φ) between 11.1% and 33.3%.Using these sensors, we were able to measure accurately increments as small as 2.4% in the water volume fraction of the emulsions. Although both methods rely on the dielectric properties of the emulsions, the main advantage of the RF resonator sensors is the fact that they can be designed to resonate at multiple frequencies of the broadband transmission line. Consequently with careful design, two or more sensors can be parallelized and read out by a single signal. Finally, a comparison between these sensors based on their sensitivity, readout cost and simplicity, and design flexibility is also discussed.


Inflammatory reactions associated with a calcium sulfate bone substitute.
Loss of bone substance is a major source of disability that often requires grafting. Recently developed synthetic bone grafts have generated a lot of enthusiasm due to the lack of immunological reactions and infectious disease transmission risk. The current work describes some peculiar complications related to the use of calcium sulfate granules. 15 implantations of calcium sulfate pellets Osteoset (Wright Medical Technology) were performed following resection of bone tumors at our service during 1999. Clinical or computerized tomography scans were available in all patients. 3 cases were encountered in which a severe inflammatory reaction developed. In one case serous drainage and an allergic reaction obligated graft removal. In another case, inflammation resolved two months following implantation. In the last case, wound breakdown occurred. A sterile inflammatory response has previously hindered the use of absorbable poly-lactic and poly-glycolic acid rods. Apparently due to rapid graft resorption, the resulting calcium-rich fluid incites inflammation. The single case of an allergic reaction is interesting. An allergy to plaster of Paris is rare and related to minor additives. These were not present in the bone substitute used. Inflammatory complications should be considered when assessing the risk-benefit ratio of using different types of bone replacement materials, and comparing allogeneic grafts to synthetic ones.


Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study.
A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.


Recommendations for the packaging and containerizing of bioinformatics software.
Software Containers are changing the way scientists and researchers develop, deploy and exchange scientific software. They allow labs of all sizes to easily install bioinformatics software, maintain multiple versions of the same software and combine tools into powerful analysis pipelines. However, containers and software packages should be produced under certain rules and standards in order to be reusable, compatible and easy to integrate into pipelines and analysis workflows. Here, we presented a set of recommendations developed by the BioContainers Community to produce standardized bioinformatics packages and containers. These recommendations provide practical guidelines to make bioinformatics software more discoverable, reusable and transparent. They are aimed to guide developers, organisations, journals and funders to increase the quality and sustainability of research software.


New Tracers and New Perspectives for Molecular Imaging in Lewy Body Diseases.
The term Lewy body diseases (LBDs) refers to a subset of neurodegenerative disorders that share the accumulation of the so-called Lewy bodies (LB) including: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD later characterized by the occurrence of dementia (PDD). Moreover, multiple system atrophy (MSA) and idiopatic Rem Sleeping behaviour disorders (RBD) complete the group of synucleinopathies and have also common symptoms with respect to LBDs. The clinical diagnosis of LBDs can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by these neurodegenerative disorders, early and accurate diagnosis can lead to improved clinical management of patients. For this reason, information obtained from molecular imaging biomarkers is playing an increasingly important role in this framework. The present narrative review discusses both established milestones and new evidence on the use of molecular imaging tracers already part of the clinical practice as well as available evidence on new molecular imaging approaches in PD, PDD and DLB.


Young voices in mental health care: Exploring children's and adolescents' service experiences and preferences.
The development of 'youth-friendly' services has become a priority across a wide range of health-care contexts. However, relatively few studies have specifically examined users' experiences of, and preferences for, child and adolescent mental health care. The current study investigated young service users' views of outpatient and community mental health clinics in Sweden, based on two data sources. First, focus group interviews were conducted with seven children and adolescents (aged 10-18 years) to explore both positive and negative experiences of mental health care. Second, written suggestions about specific service improvements were obtained from 106 children and adolescents. Qualitative content analysis revealed three overarching themes: 'Accessibility', 'Being heard and seen' and 'Usefulness of sessions'. Young people's recommendations for improving practice included more convenient appointment times, offered in welcoming settings; opportunities to communicate more openly with clinical staff, enabling sensitive discussion of mental health and wider personal issues; and more structured treatments that offer greater credibility and relevance to young people's mental health and developmental needs. Young people also discussed being compelled by parents and school professionals to engage in treatment. Attending to young people's preferences must be a priority in order to overcome ambivalence about session attendance, and enhance treatment participation and outcomes.


Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells.
HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naïve and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naïve and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL-7rα, Myc, CCR5, Fam65b, S1P1 (EDG1), CD52, Cyclin D2 and p21CIP1, indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo.