(Instrumental) activities of daily living in older adults with intellectual disabilities.
Daily living skills are important to ageing adults with intellectual disabilities (ID). The purpose of this study was to investigate the level of these skills in older adults with ID and to investigate the influence of gender, age, level of ID and mobility on these skills. Daily living skills were measured with the Barthel Index (for Activities of Daily Living, ADL) and the Lawton IADL scale (for Instrumental Activities of Daily Living, IADL) in 989 adults with ID aged 50 years and over living in community-based and institutional settings. Descriptives were presented by categories of gender, age, level of ID and mobility. Regression analysis was used to investigate the influence of these variables on total and item scores of ADL and IADL questionnaires. ADL and IADL scores in older adults with ID are comparable to those of vulnerable patient groups. Total ADL score was mainly determined by mobility, while total IADL score was mainly determined by level of ID. Of all 18 separate items of these questionnaires, 11 were determined more by mobility than level of ID. The Barthel Index and Lawton IADL scale are recommended for future use in research and clinical practice in this group. This study stresses the need to support mobility older adults with ID as much as possible, in order to optimize independency in this group.


Transverse electromagnetic modes in chiral negatively refractive fibers and a new type of space-division multiplexing.
We investigated theoretically chiral negatively refractive fibers that guide transverse electromagnetic modes. In this Letter, novel properties of such fibers are presented, including arbitrariness of modal field and arbitrarily scalable core radius. Based on these novel properties, we conceptually propose a new type of space-division multiplexing that uses different spatial positions of the core of such fascinating fibers as different data paths.


Uniform partial dissolution of bone mineral by using fluoride and phosphate ions combination.
Mineral content is one of the main predictors of the mechanical properties of bone tissue. The contribution of the bone mineral phase to the mechanical properties of bone has been investigated by reducing the mineral content of bone with different in vitro treatment techniques such as hydrochloric acid (HCl), ethylenedinitrilo tetraacetic acid (EDTA), and fluoride ion treatment. In this study, we propose a new treatment technique which combines fluoride and phosphate ions. Bovine femur specimens were used to determine the mechanical properties of cortical bone after different fluoride phosphate ion combination treatments. The treatment solutions, which contain different fluoride and phosphate ion concentrations, dissolved part of the bone mineral in a uniform manner throughout the bone samples. Dissolution by products, which precipitated in the bone tissue, contained calcium fluoride with phosphate ions (CaF(2)/P) and fluorapatite/fluorhydroxyapatite-type material (FAp/FHAp) and acted as filler. Depending on the fluoride and phosphate concentration in a treatment solution, the precipitated material's ratio of FAp/FHAp to total fluoride containing phase (FAp/FHAp + CaF(2)/P) in bone tissue also changed. High fluoride ion content in treatment solutions generated more CaF(2)/P type of precipitate, and low fluoride ion concentration generated more FAp/FHAp type precipitates as compared to high fluoride concentration treatments. These experiments show that phosphate ions are another important parameter of a treatment solution, in addition to ionic strength, pH, and the duration of treatment. In vitro, phosphate fluoride combinations partially dissolve bone mineral content in a wider range than fluoride treatment alone in a uniform manner. With this new technique one can control more precisely the partial dissolution of the bone mineral and mineral phase's contribution to mechanical properties of bone tissue.


Effect of yoghurt or yoghurt serum on microbial quality of cig kofte.
Cig kofte, raw meatball is a traditionally produced meat product in Turkey and some other Middle East countries. It is prepared from mixtures of finely minced raw beef, bulgur, onions, various spices and tap water. Cig kofte is an uncooked product and popularly consumed with lettuce and lemon juice. In this study, yoghurt or yoghurt serum (YS) were added to the mixtures of cig kofte instead of tap water to reduce microbial risks of the raw meatball. Additionally, the effects of yoghurt and YS on some physicochemical characteristics of cig kofte were investigated. Cig kofte is generally consumed within a few hours after the preparation because of its raw nature. Also, it is generally sold under unhygienic conditions in restaurants and restaurant-like places. For this purpose, reducing of the microbial load of cig kofte is important. In the results, Escherichia coli and Listeria monocytogenes were not detected in any samples. While lactic acid bacteria count increased by addition of yoghurt and YS, the number of other microorganisms except for total aerobic mesophilic bacteria (TAMB) were decreased. The aw values and% moisture contents of the samples were varied between 0.88-0.94 and 46.25-49.72, respectively. The pH values of the samples were slightly changed during the storage of 24 h while no changes detected in the control samples during the storage. In conclusion, it can be suggested that using the yoghurt or YS instead of tap water in the preparation of cig kofte might ensure the microbial safety, increase the nutritional value and its flavour or aroma.


Influence of bone volume fraction and architecture on computed large-deformation failure mechanisms in human trabecular bone.
Large-deformation bending and buckling have long been proposed as failure mechanisms by which the strength of trabecular bone can be affected disproportionately to changes in bone density, and thus may represent an important aspect of bone quality. We sought here to quantify the contribution of large-deformation failure mechanisms on strength, to determine the dependence of these effects on bone volume fraction and architecture, and to confirm that the inclusion of large-deformation effects in high-resolution finite element models improves predictions of strength versus experiment. Micro-CT-based finite element models having uniform hard tissue material properties were created from 54 cores of human trabecular bone taken from four anatomic sites (age = 70+/-11; 24 male, 27 female donors), which were subsequently biomechanically tested to failure. Strength predictions were made from the models first including, then excluding, large-deformation failure mechanisms, both for compressive and tensile load cases. As expected, strength predictions versus experimental data for the large-deformation finite element models were significantly improved (p < 0.001) relative to the small deformation models in both tension and compression. Below a volume fraction of about 0.20, large-deformation failure mechanisms decreased trabecular strength from 5-80% for compressive loading, while effects were negligible above this volume fraction. Step-wise nonlinear multiple regression revealed that structure model index (SMI) and volume fraction (BV/TV) were significant predictors of these reductions in strength (R2 = 0.83, p < 0.03). Even so, some low-density specimens having nearly identical volume fraction and SMI exhibited up to fivefold differences in strength reduction. We conclude that within very low-density bone, the potentially important biomechanical effect of large-deformation failure mechanisms on trabecular bone strength is highly heterogeneous and is not well explained by standard architectural metrics.


Direct oxygen removal technique for recycling titanium using molten MgCl2 salt.
Deoxidation of Ti, or direct removal of O dissolved in metallic Ti, is known to be extremely difficult when Mg is used as the deoxidizing agent. This difficulty arises because the chemical potential of O2, pO2, under Mg/MgO equilibrium is high (approximately 10(-41) atm at 1200 K) and is equivalent to that of Ti containing ∼2 mass% O at 1200 K. Therefore, when deoxidizing Ti to the commercial level of high-grade pure Ti (below 0.05 mass% O) using an Mg reductant at 1200 K, the activity of the reaction product MgO (aMgO) must be decreased to below ∼0.025, which is difficult in practice. In this study, the removal of O in Ti in molten MgCl2 salt using an electrochemical technique was examined at ∼1173 K with the objective of obtaining Ti containing less than 0.05 mass% O. Ti samples and graphite electrodes immersed in molten MgCl2 served as the cathode and anode, respectively. A constant voltage was applied between the electrodes using an external DC source. Molten MgCl2 was employed to produce the deoxidizing agent Mg and to facilitate deoxidation of Ti by decreasing the activity of the reaction product MgO. By applying a voltage of approximately 3.1 V between the electrodes, the chemical potential of Mg in the molten MgCl2 was increased at the surface of the Ti cathode, and the Ti samples were deoxidized. The resulting O species, mainly formed O(2-) dissolved in the molten MgCl2, was removed from the molten salt by reacting with the C anode to form CO (or CO2) gas. Ti wires containing 0.12 mass% O were deoxidized to less than 0.02 mass% O. In some cases, the O concentration in the Ti samples was reduced to the level of 0.01 mass%, which cannot be accomplished using the conventional Kroll process. The possible application of this deoxidation technique to practical industrial recycling processes is discussed.


Predicting attitudinal and behavioral responses to COVID-19 pandemic using machine learning.
At the beginning of 2020, COVID-19 became a global problem. Despite all the efforts to emphasize the relevance of preventive measures, not everyone adhered to them. Thus, learning more about the characteristics determining attitudinal and behavioral responses to the pandemic is crucial to improving future interventions. In this study, we applied machine learning on the multinational data collected by the International Collaboration on the Social and Moral Psychology of COVID-19 (N = 51,404) to test the predictive efficacy of constructs from social, moral, cognitive, and personality psychology, as well as socio-demographic factors, in the attitudinal and behavioral responses to the pandemic. The results point to several valuable insights. Internalized moral identity provided the most consistent predictive contribution-individuals perceiving moral traits as central to their self-concept reported higher adherence to preventive measures. Similar results were found for morality as cooperation, symbolized moral identity, self-control, open-mindedness, and collective narcissism, while the inverse relationship was evident for the endorsement of conspiracy theories. However, we also found a non-neglible variability in the explained variance and predictive contributions with respect to macro-level factors such as the pandemic stage or cultural region. Overall, the results underscore the importance of morality-related and contextual factors in understanding adherence to public health recommendations during the pandemic.


In vivo evaluation of mucoadhesive nanoparticulate docetaxel for intravesical treatment of non-muscle-invasive bladder cancer.
The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy. Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C(8)/C(10) alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C(8/10)-MePEG-NH(2)) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofi-aventis), and DTX-loaded HPG-C(8/10)-MePEG and/or HPG-C(8/10)-MePEG-NH(2). Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed. In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C(8/10)-MePEG-NH(2) (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C(8/10)-MePEG-NH(2) showed enhanced uptake of these nanoparticles in bladder tumor tissues. Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer.


Loss of spatial control of the mitotic spindle apparatus in a Chlamydomonas reinhardtii mutant strain lacking basal bodies.
The bld2-1 mutation in the green alga Chlamydomonas reinhardtii is the only known mutation that results in the loss of centrioles/basal bodies and the loss of coordination between spindle position and cleavage furrow position during cell division. Based on several different assays, bld2-1 cells lack basal bodies in > 99% of cells. The stereotypical cytoskeletal morphology and precise positioning of the cleavage furrow observed in wild-type cells is disrupted in bld2-1 cells. The positions of the mitotic spindle and of the cleavage furrow are not correlated with respect to each other or with a specific cellular landmark during cell division in bld2-1 cells. Actin has a variable distribution during mitosis in bld2-1 cells, but this aberrant distribution is not correlated with the spindle positioning defect. In both wild-type and bld2-1 cells, the position of the cleavage furrow is coincident with a specialized set of microtubules found in green algae known as the rootlet microtubules. We propose that the rootlet microtubules perform the functions of astral microtubules and that functional centrioles are necessary for the organization of the cytoskeletal superstructure critical for correct spindle and cleavage furrow placement in Chlamydomonas.


Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency.
Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. In vitro, KRT19 promoter methylation was analyzed and 5-aza-2'-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). KRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2'-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively). K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.


Reliable Stimulated Brillouin Scattering Compression of Nd:YAG Laser Pulses with Liquid Fluorocarbon for Long-Time Operation at 10 Hz.
Stokes pulses of high energy and high-average power were obtained by stimulated Brillouin scattering (SBS) compression of long Nd:YAG laser pulses. The SBS medium used in the single-cell compressor was liquid ultrafiltered Fluorinert FC-75 fluorocarbon. An output pulse duration of 0.9 ns and a peak-power enhancement by 1 order of magnitude were observed for 10-ns, 0.57-J input pulses at a 10-Hz repetition rate. The compressor internal SBS efficiency reached a value of eta(SBS) = 94% and the overall device efficiency a value of eta(dev) = 87%; both values are the highest reported so far to the best of our knowledge. The simple single-cell SBS geometry provided excellent energy and pointing stability of the Stokes pulse. Its temporal shape turned out to be somewhat less stable. The SBS process also partially improved the laser beam quality. The Stokes pulses proved to be capable of generating radiation in the extreme-ultraviolet and soft-x-ray regions over a period of two months without any significant output deterioration.


Assessing the impact of screening mammography: Breast cancer incidence and mortality rates in Connecticut (1943-2002).
Randomized controlled studies demonstrate that early detection and intervention reduce breast cancer mortality by approximately 25%. Though the ultimate goal of screening is to reduce breast cancer deaths, the immediate goal is to detect and treat early-stage tumors before they pose a threat to life. To assess the impact of early detection and intervention in the general population, we analyzed breast cancer incidence and mortality rates in the NCI's Historical Connecticut Tumor Registry (1943-2002). Though breast cancer rates increased for the entire study period, overall incidence rates rose faster than previously following the initiation of mammography screening in the early 1980s in the United States. Of note, stage-specific incidence rates increased 152% (53.2-133.9 per 100,000 woman-years) for early-stage tumors and fell 16% (56.1-47.2 per 100,000 woman-years) for late-stage breast cancers. Period- and cohort-age-specific incidence rates rose dramatically for early-stage tumors among women targeted for screening (ages 40-80 years), whereas rates for regional and distant stages declined modestly among women ages >50 years. Breast cancer mortality rates fell 31.6%. Along with increases in incidence rates for early-stage tumors, rates for late-stage disease and breast cancer mortality declined following widespread screening mammography, consistent with effective early detection and improved treatment over time. However, the disparity between the dramatic rise in early-stage tumors compared to the more modest declines in late-stage disease and mortality suggests that many mammography-derived early-stage lesions may never progress to late-stage cancers and pose a threat to life.


Circulating ACE2 in Cardiovascular and Kidney Diseases.
Angiotensin converting enzyme (ACE) 2 is a homologue of ACE that catalyzes the conversion of Angiotensin (Ang) II into Ang1-7, which induces vasodilation, anti-fibrotic, anti-proliferative and anti-inflammatory effects. Given that ACE2 counterbalances the effects of Ang II, it has been proposed as a biomarker in kidney disease patients. Circulating ACE2 has been studied in human and experimental studies under physiological and pathological conditions and different techniques have been assessed to determine its enzymatic activity. In patients with cardiovascular (CV) disease circulating ACE2 has been shown to be increased. In addition, hypertensive and diabetic patients have also shown higher circulating ACE2 activities. A study in type 1 diabetes patients found a negative association between circulating ACE2 and estimated glomerular filtration rate in male and female patients. Recently, it has been demonstrated that circulating ACE2 is increased in male patients with chronic kidney disease (CKD) and that it is independently associated with other classical CV risk factors, such as advanced age and diabetes. Furthermore, circulating ACE2 has been shown to be associated with silent atherosclerosis and CV outcomes in CKD patients. In diabetic nephropathy, experimental studies have demonstrated an increase in circulating ACE2 activity both at early and late stages of the disease, as well as a direct association with increased urinary albumin excretion, suggesting that it may be increased as a renoprotective mechanism in these patients. In this paper we will review the measurement of circulating ACE2 and its role in kidney disease, as well as its potential role as a renal and CV biomarker.


Atmospheric deposition of particles at a sensitive alpine lake: Size-segregated daily and annual fluxes from passive sampling techniques.
Lake Tahoe, a North American alpine lake long appreciated for its clear water and geographic setting, has experienced a trend of declining water clarity due to increasing nutrient and particle inputs. Contributions from atmospheric deposition of particulate matter (PM) could be important, yet they are inadequately quantified. This study established a yearlong deposition monitoring network in the northern Lake Tahoe Basin. Dry deposition was quantified on surrogate surfaces while wet deposition was based on particles suspended in precipitation at 24-hour resolution. The particle size ranges by these passive techniques were 1-64μm and 0.5-20μm in diameter for dry and wet deposition, respectively. Dry deposition of submicrometer (0.5-1μm) particles was also estimated by extrapolation of a lognormal size distribution. Higher daily number deposition fluxes (NDFdry and NDFwet) were found at a near-shore site, confirming substantial impacts of commercial and tourist activities. The two more isolated sites indicated a uniform regional background. On average, daily NDFdry is about one order of magnitude lower than daily NDFwet. Dry deposition velocities increased rapidly with particle size, as evidenced by collocated measurements of NDFdry and ambient particle number concentrations, though it seems less so for wet deposition due to different scavenging mechanisms. Despite fewer "wet" days than "dry" days during the monitoring period, wet processes dominated seasonal particle deposition, particularly in winter and spring when most precipitation occurred. Adopting sediment (insoluble, inorganic) particle fraction estimates from the literature, this study reports an annual particle flux of 2.9-5.2×1010#m-2yr-1 for sediment particles with 1-20μm diameter and 6.1-11×1010#m-2yr-1 for those with 0.5-20μm diameter. Implications of these findings to the current knowledge of atmospheric deposition in the Lake Tahoe Total Maximum Daily Load (TMDL) are discussed.


Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.
Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.


An anatomical study of the insertion of the zygomaticus major muscle in humans focused on the muscle arrangement at the corner of the mouth.
The aim of this study was to clarify the arrangement of the zygomaticus major muscle by means of topographic examination, and to evaluate the anatomical variations in the insertion of the zygomaticus major at the perioral region. After a detailed dissection in the modiolar region, the insertion area of the zygomaticus major was observed in 70 embalmed cadavers. At the perioral region of the dissected specimens, the anatomical aspects of the muscular arrangement and attachment of the zygomaticus major muscle were classified into four categories. In type I, the superficial muscle band of the zygomaticus major is blended and interlaced with the levator anguli oris, whereas the fibers of the deep muscle band blend into the buccinator, passing deeper to the levator anguli oris; this was the situation most commonly encountered (54.3 percent). It was found that the insertion of the zygomaticus major was divided into superficial and deep bands (types I and IV) [42 cases (60 percent)] and into three layers of superficial, middle, and deep fibers (type II) [17 cases (24.3 percent)]. The others were cases where the zygomaticus major was inserted deep into the levator anguli oris as a single muscle band (type III) [11 cases (15.7 percent)]. The arrangement and insertion patterns of the zygomaticus major in this study are expected to provide critical information for surgical planning for the procedure of facial reanimation surgery.


Factors accounting for asthma variability: achieving optimal symptom control for individual patients.
Asthma is a variable disease, and various factors can lead to an increase (or decrease) in asthma symptoms and the level of asthma control. Pub Med was searched for recent articles dealing with asthma variability, environmental factors and co-morbid conditions that affect asthma control, and for publications which identified tools to facilitate patients' response to asthma variability. Variability in asthma symptoms may be a response to the individual's environment (e.g. seasonal variation, cigarette smoke, and air pollutants) or personal factors (e.g. inhaler technique, pregnancy, exercise). Co-morbid diseases such as allergic rhinitis may also impact significantly on asthma variability and control. Documenting asthma variability and assessing both adherence and possible triggers over time may allow patients and physicians to develop treatment programmes that anticipate, rather than follow, changes in the level of asthma symptoms. Personalised asthma control plans which take into account factors affecting symptom variability may enable patients to modify medication and their environment prophylactically in anticipation of a known trigger or at the first sign of an asthma exacerbation.


What's in a link: associative and taxonomic priming effects in the infant lexicon.
Infants develop a lexical-semantic system of associatively and semantically related words by the end of the second year of life. However, the precise nature of the lexical relationships that underpin the structure-building process remains under-determined. We compare two types of lexical-semantic relationship, associative and taxonomic, using a lexical-priming adaption of the intermodal preferential looking task with 21- and 24-month-olds. Prime-target word pairs were either associatively or taxonomically related or unrelated. A further control condition evaluated the facility of a prime word, in the absence of a target word, to promote target preferences. Twenty-four-month-olds, but not 21-month-old infants, exhibited a priming effect in both associative and taxonomic conditions, pointing to the formation of a lexical-semantic network driven by both associative and taxonomic relatedness late in the second year. The pattern of priming in 24-month-olds indicates the operation of inhibitory processes: unrelated primes interfere with target recognition whereas related primes do not. We argue that taxonomic and associative relationships between words are integral to the emergence of a structured lexicon and discuss the importance of inhibitory mechanisms in shaping early lexical-semantic memory.


Mining clinical relationships from patient narratives.
The Clinical E-Science Framework (CLEF) project has built a system to extract clinically significant information from the textual component of medical records in order to support clinical research, evidence-based healthcare and genotype-meets-phenotype informatics. One part of this system is the identification of relationships between clinically important entities in the text. Typical approaches to relationship extraction in this domain have used full parses, domain-specific grammars, and large knowledge bases encoding domain knowledge. In other areas of biomedical NLP, statistical machine learning (ML) approaches are now routinely applied to relationship extraction. We report on the novel application of these statistical techniques to the extraction of clinical relationships. We have designed and implemented an ML-based system for relation extraction, using support vector machines, and trained and tested it on a corpus of oncology narratives hand-annotated with clinically important relationships. Over a class of seven relation types, the system achieves an average F1 score of 72%, only slightly behind an indicative measure of human inter annotator agreement on the same task. We investigate the effectiveness of different features for this task, how extraction performance varies between inter- and intra-sentential relationships, and examine the amount of training data needed to learn various relationships. We have shown that it is possible to extract important clinical relationships from text, using supervised statistical ML techniques, at levels of accuracy approaching those of human annotators. Given the importance of relation extraction as an enabling technology for text mining and given also the ready adaptability of systems based on our supervised learning approach to other clinical relationship extraction tasks, this result has significance for clinical text mining more generally, though further work to confirm our encouraging results should be carried out on a larger sample of narratives and relationship types.


Tailored HIV programmes and universal health coverage.
Improvements in geospatial health data and tailored human immunodeficiency virus (HIV) testing, prevention and treatment have led to greater microtargeting of the HIV response, based on location, risk, clinical status and disease burden. These approaches show promise for achieving control of the HIV epidemic. At the same time, United Nations Member States have committed to achieving broader health and development goals by 2030, including universal health coverage (UHC). HIV epidemic control will facilitate UHC by averting the need to commit ever-increasing resources to HIV services. Yet an overly targeted HIV response could also distort health systems, impede integration and potentially threaten broader health goals. We discuss current approaches to achieving both UHC and HIV epidemic control, noting potential areas of friction between disease-specific microtargeting and integrated health systems, and highlighting opportunities for convergence that could enhance both initiatives. Examples of these programmatic elements that could be better aligned include: improved information systems with unique identifiers to track and monitor individuals across health services and the life course; strengthened subnational data use; more accountable supply chains that supply a broad range of services; and strengthened community-based services and workforces. We argue that the response both to HIV and to broader health threats should use these areas of convergence to increase health systems efficiency and mitigate the harm of any potential decrease in health funding. Further investments in implementation and monitoring of these programme elements will be needed to make progress towards both UHC and HIV epidemic control.


Accuracy of five algorithms to diagnose gambiense human African trypanosomiasis.
Algorithms to diagnose gambiense human African trypanosomiasis (HAT, sleeping sickness) are often complex due to the unsatisfactory sensitivity and/or specificity of available tests, and typically include a screening (serological), confirmation (parasitological) and staging component. There is insufficient evidence on the relative accuracy of these algorithms. This paper presents estimates of the accuracy of five algorithms used by past Médecins Sans Frontières programmes in the Republic of Congo, Southern Sudan and Uganda. The sequence of tests in each algorithm was programmed into a probabilistic model, informed by distributions of the sensitivity, specificity and staging accuracy of each test, constructed based on a literature review. The accuracy of algorithms was estimated in a baseline scenario and in a worst-case scenario introducing various near worst-case assumptions. In the baseline scenario, sensitivity was estimated as 85-90% in all but one algorithm, with specificity above 99.9% except for the Republic of Congo, where CATT serology was used as independent confirmation test: here, positive predictive value (PPV) was estimated at <50% in realistic active screening prevalence scenarios. Furthermore, most algorithms misclassified about one third of true stage 1 cases as stage 2, and about 10% of true stage 2 cases as stage 1. In the worst-case scenario, sensitivity was 75-90% and PPV no more than 75% at 1% prevalence, with about half of stage 1 cases misclassified as stage 2. Published evidence on the accuracy of widely used tests is scanty. Algorithms should carefully weigh the use of serology alone for confirmation, and could enhance sensitivity through serological suspect follow-up and repeat parasitology. Better evidence on the frequency of low-parasitaemia infections is needed. Simulation studies should guide the tailoring of algorithms to specific scenarios of HAT prevalence and availability of control tools.


Apricot and other seed stones: amygdalin content and the potential to obtain antioxidant, angiotensin I converting enzyme inhibitor and hypocholesterolemic peptides.
Stones from olives and Prunus genus fruits are cheap and sustainable sources of proteins and could be potential sources of bioactive peptides. The main limitation to the use of these seeds is the presence of amygdalin. This work proposes to determine amygdalin in olive and Prunus seeds and in protein isolates obtained from them. Moreover, antioxidant, angiotensin I converting enzyme (ACE) inhibitor, and hypocholesterolemic properties will be evaluated in hydrolysates obtained from these seeds. Despite some seeds contained amygdalin, all protein isolates were free of this substance. Two different procedures to obtain bioactive peptides from protein isolates were examined: gastrointestinal digestion and processing with Alcalase, Flavourzyme or Thermolysin. Higher antioxidant, ACE inhibitor and hypocholesterolemic activities were observed when proteins were processed with Alcalase, Flavourzyme or Thermolysin. The highest antioxidant and ACE inhibitor capacities were observed for the Prunus genus seed hydrolysates while the highest capacity to reduce micellar cholesterol solubility was observed for the apricot and olive seed hydrolysates.


PET/CT-guided radiation therapy planning: from present to the future.
Molecular imaging using 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been successfully used in the diagnosis, initial staging, and response assessment of various malignant tumors. Advances in radiation therapy planning and delivery have ushered in the era of high-precision conformal radiotherapy allowing generation of dose distributions that conform closely to the shape of the target volume while minimizing high-dose regions in the surrounding normal tissues. Traditionally, radiation therapy planning has relied heavily on CT imaging, but recent times have witnessed tremendous enthusiasm for the use of PET/CT-guidance in radiotherapy planning. This has been largely stimulated by widespread availability and integration with treatment planning systems. However, several issues need to be addressed and challenges overcome to realize the full potential of this exciting technology. Integrating PET/CT fusion imaging into routine clinical practice can be challenging due to technical, administrative, financial, geographic, and personnel issues. Concerted efforts are urgently needed for the development of guidelines for appropriate application of this technology using standardized methodology. There is accumulating evidence that incorporating PET/CT imaging in radiotherapy planning for lung cancer, head and neck cancer and cervical cancer has a significant impact. This review highlights the promises and pitfalls of PET/CT imaging in radiotherapy treatment planning with a critical appraisal of the current best evidence for its application in the modern radiotherapy clinic, and provides a sneak preview into the future of such technology.


-(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia.
[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia


High-performance liquid chromatographic method for determination of 2-difluoromethyl-DL-ornithine in plasma and cerebrospinal fluid.
A simple, sensitive, selective and reproducible method based on anion-exchange liquid chromatography with post-column derivatisation was developed for the determination of eflornithine (2-difluoromethyl-DL-ornithine; DFMO) in human plasma and cerebrospinal fluid. The 1-alkylthio-2-alkyl-isoindoles fluorescent derivative of the drug was separated from the internal standard (MDL 77246A) on an anion-exchange column (PRP-X300, 250x2.1 mm, 7-microm particle size: Hamilton, USA), with retention times of 6.9 and 10.7 min, respectively. Fluorescence detection was set at 430/340 nm (emission/excitation wavelength). The elution solvent consisted of a solution of 30 mM potassium dihydrogen phosphate buffer (pH 2.2) and acetonitrile (50:50, v/v), running through the column at a flow-rate of 0.3 ml/min. The chromatographic analysis was operated at 37 degrees C. Sample preparation for either plasma or CSF (100 microl) was done by single-step protein precipitation with 20% trichloroacetic acid after incubation at 4 degrees C for 1 h. Calibration curves for plasma (100, 200, 400, 600, 800 and 1200 nmol/100 microl, and 10, 20, 40, 80, 120 and 160 nmol/100 microl for the high and low concentration range curves, respectively) and CSF (1, 2, 4, 8, 16, 32 nmol/100 microl) were all linear with correlation coefficients better than 0.999. The precision of the method based on within-day repeatability and reproducibility (day-to-day variation) at high concentration range was below 15%, whereas at low concentration range was below 20% (% coefficient of variations: %C.V.) Good accuracy was observed for both the intra-day or inter-day assays, as indicated by the minimal deviation of mean values found with measured samples from that of the theoretical values (below +/-15 and +/-20% at high and low concentration range, respectively. The limit of quantification was accepted as 0.1 nmol using 100-microl samples. The mean recovery for DFMO and the internal standard were greater than 95%. The method was free from interference from commonly used drugs including antimalarials and antihelminthics. The method appears to be robust and has been applied to a pharmacokinetic study of DFMO in patients with African trypanosomiasis following oral doses of Ornidyl (Aventis Pharma, Frankfurt, Germany) at 500 mg/kg body weight (125 mg q.i.d.) for 14 days.


Effects of sex hormones on survival of peritoneal mesothelioma.
Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM. This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily divided into assumed premenopausal (< 51 years old; n = 15) and assumed postmenopausal (≥ 51 years old, n = 9). In each gender group, patients were furthered divided into three age groups (< 40, 40-60, > 60). A significant statistical difference was defined as p < 0.05. Females with epithelial mesothelioma had a significantly higher survival than males (p = 0.023). They also had a better overall median survival (> 60 months) than males (43 months), although this difference was not statistically significant (p = 0.098). Survival of postmenopausal females became similar to males after excluding benign cystic mesothelioma. The better survival in premenopausal females could probably be explained by higher levels of oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore.


Beneficial effects of a potassium- and magnesium-enriched salt alternative.
The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.


Frequency Shifts and Depth Dependence of Premotor Beta Band Activity during Perceptual Decision-Making.
Neural activity in the premotor and motor cortices shows prominent structure in the beta frequency range (13-30 Hz). Currently, the behavioral relevance of this beta band activity (BBA) is debated. The underlying source of motor BBA and how it changes as a function of cortical depth are also not completely understood. Here, we addressed these unresolved questions by investigating BBA recorded using laminar electrodes in the dorsal premotor cortex of 2 male rhesus macaques performing a visual reaction time (RT) reach discrimination task. We observed robust BBA before and after the onset of the visual stimulus but not during the arm movement. While poststimulus BBA was positively correlated with RT throughout the beta frequency range, prestimulus correlation varied by frequency. Low beta frequencies (∼12-20 Hz) were positively correlated with RT, and high beta frequencies (∼22-30 Hz) were negatively correlated with RT. Analysis and simulations suggested that these frequency-dependent correlations could emerge due to a shift in the component frequencies of the prestimulus BBA as a function of RT, such that faster RTs are accompanied by greater power in high beta frequencies. We also observed a laminar dependence of BBA, with deeper electrodes demonstrating stronger power in low beta frequencies both prestimulus and poststimulus. The heterogeneous nature of BBA and the changing relationship between BBA and RT in different task epochs may be a sign of the differential network dynamics involved in cue expectation, decision-making, motor preparation, and movement execution.SIGNIFICANCE STATEMENT Beta band activity (BBA) has been implicated in motor tasks, in disease states, and as a potential signal for brain-machine interfaces. However, the behavioral relevance of BBA and its laminar organization in premotor cortex have not been completely elucidated. Here we addressed these unresolved issues using simultaneous recordings from multiple cortical layers of the premotor cortex of monkeys performing a decision-making task. Our key finding is that BBA is not a monolithic signal. Instead, BBA consists of at least two frequency bands. The relationship between BBA and eventual behavior, such as reaction time, also dynamically changes depending on task epoch. We also provide further evidence that BBA is laminarly organized, with greater power in deeper electrodes for low beta frequencies.


Risk factors for lymph node metastasis of ovarian, fallopian tube and primary peritoneal cancer in hereditary breast and ovarian cancer syndrome.
To establish an individualized surgical strategy for lymphadenectomy in ovarian cancer patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved in the increased risk of lymph node metastasis. We retrospectively reviewed the data of Japanese women registered in the database of the Japanese Hereditary Breast and Ovarian Cancer Consortium, who underwent BRCA1 and BRCA2 genetic testing. We evaluated the predictors of lymph node metastasis in all patients with the information of age at the diagnosis, disease site, histological subtype, 2014 FIGO stage, personal breast cancer history and family history; 233, 153 and 32 patients in the BRCA- (no pathogenic variant), BRCA1+ and BRCA2+ groups, respectively. The prevalence of lymph node metastasis was not markedly different between BRCA- (20.0%), BRCA1+ (18.4%) and BRCA2+ (26.2%). Multivariate analysis revealed an absence of a family history of ovarian cancer as an independent predictor for an increased risk of lymph node metastasis in BRCA1+, and the prevalence of lymph node metastasis was 11.7 and 42.0% in the groups with and without a family history of ovarian cancer, respectively. This subgroup without a family history of ovarian cancer did not show any correlation with a particular variant of BRCA1, including two common variants of c.188 T > A and c.2800C > T. This study suggested that certain genetic factors related to the penetrance of hereditary breast and ovarian cancer syndrome altered the frequency of lymph node metastasis in BRCA1+ ovarian cancer, and family history may be useful to personalize the indication of lymphadenectomy.


The role of high-dose chemotherapy and stem-cell transplantation in patients with multiple myeloma: a practice guideline of the Cancer Care Ontario Practice Guidelines Initiative.
The Hematology Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative has systematically reviewed the published literature and, through a consensus process, developed an evidence-based practice guideline assessing the role of stem-cell transplantation in patients with multiple myeloma. The conclusions were validated by solicited feedback from 221 practitioners across Ontario, Canada. The guideline comprises six recommendations: 1) Autologous transplantation is recommended for patients with stage II or III myeloma and good performance status. Evidence of benefit is strongest for patients who are younger than 55 years of age and have a serum creatinine level less than 150 micromol/L (<1.7 mg/dL). Physicians must use clinical judgment in recommending transplantation to other patients. 2) Allogeneic transplantation is not recommended as routine therapy. 3) Patients potentially eligible for transplantation should be referred for assessment early after diagnosis and should not be extensively exposed to alkylating agents before collection of stem cells. 4) Autologous peripheral blood stem cells should be harvested early in the patient's treatment course. The best available data suggest that transplantation is most advantageous when performed as part of initial therapy. 5) The comparative data addressing the specifics of the transplantation process are insufficient to allow definitive recommendations. In the absence of such data, a single transplant with high-dose melphalan, with or without total-body irradiation, is suggested for patients undergoing transplantation outside a clinical trial. 6) At this time, no conclusions can be reached about the role of interferon therapy after transplantation.


Role of dental institutions in tobacco cessation in India: current status and future prospects.
Tobacco abuse is a major preventable cause of premature death and disease, including various cancers. The Global Adult Tobacco Survey India (GATS) 2009-10 revealed that more than one-third of adults use tobacco in one form or the other. Nearly two in five smokers and smokeless tobacco users made attempts to quit the habit in the past 12 months. Tobacco dependence is a chronic condition characterized by susceptibility of relapse over years. It can be well handled by sustained professional support from health care providers mainly through behavioral counseling and pharmacotherapy. Dental professionals can play a pivotal role in diagnosing and effectively managing tobacco dependence. Dental Institutions have rapidly grown in last two decades across the country and so has the curriculum been adapted to improve student competencies to accommodate changing disease patterns and technological advances, but not in regard to tobacco cessation. Untapped dental manpower like undergraduates, dental hygienists and other paramedical staff need effective training to be more penetrative. The present review paper explores the potential role of dental training institutions and recommends various approaches to counter public health jeopardy of tobacco related diseases.


Minimal statistical-mechanical model for multihyperuniform patterns in avian retina.
Birds are known for their extremely acute sense of vision. The very peculiar structural distribution of five different types of cones in the retina underlies this exquisite ability to sample light. It was recently found that each cone population as well as their total population display a disordered pattern in which long-wavelength density fluctuations vanish [Jiao et al., Phys. Rev. E 89, 022721 (2014)PLEEE81539-375510.1103/PhysRevE.89.022721]. This property, known as hyperuniformity, is also present in perfect crystals. In situations like the avian retina in which both the global structure and that of each component display hyperuniformity, the system is said to be multihyperuniform. In this work, we aim at devising a minimal statistical-mechanical model that can reproduce the main features of the spatial distribution of photoreceptors in avian retina, namely the presence of disorder, multihyperuniformity, and local heterocoordination. This last feature is key to avoiding local clustering of the same type of photoreceptors, an undesirable feature for the efficient sampling of light. For this purpose, we formulate a minimal statistical-mechanical model that definitively exhibits the required structural properties: an equimolar three-component mixture (one component to sample each primary color: red, green, and blue) of nonadditive hard disks to which a long-range logarithmic repulsion is added between like particles. Interestingly, a Voronoi analysis of our idealized system of photoreceptors shows that the space-filling Voronoi polygons display a rather uniform area distribution, symmetrically centered around that of a regular lattice, a structural property also found in human retina. Disordered multihyperuniformity offers an alternative to generate photoreceptor patterns with minimal long-range concentration and density fluctuations. This is the key to overcoming the difficulties in devising an efficient visual system in which crystal-like order is absent.


Topochemical polymerization of dumbbell-shaped diacetylene monomers: relationship between chemical structure, molecular packing structure, and gelation property.
Herein, we have synthesized novel photopolymerizable dumbbell-shaped diacetylene liquid crystal (LC) monomers by locating a diacetylene dicarboxylic acid group at the center and chemically connecting swallow-tails, such as hydrophobic alkyl chains (abbreviated as AT3DI) and amphiphilic biphenyl mesogens (abbreviated as BP3DI), with bisamide groups. Major phase transitions of dumbbell-shaped diacetylene monomers were identified using differential scanning calorimetry (DSC), polarized optical microscopy (POM), and Fourier transform infrared spectroscopy (FT IR). Molecular packing structures were studied based on structure-sensitive wide-angle X-ray diffraction (WAXD) and small-angle X-ray scattering (SAXS) analyses. Mainly, due to nanophase separations and strong intermolecular hydrogen bonding, AT3DI formed a low-ordered lamellar LC phase at room temperature. BP3DI self-assembled into highly-ordered crystal phases (K1 and K2) at lower temperatures below a low-ordered lamellar LC phase, in which BP3DI were intercalated with each other to compensate the mutual volume differences. From the photopolymerization of AT3DI and BP3DI, it was realized that the topochemical reactions of dumbbell-shaped diacetylene monomers were closely related to their chemical structures as well as molecular packing structures.


Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.
TAK-875 (fasiglifam), a GPR40 agonist in development for the treatment of type 2 diabetes (T2D), was voluntarily terminated in Phase III trials due to adverse liver effects. The potential mechanisms of TAK-875 toxicity were explored by combining in vitro experiments with quantitative systems toxicology (QST) using DILIsym, a mathematical representation of drug-induced liver injury. In vitro assays revealed that bile acid transporters were inhibited by both TAK-875 and its metabolite, TAK-875-Glu. Experimental data indicated that human bile salt export pump (BSEP) inhibition by TAK-875 was mixed whereas sodium taurocholate co-transporting polypeptide (NTCP) inhibition by TAK-875 was competitive. Furthermore, experimental data demonstrated that both TAK-875 and TAK-875-Glu inhibit mitochondrial electron transport chain (ETC) enzymes. These mechanistic data were combined with a physiologically based pharmacokinetic (PBPK) model constructed within DILIsym to estimate liver exposure of TAK-875 and TAK-875-Glu. In a simulated population (SimPops) constructed to reflect T2D patients, 16/245 (6.5%) simulated individuals developed alanine aminotransferase (ALT) elevations, an incidence similar to that observed with 200 mg daily dosing in clinical trials. Determining the mode of bile acid transporter inhibition (Ki) was critical to accurate predictions. In addition, simulations conducted on a sensitive subset of individuals (SimCohorts) revealed that when either BSEP or ETC inhibition was inactive, ALT elevations were not predicted to occur, suggesting that the two mechanisms operate synergistically to produce the observed clinical response. These results demonstrate how utilizing QST methods to interpret in vitro experimental results can lead to an improved understanding of the clinically relevant mechanisms underlying drug-induced toxicity.


Activation of transcription factors AP-1 and NF-kappa B in murine Chagasic myocarditis.
The myocardium of CD1 mice was examined for the activation of signal transduction pathways leading to cardiac inflammation and subsequent remodeling during Trypanosoma cruzi infection (Brazil strain). The activity of three pathways of the mitogen-activated protein kinases (MAPKs) was determined. Immunoblotting revealed a persistent elevation of phosphorylated (activated) extracellular-signal-regulated kinase (ERK), which regulates cell proliferation. During infection there was a transient activation of p38 MAPK but no activation of Jun N-terminal kinase. Early targets of activated ERK, c-Jun and c-Fos, were elevated during infection, as demonstrated by semiquantitative reverse transcription-PCR. Immunostaining revealed that the endothelium and the interstitial cells were most intensely stained with antibodies to c-Jun and c-Fos. Soon after infection, AP-1 and NF-kappa B DNA binding activity was increased. Protein levels of cyclin D1, the downstream target of ERK and NF-kappa B, were induced during acute infection. Immunostaining demonstrated increased expression of cyclin D1 in the vascular and endocardial endothelium, inflammatory cells, and the interstitial areas. Increased expression of the cyclin D1-specific phosphorylated retinoblastoma protein (Ser780) was also evident. Immunoblotting and immunostaining also demonstrated increased expression of proliferating cellular nuclear antigen that was predominantly present in the inflammatory cells, interstitial areas (i.e., fibroblasts), and endothelium. These data demonstrate that T. cruzi infection results in activation of the ERK-AP-1 pathway and NF-kappa B. Cyclin D1 expression was also increased. These observations provide a molecular basis for the activation of pathways involved in cardiac remodeling in chagasic cardiomyopathy.


The Complexity of Jokes Is Limited by Cognitive Constraints on Mentalizing.
Although laughter is probably of deep evolutionary origin, the telling of jokes, being language-based, is likely to be of more recent origin within the human lineage. In language-based communication, speaker and listener are engaged in a process of mutually understanding each other's intentions (mindstates), with a conversation minimally requiring three orders of intentionality. Mentalizing is cognitively more demanding than non-mentalizing cognition, and there is a well-attested limit at five orders in the levels of intentionality at which normal adult humans can work. Verbal jokes commonly involve commentary on the mindstates of third parties, and each such mindstate adds an additional level of intentionality and its corresponding cognitive load. We determined the number of mentalizing levels in a sample of jokes told by well-known professional comedians and show that most jokes involve either three or five orders of intentionality on the part of the comedian, depending on whether or not the joke involves other individuals' mindstates. Within this limit there is a positive correlation between increasing levels of intentionality and subjective ratings of how funny the jokes are. The quality of jokes appears to peak when they include five or six levels of intentionality, which suggests that audiences appreciate higher mentalizing complexity whilst working within their natural cognitive constraints.


Linking proteomic and transcriptional data through the interactome and epigenome reveals a map of oncogene-induced signaling.
Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118-310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.


Left ventricular function immediately following prolonged exercise: A meta-analysis.
Evidence supporting cardiac fatigue following prolonged endurance exercise remains equivocal. The purpose of this meta-analysis was to quantify all data fulfilling the specified inclusion criteria, examining the short-term effect of prolonged endurance exercise on left ventricular function. A random effects meta-analysis of the weighted mean change in ejection fraction (EF), systolic blood pressure/end systolic volume (SBP/ESV) ratio, and early-to-late diastolic filling (E/A) was conducted on 23 studies using the SE of the between-subjects SD. HR, SBP, and left ventricular internal diameter during diastole (LVIDd) were also analyzed. Studies were coded according to exercise duration and training status: moderate duration trained (MDt) and untrained (MDu), 60-150 min; long duration (LD), 166-430 min; and ultra duration (UD), 640-1440 min. Relationships were assessed via Pearson's product-moment correlation. A significant (P < 0.05) overall decrease in EF (mean, confidence interval (CI): -1.95%, -1.03 to -2.88%), SBP/ESV (mean, CI: -0.8, -0.63 to -0.97), and E/A (mean, CI: -0.45, -0.39 to -0.51) was observed. Only UD and MDu subgroups demonstrated a reduction in EF. All subgroups demonstrated significant (P < 0.05) decreases in E/A. Alterations in LVIDd and SBP were related to respective decreases in EF and SBP/ESV, but not to E/A. The decrease in EF and SBP/ESV observed in UD and MDu indicates a reduction in systolic function, partially explained by altered cardiac loading. A decrease in E/A in all subgroups, unrelated to changes in loading, suggests an intrinsic impairment of left ventricular relaxation. Future investigators should employ load-independent indices of cardiac function and attempt to uncover the mechanisms of this phenomenon.


Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.
Purpose:fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition.Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivoResults: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR.


Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.
We have produced transgenic mice whose livers express a dominant positive NH2-terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c). Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols. We compared SREBP-1c transgenic mice with a line of transgenic mice that produces an equal amount of the NH2-terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain. The 1a protein contains a long activation domain with 12 negatively charged amino acids, whereas the 1c protein contains a short activation domain with only 6 such amino acids. As previously reported, livers of the SREBP-1a transgenic mice were massively enlarged, owing to accumulation of triglycerides and cholesterol. SREBP-1c transgenic livers were only slightly enlarged with only a moderate increase in triglycerides, but not cholesterol. The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-la transgenic mice, but not in 1c transgenic mice. The mRNAs for fatty acid synthase and acetyl CoA carboxylase were elevated 9- and 16-fold in la animals, but only 2- and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcription than SREBP-1a when both are expressed at levels approximating those found in nontransfected cells. SREBP-1c became a strong activator only when expressed at supraphysiologic levels. We conclude that SREBP-1a is the most active form of SREBP-1 and that SREBP-1c may be produced when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism.


Gene and protein expression of protease-activated receptor 2 in structural and inflammatory cells in the nasal mucosa in seasonal allergic rhinitis.
Protease-activated receptor 2 (PAR 2) has been shown to be responsible for trypsin and mast cell tryptase-induced airway inflammation. Here, the present study aimed to explore the expression of PAR 2 in the nasal mucosa of seasonal allergic rhinitis (SAR). Study subjects were recruited for the study by medical history, physical examination and laboratory screening tests. Using immunohistochemistry, laser-assisted cell picking and subsequently real-time PCR, nasal mucosa biopsies of SAR patients were investigated for PAR 2 gene and protein expression in complex tissues of the nasal mucosa. Gene and protein expression of PAR 2 was firstly detected in nasal mucosa of SAR patients. The relative gene expression level of PAR 2 was significantly increased in complex tissues of the nasal mucosa of SAR (6.21+/-4.02 vs. controls: 1.38+/-0.86, P=0.004). Moreover, PAR 2 mRNA expression in epithelial cells (SAR: 4.78+/-4.64 vs. controls: 0.84+/-0.61, P=0.003) but not in mucus (SAR: 1.51+/-1.15 vs. controls: 1.35+/-1.02, P=0.78) and endothelial cells (SAR: 1.20+/-0.57 vs. controls: 1.73+/-1.30, P=0.5) was found to be significantly changed in the nasal mucosa in SAR. Using double immunohistochemistry the present study demonstrated that the total numbers of mast cells (P=0.0003) and eosinophils (P=0.03) and the numbers of eosinophils expressing PAR 2 (P=0.006) were significantly elevated in the nasal mucosa of SAR compared with the controls. The abundant presence and distribution of gene and protein expression of PAR 2 in different cell types in the nasal mucosa under normal situation, the increased expression of PAR 2 in epithelial cells and the increased number of eosinophils with PAR 2 suggest that PAR 2 may contribute to the pathogenesis of allergic diseases such as SAR.


Fused azole-thiazolines via one-pot cyclization of functionalized N-heterocyclic carbene precursors.
A one-pot two-step methodology was exploited to synthesize fused thiazoline-azolium salts via reactions of bromoalkyl-azolium salts with KSCN and NaOH. The synthetic feasibility and versatility was demonstrated by the high yield (>80%) preparation of 13 salts with different backbones, linkers and substituents. Using methylpropionato as an N-protecting group, the resulting salts could be further derivatized to their neutral azole-thiazolines. The reaction sequence proceeds via (i) Br → SCN substitution, (ii) N-heterocyclic carbene formation, (iii) carbene attack of the S atom and CN- displacement in the alkyl-S-C[triple bond, length as m-dash]N unit, and (iv) methyl acrylate elimination.


Role of interim 18F-FDG-PET/CT for the early prediction of clinical outcomes of Non-Small Cell Lung Cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review.
Non-Small Cell Lung Cancer (NSCLC) is characterized by aggressiveness and includes the majority of thorax malignancies. The possibility of early stratification of patients as responsive and non-responsive to radiotherapy with a non-invasive method is extremely appealing. The distribution of the Fluorodeoxyglucose (18F-FDG) in tumours, provided by Positron-Emission-Tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT). In the last years, particular efforts have been focused on the possibility of using ad interim 18F-FDG PET (FDGint) to evaluate response already in the course of radiotherapy. However, controversial findings have been reported for various malignancies, although several results would support the use of FDGint for individual therapeutic decisions, at least in some pathologies. The objective of the present review is to assemble comprehensively the literature concerning NSCLC, to evaluate where and whether FDGint may offer predictive potential. Several searches were completed on Medline and the Embase database, combining different keywords. Original papers published in the English language from 2005 to 2016 with studies involving FDGint in patients affected by NSCLC and treated with radiation therapy or chemo-radiotherapy only were chosen. Twenty-one studies out of 970 in Pubmed and 1256 in Embase were selected, reporting on 627 patients. Certainly, the lack of univocal PET parameters was identified as a major drawback, while standardization would be required for best practice. In any case, all these papers denoted FDGint as promising and a challenging examination for early assessment of outcomes during CRT, sustaining its predictivity in lung cancer.


The Integration of Submicroscopic Representations Used in Chemistry Textbook Sets into Curriculum Topics.
To support the understanding of chemistry concepts and processes at the particulate level, various representations are included in learning materials. This paper focuses on how submicroscopic representations (SMRs) are integrated into Slovenian chemistry textbook sets with respect to the curriculum topics for 8th and 9th Grade. Textbook set analysis is based on four holistic SMRs descriptors (direct, indirect, combined descriptor, and SMRs without descriptors), which support learners' recognition of SMRs' informational value at different levels by providing different accompanying SMRs add-ons. The textbook sets analysis revealed that the number of SMRs varies significantly with regard to different curriculum topics. The overall proportion of the descriptors that enable the learner a direct recognition of SMRs is low in all curriculum topics. Interestingly, the descriptors that do not enable the learners a direct recognition of SMRs prevail in textbook sets. To obtain more detailed insight into the criteria based on which the textbook authors integrate SMRs with various descriptors into textbook sets, further studies are necessary.


In vitro susceptibility of Indian Plasmodium falciparum isolates to different antimalarial drugs & antibiotics.
: The in vitro assays for susceptibility of Plasmodium falciparum to antimalarial drugs are important tools for monitoring drug resistance. During the present study, efforts were made to establish long-term continuous in vitro culture of Indian field isolates of P. falciparum and to determine their sensitivity to standard antimalarial drugs and antibiotics. Four (MZR-I, -II, -III and -IV) P. falciparum isolates were obtained from four patients who showed artemisinin-based combination therapy (ACT) from Mizoram, a north-eastern State of India, and characterized for their in vitro susceptibility to chloroquine diphosphate (CQ), quinine hydrochloride dehydrate, mefloquine, piperaquine, artemether, arteether, dihydro-artemisinin (DHA), lumefantrine and atovaquone and antibiotics, azithromycin and doxycycline. These patients showed ACT treatment failure. Two-fold serial dilutions of each drug were tested and the effect was evaluated using the malaria SYBR Green I fluorescence assay. K1 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) reference strains were used as controls. Growth profile of all field isolates was identical to that of reference parasites. The IC50 values of all the drugs were also similar against field isolates and reference parasite strains, except K1, exhibited high IC50 value (275±12.5 nM) of CQ for which it was resistant. All field isolates exhibited higher IC50 values of CQ, quinine hydrochloride dihydrate and DHA compared to reference strains. The resistance index of field isolates with respect to 3D7 ranged between 260.55 and 403.78 to CQ, 39.83 and 46.42 to quinine, and 2.98 and 4.16 to DHA, and with respect to K1 strain ranged between 6.51 and 10.08, 39.26 and 45.75, and 2.65 and 3.71. MZR-I isolate exhibited highest resistance index. As the increase in IC50 and IC90 values of DHA against field isolates of P. falciparum was not significant, the tolerance to DHA-piperaquine (PPQ) combination might be because of PPQ only. Further study is required on more number of such isolates to generate data for a meaningful conclusion.


Geometric and mechanical evaluation of 3D-printing materials for skull base anatomical education and endoscopic surgery simulation - A first step to create reliable customized simulators.
Endoscopic skull base surgery allows minimal invasive therapy through the nostrils to treat infectious or tumorous diseases. Surgical and anatomical education in this field is limited by the lack of validated training models in terms of geometric and mechanical accuracy. We choose to evaluate several consumer-grade materials to create a patient-specific 3D-printed skull base model for anatomical learning and surgical training. Four 3D-printed consumer-grade materials were compared to human cadaver bone: calcium sulfate hemihydrate (named Multicolor), polyamide, resin and polycarbonate. We compared the geometric accuracy, forces required to break thin walls of materials and forces required during drilling. All materials had an acceptable global geometric accuracy (from 0.083mm to 0.203mm of global error). Local accuracy was better in polycarbonate (0.09mm) and polyamide (0.15mm) than in Multicolor (0.90mm) and resin (0.86mm). Resin and polyamide thin walls were not broken at 200N. Forces needed to break Multicolor thin walls were 1.6-3.5 times higher than in bone. For polycarbonate, forces applied were 1.6-2.5 times higher. Polycarbonate had a mode of fracture similar to the cadaver bone. Forces applied on materials during drilling followed a normal distribution except for the polyamide which was melted. Energy spent during drilling was respectively 1.6 and 2.6 times higher on bone than on PC and Multicolor. Polycarbonate is a good substitute of human cadaver bone for skull base surgery simulation. Thanks to short lead times and reasonable production costs, patient-specific 3D printed models can be used in clinical practice for pre-operative training, improving patient safety.


Depth perception in the framework of General Object Constancy.
Size constancy is a well-known example of perceptual stabilization accounting for the effect of viewing distance on retinal image size. In a recent study (Qian & Petrov, 2012), we demonstrated a similar stabilization mechanism for contrast perception and suggested that the brain accounts for effects of perceived distance on various other object features in a similar way, a hypothesis that we called General Object Constancy. Here we report a new illusion of depth further supporting this hypothesis. Pairs of disks moved across the screen in a pattern of radial optic flow. A pair comprised a small black disk floating in front of a large white disk, creating the percept of a pencil tip viewed head on. As these "pencils" moved away, they appeared to grow in contrast, in diameter, and also appeared to be getting "sharper." The contrast and size illusions replicated our previous findings, while the depth gradient (sharpness) illusion revealed a depth constancy phenomenon. We discovered that depth and size constancies were related, e.g., the two illusions were strongly correlated across observers. Whereas the illusory diameter increase could not be canceled by any degree of depth modulation, decreasing the diameter of the "pencils" during optic flow motion (thus increasing their disparity gradient) weakened the illusory depth gradient increase. This paradoxical result, as well as our other results, is explained by the General Object Constancy model: Besides using the same scaling factor to account for size, contrast, and depth variations with distance, the brain uses the apparent object size to additionally scale contrast and depth signals.


A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma.
The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities. In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0-26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6-undefined) and the median overall survival was 10.5 months (95% CI 7.1-undefined). While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.


Cytocompatibility of Magnesium Alloys with Human Urothelial Cells: A Comparison of Three Culture Methodologies.
Magnesium (Mg) is a biodegradable metallic material, which has shown great potential for medical device applications. In this study, human urothelial cells (HUCs) were cultured in vitro with Mg-based substrates to investigate their cytocompatibility for potential urological device applications. Three different in vitro culture methodologies were explored to mimic different in vivo conditions, in an attempt to establish standard methods of evaluating cytocompatibility of Mg-based biomaterials for urological device applications. Direct culture is a suitable in vitro method when it is important to evaluate direct cell attachment on the biomaterial surfaces. Direct exposure culture is a desirable in vitro method for investigating the response of well-established cells in the body with newly implanted biomaterials. The exposure culture method is appropriate for evaluating cell-biomaterial interactions in the same environment, where they are not in direct contact with each other. The results showed differences in HUC behaviors with the same Mg-based substrates when different culture methods were used. The Mg-based substrates inhibited the HUC viability with direct contact at the cell-material interface in direct culture and direct exposure culture. The faster degrading Mg alloys containing yttrium reduced HUC density in direct culture, direct exposure culture, and exposure culture. The major soluble degradation products of Mg-based materials reduced HUC density significantly when the pH increased to 8.6 and above or the Mg2+ ion concentration reached 10 mM and above. Mg-based biomaterials, especially the slower degrading alloys such as AZ31, should be further studied to determine their potential to be used for bioresorbable urological devices.


The early identification of dyslexia: children with English as an additional language.
It is generally accepted that dyslexia should be identified early for interventions to have maximum effect. However, when children speak English as an additional language (EAL), diagnosis is more complex and there is concern that these children tend to be under-identified. This paper reports a longitudinal study following the development of phonological awareness skills in relation to progress in learning to read with a cohort of British Asian children learning EAL and their monolingual peers. It also sought to determine the usefulness of a measure of phonological skills for the identification of dyslexic-type difficulties in children learning EAL. Analysis revealed that both cohorts achieved similar levels of reading accuracy in school Years 2, 4 and 6, with higher levels of reading comprehension for the monolingual children and faster reading fluency for children learning EAL in each school year. There was a similar pattern of relationships between the reading measures and measures of phonological awareness for both groups of children. However, monolingual children achieved higher levels of rhyme detection and alliteration fluency whilst the children learning EAL achieved faster number naming times. Overall, a phonological assessment battery was useful in identifying reading accuracy related difficulties in both groups of children. However, concerns are raised about the sensitivity of such measures following the introduction of the Literacy Hour.


First Report of Powdery Mildew Caused by Erysiphe heraclei on Peucedanum japonicum in Korea.
Peucedanum japonicum Thunb., belonging to the family Apiaceae, is distributed in many Asian countries, including Korea. This plant was recently developed as an edible green and is cultivated under organic farming in Korea. In June 2013, plants showing typical symptoms of powdery mildew were found with approximately 50% disease incidence in polyethylene-film-covered greenhouses in Iksan City, Korea. Symptoms first appeared as circular white colonies, which subsequently showed abundant mycelial growth on the leaves, often covering the whole surface. Infected plants were unmarketable mainly due to signs of white fungal growths and reddish discoloration on the leaves. The same symptoms were found on P. japonicum in poly-tunnels in Iksan City and Jinan County of Korea in 2014. Voucher specimens (n = 3) were deposited in the Korea University Herbarium (KUS). Appressoria were lobed, and solitary or in opposite pairs. Conidiophores were cylindrical, 80 to 145 × 8 to 10 μm, and composed of three to four cells. Foot-cells of conidiophores were straight to substraight, cylindrical, and 25 to 63 μm long. Singly produced conidia were oblong-elliptical to oblong, occasionally ovate, 35 to 50 × 13 to 16 μm with a length/width ratio of 2.3:3.1, with angular/rectangular wrinkling of outer walls, and lacked distinct fibrosin bodies. Germ tubes were produced on the perihilar position of conidia. Primary conidia were apically conical, basally truncate, and generally smaller than the secondary conidia. No chasmothecia were found. These structures are typical of the powdery mildew Pseudoidium anamorph of the genus Erysiphe. The specific measurements and morphological characteristics were consistent with those of E. heraclei DC. (2). To confirm the identification, the complete internal transcribed spacer (ITS) region of rDNA from KUS-F27872 was amplified with primers ITS1/ITS4 and sequenced. The resulting 560-bp sequence was deposited in GenBank (Accession No. KM491178). The obtained ITS sequence shared >99% similarity with those of E. heraclei from apiaceous hosts, e.g., Daucus carota (KC480605), Pimpinella affinis (AB104513), and Petroselinum crispum (KF931139). Pathogenicity was confirmed through inoculation by gently dusting conidia onto leaves of five healthy potted plants. Five non-inoculated plants served as controls. Inoculated plants developed symptoms after 6 days, whereas the control plants remained symptomless. The fungus present on the inoculated plants was identical in morphology to those observed in the field. Powdery mildew of P. japonicum caused by E. heraclei has been reported in Japan (4), and numerous reports of E. heraclei on various species of Peucedanum plants have been made in most part of Europe and East Asia (Japan and far eastern Russia) (1,3). However, this is the first report of powdery mildew caused by E. heraclei on P. japonicum in Korea. Occurrence of powdery mildews is a threat to the quality and marketability of this plant, especially in organic farming. References: (1) K. Amano. Host Range and Geographical Distribution of the Powdery Mildew Fungi. Japan Scientific Societies Press, Tokyo, 1986. (2) U. Braun and R. T. A. Cook. Taxonomic Manual of the Erysiphales (Powdery Mildews), CBS Biodiversity Series No.11. CBS, Utrecht, 2012. (3) D. F. Farr and A. Y. Rossman. Fungal Databases, Syst. Mycol. Microbiol. Lab., online publication. ARS, USDA. Retrieved August 18, 2014. (4) S. Tanda and C. Nakashima. J. Agric. Sci., Tokyo Univ. Agric. 47:54, 2002.


FOXA1 expression in breast cancer--correlation with luminal subtype A and survival.
FOXA1, a forkhead family transcription factor, is essential for optimum expression of approximately 50% of estrogen receptor alpha (ERalpha):estrogen responsive genes. FOXA1 is expressed in breast cancer cells. It segregates with genes that characterize the luminal subtypes in DNA microarray analyses. The utility of FOXA1 as a possible independent prognostic factor has not been determined in breast cancers. A tissue microarray comprising tumors from 438 patients with 15.4 years median follow-up was analyzed for FOXA1 expression by immunohistochemistry. Interpretable FOXA1 expression obtained in 404 patients was analyzed along with other prognostic factors like tumor grade, size, nodal status, ER, progesterone receptor (PR), and HER2/neu. FOXA1 expression (score >3) was seen in 300 of 404 breast cancers and it correlated with ER (P = 0.000001), PR (P = 0.00001), and luminal A subtype (P = 0.000001). Loss of expression was noted with worsening tumor grade (P = 0.001). Univariate analysis showed nodal status (P = 0.0000012), tumor size (P = 0.00001), FOXA1 (P = 0.0004), and ER (P = 0.012) to be predictors of breast cancer-specific survival. Multivariate analysis showed only nodal status (P = 0.001) and tumor size (P = 0.039) to be significant prognostic factors, whereas FOXA1 (P = 0.060) and ER (P = 0.131) were not significant. In luminal subtype A patient subgroup, FOXA1 expression was associated with better cancer-specific survival (P = 0.024) and in ER-positive subgroup, it was better predictor of cancer-specific survival (P = 0.009) than PR (P = 0.213). FOXA1 expression correlates with luminal subtype A breast cancer and it is significant predictor of cancer-specific survival in patients with ER-positive tumors. Prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in clinical treatment decisions.


Blood eosinophils, fractional exhaled nitric oxide and the risk of asthma attacks in randomised controlled trials: protocol for a systemic review and control arm patient-level meta-analysis for clinical prediction modelling.
The reduction of the risk of asthma attacks is a major goal of guidelines. The fact that type-2 inflammatory biomarkers identify a higher risk, anti-inflammatory responsive phenotype is potentially relevant to this goal. We aim to quantify the relation between blood eosinophils, exhaled nitric oxide (FeNO) and the risk of severe asthma attacks. A systematic review of randomised controlled trials (RCTs) will be conducted by searching MEDLINE from January 1993 to April 2021. We will include RCTs that investigated the effect of fixed treatment(s) regimen(s) on severe asthma exacerbation rates over at least 24 weeks and reported a baseline value for blood eosinophils and FeNO. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for RCTs. Study authors will be contacted to request anonymised individual participant data (IPD) for patients randomised to the trial's control arm. An IPD meta-analysis will be performed for multivariable prognostic modelling with performance assessment (calibration plots and the c-statistic) in a cross-validation by study procedure. The outcome to predict is the absolute number of severe asthma attacks to occur in the following 12 months if anti-inflammatory therapy is not changed (ie, annualised number of attacks requiring ≥3 days of systemic corticosteroids and/or hospitalisation if the patient was randomised to the control arm of an RCT). A summary prognostic equation and risk stratification chart will be reported as a basis for further analyses of individualised treatment benefit. The protocol has been reviewed by the relevant Oxford academic ethics committee and found to comprise fully anonymised data not requiring further ethical approbation. Results will be communicated in an international meeting and submitted to a peer-reviewed journal. CRD42021245337.


From Screening to Early Identification and Intervention: Discovering Predictors to Successful Outcomes for Children With Significant Hearing Loss.
This article summarizes the research findings from a longitudinal study of the language, speech, and social-emotional development of children who are deaf and hard of hearing, all of whom have hearing parents. This series of studies, from 1994 to the present, investigated predictors of successful developmental outcomes. The article provides information about how the findings of these studies relate to the existing literature. A description of the Colorado Home Intervention Program (CHIP) in which the participants were enrolled is also provided. During the course of these investigations, universal newborn hearing screening programs were established in Colorado, changing the age of identification of hearing loss and initiation into intervention in this program geared to families with infants and toddlers, birth through three years of age, from an average of 20 months of age to 2 months of age. Language development is positively and significantly affected by the age of identification of the hearing loss and age of initiation into intervention services. Both speech development and social-emotional variables are highly related to language development.


Serum-mediated resistance induced with immunogenic preparations of Salmonella typhimurium.
Serum obtained from animals immunized with attenuated Salmonella typhimurium strain RIA, heat-killed bacterial suspensions, or immunogenic ribosomal preparations was capable of passively conferring protection on normal recipient mice to challenge infection with virulent S. typhimurium strain SR-11. Protection was measured by the ability of a recipient animal to reduce the total number of challenge organisms significantly below that found in challenged control mice. Intraperitoneal administration of 0.1 ml of pooled sera was more effective than 0.05 ml in transferring resistance. The transfer of equivalent amounts of immune serum subcutaneously did not result in demonstrable resistance. In all cases in which serum transfer was effective, resistance was maximal at 5 days, greatly diminished by 10 days, and gone by 15 days post-transfer. Pooled serum obtained from normal donor mice or 0.2 ml of serum from mice hyperimmunized with immunogenic ribonucleic acid preparations did not possess the capacity to confer demonstrable resistance on normal recipients.