The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours.
It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.


The fim genes responsible for synthesis of type 1 fimbriae in Escherichia coli, cloning and genetic organization.
The genes responsible for the expression of type 1 fimbriae, produced by the majority of E. coli strains, have been cloned from an E. coli K12 strain. The "passenger" DNA from an initial cosmid clone was reduced in size and subcloned in pACYC184 and pBR322 vectors. A DNA fragment of around 8 kbp was found to be required for the biosynthesis of type 1 fimbriae. This was further studied by transposon-mediated insertional inactivation and by BAL31-mediated deletions. Four genes, designated fimA, B, C, and D were found to be involved in the synthesis of the fimbriae. They encoded proteins that in their processed form appeared with apparent molecular weights of 16.5 kd, 23 kd, 26 kd, and 89 kd, the 16.6 kd polypeptide being the fimbrial subunit. The order to the genes was found to be: fimB, fimA, fimC, and fimD, organized in three transcriptional units.


Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging.
Magnetic resonance imaging was used to determine the volumes of brain, subcortical gray matter nuclei, and the ventricular and sulcal cerebrospinal fluid in 27 healthy men. Subjects were divided into young (less than 35 years, n = 10) and old (greater than 60 years, n = 17) groups. Volumes were normalized as percent intracranial volume. Older subjects had significantly less brain mass and significantly larger ventricular and peripheral cerebrospinal fluid volumes than the younger men. The caudate and lenticular nuclei were significantly smaller in older than younger men. This significant difference remained when their volumes were expressed as a ratio of cerebral brain matter volume. This cross-sectional study demonstrates age-related atrophy and concurrent dilation of cerebrospinal fluid spaces in healthy subjects. Of brain regions affected, the caudate and lenticular nuclei are significantly more affected by healthy aging than is cerebral brain matter; this may account for some of the motor abnormalities in aging.


Retinoic acid combined with neurotrophin-3 enhances the survival and neurite outgrowth of embryonic sympathetic neurons.
Both nerve growth factor (NGF) and neurotrophin-3 (NT-3) are necessary for the survival of embryonic sympathetic neurons in vivo. All-trans retinoic acid (atRA) has been shown to promote neurite outgrowth and long-term survival of chick embryonic sympathetic neurons cultured in the presence of NGF. The present study shows that atRA can also potentiate the survival and neurite outgrowth-promoting activities of NT-3. This was accomplished by enhancing the survival of existing neurons, as cell proliferation was unaffected by exposure to atRA. atRA also enhanced neurite outgrowth of the NT-3-treated cells; however, the neurites appeared thicker and less branched than cells treated with atRA in combination with NGF. Using a quantitative PCR assay, trkA and p75(NTR) mRNAs, but not trkC mRNA, were increased ( approximately 1.5- to 2-fold) after 72 and 48 hr of exposure of the cultures to atRA, respectively. The atRA-induced increase in trkA mRNA may play a role in the enhanced survival of neurons cultured in the presence of either NGF or NT-3, as both neurotrophins have been shown to signal through this receptor. The time course of these mRNA changes would indicate that atRA does not regulate the neurotrophin receptor mRNA directly, rather, intervening gene transcription is required. Thus, during development, atRA may play a role in fine-tuning embryonic responsiveness to both NT-3 and NGF.


Role of Micromagnetic States on Spin-Orbit Torque-Switching Schemes.
Three-terminal spintronic memory devices based on the controlled manipulation of the proximate magnetization of a magnetic nanoelement using spin-orbit torques (SOTs) have attracted growing interest recently. These devices are nonvolatile, can operate at high speeds with low error rates, and have essentially infinite endurance, making them promising candidates for high-speed cache memory. Typically, the magnetization and spin polarization in these devices are collinear to one another, leading to a finite incubation time associated with the switching process. While switching can also be achieved when the magnetization easy axis and spin polarization are noncollinear, this requires the application of an external magnetic field for deterministic switching. Here, we demonstrate a novel SOT scheme that exploits non-uniform micromagnetic states to achieve deterministic switching when the spin polarization and magnetic moment axis are noncollinear to one another in the absence of external magnetic field. We also explore the use of a highly efficient SOT generator, oxygen-doped tungsten in the three-terminal device geometry, confirming its -50% spin Hall angle. Lastly, we illustrate how this scheme may potentially be useful for nanomagnetic logic applications.


Compact sound-speed sensor for quartz enhanced photoacoustic spectroscopy based applications.
A compact sound-speed sensor based on a phase difference method was developed. The sensor employs a U-shaped stainless steel tube with two holes located on its front and back ends, which serves as a sound wave guide. The phase difference between the two holes was measured using two mini-microphones by means of a phase-sensitive detection technique. This method offers the advantage of eliminating the influence of signal fluctuations. The frequency of a sound source offered by a loudspeaker can be scanned between 1 kHz and 50 kHz. The slope of the phase difference as a function of frequency was obtained by scanning the frequency of the sound source. The speed of sound was retrieved from the rate of change of the phase difference. The performance of the sensor was evaluated over a wide range of speeds of sound from 260 m/s to 1010 m/s in different gas mixtures. The measured speed of sound was found to be in good agreement with the theoretical value for the sound-speed sensor.


Chronic unilateral low-back pain. Predictors of outcome of facet joint injections.
One hundred nine patients with chronic (3-36 months; mean, 13.4 months) unilateral low-back pain and no signs of sciatica were subjected to facet joint injection, randomized in three therapy groups: cortisone and local anesthetic injected intra-articularly, the same mixture injected pericapsularly, and physiologic sodium hydrochloride injected intra-articularly into two facet joints. To evaluate the results, three outcome variables were formed: work, subjective, and disability outcome. The inappropriate signs (IAS) recorded before injections had the best predictability for a good outcome. The mode of injection or duration of symptoms had no significance as a predictor. It was concluded that the outcome after facet joint injection depends on the patient's biopsychosocial chances of self-facilitated improvement. If abnormal illness behavior and distress are found, it helps to estimate the response for treatment and to choose a realistic method of treatment.


Changes in expression of neuropeptides and their receptors in the hypothalamus and gastrointestinal tract of calorie restricted hens.
The list of orexigenic and anorexigenic peptides, those are known to alter feed intake, is continuously growing. However, most of them are studied in mammalian species. We aimed to investigate plasma level and mRNA expression of the pituitary adenylate cyclase-activating polypeptide (PACAP), gene expression of its receptor (PAC1), furthermore the gene expression of galanin (GAL), neuromedin U (NMU), and its two receptors (NMUR1 and NMUR2) in the hypothalamus, proventriculus, and jejunum of hens exposed to 40% calorie restriction. Feed restriction resulted in a 88% increase in mRNA and a 27% increase in peptide level of PACAP in proventriculus measured with qPCR and RIA, respectively. Increases were found in the gene expression of PAC1 (49%) and NMUR1 (63%) in the hypothalamus. Higher expressions of peptide encoding genes (76% for PACAP, 41% for NMU, 301% for NMUR1 and 308% for GAL, P < 0.05) were recorded in the jejunum of hens exposed to restricted nutrition. The results indicate that PACAP level responds to calorie restriction in the proventriculus and jejunum, but not in the hypothalamus and plasma.


A customizable 3-dimensional digital atlas of the canary brain in multiple modalities.
Songbirds are well known for their ability to learn their vocalizations by imitating conspecific adults. This uncommon skill has led to many studies examining the behavioral and neurobiological processes involved in vocal learning. Canaries display a variable, seasonally dependent, vocal behavior throughout their lives. This trait makes this bird species particularly valuable to study the functional relationship between the continued plasticity in the singing behavior and alterations in the anatomy and physiology of the brain. In order to optimally interpret these types of studies, a detailed understanding of the brain anatomy is essential. Because traditional 2-dimensional brain atlases are limited in the information they can provide about the anatomy of the brain, here we present a 3-dimensional MRI-based atlas of the canary brain. Using multiple imaging protocols we were able to maximize the number of detectable brain regions, including most of the areas involved in song perception, learning, and production. The brain atlas can readily be used to determine the stereotactic location of delineated brain areas at any desirable head angle. Alternatively the brain data can be used to determine the ideal orientation of the brain for stereotactic injections, electrophysiological recordings, and brain sectioning. The 3-dimensional canary brain atlas presented here is freely available and is easily adaptable to support many types of neurobiological studies, including anatomical, electrophysiological, histological, explant, and tracer studies.


Effects of organic matter amendments on net primary productivity and greenhouse gas emissions in annual grasslands.
Most of the world's grasslands are managed for livestock production. A critical component of the long-term sustainability and profitability of rangelands (e.g., grazed grassland ecosystems) is the maintenance of plant production. Amending grassland soils with organic waste has been proposed as a means to increase net primary productivity (NPP) and ecosystem carbon (C) storage, while mitigating greenhouse gas emissions from waste management. Few studies have evaluated the effects of amendments on the C balance and greenhouse gas dynamics of grasslands. We used field manipulations replicated within and across two rangelands (a valley grassland and a coastal grassland) to determine the effects of a single application of composted green waste amendments on NPP and greenhouse gas emissions over three years. Amendments elevated total soil respiration by 18% +/- 4% at both sites but had no effect on nitrous oxide or methane emissions. Carbon losses were significantly offset by greater and sustained plant production. Amendments stimulated both above- and belowground NPP by 2.1 +/- 0.8 Mg C/ha to 4.7 +/- 0.7 Mg C/ha (mean +/- SE) over the three-year study period. Net ecosystem C storage increased by 25-70% without including the direct addition of compost C. The estimated magnitude of net ecosystem C storage was sensitive to estimates of heterotrophic soil respiration but was greater than controls in five out of six fields that received amendments. The sixth plot was the only one that exhibited lower soil moisture than the control, suggesting an important role of water limitation in these seasonally dry ecosystems. Treatment effects persisted over the course of the study, which were likely derived from increased water-holding capacity in most plots, and slow-release fertilization from compost decomposition. We conclude that a single application of composted organic matter can significantly increase grassland C storage, and that effects of a single application are likely to carry over in time.


Diagnostic and interventional musculoskeletal ultrasound: part 1. Fundamentals.
Musculoskeletal ultrasound involves the use of high-frequency sound waves to image soft tissues and bony structures in the body for the purposes of diagnosing pathology or guiding real-time interventional procedures. Recently, an increasing number of physicians have integrated musculoskeletal ultrasound into their practices to facilitate patient care. Technological advancements, improved portability, and reduced costs continue to drive the proliferation of ultrasound in clinical medicine. This increased interest creates a need for education pertaining to all aspects of musculoskeletal ultrasound. The primary purpose of this article is to review diagnostic ultrasound technology and its potential clinical applications in the evaluation and treatment of patients with neurologic and musculoskeletal disorders. After reviewing this article, physicians should be able to (1) list the advantages and disadvantages of ultrasound compared with other available imaging modalities, (2) describe how ultrasound machines produce images using sound waves, (3) discuss the steps necessary to acquire and optimize an ultrasound image, (4) understand the different ultrasound appearances of tendons, nerves, muscles, ligaments, blood vessels, and bones, and (5) identify multiple applications for diagnostic and interventional musculoskeletal ultrasound in musculoskeletal practice. Part 1 of this 2-part article reviews the fundamentals of clinical ultrasonographic imaging, including relevant physics, equipment, training, image optimization, and scanning principles for diagnostic and interventional purposes.


Serotype changes and antimicrobial nonsusceptibility rates of invasive and non-invasive Streptococcus pneumoniae isolates after implementation of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Bulgaria.
The 10-valent pneumococcal conjugate vaccine (PCV10) has been included in Bulgarian Childhood Immunization Program since 2010. This study aimed to assess serotype distribution and antimicrobial resistance of 198 invasive and non-invasive Streptococcus pneumoniae strains that had been isolated in Bulgaria during 2011-2016 from patients with invasive (IPD) and non-invasive (NIPD) pneumococcal diseases. The most common invasive serotypes were 3 (10.1%), 19F (4.0%), and 7F (3.0%). A significant decrease in the proportion of invasive vaccine types (VTs) from 64.2% to 35.2% was found in comparison with pre-vaccine era. The most common serotypes among middle ear fluids were 3, 19A and 19F (5.6% each), and VTs fell down from 66.4% to 40.0% in post-PCV10 period. Among respiratory isolates, the most prevalent serotypes were some emergent serotypes such as 15A/B/C (5.0%), 19A, and 6C (4.0% each). VTs decreased significantly (16.3%) among vaccinated children compared to unvaccinated children and adults (44.0%). Two non-VTs (19A and 6C) have increased significantly more (p<0.05) in vaccinated children than in unvaccinated patients. The rates of antibiotic nonsusceptible S. pneumoniae in Bulgaria remained high in post-PCV10 era. Among all source of isolates, antimicrobial nonsusceptibility rates were: oral penicillin - 46.5%, trimethoprim-sulfamethoxazole - 45.4%, erythromycin - 43.9%, tetracycline - 37.4%, and multidrug-resistance (MDR) was 44%. The most common MDR serotypes were 19F, 19A, 6A/C, 15A/B/C and 23A. Our results proved that PCV10 vaccination substantially reduced VTs pneumococcal IPD and NIPD. There has been a shift in the distribution of S. pneumoniae serotypes mostly in vaccinated children but also in the whole population and strong serotype-specific antibiotic resistance was observed after vaccine implementation. Therefore, it is important to continue monitoring serotype changes and pneumococcal resistance among all patient ages in addition to aid in determining the long-term effectiveness of PCV10 interventions.


Self-rated health status and illiteracy as death predictors in a Brazilian cohort.
Cohort studies assessing predictive values of self-rated health (SRH) and illiteracy on mortality in low-to-middle income countries are missing in the literature. Aiming to determine if these two variables were death predictors, an observational prospective population-based cohort study was conducted in a Brazilian small city. The cohort was established in 2002 with a representative sample of adults living in the city, and re-assessed in 2015. Sociodemographic (including illiteracy), anthropometric, lifestyle, previous CVD, and SRH data were collected. Cox proportional hazard models were designed to assess SRH and illiteracy in 2002 as death (all causes, CVD and non-CVD) predictors in 2015. From a total of 1066 individuals included in this study, 95(9%) died of non-CVD causes and 53(5%) from CVD causes. Mortality rates were higher among those with worse SRH in comparison to better health status categories for all causes of death, CVD and non-CVD deaths (p<0.001 for all outcomes). Similarly, illiterate individuals had higher mortality rates in comparison to non-illiterate for all causes of death (p<0.001), CVD (p = 0.004) and non-CVD death (p<0.001). Higher SRH negatively predicted CVD death (HR 0.44; 95%CI 0.44-0.95; p = 0.027) and all causes of death (OR 0.40; 95%CI 0.20-0.78; p = 0.008) while illiteracy positively predicted Non-CVD death (OR 1.59; 95%CI 1.03-2.54; p = 0.046). In conclusion, we found in this large Brazilian cohort followed for 13 years that better health perception was a negative predictor of death from all causes and CVD deaths, while illiteracy was a positive predictor of non-CVD deaths.


Should the History of Science Be Rated X?: The way scientists behave (according to historians) might not be a good model for students.
I suggest that the teacher who wants to indoctrinate his students in the traditional role of the scientist as a neutral fact finder should not use historical materials of the kind now being prepared by historians of science: they will not serve his purposes. He may wish to follow the advice of philosopher J. C. C. Smart, who recently suggested that it is legitimate to use fictionalized history of science to illustrate one's pronouncements on scientific method (56). On the other hand, those teachers who want to counteract the dogmatism of the textbooks and convey some understanding of science as an activity that cannot be divorced from metaphysical or esthetic considerations may find some stimulation in the new history of science. As historian D. S. L. Cardwell has argued (57, p. 120): . . . [I]f the history of science is to be used as an educational discipline, to inculcate an enlightened and critical mind, then the Whig view . . . cannot do this. For it must emphasize the continuities, the smooth and successive developments from one great achievement to the next and so on; and in doing so it must automatically endow the present state of science with all the immense authority of history. He suggests that the critical mind might be inhibited by seeing the present as the inevitable, triumphant product of the past. The history of science could aid the teaching of science by showing that "such puzzling concepts as force, energy, etc., are man-made and were evolved in an understandable sequence in response to acutely felt and very real problems. They were not handed down by some celestial textbook writer to whom they were immediately self-evident" (57, p. 120). The past may give some hints on how to survive the most recent recurrence of public hostility to science. Rather than blaming historians such as Kuhn for encouraging antiscientific attitudes, as one physicist did in a public address in 1972 (58), one might consider this criticism of the older style of science history, published in 1940 by W. James Lyons (59, p. 381): The historians of science are responsible, it would appear, for the unpopularity of science among those most acutely affected by the depression. In their clamor to enhance the scientific tradition, and hoard for science all credit for the remarkable and unprecedented material advances which studded the century and a quarter preceding 1930, these historians have been more enthusiastic than accurate . . . science emerged [in the popular mind] as the most prominent force responsible for making this modern world so startlingly different from all preceding ages. Thus when, for many people, the modern world, in spite of all its resources, began to slip from its role of "best of all imaginable worlds," science came in for a proportionate share of blame. Had a more accurate picture of the part science has played been presented, science would not now be the object of so much suspicion and resentment. In more recent times, hostility to science has been intensified by the image of the "objective," robot-like scientist lacking emotions and moral values. If the new approach to the history of science really does give a more realistic picture of the behavior of scientists, perhaps it has a "redeeming social significance." Then, rather than limiting the conception of science to the strict pattern allowed by traditional local standards, one might try to change those standards in such a way as to reflect the freedom that the boldest natural philosophers have always exercised.


Computational models and tools.
In this chapter, we describe two different methods, analytical (pencil beam) algorithms and Monte Carlo simulations, used to obtain the intended dose distributions in patients and evaluate their strengths and shortcomings. We discuss the difference between the prescribed physical dose and the biologically effective dose, the relative biological effectiveness (RBE) between ions and photons and the dependence of RBE on the linear energy transfer (LET). Lastly, we show how LET- or RBE-based optimization can be used to improve treatment plans and explore how the availability of multimodality ion beam facilities can be used to design a tumor-specific optimal treatment.


Trends and Determinants of Antiretroviral Therapy Patient Monitoring Practices in Kenya and Uganda.
Patients receiving antiretroviral therapy (ART) require routine monitoring to track response to treatment and assess for treatment failure. This study aims to identify gaps in monitoring practices in Kenya and Uganda. We conducted a systematic retrospective chart review of adults who initiated ART between 2007 and 2012. We assessed the availability of baseline measurements (CD4 count, weight, and WHO stage) and ongoing CD4 and weight monitoring according to national guidelines in place at the time. Mixed-effects logistic regression models were used to analyze facility and patient factors associated with meeting monitoring guidelines. From 2007 to 2012, at least 88% of patients per year in Uganda had a recorded weight at initiation, while in Kenya there was a notable increase from 69% to 90%. Patients with a documented baseline CD4 count increased from 69% to about 80% in both countries. In 2012, 83% and 86% of established patients received the recommended quarterly weight monitoring in Kenya and Uganda, respectively, while semiannual CD4 monitoring was less common (49% in Kenya and 38% in Uganda). Initiating at a more advanced WHO stage was associated with a lower odds of baseline CD4 testing. On-site CD4 analysis capacity was associated with increased odds of CD4 testing at baseline and in the future. Substantial gaps were noted in ongoing CD4 monitoring of patients on ART. Although guidelines have since changed, limited laboratory capacity is likely to remain a significant issue in monitoring patients on ART, with important implications for ensuring quality care.


The effects of midazolam on intraocular pressure in children during examination under sedation.
To obtain reliable and accurate measurements of the intraocular pressure (IOP) in children often requires sedation or anaesthesia. Therefore, we investigated the effects of oral midazolam on IOP in children. In a prospective study, IOP was measured in 72 eyes of 36 cooperative children without glaucoma requiring general anaesthesia (mean age 3.5±1.3 years, body weight ≤20 kg) by using a Perkins hand-held tonometer. Measurements of IOP were performed before, and 15 and 30 min after sedation with orally administered midazolam (1 mg/kg) given as preoperative medication, and 5 and 15 min after induction of general anaesthesia. The individual IOP courses were analysed. In all of the cooperative children, IOP measurement was possible after sedation with midazolam. Mean IOP was 11.2±0.3 mmHg before sedation, 10.9±0.2 mmHg at 15 min, and 10.7±0.3 mmHg 30 min after administration of midazolam. This small decrease was not statistically significant, whilst the IOP decline at 5 and 15 min after induction of general anaesthesia was statistically significant (p<0.0001). Sedation with midazolam can be assumed to be an applicable, well-tolerated, safe method for IOP measurements in children.


Scaffold library for tissue engineering: a geometric evaluation.
Tissue engineering scaffold is a biological substitute that aims to restore, to maintain, or to improve tissue functions. Currently available manufacturing technology, that is, additive manufacturing is essentially applied to fabricate the scaffold according to the predefined computer aided design (CAD) model. To develop scaffold CAD libraries, the polyhedrons could be used in the scaffold libraries development. In this present study, one hundred and nineteen polyhedron models were evaluated according to the established criteria. The proposed criteria included considerations on geometry, manufacturing feasibility, and mechanical strength of these polyhedrons. CAD and finite element (FE) method were employed as tools in evaluation. The result of evaluation revealed that the close-cellular scaffold included truncated octahedron, rhombicuboctahedron, and rhombitruncated cuboctahedron. In addition, the suitable polyhedrons for using as open-cellular scaffold libraries included hexahedron, truncated octahedron, truncated hexahedron, cuboctahedron, rhombicuboctahedron, and rhombitruncated cuboctahedron. However, not all pore size to beam thickness ratios (PO:BT) were good for making the open-cellular scaffold. The PO:BT ratio of each library, generating the enclosed pore inside the scaffold, was excluded to avoid the impossibility of material removal after the fabrication. The close-cellular libraries presented the constant porosity which is irrespective to the different pore sizes. The relationship between PO:BT ratio and porosity of open-cellular scaffold libraries was displayed in the form of Logistic Power function. The possibility of merging two different types of libraries to produce the composite structure was geometrically evaluated in terms of the intersection index and was mechanically evaluated by means of FE analysis to observe the stress level. The couples of polyhedrons presenting low intersection index and high stress level were excluded. Good couples for producing the reinforced scaffold were hexahedron-truncated hexahedron and cuboctahedron-rhombitruncated cuboctahedron.


Influence of N-butylscopolamine on SUV in FDG PET of the bowel.
Peristalsis can lead to confusing FDG PET bowel uptake artefacts and potential for recording inaccurate mean standardised uptake value (SUV) measurements in PET-CT scans. Accordingly, we investigate the influence of different SUV normalisations on FDG PET uptake of the bowel and assess which one(s) have least dependence on body size factors in patients with and without the introduction of the anti-peristalsis agent N-butylscopolamine (Buscopan). This study consisted of 92 prospective oncology patients, each having a whole body (18)F-FDG PET scan. Correlations were investigated between height, weight, glucose, body mass index (bmi), lean body mass (lbm) and body surface area (bsa) with maximum and mean SUV recorded for bowel normalised to weight (SUV(w)), lbm (SUV(lbm)), bsa (SUV(bsa)) and blood glucose corrected versions (SUV(wg), SUV(lbmg), SUV(bsag)). Standardised uptake value normalisations were significantly different between control and Buscopan groups with less variability experienced within individual SUV normalisations by the administration of Buscopan. Mean SUV normalisations accounted for 80% of correlations in the control group and 100% in the Buscopan group. Further, >86% of all correlations across both groups were dominated by mean SUV normalisations of which, about 69% were accounted for by SUV(bsa) and SUV(bsag). We recommend avoiding mean SUV(bsa) and individual glucose normalisations especially, mean SUV(bsag) as these dominated albeit relatively weak correlations with body size factors in control and Buscopan groups. Mean and maximum SUV(w) and SUV(lbm) were shown to be independent of any body size parameters investigated in both groups and therefore considered suitable for monitoring FDG PET uptake in the normal bowel for our patient cohort.


Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.
The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. http://www.clinicaltrials.gov. Unique identifier: NCT01090362.


Traditionally used Thai medicinal plants: in vitro anti-inflammatory, anticancer and antioxidant activities.
In order to assess traditional Thai claims about the therapeutic potential of medicinal plants and to select plants for future phytochemical research, nine plant species with anti-inflammatory uses were selected from Thai textbooks and assessed for their in vitro anti-inflammatory, antiproliferative and antioxidant activities. Nuclear factor-kappaB (NF-kappaB) inhibitory effects in stably transfected HeLa cells were determined by luciferase assay, and effects on LPS-induced pro-inflammatory mediators prostaglandin E2 (PGE2), interleukin (IL)-6, IL-1beta, and tumour necrosis factor (TNF)alpha in primary monocytes were assessed by ELISA. Cytotoxic activities were examined against HeLa cells, human leukaemia CCRF-CEM cells and the multidrug-resistant CEM/ADR5000 subline using the MTT and XTT tests. However, a redox status has been linked with both inflammation and cancer, antioxidant effects were also assessed using the DPPH, lipid-peroxidation, and Folin-Ciocalteau methods. Among all the nine species, Gynura pseudochina var. hispida and Oroxylum indicum showed the most promising NF-kappaB inhibitory effects with the lowest IC(50) values (41.96 and 47.45 microg/ml, respectively). Muehlenbeckia platyclada did not inhibit the NF-kappaB activation but effectively inhibited the release of IL-6, IL-1beta and TNF-alpha with IC(50) values ranging between 0.28 and 8.67 microg/ml. Pouzolzia indica was the most cytotoxic against CCRF-CEM cells and the multidrug-resistant CEM/ADR5000 cells (9.75% and 10.48% viability, at 10 microg/ml, respectively). Rhinacanthus nasutus was the most potent cytotoxicity against HeLa cells (IC(50) 3.63 microg/ml) and showed specific cytotoxicity against the multidrug-resistant CEM/ADR5000 cells (18.72% viability at 10 microg/ml, p<0.0001 when compared to its cytotoxicity against CCRF-CEM cells). Moreover, Oroxylum indicum showed a high level of antioxidant activity by inhibiting lipid-peroxidation (IC(50) 0.08 microg/ml). This study provides in vitro evidence for the use of the Thai plants, most importantly Gynura pseudochina var. hispida, Oroxylum indicum and Muehlenbeckia platyclada as Thai anti-inflammatory remedies and these plants are now a priority for further phytochemical research.


Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells.
The cellular response to DNA double-strand breaks involves direct activation of ataxia telangiectasia mutated (ATM) and indirect activation of ataxia telangiectasia and Rad3 related (ATR) in an ATM/Mre11/cell-cycle-dependent manner. Here, we report that the crucial checkpoint signalling proteins-p53, structural maintainance of chromosomes 1 (SMC1), p53 binding protein 1 (53BP1), checkpoint kinase (Chk)1 and Chk2-are phosphorylated rapidly by ATR in an ATM/Mre11/cell-cycle-independent manner, albeit at low levels. We observed the sequential recruitment of replication protein A (RPA) and ATR to the sites of DNA damage in ATM-deficient cells, which provides a mechanistic basis for the observed phosphorylations. The recruitment of ATR and consequent phosphorylations do not require Mre11 but are dependent on Exo1. We show that these low levels of phosphorylation are biologically important, as ATM-deficient cells enforce an early G2/M checkpoint that is ATR-dependent. ATR is also essential for the late G2 accumulation that is peculiar to irradiated ATM-deficient cells. Interestingly, phosphorylation of KRAB associated protein 1 (KAP-1), a protein involved in chromatin remodelling, is mediated by DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in a spatio-temporal manner in addition to ATM. We posit that ATM substrates involved in cell-cycle checkpoint signalling can be minimally phosphorylated independently by ATR, while a small subset of proteins involved in chromatin remodelling are phosphorylated by DNA-PKcs in addition to ATM.


Deliberate Self-harm seen in a Government Licensed Private Psychiatric Hospital and Institute.
Majority of the published studies on suicide deal with identifying the sociodemographic and psychosocial aspects of suicide attempters and those who have completed suicide or to identify the characteristic differences between the two groups. There are very few studies focusing mainly or only on deliberate self harm. Most of these are hospital based studies or in a setting of general hospital psychiatry units. The present study is from Ram Psychiatry Hospital and Institute, a government licensed private psychiatric institute at Madurai, Tamil Nadu. It is a prospective study of individuals with self harm behavior mostly without the intention to kill, attending the psychiatry outpatient department of the hospital for the period of one year (January to December 2014) a total number of 140 cases are registered. Sociodemographic, clinical profiles with Axis I or Axis II diagnosis or otherwise, and the initiating or precipitating cause or mode of self-injury or self-harm are studied. The results are presented and discussed.


Human TOB, an antiproliferative transcription factor, is a poly(A)-binding protein-dependent positive regulator of cytoplasmic mRNA deadenylation.
In mammalian cells, mRNA decay begins with deadenylation, which involves two consecutive phases mediated by the PAN2-PAN3 and the CCR4-CAF1 complexes, respectively. The regulation of the critical deadenylation step and its relationship with RNA-processing bodies (P-bodies), which are thought to be a site where poly(A)-shortened mRNAs get degraded, are poorly understood. Using the Tet-Off transcriptional pulsing approach to investigate mRNA decay in mouse NIH 3T3 fibroblasts, we found that TOB, an antiproliferative transcription factor, enhances mRNA deadenylation in vivo. Results from glutathione S-transferase pull-down and coimmunoprecipitation experiments indicate that TOB can simultaneously interact with the poly(A) nuclease complex CCR4-CAF1 and the cytoplasmic poly(A)-binding protein, PABPC1. Combining these findings with those from mutagenesis studies, we further identified the protein motifs on TOB and PABPC1 that are necessary for their interaction and found that interaction with PABPC1 is necessary for TOB's deadenylation-enhancing effect. Moreover, our immunofluorescence microscopy results revealed that TOB colocalizes with P-bodies, suggesting a role of TOB in linking deadenylation to the P-bodies. Our findings reveal a new mechanism by which the fate of mammalian mRNA is modulated at the deadenylation step by a protein that recruits poly(A) nuclease(s) to the 3' poly(A) tail-PABP complex.


Defining and implementing a national policy for science, technology, and innovation in health: lessons from the Brazilian experience.
The need for clearly-defined health research policies and priorities has been emphasized in the international scenario. In Brazil, this process began in 2003, when a group appointed by the National Health Council proposed 20 sub-agendas to account for the various health research specificities. The second step was to identify research priorities for each sub-agenda during national seminars involving 510 researchers and policymakers. The 2nd National Conference on Science, Technology, and Innovation in Health was held in July 2004. During the preparatory phase, 307 cities and 24 States organized local conferences, involving 15,000 participants. Some 360 health sector delegates were appointed during the local conferences, in addition to those from the education and science and technology sectors. During the Conference, the national policy was approved and 3 other sub-agendas were introduced and approved. The national policy and the priority agenda are currently guiding investments by the Ministry of Health for research and development, and to a certain extent those from the Ministry of Science and Technology as well. From 2003 to 2005, 24 calls for proposals were launched; as a result, 3,962 research projects were submitted and 1,300 financed.


Effect of Quorum Sensing by Staphylococcus epidermidis on the Attraction Response of Female Adult Yellow Fever Mosquitoes, Aedes aegypti aegypti (Linnaeus) (Diptera: Culicidae), to a Blood-Feeding Source.
Aedes aegypti, the principal vector of yellow fever and dengue fever, is responsible for more than 30,000 deaths annually. Compounds such as carbon dioxide, amino acids, fatty acids and other volatile organic compounds (VOCs) have been widely studied for their role in attracting Ae. aegypti to hosts. Many VOCs from humans are produced by associated skin microbiota. Staphyloccocus epidermidis, although not the most abundant bacteria according to surveys of relative 16S ribosomal RNA abundance, commonly occurs on human skin. Bacteria demonstrate population level decision-making through quorum sensing. Many quorum sensing molecules, such as indole, volatilize and become part of the host odor plum. To date, no one has directly demonstrated the link between quorum sensing (i.e., decision-making) by bacteria associated with a host as a factor regulating arthropod vector attraction. This study examined this specific question with regards to S. epidermidis and Ae. aegypti. Pairwise tests were conducted to examine the response of female Ae. aegypti to combinations of tryptic soy broth (TSB) and S. epidermidis wildtype and agr- strains. The agr gene expresses an accessory gene regulator for quorum sensing; therefore, removing this gene inhibits quorum sensing of the bacteria. Differential attractiveness of mosquitoes to the wildtype and agr- strains was observed. Both wildtype and the agr- strain of S. epidermidis with TSB were marginally more attractive to Ae. aegypti than the TSB alone. Most interestingly, the blood-feeder treated with wildtype S. epidermidis/TSB attracted 74% of Ae. aegypti compared to the agr- strain of S. epidermidis/TSB (P ≤ 0.0001). This study is the first to suggest a role for interkingdom communication between host symbiotic bacteria and mosquitoes. This may have implications for mosquito decision-making with regards to host detection, location and acceptance. We speculate that mosquitoes "eavesdrop" on the chemical discussions occurring between host-associated microbes to determine suitability for blood feeding. We believe these data suggest that manipulating quorum sensing by bacteria could serve as a novel approach for reducing mosquito attraction to hosts, or possibly enhancing the trapping of adults at favored oviposition sites.


Abundance-ratio-based semiquantitative analysis of site-specific N-linked glycopeptides present in the plasma of hepatocellular carcinoma patients.
Aberrant structures of site-specific N-linked glycans are closely associated with the tumorigenesis of hepatocellular carcinoma (HCC), one of the most common fatal cancers worldwide. Vitronectin (VTN) is considered a candidate glycobiomarker of HCC. In this study, we describe a reliable and simple quantification strategy based on abundance ratios of site-specific N-linked glycopeptides of VTN to screen for potential biomarkers. A total of 14 unique N-linked glycans corresponding to 27 unique N-linked glycopeptides were characterized at three N-linked sites (Asn-86, -169, and -242) present in VTN. These glycans could be good candidate markers for HCC. Among these glycans, the abundance ratio of two representative glycoforms (fucosyl vs non-fucosyl) was significantly increased in HCC plasma relative to normal plasma. This strategy was also successfully applied to another potential HCC biomarker, haptoglobin. Furthermore, we demonstrate that our approach employing tandem mass tag (TMT) and target N-linked glycopeptides of VTN is a useful tool for quantifying specific glycans in HCC plasma relative to normal plasma. Our strategy represents a simple and potentially useful screening platform for the discovery of cancer-specific glycobiomarkers.


Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism.
Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (i.e., transgenic [TG] mice) are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle. We observed that the expression of several nuclear and mitochondrially encoded mitochondrial enzymes was decreased in TG mice but that mitochondrial number, size, and fatty acid respiration rates were unchanged. Interestingly, both pyruvate and glutamate respiration rates were decreased in TG mice. Metabolomics analyses of skeletal muscle samples revealed that increased GLUT4 transgene expression was associated with decreased levels of some tricarboxylic acid intermediates and amino acids, whereas the levels of several glucogenic amino acids were elevated. Furthermore, fasting acyl carnitines in obese TG mice were decreased, indicating that increased GLUT4-dependent glucose flux decreases nutrient stress by altering lipid and amino acid metabolism in skeletal muscle.


Structural characteristics of the alloantigens determined by the major histocompatibility complex of the guinea pig.
The GPLA B and Ia (I region-associated) antigens are the products of genes found in the guinea pig major histocompatibility complex. Because of their importance in immune response phenomena, a structural study of these antigens was undertaken. [3H]leucine and [3H]fucose were internally incorporated into guinea pig lymph node cells. The GPLA B and Ia antigens were solubilized by the nonionic detergent Nonidet P-40, purified by affinity chromatography using an adsorbent column of lentil lectin, isolated by immunoprecipitation, and examined by discontinuous polyacrylamide-sodium dodecyl sulfate gel electrophoresis. The GPLA antigens B.1, B.2, B.3, and B.4, were shown to be glycoproteins of mol wt 40,000 daltons and to be noncovalently associated with a 12,000 dalton protein. The molecules bearing B.2 and B.3 in a B.2/B.3 heterozygote are shown to be separable, suggesting the antigenic determinant is a primary gene product. In addition, a new GPLA determinant, S, which resembles the B antigen in that it is found on a molecule of approximately 40,000 daltons, was studied. In a B.2/B.3 S+ animal the molecule bearing antigen S was shown to be independent of those bearing B.2 and B.3, providing evidence that the genes determining B and S are at separate loci. The Ia-bearing molecules identified by anti-Ia.2,4 are glycoproteins of mol wt 58,000 daltons which are composed of two subunits of 33,000 and 25,000 daltons, respectively, linked by disulfide bonds. The Ia-bearing molecules are independent of GPLA-bearing molecules, indicating different loci determining these antigens. By all criteria, the guinea pig GPLA B antigens appear homologous to the murine H-2D and H-2K antigens, while the guinea pig Ia antigens appear homologous to the Ia antigens of the mouse.


Prevalence of genetically modified rice, maize, and soy in Saudi food products.
Qualitative and quantitative DNA-based methods were applied to detect genetically modified foods in samples from markets in the Kingdom of Saudi Arabia. Two hundred samples were collected from Al-Qassim, Riyadh, and Mahdina in 2009 and 2010. GMOScreen 35S and NOS test kits for the detection of genetically modified organism varieties in samples were used. The positive results obtained from GMOScreen 35S and NOS were identified using specific primer pairs. The results indicated that all rice samples gave negative results for the presence of 35S and NOS terminator. About 26 % of samples containing soybean were positive for 35S and NOS terminator and 44 % of samples containing maize were positive for the presence of 35S and/or NOS terminator. The results showed that 20.4 % of samples was positive for maize line Bt176, 8.8 % was positive for maize line Bt11, 8.8 % was positive for maize line T25, 5.9 % was positive for maize line MON 810, and 5.9 % was positive for StarLink maize. Twelve samples were shown to contain <3 % of genetically modified (GM) soy and 6 samples >10 % of GM soy. Four samples containing GM maize were shown to contain >5 % of GM maize MON 810. Four samples containing GM maize were shown to contain >1 % of StarLink maize. Establishing strong regulations and certified laboratories to monitor GM foods or crops in Saudi market is recommended.


A Phylogeny-Based Global Nomenclature System and Automated Annotation Tool for H1 Hemagglutinin Genes from Swine Influenza A Viruses.
The H1 subtype of influenza A viruses (IAVs) has been circulating in swine since the 1918 human influenza pandemic. Over time, and aided by further introductions from nonswine hosts, swine H1 viruses have diversified into three genetic lineages. Due to limited global data, these H1 lineages were named based on colloquial context, leading to a proliferation of inconsistent regional naming conventions. In this study, we propose rigorous phylogenetic criteria to establish a globally consistent nomenclature of swine H1 virus hemagglutinin (HA) evolution. These criteria applied to a data set of 7,070 H1 HA sequences led to 28 distinct clades as the basis for the nomenclature. We developed and implemented a web-accessible annotation tool that can assign these biologically informative categories to new sequence data. The annotation tool assigned the combined data set of 7,070 H1 sequences to the correct clade more than 99% of the time. Our analyses indicated that 87% of the swine H1 viruses from 2010 to the present had HAs that belonged to 7 contemporary cocirculating clades. Our nomenclature and web-accessible classification tool provide an accurate method for researchers, diagnosticians, and health officials to assign clade designations to HA sequences. The tool can be updated readily to track evolving nomenclature as new clades emerge, ensuring continued relevance. A common global nomenclature facilitates comparisons of IAVs infecting humans and pigs, within and between regions, and can provide insight into the diversity of swine H1 influenza virus and its impact on vaccine strain selection, diagnostic reagents, and test performance, thereby simplifying communication of such data. IMPORTANCE A fundamental goal in the biological sciences is the definition of groups of organisms based on evolutionary history and the naming of those groups. For influenza A viruses (IAVs) in swine, understanding the hemagglutinin (HA) genetic lineage of a circulating strain aids in vaccine antigen selection and allows for inferences about vaccine efficacy. Previous reporting of H1 virus HA in swine relied on colloquial names, frequently with incriminating and stigmatizing geographic toponyms, making comparisons between studies challenging. To overcome this, we developed an adaptable nomenclature using measurable criteria for historical and contemporary evolutionary patterns of H1 global swine IAVs. We also developed a web-accessible tool that classifies viruses according to this nomenclature. This classification system will aid agricultural production and pandemic preparedness through the identification of important changes in swine IAVs and provides terminology enabling discussion of swine IAVs in a common context among animal and human health initiatives.


Public Knowledge and Attitude toward Essential Tremor: A Questionnaire Survey.
Public awareness of and attitude toward disease is an important issue for patients. Public awareness of essential tremor (ET) has never been studied. We administered a 10-min, 31-item questionnaire to 250 consecutive enrollees. These included three samples carefully chosen to have a potential range of awareness of ET: 100 individuals ascertained from a vascular disease clinic, 100 individuals from a general neurology clinic, and 50 Parkinson's disease (PD) patients. Leaving aside PD patients, only 10-15% of enrollees had ever heard of or read about "ET." Even among PD patients, only 32.7% had ever heard of or read about ET. After providing enrollees with three synonymous terms for ET ("benign tremor," "kinetic tremor," "familial tremor"), ~40% of non-PD enrollees and 51.0% with PD had ever heard or read about the condition. Even among participants who had heard of ET, ~10% did not know what the main symptom was, 1/3 were either unsure or thought ET was the same disease as PD, 1/4 thought that ET was the same condition as frailty- or aging-associated tremor, 2/3 attributed it to odd causes (e.g., trauma or alcohol abuse), only 1/3 knew of the existence of therapeutic brain surgery, fewer than 1/2 knew that children could have ET, and 3/4 did not know of a celebrity or historical figure with ET. Hence, lack of knowledge and misconceptions were common. Public knowledge of the existence and features of ET is overall poor. Greater awareness is important for the ET community.


Assessment of laminin-mediated glioma invasion in vitro and by glioma tumors engrafted within rat spinal cord.
Cell motility within central nervous system (CNS) neuropil may be largely restricted yet infiltration by glioma cells is commonly observed. Glioma cells remodel nervous tissue and may assemble extracellular matrix in order to migrate. We examined the rat C6 glioma cell line for laminin expression and response in vitro and following engraftment into rat spinal cord. C6 cell cultures expressed laminin-2. C6 cells attached equally well to substrates of purified laminin-1 and laminin-2 and laminin-2-enriched C6 conditioned medium. In contrast, C6 cell migration was substantially greater on laminin-2 and C6-derived substrata than on laminin-1. Glioma cell attachment to laminin-1 and -2 was largely inhibited by antibody to the laminin receptor LBP110 and by an IKVAV peptide but not by YIGSR or control peptides. IKVAV peptide and anti-LBP110 antibodies also inhibited glioma cell invasion through synthetic basement membrane. Anti-beta 1 integrin antibody selectively inhibited cell migration and invasion on laminin-2 substrata without affecting percent cell attachment. These findings suggest C6 cell migration and invasion are promoted by autocrine release of laminin-2 and involve LPB110 and beta 1 integrin laminin receptors. A possible role for laminin-2 in CNS infiltration in vivo was examined following glioma engraftment into rat spinal cord. Engrafted C6 tumors share many histologic features of invasive human glioma. Engrafted glioma cells expressed laminin, LBP110 and beta 1 integrin antigens, indicating the molecular mechanisms of C6 motility observed in culture may contribute to glioma invasion in vivo. NMR and corroborative immunocytochemistry provided precise means to monitor tumor progression following glioma engraftment into rat spinal cord. Advantages of this glioma model are discussed regarding the assessment of anti-adhesive therapies in vivo.


Dendritic cells in semen of infertile men: association with sperm quality and inflammatory status of the epididymis.
To determine whether dendritic cells (DCs) are present in semen and whether their abundance and activation correlate with sperm quality and inflammatory status of the male genital tract. In vitro prospective study. University hospital laboratory. Eighty infertile men and twelve control fertile men were enrolled in this study. None. The percentages of DCs, intracellular staining of cytokines, and spermatozoa DNA fragmentation index were assessed by flow cytometry. Seminal cytokines, neutral α-glucosidase, zinc, and fructose were measured with commercial kits. A significant number of CD11c(+) HLA-DR(+) DCs were detected in ejaculates from patients with chronic inflammation of genital tract, which was negatively correlated with spermatozoa motility, vitality, and DNA integrity. Intracellular staining of cytokines of seminal DCs showed enhanced ability to secrete inflammatory cytokines (interleukin [IL] 23p19, tumor necrosis factor [TNF]-related apoptosis-inducing ligand [TRAIL], and TNF-α). Furthermore, a significant correlation was found between DCs and the seminal concentrations of IL-6, IL-17, IL-23, TRAIL, and neutral α-glucosidase, the marker of epididymal function, in the inflammatory group but not in the noninflammatory and fertile groups. The abundance and activation of seminal DCs of infertile men may be closely associated with poor epididymal function and sperm quality.


How do people with persecutory delusions evaluate threat in a controlled social environment? A qualitative study using virtual reality.
Environmental factors have been associated with psychosis but there is little qualitative research looking at how the ongoing interaction between individual and environment maintains psychotic symptoms. The current study investigates how people with persecutory delusions interpret events in a virtual neutral social environment using qualitative methodology. 20 participants with persecutory delusions and 20 controls entered a virtual underground train containing neutral characters. Under these circumstances, people with persecutory delusions reported similar levels of paranoia as non-clinical participants. The transcripts of a post-virtual reality interview of the first 10 participants in each group were analysed. Thematic analyses of interviews focusing on the decision making process associated with attributing intentions of computer-generated characters revealed 11 themes grouped in 3 main categories (evidence in favour of paranoid appraisals, evidence against paranoid appraisals, other behaviour). People with current persecutory delusions are able to use a range of similar strategies to healthy volunteers when making judgements about potential threat in a neutral environment that does not elicit anxiety, but they are less likely than controls to engage in active hypothesis-testing and instead favour experiencing "affect" as evidence of persecutory intention.


Activin A induction of erythroid differentiation sensitizes K562 chronic myeloid leukemia cells to a subtoxic concentration of imatinib.
Chronic myeloid leukemia (CML) is a hematopoietic stem/progenitor cell disorder in which Bcr-Abl oncoprotein inhibits cell differentiation. Differentiation induction is considered an alternative strategy for treating CML. Activin A, a member of the transforming growth factor-β superfamily, induces erythroid differentiation of CML cells through the p38 MAPK pathway. In this study, treatment of the K562 CML stem/progenitor cell line with activin A followed by a subtoxic concentration of the Bcr-Abl inhibitor imatinib strongly induced growth inhibition and apoptosis compared with simultaneous treatment with activin A and imatinib. Imatinib-induced growth inhibition and apoptosis following activin A pretreatment were dose- and time-dependent. Imatinib-induced growth inhibition and apoptosis were also dependent on the pretreatment dose of activin A. More than 90% of the activin A-induced increases in glycophorin A-positive cells were sensitive to imatinib. However, only some of original glycophorin A-positive cells in the activin A treatment group were sensitive to imatinib. Sequential treatment with activin A and imatinib decreased Bcr-Abl, procaspase-3, Mcl-1, and Bcl-xL and also induced cleavage of procaspase-3/poly(ADP-ribose)polymerase. The reduction of erythroid differentiation in p38 MAPK dominant-negative mutants or by short hairpin RNA knockdown of p38 MAPK decreased the growth inhibition and apoptosis mediated by sequential treatment with activin A and imatinib. Furthermore, the same inhibition level of multidrug resistance 1 expression was observed in cells treated with activin A alone, treated sequentially with activin A and imatinib, or treated simultaneously with activin A and imatinib. The p38 MAPK inhibitor SB-203580 can restore activin A-inhibited multidrug resistance 1 expression. Taken together, our results suggest that a subtoxic concentration of imatinib could exhibit strong cytotoxicity against erythroid-differentiated K562 CML cells.


Detection of coliforms in drinking water using skin patches: a rapid, reliable method that does not require an external energy source.
The detection of coliforms requires incubation in a laboratory, generally powered using electricity. In many parts of the developing world, however, external energy sources such as electricity are not readily available. To develop a fast, reliable method for detecting coliforms in water without an external energy source, we assessed the efficacy of six test kits for the identification of coliforms in water samples. To assess the possibility of using body temperature as the sole source of heat for incubation, bacterial samples were then mixed with the enzymatic test kit reagent and attached to the human body surface using a patch system. The patches were attached to the bodies of volunteers for 24 hours and the practicality and accuracy of the patches were assessed. Coliforms were detected within 24 hours in all patches. This innovation will facilitate the testing of water quality by researchers and by economically disadvantaged people without electricity.


Risky Treatments: A Jewish Medical Ethics Perspective.
The Jewish principle concerning a decision with regard to a dangerous treatment is as following: A patient who is estimated to die within 12 months because of a fatal illness is permitted to undergo a treatment that on the one hand may extend his life beyond 12 months, but on the other hand may hasten his death. There are, however, several limitations to this ruling related to the chances of success with the proposed treatment, the nature of the treatment, whether it is intended to be curative or merely to postpone the danger and death, whether the treatment is absolutely necessary, and others. One is not obligated to undergo a dangerous treatment, but one is permitted to do so. The permissibility to forfeit a short life expectancy in order to achieve more prolonged life applies only with the patient's consent. That consent is valid and is not considered a form of attempted suicide. Neither is a refusal to submit to treatment considered an act of suicide; the patient has the right to refuse a dangerous procedure. In all situations where a permissive ruling is granted for a patient to endanger his short life expectancy, the ruling should be arrived at after careful reflection and with the approval of the rabbinic authorities acting on the recommendation of the most expert physicians.


Effects of insulin receptor down-regulation on hexose transport in human erythrocytes.
D-Glucose and D-galactose influx and efflux rates in human erythrocytes were studied using infinite-cis and zero-trans assay methods. It was found that insulin decreased the infinite-cis Km for both D-glucose and D-galactose influx by 44 and 56%, respectively, while the Vmax was unchanged. The Km for D-glucose efflux in the presence of insulin decreased by 47% when compared to controls, and the change in Vmax was statistically insignificant. If insulin receptors were first down regulated, and then influx and efflux assays were performed, decreases in the infinite-cis and zero-trans Km values were also observed in the absence of exogenous insulin. These affinity changes were not due to persistent surface insulin receptor occupation by the insulin which was used to induce down-regulation. These affinity changes were comparable to those observed in non-down-regulated cells in the presence of insulin.


Contrast-enhanced hepatic magnetic resonance angiography at 3 T: does parallel imaging improve image quality?
To evaluate whether hepatic magnetic resonance angiography (MRA) performed at 3 T and acquired with a parallel imaging acceleration factor of 2 provides satisfactory image quality and adequate contrast-to-noise, compared with an acquisition without parallel imaging. Ten volunteers underwent both a standard (A) and an experimental (B) MRA protocol. Both protocols used a gadoteridol dose of 20 mL injected at 2 mL/s in a 3-T magnetic resonance (MR) system. Protocol B was identical to protocol A, except protocol B was performed with a parallel imaging acceleration factor of 2. Contrast-to-noise ratios (CNRs) were calculated in the suprarenal abdominal aorta, the common hepatic artery, and the right and left hepatic arteries. The same 4 vessels were rated for quality of arterial visualization using a 5-point scale (1 = poor to 5 = excellent). The paired t test and Wilcoxon rank sum test were used for statistical analysis. The CNRs and qualitative scores were higher in all 4 vessels using protocol B. Mean CNRs in the suprarenal abdominal aorta, common hepatic artery, and the right and left hepatic arteries were 31, 33, 28, and 22 for protocol A and 36, 40, 36, and 25 for protocol B, respectively (P < 0.05 except the left hepatic arteries [P = 0.35]). Mean qualitative scores of the same vessels were 4.3, 3.7, 3.1, and 2.9 using protocol A and 4.4, 3.8, 3.5, and 3.2 for protocol B, respectively (P > 0.44). Parallel imaging performed in a 3-T MR system improves hepatic MRA both quantitatively and qualitatively.


Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury.
A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock and ischemia/reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species in shock, inflammation and ischemia/reperfusion injury. The second part of the review described the pharmacological action of melatonin in shock, ischemia/reperfusion, and inflammation. The role of reactive oxygen species: Immunohistochemical and biochemical evidence demonstrate the production of reactive oxygen species in shock, inflammation and ischemia/reperfusion injury. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include the initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3 phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation and ischemia and reperfusion. Treatment with melatonin has been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock, inflammation and ischemia/reperfusion injury. Reactive oxygen species (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, with subsequent activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently, it has been demonstrated that melatonin inhibits the activation of poly (ADP-ribose) synthetase, and prevents the organ injury associated with shock, inflammation and ischemia and reperfusion.


Visualization of the Mechanical Wave Effect on Liquid Microphases and Its Application for the Tuning of Dissipative Soft Microreactors.
The development of approaches for creation of adaptive and stimuli-responsive chemical systems is particularly important for chemistry, materials science, and biotechnology. The understanding of response mechanisms for various external forces is highly demanded for the rational design of task-specific systems. Here, we report direct liquid-phase scanning electron microscopy (SEM) observations of the high frequency sound-wave-driven restructuring of liquid media on the microlevel, leading to switching of its chemical behavior. We show that under the action of ultrasound, the microstructured ionic liquid/water mixture undergoes rearrangement resulting in formation of separated phases with specific compositions and reactivities. The observed effect was successfully utilized for creation of dissipative soft microreactors formed in ionic liquid/water media during the sonication-driven water transfer. The performance of the microreactors was demonstrated using the example of controlled synthesis of small and uniform gold and palladium nanoparticles. The microsonication stage, designed and used in the present study, opened unique opportunities for direct sonochemical studies with the use of electron microscopy.


Estimating the effective sample size in association studies of quantitative traits.
The effective sample size (ESS) is a metric used to summarize in a single term the amount of correlation in a sample. It is of particular interest when predicting the statistical power of genome-wide association studies (GWAS) based on linear mixed models. Here, we introduce an analytical form of the ESS for mixed-model GWAS of quantitative traits and relate it to empirical estimators recently proposed. Using our framework, we derived approximations of the ESS for analyses of related and unrelated samples and for both marginal genetic and gene-environment interaction tests. We conducted simulations to validate our approximations and to provide a quantitative perspective on the statistical power of various scenarios, including power loss due to family relatedness and power gains due to conditioning on the polygenic signal. Our analyses also demonstrate that the power of gene-environment interaction GWAS in related individuals strongly depends on the family structure and exposure distribution. Finally, we performed a series of mixed-model GWAS on data from the UK Biobank and confirmed the simulation results. We notably found that the expected power drop due to family relatedness in the UK Biobank is negligible.


The occurrence of microplastic contamination in littoral sediments of the Persian Gulf, Iran.
Microplastics (MPs; <5 mm) in aquatic environments are an emerging contaminant of concern due to their possible ecological and biological consequences. This study addresses that MP quantification and morphology to assess the abundance, distribution, and polymer types in littoral surface sediments of the Persian Gulf were performed. A two-step method, with precautions taken to avoid possible airborne contamination, was applied to extract MPs from sediments collected at five sites during low tide. MPs were found in 80% of the samples. Across all sites, fiber particles were the most dominate shape (88%), followed by films (11.2%) and fragments (0.8%). There were significant differences in MP particle concentration between sampling sites (p value <0.05). The sediments with the highest numbers of MPs were from sites in the vicinity of highly populated centers and municipal effluent discharges. FTIR analysis showed that polyethylene (PE), nylon, and polyethylene terephthalate (PET) were the most abundant polymer types. More than half of the observed MPs (56%) were in the size category of 1-4.7 mm length, with the remaining particles (44%) being in the size range of 10 μm to <1 mm. Compared to literature data from other regions, intertidal sediments in the Persian Gulf cannot be characterized as a hot spot for MP pollution. The present study could, however, provide useful background information for further investigations and management policies to understand the sources, transport, and potential effects on marine life in the Persian Gulf.


A comparison of five standard methods for evaluating image intensity uniformity in partially parallel imaging MRI.
To investigate the utility of five different standard measurement methods for determining image uniformity for partially parallel imaging (PPI) acquisitions in terms of consistency across a variety of pulse sequences and reconstruction strategies. Images were produced with a phantom using a 12-channel head matrix coil in a 3T MRI system (TIM TRIO, Siemens Medical Solutions, Erlangen, Germany). Images produced using echo-planar, fast spin echo, gradient echo, and balanced steady state free precession pulse sequences were evaluated. Two different PPI reconstruction methods were investigated, generalized autocalibrating partially parallel acquisition algorithm (GRAPPA) and modified sensitivity-encoding (mSENSE) with acceleration factors (R) of 2, 3, and 4. Additionally images were acquired with conventional, two-dimensional Fourier imaging methods (R=1). Five measurement methods of uniformity, recommended by the American College of Radiology (ACR) and the National Electrical Manufacturers Association (NEMA) were considered. The methods investigated were (1) an ACR method and a (2) NEMA method for calculating the peak deviation nonuniformity, (3) a modification of a NEMA method used to produce a gray scale uniformity map, (4) determining the normalized absolute average deviation uniformity, and (5) a NEMA method that focused on 17 areas of the image to measure uniformity. Changes in uniformity as a function of reconstruction method at the same R-value were also investigated. Two-way analysis of variance (ANOVA) was used to determine whether R-value or reconstruction method had a greater influence on signal intensity uniformity measurements for partially parallel MRI. Two of the methods studied had consistently negative slopes when signal intensity uniformity was plotted against R-value. The results obtained comparing mSENSE against GRAPPA found no consistent difference between GRAPPA and mSENSE with regard to signal intensity uniformity. The results of the two-way ANOVA analysis suggest that R-value and pulse sequence type produce the largest influences on uniformity and PPI reconstruction method had relatively little effect. Two of the methods of measuring signal intensity uniformity, described by the (NEMA) MRI standards, consistently indicated a decrease in uniformity with an increase in R-value. Other methods investigated did not demonstrate consistent results for evaluating signal uniformity in MR images obtained by partially parallel methods. However, because the spatial distribution of noise affects uniformity, it is recommended that additional uniformity quality metrics be investigated for partially parallel MR images.


Growth of left ventricular mass in African American and European American youth.
Increased left ventricular mass has been established as a strong risk factor for cardiovascular morbidity and mortality. To evaluate growth of left ventricular mass from childhood into early adulthood and its possible sociodemographic, anthropometric, and hemodynamic moderators, individual growth curves across age of left ventricular mass were created for 687 African American and European American males and females with a maximum of 10 annual assessments (age, 8.2 to 27.5 years). African Americans and males had significantly greater left ventricular mass (P<0.001) than did European Americans and females, respectively. Males also showed a larger rate of change in left ventricle mass than did girls (P<0.001). The ethnicity and gender effects on left ventricular mass only became apparent in early adolescence, and they persisted when controlling for socioeconomic status and anthropometric and hemodynamic variables. Body mass index and height were the strongest anthropometric predictors, and pulse pressure was the strongest hemodynamic predictor of left ventricular mass. Although significant, the contribution of pulse pressure to the prediction of left ventricular mass was small, once body mass index and height were entered into the model. The results of the present study suggest that increased left ventricular mass in boys and African Americans has its origin in late childhood. Apart from these ethnicity and gender effects, individual differences in cardiac growth can mainly be explained by body growth and increases in general adiposity.


Effect of tonsillar herniation on cyclic CSF flow studied with computational flow analysis.
The Chiari I malformation, characterized by tonsils extending below the foramen magnum, has increased CSF velocities compared with those in healthy subjects. Measuring the effect of tonsillar herniation on CSF flow in humans is confounded by interindividual variation. The goal of this study was to determine the effect of herniated tonsils on flow velocity and pressure dynamics by using 3D computational models. A previously described 3D mathematic model of the normal subarachnoid space was modified by extending the tonsils inferiorly. The chamber created was compared with the anatomy of the subarachnoid space. Pressures and velocities were calculated by CFA methods for sinusoidal flow of a Newtonian fluid. Results were displayed as 2D color-coded plots and 3D animations. Pressure gradients and flow velocities were compared with those in the normal model. Velocity distributions were also compared with those in clinical images of CSF flow. The model represented grossly the subarachnoid space of a patient with Chiari I malformation. Fluid flow patterns in the Chiari model were complex, with jets in some locations and stagnant flow in others. Flow jets, synchronous bidirectional flow, and pressure gradients were greater in the Chiari model than in the normal model. The distribution of flow velocities in the model corresponded well with those observed in clinical images of CSF flow in patients with Chiari I. Tonsillar herniation per se increases the pressure gradients and the complexity of flow patterns associated with oscillatory CSF flow.


Emotions and family interactions in childhood: Associations with leukocyte telomere length emotions, family interactions, and telomere length.
Conceptualizations of links between stress and cellular aging in childhood suggest that accumulating stress predicts shorter leukocyte telomere length (LTL). At the same time, several models suggest that emotional reactivity to stressors may play a key role in predicting cellular aging. Using intensive repeated measures, we tested whether exposure or emotional "reactivity" to conflict and warmth in the family were related to LTL. Children (N=39; 30 target children and 9 siblings) between 8 and 13 years of age completed daily diary questionnaires for 56 consecutive days assessing daily warmth and conflict in the marital and the parent-child dyad, and daily positive and negative mood. To assess exposure to conflict and warmth, diary scale scores were averaged over the 56 days. Mood "reactivity" was operationalized by using multilevel modeling to generate estimates of the slope of warmth or conflict scores (marital and parent-child, separately) predicting same-day mood for each individual child. After diary collection, a blood sample was collected to determine LTL. Among children aged 8-13 years, a stronger association between negative mood and marital conflict, suggesting greater negative mood reactivity to marital conflict, was related to shorter LTL (B=-1.51, p<.01). A stronger association between positive mood and marital affection, suggesting positive mood reactivity, was related to longer LTL (B=1.15, p<.05). These effects were independent of exposure to family and marital conflict and warmth, and positive and negative mood over a two-month period. To our knowledge, these findings, although cross-sectional, represent the first evidence showing that link between children's affective responses and daily family interactions may have implications for telomere length.


A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment.
While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. Here we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. Finally, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.


Transmission dynamics, border entry screening, and school holidays during the 2009 influenza A (H1N1) pandemic, China.
Pandemic influenza A (H1N1) 2009 virus spread rapidly around the world in 2009. We used multiple data sources from surveillance systems and specific investigations to characterize the transmission patterns of this virus in China during May-November 2009 and analyze the effectiveness of border entry screening and holiday-related school closures on transmission. In China, age distribution and transmission dynamic characteristics were similar to those in Northern Hemisphere temperate countries. The epidemic was focused in children, with an effective reproduction number of ≈1.2-1.3. The 8 days of national holidays in October reduced the effective reproduction number by 37% (95% credible interval 28%-45%) and increased underreporting by ≈20%-30%. Border entry screening detected at most 37% of international travel-related cases, with most (89%) persons identified as having fever at time of entry. These findings suggest that border entry screening was unlikely to have delayed spread in China by >4 days.


Cost-effectiveness of comprehensive medication reviews versus noncomprehensive medication review interventions and subsequent successful medication changes in a Medicare Part D population.
An estimated 1.5 million preventable medication-related adverse events occur annually, with some resulting in serious injury and even death. To help address this issue, the Centers for Medicare Medicaid Services (CMS) now require medication therapy management (MTM) programs to offer comprehensive medication reviews (CMRs) to all Medicare Part D beneficiaries at least once a year. During a CMR, patients receive an extensive amount of medication and educational information. In contrast, noncomprehensive medication reviews (non-CMRs) are more targeted and focus on resolving a particular medication-related problem (MRP) via short patient consultations, patient letters, and direct provider interventions. To conduct a cost-effectiveness analysis comparing CMRs with non-CMR interventions on successful medication regimen changes and reductions in adverse drug events (ADEs). This decision analytic model compared the cost-effectiveness of CMRs with other intervention methods (non-CMRs) from a payer's perspective. For this model, a successful outcome was defined as a beneficiary case devoid of an ADE due to MRPs. The model was extensively tested and subjected to a thorough one-way sensitivity analysis and a second-order probabilistic sensitivity analysis with 10,000 iterations from the variable distributions. Non-CMR interventions were less costly and more effective than CMRs. The point estimate for direct medical costs was $193 for CMRs and $157 for non-CMRs, and the estimated probability of avoiding an ADE was 0.93 and 0.94 for CMRs and non-CMRs, respectively. The 10,000 iteration-Monte Carlo simulation scatterplot and cost-effectiveness acceptability curve (CEAC) revealed a dominance by non-CMRs in preventing harmful ADEs from cost and effectiveness perspectives; however, there was an overlap in the 95% CIs for both cost and ADEs prevented. Despite this, a non-CMR intervention saved estimated $5,377.08 per ADE prevented. One-way sensitivity analysis indicated the results were sensitive to the cost of treating a preventable ADE. In 100% of cases, the CEAC demonstrated that non-CMRs were likely the most cost-effective intervention regardless of the health plan's willingness to pay. The cost-effectiveness acceptability curve suggests that non-CMR interventions were less costly and more effective than CMRs; however, there was overlap in the 95% CIs for costs and ADEs prevented. In all cases, the CEAC demonstrated that non-CMRs were the most economical intervention with regard to time and cost. Non-CMRs show promise as a viable method to address MRPs, reduce ADEs, and improve patient-related health outcomes.


Intense directional lasing from a deformed square-shaped organic-inorganic hybrid glass microring cavity.
Intense directional light emission from a deformed square-shaped organic light-emitting microring cavity was observed. The ring cavity was a dye-doped organic-inorganic hybrid glass film coated upon a square-shaped fiber. From the near-field and far-field emission patterns and their emission spectra we found, for the first time to our knowledge, the simultaneous existence of chaotic whispering-gallery modes and four-bounce reflection modes. The two types of mode have different emission directions, different lasing thresholds, and different spectral linewidths. High-contrast angle-modulated light emission was also observed. We could control modulation and angular spread of emission by controlling the deformation of the cavity.


Evidence for a midlife crisis in great apes consistent with the U-shape in human well-being.
Recently, economists and behavioral scientists have studied the pattern of human well-being over the lifespan. In dozens of countries, and for a large range of well-being measures, including happiness and mental health, well-being is high in youth, falls to a nadir in midlife, and rises again in old age. The reasons for this U-shape are still unclear. Present theories emphasize sociological and economic forces. In this study we show that a similar U-shape exists in 508 great apes (two samples of chimpanzees and one sample of orangutans) whose well-being was assessed by raters familiar with the individual apes. This U-shaped pattern or "midlife crisis" emerges with or without use of parametric methods. Our results imply that human well-being's curved shape is not uniquely human and that, although it may be partly explained by aspects of human life and society, its origins may lie partly in the biology we share with great apes. These findings have implications across scientific and social-scientific disciplines, and may help to identify ways of enhancing human and ape well-being.


Indoor nature exposure (INE): a health-promotion framework.
Engaging in outdoor nature-based spaces has significant positive physiological and psychological health benefits. Although the integration of nature into indoor spaces is rarely considered a health-promoting tool, it may be an effective method for increasing nature engagement in a largely urbanized world. This paper presents an overview of indoor nature exposure (INE) by summarizing the current evidence of INE through the use of a scoping methodology. Results show that INE can be a health-promoting tool through the interaction of nature-based stimuli and individual characteristics (e.g. gender, age). Moreover, the results of the current literature need to be interpreted with consideration to methodological issues, such as the lack of participant characteristics, the issue of exposure realism and little qualitative data to highlight individual experiences. The scoping review process allowed for the summation of results and for a framework to be created in order to better understand how INE is facilitated.


Pediatric low-grade gliomas and the need for new options for therapy: Why and how?
Pediatric low-grade gliomas are the most common tumors of the central nervous system in children, accounting for almost 50% of all childhood brain tumors. They are a heterogeneous group of tumors with different histologic subtypes. Most treatment studies address low-grade gliomas as a single entity, depriving us of histology-specific treatment outcomes. This is mostly due to a lack of understanding of tumor biology at the molecular level. Pediatric low-grade gliomas are not benign, and most incompletely resected tumors will progress and negatively affect quality of life. The advancements made in understanding sporadic pilocytic astrocytoma and neurofibromatosis 1-associated pilocytic astrocytoma in particular have paved the way for potential targeted therapy and biological stratification. Such progress in pilocytic astrocytoma needs to be consolidated and expanded to other histologic varieties of pediatric low-grade gliomas.


Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: A comparative analysis.
In Egypt, hepatocellular carcinoma (HCC) is the most common form of cancer and direct-acting antivirals (DAA) are administered on a large scale to patients with chronic HCV infection to reduce the risk. In this unique setting, we aimed to determine the association of DAA exposure with early-phase HCC recurrence in patients with a history of HCV-related liver cancer. This was a prospective cohort study of an HCV-infected population from one Egyptian specialized HCC management centre starting from the time of successful HCC intervention. The incidence rates of HCC recurrence between DAA-exposed and nonexposed patients were compared, starting from date of HCC complete radiological response and censoring after 2 years. DAA exposure was treated as time varying. Two Poisson regressions models were used to control for potential differences in the exposed and nonexposed group; multivariable adjustment and balancing using inverse probability of treatment weighting (IPTW). We included 116 patients: 53 treated with DAAs and 63 not treated with DAAs. There was 37.7% and 25.4% recurrence in each group after a median of 16.0 and 23.0 months of follow-up, respectively. Poisson regression using IPTW demonstrated an association between DAAs and HCC recurrence with an incidence rate ratio of 3.83 (95% CI: 2.02-7.25), which was similar in the multivariable-adjusted model and various sensitivity analyses. These results add important evidence towards the possible role of DAAs in HCC recurrence and stress the need for further mechanistic studies and clinical trials to accurately confirm this role and to identify patient characteristics that may be associated with this event.


SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia.
Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2's Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) - a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A 'silencing' of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.


Immune function across generations: integrating mechanism and evolutionary process in maternal antibody transmission.
The past 30 years of immunological research have revealed much about the proximate mechanisms of maternal antibody transmission and utilization, but have not adequately addressed how these issues are related to evolutionary and ecological theory. Much remains to be learned about individual differences within a species in maternal antibody transmission as well as differences among species in transmission or utilization of antibodies. Similarly, maternal-effects theory has generally neglected the mechanisms by which mothers influence offspring phenotype. Although the environmental cues that generate maternal effects and the consequent effects for offspring phenotype are often well characterized, the intermediary physiological and developmental steps through which the maternal effect is transmitted are generally unknown. Integration of the proximate mechanisms of maternal antibody transmission with evolutionary theory on maternal effects affords an important opportunity to unite mechanism and process by focusing on the links between genetics, environment and physiology, with the ultimate goal of explaining differences among individuals and species in the transfer of immune function from one generation to the next.


[Diagnostic value of bone marrow biopsy for bone marrow metastatic tumor with unknown primary tumor site].
To explore the diagnostic value of bone marrow biopsy for bone marrow metastatic tumor with unknown primary tumor site. Thirty-eight cases of metastatic bone marrow tumors were diagnosed by light microscopy, and the bone marrow samples from these cases with unknown primary tumor sites were examined by immunohistochemistry. In all the cases, the bone marrow was infiltrated by tumor cells between the bone trabecula. Twenty patients were identified to have poorly differentiated adenocarcinomas, 6 had mucinous adenocarcinomas, 6 had mucinous carcinomas, 4 had poorly differentiated squamous cell carcinomas, and 2 had melanoma. Immunohistochemistry identified the primary tumor sites in these cases, including 12 stomach cancers, 10 breast cancers, 8 prostate cancers, 4 lung cancers, 1 dorsal melanoma, 1 left foot melanoma, and 2 nasopharyngeal cancers. Proper immunohistochemistry can help determine the primary tumor sites in patients with metastatic bone marrow tumor with unknown primary tumor sites.


Prostate stem-cell antigen gene is associated with diffuse and intestinal gastric cancer in Caucasians: results from the EPIC-EURGAST study.
A genome-wide study performed in a Japanese population identified a strong association between SNP rs2294008 (Met1Thr) in the Prostate Stem Cell Antigen gene (PSCA) and diffuse-type gastric cancer (GC). This association was validated in different Asian populations, and, very recently, a study has been published in Caucasians. In this study, we analyzed the association between PSCA variation and GC risk in Caucasians from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Six tagSNPs covering the PSCA gene region were genotyped in 411 incident gastric adenocarcinoma cases and 1530 matched controls from a nested case-control study in the EPIC cohort. Associations were analyzed by unconditional logistic regression, adjusting for age, sex and country. The T allele of rs2294008 in PSCA was found to be a highly significant risk factor for GC (per allele OR = 1.42, 95% CI: 1.23-1.66, p-value = 6.5 × 10(-6) ), particularly of the noncardia-type (per allele OR = 1.47, 95% CI: 1.19-1.81, p-value = 3 × 10(-4) ). At contrast with previous studies, no significant differences were observed between the diffuse (per allele OR = 1.54, 95% CI: 1.20-1.96, p-value = 5 × 10(-4) ) and the intestinal (per allele OR = 1.52, 95% CI: 1.20-1.93, p-value = 5 × 10(-4) ) GC histological subtypes. Although rs12155758 and rs9297976 were also found associated with GC, this association appeared to be due to linkage disequilibrium with rs2294008. Haplotype analysis did not provide additional information. These results confirm the association between variation in the promoter region of PSCA and GC risk in Caucasians and also indicate that the rs2294008 variant is a similar risk factor for both the diffuse and intestinal-types of GC.