Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3-not calculable] vs 4·3 months [3·0-5·4]; HR 0·18 [0·10-0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5-10·3] vs 5·5 months [3·7-5·6]; HR 0·54 [0·34-0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64-1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45-1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63-1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population. These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. AstraZeneca.


Myricetin, the Main Flavonoid in Syzygium cumini Leaf, Is a Novel Inhibitor of Platelet Thiol Isomerases PDI and ERp5.
Flavonoids have been characterized as a prominent class of compounds to treat thrombotic diseases through the inhibition of thiol isomerases. Syzygium cumini is a flavonoid-rich medicinal plant that contains myricetin and gallic acid. Little is known about the potential antiplatelet properties of S. cumini and its constituent flavonoids. To evaluate the antiplatelet effects and mechanism of action of a polyphenol-rich extract (PESc) from S. cumini leaf and its most prevalent polyphenols, myricetin and gallic acid. PESc, myricetin, and gallic acid were incubated with platelet-rich plasma and washed platelets to assess platelet aggregation and activation. In vitro platelet adhesion and thrombus formation as well as in vivo bleeding time were performed. Finally, myricetin was incubated with recombinant thiol isomerases to assess its potential to bind and inhibit these, while molecular docking studies predicted possible binding sites. PESc decreased platelet activation and aggregation induced by different agonists. Myricetin exerted potent antiplatelet effects, whereas gallic acid did not. Myricetin reduced the ability of platelets to spread on collagen, form thrombi in vitro without affecting hemostasis in vivo. Fluorescence quenching studies suggested myricetin binds to different thiol isomerases with similar affinity, despite inhibiting only protein disulfide isomerase (PDI) and ERp5 reductase activities. Finally, molecular docking studies suggested myricetin formed non-covalent bonds with PDI and ERp5. PESc and its most abundant flavonoid myricetin strongly inhibit platelet function. Additionally, myricetin is a novel inhibitor of ERp5 and PDI, unveiling a new therapeutic perspective for the treatment of thrombotic disorders.


Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms.
Blood vessels are conduits distributed throughout the body, supporting tissue growth and homeostasis by the transport of cells, oxygen and nutrients. Endothelial cells (ECs) form the linings of the blood vessels, and together with pericytes, are essential for organ development and tissue homeostasis through producing paracrine signalling molecules, called angiocrine factors. In the skeletal system, ECs - derived angiocrine factors, combined with bone cells-released angiogenic factors, orchestrate intercellular crosstalk of the bone microenvironment, and the coupling of angiogenesis-to-osteogenesis. Whilst the involvement of angiogenic factors and the blood vessels of the skeleton is relatively well established, the impact of ECs -derived angiocrine factors on bone and cartilage homeostasis is gradually emerging. In this review, we survey ECs - derived angiocrine factors, which are released by endothelial cells of the local microenvironment and by distal organs, and act specifically as regulators of skeletal growth and homeostasis. These may potentially include angiocrine factors with osteogenic property, such as Hedgehog, Notch, WNT, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF). Understanding the versatile mechanisms by which ECs-derived angiocrine factors orchestrate bone and cartilage homeostasis, and pathogenesis, is an important step towards the development of therapeutic potential for skeletal diseases.


Regulation of iodothyronine 5'-deiodination in lean and obese (ob/ob) mice.
Obese (ob/ob) mice exhibit impaired cold- and diet-induced thermogenesis, which may result in part from a defect in thyroid hormone action at the level of peripheral deiodination of thyroxine (T4) to 3,5,3'-triiodothyronine (T3). The latter possibility was examined by comparing kinetic parameters of 5'-deiodination (5'-D) in hepatic and renal microsomes of lean and obese mice during various physiological conditions. 5'-D Was adaptive to changes in age (1 to 8-10 wk), environmental temperature (14, 25, and 33 degrees C), and thyroid hormone status in both lean and obese mice. The magnitude of enzyme response, however, varied between phenotypes. 5'-D Response to age and environmental temperature was also dependent on tissue type, indicating that different isozymes for 5'-D may exist in liver and kidney. Under basal conditions at 25 degrees C, maximal hepatic and renal 5'-D was lower in obese mice than in lean mice. Differences in Vmax were observed as early as 1 wk of age. Km values for 5'-D were similar in lean and obese mice. These findings suggest that T3 availability to thermogenic target tissues may be impaired in obese mice, which may contribute to diminished thyroid hormone expression and heat production in these animals.


A novel carbon tipped single micro-optrode for combined optogenetics and electrophysiology.
Optical microelectrodes (optrodes) are used in neuroscience to transmit light into the brain of a genetically modified animal to evoke and record electrical activity from light-sensitive neurons. Our novel micro-optrode solution integrates a light-transmitting 125 micrometer optical fiber and a 9 micrometer carbon monofilament to form an electrical lead element, which is contained in a borosilicate glass sheathing coaxial arrangement ending with a micrometer-sized carbon tip. This novel unit design is stiff and slender enough to be used for targeting deep brain areas, and may cause less tissue damage compared with previous models. The center-positioned carbon fiber is less prone to light-induced artifacts than side-lit metal microelectrodes previously presented. The carbon tip is capable of not only recording electrical signals of neuronal origin but can also provide valuable surface area for electron transfer, which is essential in electrochemical (voltammetry, amperometry) or microbiosensor applications. We present details of design and manufacture as well as operational examples of the newly developed single micro-optrode, which includes assessments of 1) carbon tip length-impedance relationship, 2) light transmission capabilities, 3) photoelectric artifacts in carbon fibers, 4) responses to dopamine using fast-scan cyclic voltammetry in vivo, and 5) optogenetic stimulation and spike or local field potential recording from the rat brain transfected with channelrhodopsin-2. With this work, we demonstrate that our novel carbon tipped single micro-optrode may open up new avenues for use in optogenetic stimulation when needing to be combined with extracellular recording, electrochemical, or microbiosensor measurements performed on a millisecond basis.


Quantum-well states as fabry-Perot modes in a thin-film electron interferometer
Angle-resolved photoemission from atomically uniform silver films on iron (100) shows quantum-well states for absolutely determined film thicknesses ranging from 1 to approximately 100 monolayers. These states can be understood in terms of Fabry-Perot modes in an electron interferometer. A quantitative line shape analysis over the entire two orders of magnitude of thickness range yields an accurate measurement of the band structure, quasiparticle lifetime, electron reflectivity, and phase shift. Effects of confinement energy gap, reflection loss, and surface scattering caused by controlled roughness are demonstrated.


Protracted development of executive and mnemonic brain systems underlying working memory in adolescence: A longitudinal fMRI study.
Working memory (WM), the ability to hold information on-line to guide planned behavior, improves through adolescence in parallel with continued maturation of critical brain systems supporting cognitive control. Initial developmental neuroimaging studies with one or two timepoints have provided important though varied results limiting our understanding of which and how neural systems change during this transition into mature WM. In this study, we leverage functional magnetic resonance imaging (fMRI) longitudinal data spanning up to 9 years in 129 normally developing individuals to identify which systems demonstrate growth changes that accompany improvements in WM performance. We used a memory guided saccade task that allowed us to probe encoding, pure maintenance, and retrieval neural processes of WM. Consistent with prior research, we found that WM performance continued to improve into the early 20's. fMRI region of interest (ROI) analyses revealed developmental (1) increases in sensorimotor-related (encoding/retrieval) activity in visual cortex from childhood through early adulthood that were associated with WM accuracy and (2) decreases in sustained (maintenance) activity in executive regions from childhood through mid-adolescence that were associated with response latency in childhood and early adolescence. Together these results provide compelling evidence that underlying the maturation of WM is a transition from reliance on executive systems to specialized regions related to the domain of mnemonic requirements of the task leading to optimal performance.


Surface energy engineering for tunable wettability through controlled synthesis of MoS2.
MoS2 is an important member of the transition metal dichalcogenides that is emerging as a potential 2D atomically thin layered material for low power electronic and optoelectronic applications. However, for MoS2 a critical fundamental question of significant importance is how the surface energy and hence the wettability is altered at the nanoscale in particular, the role of crystallinity and orientation. This work reports on the synthesis of large area MoS2 thin films on insulating substrates (SiO2/Si and Al2O3) with different surface morphology via vapor phase deposition by varying the growth temperatures. The samples were examined using transmission electron microscopy and Raman spectroscopy. From contact angle measurements, it is possible to correlate the wettability with crystallinity at the nanoscale. The specific surface energy for few layers MoS2 is estimated to be about 46.5 mJ/m(2). Moreover a layer thickness-dependent wettability study suggests that the lower the thickness is, the higher the contact angle will be. Our results shed light on the MoS2-water interaction that is important for the development of devices based on MoS2 coated surfaces for microfluidic applications.


Characteristics of dissolved organic matter (DOM) and relationship with dissolved mercury in Xiaoqing River-Laizhou Bay estuary, Bohai Sea, China.
Because of heterogeneous properties, dissolved organic matter (DOM) is known to control the environmental fate of a variety of organic pollutants and trace metals in aquatic systems. Here we report absorptive and fluorescence properties of DOM, in concurrence with concentrations of dissolved mercury (Hg), along the Xiaoqing River-Laizhou Bay estuary system located in the Bohai Sea of China. A mixing model consisting of the two end-members terrestrial and aquatic DOM demonstrated that terrestrial signatures decreased significantly from the river into the estuary. Quasi-conservative mixing behavior of DOM sources suggests that the variations in the average DOM composition were governed by physical processes (e.g., dilution) rather than by new production and/or degradation processes. In contrast to some previous studies of river-estuary systems, the Xiaoqing River-Laizhou Bay estuary system displayed a non-significant correlation between DOM and Hg quantities. Based on this and the variation of Hg concentration along the salinity gradient, we concluded that Hg showed a non-conservative mixing behavior of suggested end-member sources. Thus, rather than mixing, Hg concentration variations seemed to be controlled by biogeochemical processes.


Fluorescence imaging and spectroscopy of ethyl nile blue A in animal models of (pre)malignancies.
Discrimination between normal and premalignant tissues by fluorescence imaging and/or spectroscopy may be enhanced by a tumor-localizing fluorescent drug. Ethyl Nile Blue A (EtNBA), a dye with no phototoxic activity, was investigated for this purpose. The pharmacokinetics and tissue-localizing properties were investigated in a rat palate model with chemically induced premalignant mucosal lesions (0.5 mg/kg EtNBA intravenous [i.v.]), a hairless mouse model with UVB-induced premalignant skin lesions (1 mg/kg EtNBA intraperitoneal) and in a rat skin-fold observation chamber model on the back of a rat with a transplanted solid tumor (2.5 mg/kg EtNBA i.v.). Fluorescence images and spectra were recorded in vivo (600 nm excitation, 665-900 nm detection) and in frozen tissue sections at several time points after EtNBA administration. In the rat palate the EtNBA fluorescence was maximum almost immediately after injection, whereas in the mouse skin and the observation chamber the fluorescence maximum was reached between 2 and 3 h after injection. EtNBA cleared from tissues after 8-24 h. EtNBA localizes in the transplantable solid tumor, but is not targeted specifically to the dysplastic location in the rat palate and mouse skin. However, in the rat palate the EtNBA fluorescence increased significantly with increasing dysplasia, apparently due to the increasing thickness of the upper keratinized layer of the epithelium where the dye was found to localize. Localization in this layer occurred both in the rat palate and in hairless mouse skin.


Acute Shame Predicts Urges for Suicide but not for Substance Use in a Veteran Population.
There is an urgent need to identify ways to reduce rates of suicide among Veterans with a substance use disorder. Since co-occurring disorders can make diagnosis and treatment complex, it is useful for the mental health field to examine common factors that may underlie both problems. One common factor that underlies both substance use and suicidal behavior is shame. This brief report presents data collected in an experimental study examining shame as an acute risk factor for suicide and substance use in Veterans. Thirty-eight Veterans admitted to an inpatient Veterans Affairs Medical Center unit with suicidal ideation completed measures on depression, hopelessness, addiction, and suicidality. Participants were randomized to either a shame mood induction group or a control group, and completed pre- and postexperiment measures on urges for suicide, urges for substance use, and level of shame. Results indicate that an acute increase in shame resulted in an increase in an urge for suicide, but was not associated with changes in urges for substance use. Acute feelings of shame may be a risk factor for increases in suicidal ideation. Limitations and suggestions for future directions are discussed.


Pesticide transport with runoff from creeping bentgrass turf: Relationship of pesticide properties to mass transport.
The off-site transport of pesticides with runoff is both an agronomic and environmental concern, resulting from reduced control of target pests in the area of application and contamination of surrounding ecosystems. Experiments were designed to measure the quantity of pesticides in runoff from creeping bentgrass (Agrostis palustris) turf managed as golf course fairway to gain a better understanding of factors that influence chemical availability and mass transport. Less than 1 to 23% of applied chloropyrifos, flutolanil, mecoprop-p (MCPP), dimethylamine salt of 2,4-dichlorophenoxyacetic acid (2,4-D), or dicamba was measured in edge-of-plot runoff when commercially available pesticide formulations were applied at label rates 23 +/- 9 h prior to simulated precipitation (62 +/- 13 mm). Time differential between hollow tine core cultivation and runoff did not significantly influence runoff volumes or the percentage of applied chemicals transported in the runoff. With the exception of chlorpyrifos, all chemicals of interest were detected in the initial runoff samples and throughout the runoff events. Chemographs of the five pesticides followed trends in agreement with mobility classifications associated with their soil organic carbon partition coefficient (K(OC).) Data collected from the present study provides information on the transport of chemicals with runoff from turf, which can be used in model simulations to predict nonpoint source pollution potentials and estimate ecological risks.


Prognostic significance of sICAM-1 and sVCAM-1 molecules for cardiac surgery in pediatric patients with pulmonary hypertension.
To investigate preoperative and postoperative blood levels of soluble intercellular and vascular cell adhesion molecules (sICAM-1, sVCAM-1) in patients with and without pulmonary hypertension (PAH) due to congenital heart disease and left to right (L-R) shunt and to determine whether these molecules can be used as reliable prognostic markers of endothelial activity to predict surgical outcomes. In this observational prospective cohort study; 42 patients, operated for L-R shunt were divided into three groups. Group 1: L-R shunt without PAH, Group 2: L-R shunt with PAH, Group 3: L-R shunt with PAH and postoperative low cardiac output syndrome (LCOS). Their sICAM-1 and sVCAM-1 levels were measured preoperatively (sICAM-0, sVCAM-0) and on the first (sICAM-1, sVCAM-1) and fifth postoperative days (sICAM-2, sVCAM-2).ROC curve for various cut-off levels of sICAM-0, sVCAM-0 in differentiating PAH patients with and without LCOS. In Group 3, sICAM-0 and sVCAM-2 levels were higher than Group 1 and 2. The ROC curve demonstrated a significant association between sICAM-0 in patients with L-R shunt and PAH (Group 2 and 3) and the development of LCOS (area under the curve: 0.98, p<0.01 and 0.97, p<0.01, respectively). At a sICAM-0 concentration >359 ng/mL, there was a sensitivity of 90% and specificity of 95% for identification of LCOS in patients with L-R shunt and PAH (AUC: 0.98, 95% CI: 0.95-1.02, p<0.01). High preoperative sICAM-1 molecule may be used to predict postoperative dichotomous outcome in patients with PAH associated with L-R shunt.


[Work organization experience of the Medequipment joint research and manufacturing association].
The results of the activity of the Medoborudovaniye Joint Research and Manufacturing Organization for the period of 1976--1980 are briefly summarized. The organizational, technical and economic measures carried out by the Medoborudovaniye Organization to ensure the successful fulfillment of the tasks set by the XXV Congress of the CPSU for 1976--1980 are described. The measures for the further improvement of various aspects of the activity of the Medoborudovaniye Organization, facilitating the fulfillment of the tasks set by the XXVI Congress of the CPSU ate outlined.


Glucocorticoids and metabolic acidosis-induced renal transports of inorganic phosphate, calcium, and NH4.
The initial rate (5 s) of Na+-dependent inorganic phosphate (Pi) uptake in brush-border membrane vesicles isolated from rat proximal tubule was decreased in metabolic acidosis, 0.42 +/- 0.02 vs. 0.59 +/- 0.05 nmol/mg protein, in vesicles from control animals. Phosphate, ammonium, and Ca2+ excretions were increased 100, 600, and 56%, respectively. These changes in brush-border Pi transport and urinary excretion of ions were largely dependent on intact adrenal glands. After adrenalectomy there were no significant changes in brush-border Pi transport, Pi, and Ca2+ excretion, whereas ammonium excretion increased only 300% compared with controls. When the glucocorticoid dexamethasone was administered to adrenalectomized animals, it mimicked the effects of metabolic acidosis both in the presence and the absence of metabolic acidosis. The initial rate of brush-border Pi transport was decreased by dexamethasone administration to 0.37 +/- 0.04 nmol/mg protein in adrenalectomized acidotic animals and 0.39 +/- 0.03 nmol/mg protein in adrenalectomized animals. Dexamethasone administered to adrenalectomized acidotic animals increased Pi, ammonium, and Ca2+ excretion 190, 690, and 23%, respectively. Dexamethasone administered to nonacidotic adrenalectomized animals increased Pi ammonium and Ca2+ excretion 165, 240, and 31%, respectively. We conclude that changes in Pi, ammonium, and Ca2+ excretion observed during metabolic acidosis were dependent on intact adrenal glands and that glucocorticoids administered to adrenalectomized acidotic or nonacidotic animals mimicked the changes observed in acidotic animals with intact adrenal glands.


The site of action of epidural fentanyl infusions in the presence of local anesthetics: a minimum local analgesic concentration infusion study in nulliparous labor.
We have previously demonstrated that continuous epidural infusions of fentanyl without local anesthetics elicit analgesia by a systemic mechanism. In this study, we examined the hypothesis that, in the presence of epidural bupivacaine, continuous infusions of epidural fentanyl elicit analgesia by a spinal mechanism. Forty-eight nulliparous women in active labor participated in this prospective, randomized, double-blinded study. Women received lumbar epidural analgesia with 20-30 mL bupivacaine 0.125% until pain free. Subjects were then randomized to either IV or epidural (EPI) fentanyl infusion groups. Each infusion delivered fentanyl 30 microg/h. All women received an epidural infusion of bupivacaine at a rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. Unlike previous studies that assessed the minimum local analgesic concentration (MLAC) for bolus administration at the initiation of analgesia, this study assessed MLAC(infusion) for the maintenance of analgesia throughout the first stage of labor. MLAC(infusion) was determined using the up-down sequential analysis described by Dixon and Massey. The MLAC(infusion) of epidural bupivacaine was 0.063% (95% confidence interval, 0.058-0.068) and 0.019% (95% confidence interval, 0.000-0.038) in the IV and EPI groups respectively. A continuous infusion of fentanyl was more than three times as potent when administered by the epidural than by the IV route. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study. This study determined the median effective concentration for epidural infusions of bupivacaine during labor analgesia. Coadministered epidural fentanyl infusions were more than three times more potent than IV fentanyl infusions, suggesting a predominantly spinal mechanism of opioid action under these study conditions.


Estimation of tsunami debris on seafloors towards future disaster preparedness: Unveiling spatial varying effects of combined land use and oceanographic factors.
A large amount of tsunami debris from the Great East Japan Earthquake in 2011 was sunk on the seafloor and threatened the marine ecosystem and local communities' economy, especially in fisheries. However, few studies estimated spatial accumulations of tsunami benthic debris, comparing to their flows on the ocean surface. Here, a spatially varying coefficient model was used to estimate tsunami debris accumulation considering the spatial structure of the data off the Tohoku region. Our model revealed the number of vessels nearest the coast at the tsunami event had the highest positive impact, whereas the distance from the coast and kinetic energy influenced negatively. However, the effect of the proximity to the coast wasn't detected in the Sendai bay, indicating spatial dependency of these effects. Our model estimation provides the fundamental information of tsunami debris accumulation on the seafloor, supporting early reconstruction and risk reduction in marine ecosystems and local communities.


No independent or synergistic effects of carbohydrate-caffeine mouth rinse on repeated sprint performance during simulated soccer match play in male recreational soccer players.
The study examined the synergistic and independent effects of carbohydrate-caffeine mouth rinse on repeated sprint performance during simulated soccer match play. Nine male soccer players (21 ± 3 years, 1.75 ± 0.05 m, 68.0 ± 9.0 kg) completed four trials with either 6 mg·kg-1 caffeine + 10% maltodextrin (CHO+CAFMR), 6 mg·kg-1 caffeine (CAFMR), 10% maltodextrin (CHOMR), water (PLA) in a block randomised, double-blinded, counterbalanced and crossover manner separated by minimum 96 h. All solutions were taste-matched and a carbohydrate-rich meal (2 g·kg-1body mass) was provided 2 h before each trial. Each trial consisted of a 90-min soccer-specific aerobic field test (SAFT90) and two bouts of repeated sprint ability tests (RSAT; 6 × 6 s sprints with 24 s recovery) completed at 0 min and 75th min of SAFT90. A 25 ml solution of either CHO+CAFMR, CAFMR, CHOMR or PLA was rinsed immediately before the second RSAT (75 min). Mean power output, peak power output (PPO) or fatigue index (FI) was not impacted by any treatment during the 75th min RAST (p > 0.05). These results suggest that carbohydrate and/or caffeine mouth rinses do not have an ergogenic effect during simulated soccer exercise after a high carbohydrate meal.


[Cytogenetic activity of metabolites of pesticides representing different classes of chemical compounds].
The cytogenetic activity of some substances formed in agricultural plants during metabolism of pesticides of four classes of chemical compounds was studied in the culture of human peripheric blood lymphocytes. Metabolites were shown either to have mutagenic properties similar to those of the initial compounds (ziramtetramethylthiourea, both being mutagens; captan-phthalimide, both possessing no cytogenetic activity) or to be considerably transformed in comparison with them as a result of deactivation (benomile-MBC) or activation (betanal-MHPC) processes. The latter variant if being determined for the genetic hazard of the pesticide necessitates to take into account data on the mutagenic character of those metabolites which really might enter the human organism.


Metastatic prostatic carcinoma to testis: histological features mimicking lymphoma.
We report a case of prostatic carcinoma with testicular metastasis, which mimicked malignant lymphoma of the testis. The patient was a 71 year-old man with a history of prostate adenocarcinoma of Gleason score 9 (4+5) diagnosed in 2001 for which he received hormonal therapy. Four years later, the patient developed multiple osteoblastic bone metastases. Radiotherapy of the bone metastases was given with subsequently bilateral orchiectomy for hormonal deprivation therapy in May 2005. Grossly, one of the testes had a subcapsular rubbery 0.9 cm nodule. Microscopically, the nodule was composed of malignant discohesive cells predominantly infiltrating in the interstitium with an appearance of malignant lymphoma. However, immunohistochemical stains were positive for prostate-specific antigen and prostate acid phosphatase and negative for leukocyte common antigen, which confirmed the diagnosis of metastatic prostate adenocarcinoma.


Awareness and Knowledge Among Dental and Medical Undergraduate Students Regarding Human Papilloma Virus and Its Available Preventive Measures.
India is a major contributor to the global burden of human papilloma virus (HPV) infection and associated diseases like cervical and oropharyngeal cancers. Hence, it is essential to recognize the existing knowledge pool of current healthcare students about HPV and its preventive measures to translate this into benefits for the society in the future. To determine the awareness and knowledge among dental and medical undergraduate students regarding HPV and its diagnosis and prevention. This cross-sectional study enrolled in 577 dental and undergraduate medical students from a tertiary-care teaching hospital. A questionnaire containing 20 closed-ended multiple-choice questions was used to assess their knowledge regarding HPV and its transmission, cervical cancer and its screening, as well as HPV vaccines and their attitude towards them. Descriptive statistics, Mann Whitney U test, and Chi square test were employed for statistical analysis. p ≤ 0.05 was considered statistically significant. The study consisted of 52.68% dental and 47.31% medical students, with a mean age of 20.95 ± 1.82 years, M:F ratio of 0.7:1, and a mean overall score of 10.75 ± 5.18 (average). The mean scores for knowledge about HPV, its vaccination, and its diagnosis were 7.98 ± 3.26 (good), 1.61 ± 0.95 (average), and 1.15 ± 1.16 (average), respectively. These scores showed no significant difference between the courses as well as the genders (p > 0.05). Overall, the dental and medical undergraduate students presented an average level of knowledge and awareness regarding HPV and its prevention. This reflects a greater need for educating healthcare professionals in order to have a ripple effect on society at large.


Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development.
Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development. Clin Cancer Res; 23(7); 1638-46. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."


A comparison of acepromazine-buprenorphine and medetomidine-buprenorphine for preanesthetic medication of dogs.
To assess sedative and cardiopulmonary effects of premedication with a medetomidine-buprenorphine or acepromazine-buprenorphine combination in dogs anesthetized with propofol and isoflurane. Randomized controlled clinical trial. 90 dogs undergoing routine surgical and diagnostic procedures. Dogs were randomly assigned to 1 of 3 premedication groups: group 1 (acepromazine, 0.03 mg/kg [0.014 mg/lb], IM; buprenorphine, 0.02 mg/kg [0.009 mg/lb], IM), 2 (medetomidine, 5 μg/kg [2.3 μg/lb], IM; buprenorphine, 0.02 mg/kg, IM), or 3 (medetomidine, 10 μg/kg [4.5 μg/lb], IM; buprenorphine, 0.02 mg/kg, IM). Anesthesia was induced with propofol and maintained with isoflurane in oxygen. Simple descriptive scores for sedation were assigned 15 minutes (groups 2 and 3) and 30 minutes (group 1) after premedication administration. Basic cardiopulmonary data were recorded throughout the anesthetic period. Times to recovery from anesthesia were recorded. Sedation scores did not differ significantly among groups. Mean and diastolic blood pressures were significantly lower and heart rate was significantly higher in group 1 than in the other groups. Mean end-tidal partial pressure of CO(2) was significantly lower and respiratory rate was significantly higher in group 1 than in the other groups. There were no significant differences in anesthetic recovery times between groups. Results suggested that either acepromazine or medetomidine could be used in combination with buprenorphine for premedication of dogs anesthetized with propofol and isoflurane for routine surgical and diagnostic procedures. Arterial blood pressure was better maintained with the medetomidine-buprenorphine combinations, but tissue perfusion was not investigated.


Hemodynamic and electrophysiological study of the role of the anterior cingulate in target-related processing and selection for action.
A number of experiments requiring attention or other complex cognitive functions have found substantial activation in the anterior cingulate cortex (ACC). Some of these studies have suggested that this area may be involved in "selection for action," such as for selecting to respond to a target stimulus. Here, positron emission tomography (PET) and event-related potentials (ERPs) were used to study the effects of target probability during a demanding visual spatial attention task, in which the target percentage was either low (2%, 1 per approximately 26 sec) or high (16%, 1 per approximately 3.5 sec). As expected, ERPs to detected targets evoked large, bilaterally distributed P300 waves. The PET showed strong activation of the ACC, particularly dorsally, during all the attend conditions relative to passive. However, these PET activations did not significantly differ between the few-target and many-target conditions, showing only a small trend to be larger in the many-target case. Such results indicate that the bulk of the ACC activation does not reflect selection for action per se, while also suggesting that the ACC is not a likely source of the P300 effect. The current data, however, do not argue against the ACC serving a role in maintaining a vigilant or anticipatory state in which one may need to select for action, or in continually or repeatedly (i.e., for each stimulus) needing to resolve whether to select to act or to not act.


Excretion profiles and half-lives of ten urinary polycyclic aromatic hydrocarbon metabolites after dietary exposure.
Human exposure to polycyclic aromatic hydrocarbons (PAHs) can be assessed by biomonitoring of their urinary monohydroxylated metabolites (OH-PAHs). Limited information exists on the human pharmacokinetics of OH-PAHs. This study aimed to investigate the excretion half-life of 1-hydroxypyrene (1-PYR), the most used biomarker for PAH exposure, and 9 other OH-PAHs following a dietary exposure in 9 nonsmoking volunteers with no occupational exposure to PAHs. Each person avoided food with known high PAH-content during the study period, except for a high PAH-containing lunch (barbecued chicken) on the first day. Individual urine samples (n = 217) were collected from 15 h before to 60 h following the dietary exposure. Levels of all OH-PAHs in all subjects increased rapidly by 9-141-fold after the exposure, followed by a decrease consistent with first-order kinetics, and returned to background levels 24-48 h after the exposure. The average time to reach maximal concentration ranged from 3.1 h (1-naphthol) to 5.5 h (1-PYR). Creatinine-adjusted urine concentrations for each metabolite were analyzed using a nonlinear mixed effects model including a term to estimate background exposure. The background-adjusted half-life estimate was 3.9 h for 1-PYR and ranged 2.5-6.1 h for the other 9 OH-PAHs, which in general, were shorter than those previously reported. The maximum concentrations after barbecued chicken consumption were comparable to the levels found in reported occupational settings with known high PAH exposures. It is essential to consider the relatively short half-life, the timing of samples relative to exposures, and the effect of diet when conducting PAH exposure biomonitoring studies.


Phosphoinositides as regulators of membrane trafficking in health and disease.
Membrane trafficking is crucial in the homeostasis of the highly compartmentalized eukaryotic cells. This compartmentalization occurs both at the organelle level, with distinct organelles maintaining their identities while also intensely interchanging components, and at a sub-organelle level, with adjacent subdomains of the same organelle containing different sets of lipids and proteins. A central question in the field is thus how this compartmentalization is established and maintained despite the intense exchange of components and even physical continuities within the same organelle. The phosphorylated derivatives of phosphatidylinositol, known as the phosphoinositides, have emerged as key components in this context, both as regulators of membrane trafficking and as finely tuned spatial and temporal landmarks for organelle and sub-organelle domains. The central role of the phosphoinositides in cell homeostasis is highlighted by the severe consequences of the derangement of their metabolism caused by genetic deficiencies of the enzymes involved, and from the systematic hijacking of phosphoinositide metabolism that pathogens operate to promote their entry and/or survival in host cells.


Treatment of infected arthrodesis of the ankle.
In arthrodesis of the ankle joint the use of external fixation can cause severe problems owing to pintrack infections. As long as infection is active, bony consolidation of the arthrodesis is delayed. In the potentially infected area a normal internal osteosynthesis is risky. Our treatment rationale comprises a two-stage procedure with treatment of infection first by implant removal, thorough debridement and implantation of Septopal beads and then secondary internal stabilization with an antibiotic-releasing bone plate. Of the 42 cases amputation had to be performed in 3; of the remaining 39, infection was cured long-term in 36. In all 39 a stable bony fusion was achieved.


NK cells and exercise: implications for cancer immunotherapy and survivorship.
Natural Killer (NK) cells are cytotoxic effectors of the innate immune system that are able to recognize and eradicate tumor cells without prior antigenic exposure. Tumor infiltration by NK-cells is associated with prolonged survival in cancer patients and high NK-cell cytotoxicity has been linked to decreased cancer risk. Allogeneic adoptive transfer of NK-cells from healthy donors to cancer patients has shown promise as a means of controlling or reversing the spread of multiple human malignancies including multiple myeloma and acute myeloid leukemia. However, multiple issues remain that undermine the efficacy of long-term cancer treatment using adoptive transfer of NK-cells including loss of activating receptors and cytotoxic potential in transferred NK-cells. Moreover, chronic exercise has been linked to improved NK-cell cytotoxicity, prognosis, and survival in cancer patients, and cytomegalovirus (CMV) reactivation is associated with enhanced NK-cell function after hematopoietic stem cell transplantation and decreased relapse risk in AML patients. In this work, we explore the potential of exercise- and CMV-driven alterations in NK-cell phenotype and function to increase the efficacy of NK-cells for cancer immunotherapy and prolong survival in cancer patients. We conclude that acute exercise and CMV are both capable of enhancing NK-cell cytotoxicity through distinct mechanisms; however, these effects are not additive as CMV infection is associated with an impaired acute exercise response. Thus, we suggest that either acute exercise or in vitro expansion of NKG2C+/NKG2A- NK-cells (as seen in those with CMV) could serve as a simple strategy for enhancing the anti-tumor cytotoxicity of NK-cells for immunotherapy, and that exercise training could be used to improve survivorship in cancer patients being treated with either HSCT or NK-cell infusions.


Pharmacokinetics and pharmacodynamics of milrinone in chronic congestive heart failure.
The acute hemodynamic effects and pharmacokinetics of bolus intravenous milrinone administration were assessed in 13 patients with severe congestive heart failure. Serial hemodynamics were measured and blood samples were obtained to determine plasma milrinone concentration and calculation of pharmacokinetic variables after administration of milrinone at 12.5, 25, 50 and 75 micrograms/kg, allowing at least 6 hours to elapse between consecutive milrinone doses. At each dose milrinone effected prompt but very short-lived increases in cardiac output and left ventricular stroke work and decreases in pulmonary artery pressure, right atrial pressure and systemic and pulmonary vascular resistance in a non-dose-dependent fashion. Pulmonary artery wedge pressure decreased in a dose-related manner. Heart rate increased significantly after the 75-micrograms/kg dose and mean arterial pressure decreased significantly only after the 50- and 75-micrograms/kg milrinone dose. The time-dependent decline in plasma milrinone concentration was biexponential and log linear, conforming to an open 2-compartment model of drug distribution and elimination. Mean plasma milrinone clearance (+/- standard error) was 0.15 +/- 0.03 liters/min/kg, volume of distribution was 0.35 +/- 0.02 liters/kg and mean elimination half-life was 1.7 hours.


[Functional role of vitamin K].
Three basic functions of vitamin K in organism are considered. Besides (vitamin K-dependent) posttranslational modification of Ca-binding proteins, this vitamin can operate via vitamin D hormonal system, and can directly influence membranes.


1, 2, 3, 4: infusing quantitative literacy into introductory biology.
Biology of the twenty-first century is an increasingly quantitative science. Undergraduate biology education therefore needs to provide opportunities for students to develop fluency in the tools and language of quantitative disciplines. Quantitative literacy (QL) is important for future scientists as well as for citizens, who need to interpret numeric information and data-based claims regarding nearly every aspect of daily life. To address the need for QL in biology education, we incorporated quantitative concepts throughout a semester-long introductory biology course at a large research university. Early in the course, we assessed the quantitative skills that students bring to the introductory biology classroom and found that students had difficulties in performing simple calculations, representing data graphically, and articulating data-driven arguments. In response to students' learning needs, we infused the course with quantitative concepts aligned with the existing course content and learning objectives. The effectiveness of this approach is demonstrated by significant improvement in the quality of students' graphical representations of biological data. Infusing QL in introductory biology presents challenges. Our study, however, supports the conclusion that it is feasible in the context of an existing course, consistent with the goals of college biology education, and promotes students' development of important quantitative skills.


Thromboxane B2 and prostaglandin E2 in the K+-depleted rat kidney.
There is a considerable amount of interest in prostaglandin E2 (PGE2) metabolism in potassium depletion, but the findings remain inconclusive. Thromboxane A2 (TXA2) is another type of prostaglandin with a vasoconstrictive property and its biosynthesis in the kidney is altered under pathophysiological conditions. We investigated the production of both immunoassayable PGE2 and thromboxane B2 (TXB2), a chemically stable metabolite of TXA2, in the chronically K+-depleted rat kidney. During a 90-min in vitro incubation of papillary slices obtained from K+-depleted rats, TXB2 production was increased, but PGE2 biosynthesis was decreased and PGF2 alpha remained unaltered compared with control rats. In the cortex, TXB2 production was low, but it was greater in K+-depleted rats compared with control rats. Deletion of K+ from the incubation medium had no measurable effect on either TXB2 or PGE2 production in both K+-depleted and control rats. Formation of [14C]TXB2 from [14C]PGH2 by microsomes from renal papilla was greater in K+-depleted rats compared with control rats, suggesting that the increased TXB2 production in the K+-depleted rat kidney is probably due to an activation of TXA2 synthetase.


Active versus Passive Hard Disks against a Membrane: Mechanical Pressure and Instability.
We experimentally study the mechanical pressure exerted by a set of respectively passive isotropic and self-propelled polar disks onto two different flexible unidimensional membranes. In the case of the isotropic disks, the mechanical pressure, inferred from the shape of the membrane, is identical for both membranes and follows the equilibrium equation of state for hard disks. On the contrary, for the self-propelled disks, the mechanical pressure strongly depends on the membrane in use and thus is not a state variable. When self-propelled disks are present on both sides of the membrane, we observe an instability of the membrane akin to the one predicted theoretically for active Brownian particles against a soft wall. In that case, the integrated mechanical pressure difference across the membrane cannot be computed from the sole knowledge of the packing fractions on both sides, further evidence of the absence of an equation of state.


HAART-associated dyslipidemia varies by biogeographical ancestry in the multicenter AIDS cohort study.
Highly active antiretroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV-1-infected individuals. Exposure to HAART can result in metabolic side effects, such as dyslipidemia, in a subset of recipients. Longitudinal data and frozen peripheral blood mononuclear cell pellets were obtained from 1,945 men enrolled in the Multicenter AIDS Cohort. Individuals were genotyped for ancestry informative markers (AIMs) and stratified by biogeographical ancestry (BGA). Then serum levels of total cholesterol (TCHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TRIG) were examined controlling for a number of HIV and HAART-related covariates using multivariate mixed-effects linear regression. HIV-1 infection, in the absence of HAART, was associated with altered lipid levels for all phenotypes tested when compared to HIV-negative men. HIV-1-infected men receiving HAART also had significantly different lipid levels compared to HIV-negative men, except for LDL-C. There were statistically significant interactions between BGA and HIV/HAART status for all lipids tested. BGA remained significantly associated with lipid levels after controlling for other HIV and HAART-related covariates. There was low concordance between self-reported race (SRR) and BGA in admixed populations. BGA performed better than SRR in our statistical models. Lipid profiles in untreated HIV-1-positive men and HIV-1-positive men receiving HAART differ from HIV-negative men and this effect varies by BGA. BGA performed better in our statistical analysis as a racial classifier but SRR remains a good clinical surrogate for BGA.


Focused laser differential interferometry post-processing methodology for flowfields with circular symmetry.
An analytic methodology is presented to reconstruct the pressure waveform of flowfields with circular symmetry from the phase shift detected with Focused Laser Differential Interferometry (FLDI). A weak blast wave generated by an electric spark in ambient air is investigated with the proposed approach. Values of separation distance between the differentiating foci of the FLDI Δx of 76, 120, 175, and 252 μm are employed to probe the flowfield at locations between 3 and 50 mm from the spark source. In a subset of these distances, reference measurements of peak pressure obtained with a surface pressure sensor indicate good agreement with the reconstructed data when small separation distances are used. Further analysis of FLDI reconstructed data is conducted using theoretical correlations for N-waves in terms of the distribution of pressure peak amplitude and compression phase as the wave front propagates. Agreement with theory is verified for all differentiation separation distances except the largest, for which peak pressure comparison shows a 10% loss of measured vs predicted value. A computational FLDI is employed to scrutinize the simplifying hypotheses supporting the waveform reconstruction approach. The direct comparison between experimental and computational FLDI output reveals additional discrepancies for intermediate Δx values but very good agreement for the smallest Δx. The proposed methodology is thus verified to be reasonable, upon appropriate minimization of the FLDI differentiation distance. A parametric analysis using computational FLDI indicates the adequate value of FLDI Δx to be 20% or less of the flowfield characteristic length in terms of density gradient.


Effects of TNF-α on penile structure alteration in rats with hyperprolactinemia.
This study aimed to investigate the effects of anti-tumor necrosis factor (TNF)-α antibody (Ab) on alteration of penile structure in the hyperprolactinemia (hyperPRL) rat model. HyperPRL was induced in 8-week-old male Sprague-Dawley rats by allografting anterior pituitary (AP) glands under the renal capsule (+AP rats). Rats implanted with cerebral cortex (CX) were used as sham control (+CX rats). At 6 weeks post implantation, rats received either a single intra-testicular dose of TNF-α Ab (12.5 μg/kg) or testosterone replacement (2 doses of testosterone enanthate [TE], 3 mg/kg), and they were sacrificed 1 week later. Blood and penile tissue was collected for analysis. Compared to +CX rats, the +AP group had lower serum testosterone concentration and neuronal nitric oxide synthase (nNOS) expression, but exhibited a higher ratio of collagen III/I in the corpus cavernosum. Smooth muscle content exhibited no significant changes. At 1 week post TNF-α Ab injection, the collagen III/I ratio in the +AP group was decreased, and the smooth muscle content and nNOS expression increased significantly. These findings were comparable to those observed in +AP rats receiving TE. Testicular TNF-α suppresses testosterone release, which in turn results in the erectile dysfunction (ED) seen in hyperPRL. Intra-testicular TNF-α Ab treatment is as effective as testosterone supplementation on penile structure normalization in the hyperPRL model.


Hippocampal-Prefrontal Reactivation during Learning Is Stronger in Awake Compared with Sleep States.
Hippocampal sharp-wave ripple (SWR) events occur during both behavior (awake SWRs) and slow-wave sleep (sleep SWRs). Awake and sleep SWRs both contribute to spatial learning and memory, thought to be mediated by the coordinated reactivation of behavioral experiences in hippocampal-cortical circuits seen during SWRs. Current hypotheses suggest that reactivation contributes to memory consolidation processes, but whether awake and sleep reactivation are suited to play similar or different roles remains unclear. Here we addressed that issue by examining the structure of hippocampal (area CA1) and prefrontal (PFC) activity recorded across behavior and sleep stages in male rats learning a spatial alternation task. We found a striking state difference: prefrontal modulation during awake and sleep SWRs was surprisingly distinct, with differing patterns of excitation and inhibition. CA1-PFC synchronization was stronger during awake SWRs, and spatial reactivation, measured using both pairwise and ensemble measures, was more structured for awake SWRs compared with post-task sleep SWRs. Stronger awake reactivation was observed despite the absence of coordination between network oscillations, namely hippocampal SWRs and cortical delta and spindle oscillations, which is prevalent during sleep. Finally, awake CA1-PFC reactivation was enhanced most prominently during initial learning in a novel environment, suggesting a key role in early learning. Our results demonstrate significant differences in awake and sleep reactivation in the hippocampal-prefrontal network. These findings suggest that awake SWRs support accurate memory storage and memory-guided behavior, whereas sleep SWR reactivation is better suited to support integration of memories across experiences during consolidation.SIGNIFICANCE STATEMENT Hippocampal sharp-wave ripples (SWRs) occur both in the awake state during behavior and in the sleep state after behavior. Awake and sleep SWRs are associated with memory reactivation and are important for learning, but their specific memory functions remain unclear. Here, we found profound differences in hippocampal-cortical reactivation during awake and sleep SWRs, with key implications for their roles in memory. Awake reactivation is a higher-fidelity representation of behavioral experiences, and is enhanced during early learning, without requiring coordination of network oscillations that is seen during sleep. Our findings suggest that awake reactivation is ideally suited to support initial memory formation, retrieval and planning, whereas sleep reactivation may play a broader role in integrating memories across experiences during consolidation.


Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability.
Familial cases of frontotemporal dementia (FTD) provide an opportunity to study the pathophysiology of this clinically diverse condition. The C9ORF72 mutation is the most common cause of familial FTD, recent pathological descriptions challenge existing TDP-43 based hypotheses of sporadic FTD pathogenesis. Non-ATG dependent translation of the hexanucleotide expansion into aggregating dipeptide repeat (DPR) proteins may represent a novel pathomechanism. We report detection of the DPR aggregates very early in C9ORF72 FTD development and also describe childhood intellectual disability as a clinical feature preceding dementia. The index case presented with psychiatric symptoms, progressing into typical FTD. Autopsy revealed extensive neuronal DPR aggregates but only minimal TDP-43 pathology. Her intellectually disabled elder son, also carrying the C9ORF72 mutation, died aged 26 years and at autopsy only DPR aggregates without TDP-43 were found. A second son also has intellectual disability, his C9ORF72 status is unknown, but chromosomal microarray revealed no other cause of disability. These cases both extend the existing phenotype of C9ORF72 mutation and highlight the potential significance of DPR translation early in disease development.


Pathways in the association between sugar sweetened beverages and child asthma traits in the 2nd year of life: Findings from the BRISA cohort.
Studies on the exposure of children to sugar-sweetened beverages (SSBs) at an early age may contribute to better understand the common causes and the temporal order of the relationships between obesity and asthma in early childhood. The objective of this study was to estimate the association between SSB and child asthma traits in the 2nd year of life, modeling direct and indirect pathways mediated by the highest BMI-z of the child and allergic inflammation. Data from the BRISA cohort, São Luís-MA, Brazil (n = 1140), were obtained from the baseline and from the follow-up performed at the 2nd year of life. The main explanatory variable was the calories from added sugars in SSBs as a percentage of the total daily energy intake. The outcome child asthma traits was a latent variable deduced from four indicators: medical diagnosis of asthma, wheezing, emergency visit due to intense wheezing, and medical diagnosis of rhinitis. A high percentage of daily calories from sugars added to SSBs was directly associated with higher values of child asthma traits (standardized coefficient (SC = 0.073; P = .030)). High levels of eosinophils were also directly associated with child asthma traits (SC = 0.118; P = .049). No mediation pathways were observed via greater BMI-z or eosinophil counts. Therefore, early exposure of children to SSB may contribute to increased risk of childhood asthma, preceding the link between sugar consumption and overweight/obesity, not yet evident in children in the first 2 years of life.


The Impact of Residual Subgingival Cement on Biological Complications Around Dental Implants: A Systematic Review.
To perform a systematic review on the impact of residual subgingival cement on peri-implant diseases and crestal bone loss. MEDLINE, SCOPUS, ISI Web of Knowledge and Cochrane Central Register of Controlled Trials (CENTRAL) databases were used to identify articles published without time limits. A total of 6 articles were selected for a total of 389 patients (687 implants). The studies were heterogeneous and had a moderate-to-high risk of bias, but met the inclusion criteria. Four of 6 studies were published by the same research group and assessed similar populations over time. A positive relationship between residual cement and peri-implant inflammation was observed. Data on peri-implant probing depths and crestal bone loss were reported in 1 study. Residual subgingival cement seems to be strongly associated with peri-implant mucositis which is a risk factor for increased probing depths crestal bone loss and peri-implantitis. Zinc oxide eugenol cements should be preferred to resin cements especially in patients with a history of periodontitis.


Biotransformation of organic selenium compounds in budding yeast, Saccharomyces cerevisiae.
Selenium (Se) is not essential for yeast growth, but it has a metabolic capacity to transform inorganic Se species to organic Se compounds such as selenomethionine (SeMet). Although the metabolism of inorganic Se species has been well discussed, there are no studies revealing how organic Se compounds are metabolized in yeast. The aim of this study was to show the specific metabolic pathway of organic Se species in yeast. We performed the speciation analysis of selenometabolites in budding yeast, Saccharomyces cerevisiae, exposed to selenometabolites produced by animals, plants, and microorganisms, such as methyl-2-acetamido-2-deoxy-1-seleno-β-d-galactopyranoside (SeSug1, selenosugar 1), methyl-2-acetamido-2-deoxy-1-seleno-β-d-glucopyranoside (SeSug2, selenosugar 2), trimethylselenonium ions (TMSe), Se-methylselenocysteine (MeSeCys), and SeMet. Four selenometabolites, SeSug1, SeSug2, SeMet, and MeSeCys, were commonly metabolized into SeMet in yeast. Yeast was able to incorporate TMSe but could not metabolize it. Since MeSeCys and selenosugars are the major selenometabolites in plants and animals, respectively, yeast is useful for recovering Se as SeMet from the selenometabolites produced by other organisms in the ecosystem.


Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.


14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival.
Integrated cascades of protein tyrosine and serine/threonine phosphorylation play essential roles in transducing signals in response to growth factors and cytokines. How adaptor or scaffold proteins assemble signaling complexes through both phosphotyrosine and phosphoserine/threonine residues to regulate specific signaling pathways and biological responses is unclear. We show in multiple cell types that endogenous 14-3-3zeta is phosphorylated on Tyr(179) in response to granulocyte macrophage colony-stimulating factor. Importantly, 14-3-3zeta can function as an intermolecular bridge that couples to phosphoserine residues and also directly binds the SH2 domain of Shc via Tyr(179). The assembly of these 14-3-3:Shc scaffolds is specifically required for the recruitment of a phosphatidylinositol 3-kinase signaling complex and the regulation of CTL-EN cell survival in response to cytokine. The biological significance of these findings was further demonstrated using primary bone marrow-derived mast cells from 14-3-3zeta(-/-) mice. We show that cytokine was able to promote Akt phosphorylation and viability of primary mast cells derived from 14-3-3zeta(-/-) mice when reconstituted with wild type 14-3-3zeta, but the Akt phosphorylation and survival response was reduced in cells reconstituted with the Y179F mutant. Together, these results show that 14-3-3:Shc scaffolds can act as multivalent signaling nodes for the integration of both phosphoserine/threonine and phosphotyrosine pathways to regulate specific cellular responses.


Adolescent coping: the different ways in which boys and girls cope.
In order to investigate the ways in which boys and girls cope with their concerns, 650 Year 11 and Year 12 students from seven post-primary schools in Melbourne, Australia were asked to describe how they cope with the main concerns in their lives. In addition to elicitation of spontaneous responses, a modified form of the Ways of Coping Checklist (Folkman and Lazarus, 1980; 1985b) was also administered to obtain an assessment of students coping strategies. Clear differences were found between the ways in which boys and girls cope. Girls seek more social support and generally are more likely than boys to focus on relationships. They also employ more strategies related to hoping for the best and wishful thinking. The question of how boys and girls can develop their coping repertoire so as to increase the adaptability of their responses in difficult situations is also addressed.


Intelligent Sea States Identification Based on Maximum Likelihood Evidential Reasoning Rule.
It is necessary to switch the control strategies for propulsion system frequently according to the changes of sea states in order to ensure the stability and safety of the navigation. Therefore, identifying the current sea state timely and effectively is of great significance to ensure ship safety. To this end, a reasoning model that is based on maximum likelihood evidential reasoning (MAKER) rule is developed to identify the propeller ventilation type, and the result is used as the basis for the sea states identification. Firstly, a data-driven MAKER model is constructed, which fully considers the interdependence between the input features. Secondly, the genetic algorithm (GA) is used to optimize the parameters of the MAKER model in order to improve the evaluation accuracy. Finally, a simulation is built to obtain experimental data to train the MAKER model, and the validity of the model is verified. The results show that the intelligent sea state identification model that is based on the MAKER rule can identify the propeller ventilation type more accurately, and finally realize intelligent identification of sea states.


Pathogenesis of cognitive dysfunction in patients with obstructive sleep apnea: a hypothesis with emphasis on the nucleus tractus solitarius.
OSA is characterized by the quintessential triad of intermittent apnea, hypoxia, and hypoxemia due to pharyngeal collapse. This paper highlights the upstream mechanisms that may trigger cognitive decline in OSA. Three interrelated steps underpin cognitive dysfunction in OSA patients. First, several risk factors upregulate peripheral inflammation; these crucial factors promote neuroinflammation, cerebrovascular endothelial dysfunction, and oxidative stress in OSA. Secondly, the neuroinflammation exerts negative impact globally on the CNS, and thirdly, important foci in the neocortex and brainstem are rendered inflamed and dysfunctional. A strong link is known to exist between neuroinflammation and neurodegeneration. A unique perspective delineated here underscores the importance of dysfunctional brainstem nuclei in etiopathogenesis of cognitive decline in OSA patients. Nucleus tractus solitarius (NTS) is the central integration hub for afferents from upper airway (somatosensory/gustatory), respiratory, gastrointestinal, cardiovascular (baroreceptor and chemoreceptor) and other systems. The NTS has an essential role in sympathetic and parasympathetic systems also; it projects to most key brain regions and modulates numerous physiological functions. Inflamed and dysfunctional NTS and other key brainstem nuclei may play a pivotal role in triggering memory and cognitive dysfunction in OSA. Attenuation of upstream factors and amelioration of the NTS dysfunction remain important challenges.


Current Opinion on Optimal Treatment Choices in First-line Therapy for Advanced or Metastatic Colorectal Cancer: Report From the Adelaide Colorectal Tumour Group Meeting; Stockholm, Sweden; September 2008.
The medical treatment of patients with metastatic colorectal cancer (mCRC) has evolved greatly in the past 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of the targeted monoclonal antibodies bevacizumab, cetuximab, and panitumumab in the treatment of patients with mCRC is now well-established, but the optimal timing of their use requires careful consideration in order to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and epidermal growth factor receptor-targeted biologic agents (cetuximab and panitumumab) in the treatment of patients with mCRC. This article reviews the evidence in support of modern treatments for mCRC and the decision making behind the treatment choices as well as their benefits and toxicities. An evidence-based algorithm is proposed that incorporates the use of these biologic agents early in the treatment of patients with initially nonresectable mCRC based on clearly defined tumor-related factors dependent on the immediate treatment goal. Real-world application of this algorithm is dependent on an individual countries' approval of access to new biologic agents.


Parental management of peer relationships and early adolescents' social skills.
Despite a growing body of research on parental management of peer relationships, little is known about the relationship between parental management of peers and early adolescents' social skills or the precursors to parental management of peer relationships. The goals of this short-term longitudinal investigation were to examine the relationship between parental management of peers (consulting and guiding), conflict about peers, and adolescents' social skills (cooperation, assertion, responsibility, empathy, and self-control) and to examine potential precursors (goals of improving peer relationships and beliefs about authority over peer relationships) to parental management of peer relationships. A predominantly White sample (71%) of 75 seventh-graders (57% female) and their primary caregivers participated in the 9-month investigation. Caregivers completed questionnaires regarding goals of improving their adolescents' peer relationships, beliefs about parental authority over peer relationships, parental management of peers, and adolescents' social skills. Adolescents completed questionnaires regarding their social skills. Path analyses suggest that a greater number of caregivers' goals of improving peer relationships and higher beliefs about parental authority over peers were related to higher levels of consulting, guiding, and conflict about peers. Higher levels of conflict about peers in conjunction with higher levels of consulting were related to lower levels of assertion and responsibility in peer relationships over time. When parents reported having a greater number of goals of improving peer relationships, adolescents reported higher levels of cooperation, assertion, empathy, and self control over time. Findings suggest that caregivers' goals and beliefs are important in predicting parental management of peer relationships and adolescents' social skills over time, and that conflict about peers undermines caregivers' efforts to be positively involved in adolescents' peer relationships.


Administration-dependent efficacy of ferrociphenol lipid nanocapsules for the treatment of intracranial 9L rat gliosarcoma.
The anti-tumour effect of ferrociphenol (FcdiOH)-loaded lipid nanocapsules (LNCs), with or without a DSPE-mPEG2000 coating, was evaluated on an orthotopic gliosarcoma model after administration by convection-enhanced delivery (CED) technique or by intra-carotid injection. No toxicity was observed by MRI nor by MRS in healthy rats receiving a CED injection of FcdiOH-LNCs (60μL, 0.36mg of FcdiOH/rat) when the pH and osmolarity had been adjusted to physiological values prior to injection. At this dose, the treatment by CED with FcdiOH-LNCs significantly increased the survival time of tumour-bearing rats in comparison with an untreated group (28.5 days vs 25 days, P=0.0009) whereas DSPE-mPEG2000-FcdiOH-LNCs did not exhibit any efficacy with a median survival time of 24 days. After intra-carotid injection (400μL, 2.4mg of FcdiOH/rat), hyperosmolar DSPE-mPEG2000-FcdiOH-LNCs markedly increased the median survival time (up to 30 days, P=0.0008) as compared to the control (20%). This was strengthened by their evidenced accumulation in the tumour zone and by the measure of the fluorescent brain surface obtained on brain slides for these DiI-labelled LNCs, being 3-fold higher than for the control. These results demonstrated that, depending upon the administration route used, the characteristics of LNC suspensions had to be carefully adapted.


Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3.
Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate dehydrogenase complex component X (PDHX) was demonstrated to be associated with sperm metabolism and affected the boar sperm viability, motility, and fertility. Pyruvate Dehydrogenase Kinases (PDKs) are the key metabolic enzymes that regulate pyruvate dehydrogenase complex (PDHC) activity and also the conversion from glycolysis to oxidative phosphorylation. In the present study, two PDK inhibitors, Dichloroacetate (DCA) and Phenylbutyrate (4-PBA), were added to an extender and investigated to determine their regulatory roles in liquid-stored boar sperm at 17 °C. The results indicated that PDK1 and PDK3 were predominantly located at the head and flagella of the boar sperm. The addition of 2 mM DCA and 0.5 mM 4-PBA significantly enhanced the sperm motility, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), and ATP content. In addition, DCA and 4-PBA exerted their effects by inhibiting PDK1 and PDK3, respectively. In conclusion, DCA and 4-PBA were found to regulate the boar sperm metabolic activities via PDK1 and PDK3. These both can improve the quality parameters of liquid-stored boar sperm, which will help to improve and optimize liquid-stored boar semen after their addition in the extender.


[Preventive systemic cyclosporin A in risk keratoplasty].
Systemic cyclosporin A prophylaxis was applied in 18 high-risk corneal transplants. Immunoreactions occurred in three cases. They correlated with too low serum level of cyclosporin A. Two of them could be reversed by an increase of cyclosporin A dosage in combination with an intensive corticosteroid therapy. Four corneal transplants failed from persistent severe basic disease. Eleven corneal transplants remained clear during the follow-up (5-33 months). A constant trough cyclosporin A serum level of 100-120 ng/ml has been shown to exert efficient immunomodulating effects. We currently judge a postoperative prophylaxis period of 6 to 12 months with cyclosporin A to be sufficient in most high-risk cases.


Androstanediol and 5-androstenediol profiling for detecting exogenously administered dihydrotestosterone, epitestosterone, and dehydroepiandrosterone: potential use in gas chromatography isotope ratio mass spectrometry.
The basis of a potential method for confirming intake of four natural androgens (testosterone, epitestosterone, dihydrotestosterone, and dehydroepiandrosterone is presented. The method relies on isolating from urine a steroid fraction containing androstenediol and androstanediol metabolites of these natural steroids and analyzing their 13C content by gas chromatography, combustion, isotope ratio mass spectrometry. The steroids were recovered from urine by conjugate hydrolysis with a Helix pomatia preparation (sulfatase and beta-glucuronidase), Girard T reagent separation to obtain a nonketonic fraction, and Sephadex LH-20 chromatography for purification. Metabolites appropriate for all of the natural steroids could be separated (as diacetates) by gas chromatography on a DB-17 capillary column viz.: 5 alpha (and beta)-androstane-3 alpha,17 alpha-diol (epitestosterone as precursor); 5 alpha (and beta)-androstane-3 alpha,17 beta-diol (testosterone as precursor); 5-androstene-3 beta,17 beta-diol (dehydroepiandrosterone precursor); and 5 alpha-androstane-3 alpha,17 beta- (and 17 alpha-) diol (dihydrotestosterone precursor). Measurement of the 13C content of the specific analytes after ingestion of the androgen precursors demonstrated a lowering of delta 13C/1000 value compared to normal values. Typically, in the male individual studied, delta 13C/1000 values for all components were -26 to -27 before drug administration and -29 to -30 at 6 h after, the latter values reflecting those obtaining for commercial synthetic steroid compared to in vivo synthesized steroid. While generally the metabolism of the steroids was as expected, this was not the case for 5 alpha-dihydrotestosterone. A major metabolite was 5 alpha-androstane-3 alpha,17 alpha-diol, which had presumably been formed by 17 beta/17 alpha isomerization, a process previously known for unnatural anabolics but not for natural hormones. The isolation, purification, and isotope ratio mass spectrometry techniques described may form the basis of a general method for confirming natural steroid misuse by sports participants.


The morbidity and mortality of vermiculite miners and millers exposed to tremolite-actinolite: Part III. Radiographic findings.
A study was conducted to estimate the exposure-response relationship for tremolite-actinolite fiber exposure and radiographic findings among 184 men employed at a Montana vermiculite mine and mill. Workers were included if they had been employed during 1975-1982 and had achieved at least 5 years tenure at the Montana site. Past fiber exposure was associated with an increased prevalence of parenchymal and pleural radiographic abnormalities. Smoking was not significantly related to the prevalence of small opacities. However, the number of workers who had never smoked was small, and this prevented measurement of the smoking effect. Under control for smoking and age, the prevalence of small opacities was significantly greater for vermiculite workers with greater than 100 fiber/cc-years exposure than for comparison groups (cement workers, blue collar workers, and coal miners) who had no known occupational fiber exposure. A logistic model predicted an increase of 1.3% in the odds ratio for small opacities at an additional exposure of 5 fiber-years.


DNA conserved in diverse animals since the Precambrian controls genes for embryonic development.
DNA that controls gene expression (e.g. enhancers, promoters) has seemed almost never to be conserved between distantly-related animals, like vertebrates and arthropods. This is mysterious, because development of such animals is partly organized by homologous genes with similar complex expression patterns, termed "deep homology". Here we report twenty-five regulatory DNA segments conserved across bilaterian animals, of which seven are also conserved in cnidaria (coral and sea anemone). They control developmental genes (e.g. Nr2f, Ptch, Rfx1/3, Sall, Smad6, Sp5, Tbx2/3), including six homeobox genes: Gsx, Hmx, Meis, Msx, Six1/2, and Zfhx3/4. The segments contain perfectly or near-perfectly conserved CCAAT boxes, E-boxes, and other sequences recognized by regulatory proteins. More such DNA conservation will surely be found soon, as more genomes are published and sequence comparison is optimized. This reveals a control system for animal development conserved since the Precambrian.


[Achondroplasia: molecular study of 28 patients].
The main goal of the study is to investigate in the Spanish population the value of searching for the Gly380Arg mutation in the transmembrane domain of fibroblast growth factor receptor-3 (FGFR3#) as the basis for the molecular diagnosis of achondroplasia. Twenty eight achondroplastic patients were studied. Genomic DNA obtained from blood was used to amplify using PCR a 164 bp segment of FGFR3 encompassing the transmembrane domain. The occurrence of the G-->A transition and of the G-->C transversion at the first base of codon 380 were investigated by digestion with the restriction enzymes Sfcl and Mspl followed by electrophoretic analysis of the products. All achondroplastic patients were found to be heterozygous for the Gly380Arg mutation, as a consequence of the G-->A transition in 27 cases and of the G-->C transversion in the remaining patient. None of these changes were found in control subjects including a hypochondroplastic patient. The identification of the Gly380Arg mutation can be used in Spain for conclusive diagnosis of achondroplasia. The guanine at the first position of codon 380 of FGFR3 exhibits similarly increased frequency of mutation than in other populations, an thus it is unlikely that the genetic background of the population determines the mutation potential of this guanine.


Excitation energies of retinal chromophores: critical role of the structural model.
We employ a variety of highly-correlated approaches including quantum Monte Carlo (QMC) and the n-electron valence state perturbation theory (NEVPT2) to compute the vertical excitation energies of retinal protonated Schiff base (RPSB) models in the gas phase. We find that the NEVPT2 excitation energies are in good agreement with the QMC values and confirm our previous findings that the complete-active-space perturbation (CASPT2) approach yields accurate excitations for RPSB models only when the more recent zero-order IPEA Hamiltonian is employed. The excitations computed with the original zero-order formulation of CASPT2 are instead systematically red-shifted by more than 0.3 eV. We then focus on the full 11-cis retinal chromophore and show that the M06-2X and MP2 approaches provide reliable ground-state equilibrium structures for this system while the complete-active-space self-consistent field (CASSCF) geometry is characterized by significantly higher ground-state energies at the NEVPT2 and CASPT2 level. Our calibration of the structural model together with the general agreement of all highly-correlated excited-state methods allows us to reliably assign a value of about 2.3 eV to the vertical excitation of 11-cis RPSB in the gas-phase.


Working Memory in Unilateral Spatial Neglect: Evidence for Impaired Binding of Object Identity and Object Location.
Working memory (WM) is known to be impaired in patients with stroke experiencing unilateral spatial neglect (USN). Here, we examined in a systematic manner three WM components: memory of object identity, memory of object location, and binding between object identity and location. Moreover, we used two different retention intervals to isolate maintenance from other mnemonic and perceptual processes. Fourteen USN first-event stroke patients with right-hemisphere damage were tested in two different WM experiments using long and short retention intervals and an analog response scale. Patients exhibited more identification errors for items displayed on the contralesional side. Localization errors were also more prominent in the contralesional side, especially after a long retention interval. These localization errors were often a result of swap errors, that is, erroneous localizations of correctly identified contralesional objects in correctly memorized locations of ipsilesional objects. We conclude that a key WM deficit in USN is a lateralized impairment in binding between the identity of an object and its spatial tag.


Pediatric cranial deformations: demographic associations.
No study has established a relationship between cranial deformations and demographic factors. While the connection between the Back to Sleep campaign and cranial deformation has been outlined, considerations toward cultural or anthropological differences should also be investigated. The authors conducted a retrospective review of 1499 patients (age range 2 months to less than 19 years) who presented for possible trauma in 2018 and had a negative CT scan. The cranial vault asymmetry index (CVAI) and cranial index (CI) were used to evaluate potential cranial deformations. The cohort was evaluated for differences between sex, race, and ethnicity among 1) all patients and 2) patients within the clinical treatment window (2-24 months of age). Patients categorized as "other" and those for whom data were missing were excluded from analysis. In the CVAI cohort with available data (n = 1499, although data were missing for each variable), 800 (56.7%) of 1411 patients were male, 1024 (79%) of 1304 patients were Caucasian, 253 (19.4%) of 1304 patients were African American, and 127 (10.3%) of 1236 patients were of Hispanic/Latin American descent. The mean CVAI values were significantly different between sex (p < 0.001) and race (p < 0.001). However, only race was associated with differences in positional posterior plagiocephaly (PPP) diagnosis (p < 0.001). There was no significant difference in CVAI measurements for ethnicity (p = 0.968). Of the 520 patients in the treatment window cohort, 307 (59%) were male. Of the 421 patients with data for race, 334 were Caucasian and 80 were African American; 47 of the 483 patients with ethnicity data were of Hispanic/Latin American descent. There were no differences between mean CVAI values for sex (p = 0.404) or ethnicity (p = 0.600). There were significant differences between the mean CVAI values for Caucasian and African American patients (p < 0.001) and rate of PPP diagnosis (p = 0.02). In the CI cohort with available data (n = 1429, although data were missing for each variable), 849 (56.8%) of 1494 patients were male, 1007 (67.4%) of 1283 were Caucasian, 248 (16.6%) of 1283 were African American, and 138 patients with ethnicity data (n = 1320) of Hispanic/Latin American descent. Within the clinical treatment window cohort with available data, 373 (59.2%) of 630 patients were male, 403 were Caucasian (81.9%), 84 were African American (17.1%), and 55 (10.5%) of 528 patients were of Hispanic/Latin American descent. The mean CI values were not significantly different between sexes (p = 0.450) in either cohort. However, there were significant differences between CI measurements for Caucasian and African American patients (p < 0.001) as well as patients of Hispanic/Latin American descent (p < 0.001) in both cohorts. The authors found no significant associations between cranial deformations and sex. However, significant differences exist between Caucasian and African American patients as well as patients with Hispanic/Latin American heritage. These findings suggest cultural or anthropological influences on defining skull deformations. Further investigation into the factors contributing to these differences should be undertaken.


Reducing mental health disparities through transformative learning: a social change model with refugees and students.
Distribution of power and resources greatly impacts the mental health of individuals and communities. Thus, to reduce mental health disparities, it is imperative to address these social determinants of mental health through social change. Engaging in social change efforts requires people to critically engage with present conditions on personal, local, national, and global levels and to develop knowledge, capacity, and experience with envisioning and creating more equitable conditions. This critical engagement can be fostered through a process of transformative learning. In this article, we examine the Refugee Well-being Project (RWP), a program that aims to improve the mental health of refugees in the United States. From 2007 to 2009, participants in the RWP in New Mexico were refugees from the Great Lakes region of Africa. The RWP paired undergraduate students with refugees to engage in mutual learning and advocacy. Data from in-depth qualitative interviews with 72 refugees and 53 undergraduate students suggest that participation in the RWP constituted a transformative learning experience through which refugees and students came to new understandings of the relationship between social inequities and well-being. For many, this provided an impetus to work toward change at multiple levels.


A unified simulation model for understanding the diversity of cancer evolution.
Because cancer evolution underlies the therapeutic difficulties of cancer, it is clinically important to understand the evolutionary dynamics of cancer. Thus far, a number of evolutionary processes have been proposed to be working in cancer evolution. However, there exists no simulation model that can describe the different evolutionary processes in a unified manner. In this study, we constructed a unified simulation model for describing the different evolutionary processes and performed sensitivity analysis on the model to determine the conditions in which cancer growth is driven by each of the different evolutionary processes. Our sensitivity analysis has successfully provided a series of novel insights into the evolutionary dynamics of cancer. For example, we found that, while a high neutral mutation rate shapes neutral intratumor heterogeneity (ITH) characterized by a fractal-like pattern, a stem cell hierarchy can also contribute to shaping neutral ITH by apparently increasing the mutation rate. Although It has been reported that the evolutionary principle shaping ITH shifts from selection to accumulation of neutral mutations during colorectal tumorigenesis, our simulation revealed the possibility that this evolutionary shift is triggered by drastic evolutionary events that occur in a short time and confer a marked fitness increase on one or a few cells. This result helps us understand that each process works not separately but simultaneously and continuously as a series of phases of cancer evolution. Collectively, this study serves as a basis to understand in greater depth the diversity of cancer evolution.


The roles of cytochrome p450 in ischemic heart disease.
Cytochrome P450 (CYP) represents a large family of enzymes that catalyze the oxidation of endogenous and exogenous compounds. The functions of CYP enzymes in the metabolism of xenobiotics have well been established in the liver. However, some CYP enzymes are highly expressed in the heart and catalyze arachidonic acid oxidation to a variety of eicosanoids, which attenuates ischemia-reperfusion injury of the heart. CYP-mediated cardioprotection is associated with activation of multiple pathways such as sarcolemmal and mitochondrial potassium channels, p42/p44 MAPK and PI3K-AKT signaling in cells. CYP enzymes also represent a significant source of reactive oxygen species (ROS) that may target cellular homeostatic mechanisms and mitochondria. CYP isoforms expressed in the heart are critical for generation of epoxyeicosatrienoic acids (EETs) and ROS. It has been demonstrated that CYP2J2 generates cardioprotective EETs, whereas another isozyme in the heart, CYP2C, generates EETs as well as detrimental ROS. Genetic polymorphisms of CYP2C or CYP2J2 have a pathologic impact on coronary artery diseases. Cardiac CYP enzymes can be involved in drug metabolism within the heart and influence pharmacologic efficacy. Metabolism mediated by CYP enzymes influences the survival of cardiomyocytes during ischemia, which is critical for treatment of human ischemic heart disease. In this review, we summarize current knowledge of this enzyme family and discuss the roles of CYP in ischemia-reperfusion injury of the heart.


Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.
To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.


Glucocorticoid receptors and steroid sensitivity in normal and neoplastic human lymphoid tissues: a review.
The determination of estrogen and progesterone receptors in breast cancer has been shown to be useful in predicting the response to endocrine therapy. Given their well-known inhibitory effects on lymphoid tissue, glucocorticoids have been used widely in the treatment of leukemia. Given these facts, over the last 10 years, several investigators have measured the number of glucocorticoid receptors in normal and neoplastic lymphoid tissue to see whether their number correlated with glucocorticoid responsiveness in vitro or in vivo. No clear correlation could be established between the level of glucocorticoid receptor and the in vitro action of steroids in normal and neoplastic lymphoid tissue. In contrast, attempts to correlate glucocorticoid receptor levels in acute lymphocytic leukemia to in vivo steroid responsiveness and immunological type using the whole-cell-binding assay for receptor determination and selecting the patients according to age and immunological criteria have been more successful.


["Doctor, the child does not eat": a motive for consultation].
To find the incidence of "Doctor, the child's not eating" as a motive for requesting a consultation and to check whether there is an accompanying pathology and/or poor nutritional habits. Descriptive, crossover study. Rural Health Centre, Santa Amalia (Badajoz). Family members with 148 children, attending on their own initiative and seeking care for "he/she's not eating" between August and October 1996. 148 of 1,244 consultations were for "he/she not eating" (incidence 11.89%). 52.02% of them were male. The age group which attended most was from 1 to 4 years old (48.64%), followed by 36 cases between 7 and 12 months (24.32%). We observed an accompanying pathology in 71 (41.98%), most frequently catarrh of the upper passages and urinary tract infection. The fact that one of every 12 consultations was because a child had lost his/her appetite had two main interpretations: it is a common occurrence which worries parents quite a lot; and many parents lack information about feeding their children, as to quantity and the ways of administering the food.


Donor Recruitment for Fecal Microbiota Transplantation.
Increasing demand for fecal microbiota transplantation (FMT) has created a need for stool banks sourced from long-term healthy donors. Here, we describe our experience in recruiting and screening fecal donors. Mailbox, newspaper, and online advertisements were used. Potential donors were required to satisfy a prescreen telephone conversation, pass blood and stool investigations, then undertake a screening interview including medical history, physical examination, and evaluation of donor selection criteria. One hundred sixteen potential donors were prescreened of whom 74 failed-47 declined based on study donation requirements (primarily related to frequency and duration of donations), 13 had medical comorbidities, 6 variant Creutzfeldt-Jakob disease risk factors, 8 for other reasons. Thirty-eight completed stool and blood testing-1 failed blood testing (indeterminate hepatitis C serology), whereas 15 failed stool investigations (5 Dientamoeba fragilis, 5 Blastocystis hominis, 1 B. hominis and D. fragilis, 1 Giardia intestinalis plus D. fragilis, 1 Norovirus plus Clostridium difficile toxin positive, and 2 leucocytes or erythrocytes on stool microscopy). Of the 18 potential donors proceeding to screening interview, 6 were excluded (3 body mass index >30, 1 illicit drug use, 1 uncontrolled anxiety and concerns regarding compliance, 1 irregular bowel movements after new medication commencement). In total, only 12 of 116 (10%) potential donors were enrolled as study donors. Recruitment of fecal donors for FMT is challenging with only a small percentage ultimately serving as donors. Many were unable or unwilling to meet the donor commitment requirements. A surprisingly large proportion of healthy asymptomatic donors failed stool testing, primarily due to gastrointestinal parasites.


Control Measurements of Crane Rails Performed by Terrestrial Laser Scanning.
This article presents a method for measuring the geometry of crane rails with terrestrial laser scanning (TLS). Two sets of crane rails were divided into segments, their planes were adjusted, and the characteristic rail lines were defined. We used their profiles to define the positional and altitude deviations of the rails, the span and height difference between the two rails, and we also verified that they complied with the Eurocode 3 standard. We tested the method on crane rails at the hydroelectric power plant in Krško and the thermal power plant in Brestanica. We used two scanning techniques: "pure" TLS (Riegel VZ-400) and "hybrid" TLS (Leica MS50) scanning. This article's original contribution lies in the detailed presentation of the computations used to define the characteristic lines of the rails without using the numeric procedures from existing software packages. We also analysed the influence of segment length and point density on the rail geometry results, and compared the two laser scanning techniques. We also compared the results obtained by terrestrial laser scanning with the results obtained from the classic polar method, which served as a reference point for its precision.