Discordance Between Invasive and NonInvasive Oxygen Saturation in Critically Ill COVID-19 Patients.
To investigate discordance in oxy-hemoglobin saturation measured both by pulse oximetry (SpO2) and arterial blood gas (ABG, SaO2) among critically ill coronavirus disease 2019 (COVID-19(+)) patients compared to COVID-19(-) patients. Paired SpO2 and SaO2 readings were collected retrospectively from consecutive adult admissions to four critical care units in the United States between March and May 2020. The primary outcome was the rate of discordance (|SaO2-SpO2|>4%) in COVID-19(+) versus COVID-19(-) patients. The odds each cohort could have been incorrectly categorized as having a PaO2/FiO2 above or below 150 by their SpO2: Fractional inhaled oxygen ratio (pulse oximetry-derived oxyhemoglobin saturation:fraction of inspired oxygen ratio [SF]) was examined. A multivariate regression analysis assessed confounding by clinical differences between cohorts including pH, body temperature, renal replacement therapy at time of blood draw, and self-identified race. There were 263 patients (173 COVID-19(+)) included. The rate of saturation discordance between SaO2 and SpO2 in COVID-19(+) patients was higher than in COVID-19(-) patients (27.9% vs 16.7%, odds ratio [OR] 1.94, 95% confidence interval [CI]: 1.11 to 2.27). The average difference between SaO2 and SpO2 for COVID-19(+) patients was -1.24% (limits of agreement, -13.6 to 11.1) versus -0.11 [-10.3 to 10.1] for COVID-19(-) patients. COVID-19(+) patients had higher odds (OR: 2.61, 95% CI: 1.14-5.98) of having an SF that misclassified that patient as having a PaO2:FiO2 ratio above or below 150. There was not an association between discordance and the confounders of pH, body temperature, or renal replacement therapy at time of blood draw. After controlling for self-identified race, the association between COVID-19 status and discordance was lost. Pulse oximetry was discordant with ABG more often in critically ill COVID-19(+) than COVID-19(-) patients. However, these findings appear to be driven by racial differences between cohorts.


Effects of dietary mixtures of amino acids on fetal growth and maternal and fetal amino acid pools in experimental maternal phenylketonuria.
Branched-chain amino acids have been reported to improve fetal brain development in a rat model in which maternal phenylketonuria (PKU) is induced by the inclusion of an inhibitor of phenylalanine hydroxylase, DL-p-chlorophenylalanine, and L-phenylalanine in the diet. We studied whether a dietary mixture of several large neutral amino acids (LNAAs) would improve fetal brain growth and normalize the fetal brain amino acid profile in a rat model of maternal PKU induced by DL-alpha-methylphenylalanine (AMPhe). Long-Evans rats were fed a basal diet or a similar diet containing 0.5% AMPhe + 3.0% L-phenylalanine (AMPhe + Phe diet) from day 11 until day 20 of gestation in experiments to test various mixtures of LNAAs. Maternal weight gains and food intakes to day 20, fetal body and brain weights at day 20, and fetal brain and fetal and maternal plasma amino acid concentrations at day 20 were measured. Concentrations of phenylalanine and tyrosine in fetal brain and in maternal and fetal plasma were higher and fetal brain weights were lower in rats fed the AMPhe + Phe diet than in rats fed the basal diet. However, fetal brain growth was higher and concentrations of phenylalanine and tyrosine in fetal brain and in maternal and fetal plasma were lower in rats fed the AMPhe + Phe diet plus LNAAs than in rats fed the diet containing AMPhe + Phe alone. LNAA supplementation of the diet improved fetal amino acid profiles and alleviated most, but not all, of the depression in fetal brain growth observed in this model of maternal PKU.


IBSEM: An Individual-Based Atlantic Salmon Population Model.
Ecology and genetics can influence the fate of individuals and populations in multiple ways. However, to date, few studies consider them when modelling the evolutionary trajectory of populations faced with admixture with non-local populations. For the Atlantic salmon, a model incorporating these elements is urgently needed because many populations are challenged with gene-flow from non-local and domesticated conspecifics. We developed an Individual-Based Salmon Eco-genetic Model (IBSEM) to simulate the demographic and population genetic change of an Atlantic salmon population through its entire life-cycle. Processes such as growth, mortality, and maturation are simulated through stochastic procedures, which take into account environmental variables as well as the genotype of the individuals. IBSEM is based upon detailed empirical data from salmon biology, and parameterized to reproduce the environmental conditions and the characteristics of a wild population inhabiting a Norwegian river. Simulations demonstrated that the model consistently and reliably reproduces the characteristics of the population. Moreover, in absence of farmed escapees, the modelled populations reach an evolutionary equilibrium that is similar to our definition of a 'wild' genotype. We assessed the sensitivity of the model in the face of assumptions made on the fitness differences between farm and wild salmon, and evaluated the role of straying as a buffering mechanism against the intrusion of farm genes into wild populations. These results demonstrate that IBSEM is able to capture the evolutionary forces shaping the life history of wild salmon and is therefore able to model the response of populations under environmental and genetic stressors.


Young People Who Display Harmful Sexual Behaviors and Their Families: A Qualitative Systematic Review of Their Experiences of Professional Interventions.
It is estimated that 30-50% of all childhood sexual abuse involves other young people as perpetrators. The treatment of harmful sexual behavior (HSB) in young people has evolved from interventions developed for use with adult perpetrators of sexual offenses. Increasingly, these approaches were not seen as appropriate for use with young people. The purpose of this qualitative systematic review was to establish what intervention components are viewed as acceptable or useful by young people and their families in order to inform the development of interventions for young people with HSB. We conducted searches across 14 electronic databases as well as contacting experts to identify relevant studies. Thirteen qualitative studies were included in the analysis, reporting findings from intervention studies from the United Kingdom, United States, New Zealand, Australia, and Ireland. Thematic analysis was used to combine findings from the studies of young people and parent/carers views. Five key themes were identified as critical components of successful interventions for young people with HSB. These included the key role of the relationship between the young person and practitioner, the significance of the role of parents and carers, the importance of considering the wider context in which the abuse has occurred, the role of disclosure in interventions, and the need to equip young people with skills as well as knowledge. The evidence was limited by the small number of studies that were mainly from the perspectives of adolescent males.


Final thermal conditions override the effects of temperature history and dispersal in experimental communities.
Predicting the effect of climate change on biodiversity is a multifactorial problem that is complicated by potentially interactive effects with habitat properties and altered species interactions. In a microcosm experiment with communities of microalgae, we analysed whether the effect of rising temperature on diversity depended on the initial or the final temperature of the habitat, on the rate of change, on dispersal and on landscape heterogeneity. We also tested whether the response of species to temperature measured in monoculture allowed prediction of the composition of communities under rising temperature. We found that the final temperature of the habitat was the primary driver of diversity in our experimental communities. Species richness declined faster at higher temperatures. The negative effect of warming was not alleviated by a slower rate of warming or by dispersal among habitats and did not depend on the initial temperature. The response of evenness, however, did depend on the rate of change and on the initial temperature. Community composition was not predictable from monoculture assays, but higher fitness inequality (as seen by larger variance in growth rate among species in monoculture at higher temperatures) explained the faster loss of biodiversity with rising temperature.


Non-steroidal anti-inflammatory drugs in prevention of gastric cancer.
Non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase 2 (COX-2) selective inhibitors, are potential agents for the chemoprevention of gastric cancer. Epidemiological and experimental studies have shown that NSAID use is associated with a reduced risk of gastric cancer although many questions remain unanswered such as the optimal dose and duration of treatment. The possible mechanisms for the suppressor effect of NSAIDs on carcinogenesis are the ability to induce apoptosis in epithelial cells and regulation of angiogenesis. Both COX-dependent and COX-independent pathways have a role in the biological activity of NSAIDs. Knowledge of how NSAIDs prevent neoplastic growth will greatly aid the design of better chemopreventive drugs and novel treatments for gastric cancer.


The prevalence of irritable bowel syndrome-type symptoms in inflammatory bowel disease patients in remission.
Symptoms of irritable bowel syndrome (IBS) are common in inflammatory bowel disease (IBD) and are believed to reflect ongoing inflammation. Consequently, a low prevalence of IBS-type symptoms in IBD patients with normal inflammatory markers is expected. We aimed to investigate the prevalence of IBS-type symptoms in IBD patients in biochemical remission (evidenced by low fecal calprotectin levels) and the relationship of these symptoms with fecal calprotectin levels. In this observational, cross-sectional study, we included all adults with a history of IBD who had calprotectin levels less than 200 µg/g during routine follow-up between August 2014 and May 2015 at our hospital. Patients were excluded if calprotectin was measured because of gastrointestinal complaints. All patients were approached by telephone to evaluate the presence of IBS-type symptoms using Rome III questionnaires. Patients fulfilling IBS criteria were subclassified according to bowel habits. In total, 74 patients were included; 33 (45%, 95% confidence interval: 34-56%) fulfilled the IBS criteria. A larger proportion of Crohn's disease patients with IBS-type symptoms had ileal disease compared with Crohn's disease patients without IBS symptoms (55 vs. 24%; P=0.03). Other characteristics were similar between groups. No difference was found in calprotectin levels between patients with and without IBS-type symptoms (P=0.91). The majority of patients with IBS-type symptoms had diarrhea-predominant or mixed-type IBS (64 and 27% of patients with IBS-type symptoms, respectively). The prevalence of IBS-type symptoms in IBD patients in biochemical remission is high. A significant proportion of IBS-type symptoms is unrelated to ongoing inflammation and probably reflects 'true IBS'.


Assessment of chemical mixtures using biomarkers of combined biological activity: A screening study in human placentas.
Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Biomonitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling. Correlations among bioassays and their functional shapes were evaluated. Results showed that all placental extracts agonized or antagonized at least three of the abovementioned endpoints. Most placentas induced ER-mediated transactivation and ER-dependent cell proliferation, together with a strong inhibition of TH signaling and the AR transactivity; while the induction of the AhR was found in only one placental extract. The effects in the two estrogenic bioassays were positively and significantly correlated and the AR-antagonism activity showed a positive borderline-significant correlation with both estrogenic bioassay activities. However, the in vivo anti-thyroid activities of placental extracts were not correlated with any of the tested in vitro assays. Findings highlight the importance of comprehensively mapping the biological effects of "real-world" chemical mixtures present in human samples, through a battery of in vitro and in vivo bioassays. This approach should be a complementary tool for epidemiological studies to further elucidate the combined biological fingerprint triggered by chemical mixtures.


Effect of Chronotype on Sleep Quality in a Laboratory Setting.
Sleep is undoubtedly important for human health as insufficient sleep has been associated with a plethora of diseases. Adequate sleep assessment is critical in clinical and research settings, however current sleep assessment protocols fail to account for circadian rhythms, despite the fact that sleep is a well-recognized circadian process. The purpose of this study was to determine if circadian parameters, such as chronotype, influence sleep quality in a sleep laboratory setting. In order to investigate this, twenty participants (10 men and 10 women) aged 18-31 years old had their sleep recorded by electroencephalography in a sleep lab. Participants also complete surveys which provided data on chronotype, social jet lag and subjective sleep quality. Participants were allowed to self-select sleep time for the study, and sleep discrepancy, defined as the difference between reported and experienced mid-sleep, was determined. Interestingly, results indicated a significant correlation between self-reported sleep quality and social jet lag, with those who typically experience more social jet lag being more satisfied with their sleep during the study (r = 0.549, p = 0.012). In addition, when participants were separated into groups based on chronotype, sleep discrepancy and social jet lag, sizeable differences were noted for parameters such as sleep onset latency, number of awakenings, and percent of time spent in REM sleep. These results suggest circadian parameters serve as predictors of both subjective and objective sleep quality, and thus illuminates a necessity for these parameters to be taken into account in the assessment and research of sleep.


Febrile neutropenia and related complications in breast cancer patients receiving pegfilgrastim primary prophylaxis versus current practice neutropaenia management: results from an integrated analysis.
Granulocyte colony-stimulating factors (G-CSFs) reduce febrile neutropaenia (FN) incidence but may be used inconsistently in current practice (CP). This study compared the efficacy of pegfilgrastim primary prophylaxis (PPP) with CP neutropaenia management in breast cancer. Individual patient data (N=2282) from 11 clinical trials and observational studies using chemotherapy regimens with > or =15% FN risk and PPP (6 mg, all cycles) or CP (no G-CSF or any cycle G-CSF/pegfilgrastim) were included in an integrated analysis. Most patients received docetaxel-containing regimens. A generalised linear mixed model was fitted (N=2210). Neutropaenia prophylaxis (PPP versus CP), age and disease stage influenced the incidence of FN. Overall, FN was less frequent with PPP than with CP (odds ratio [OR]: 0.124; 95% confidence interval [CI]: 0.08, 0.194; P<0.0001). Odds for cycle 1 FN, dose reductions > or =15% and FN-related hospitalisation were also significantly lower with PPP. These data support PPP in breast cancer patients receiving chemotherapy with moderately high/high FN risk.


Ticagrelor Use in Acute Myocardial Infarction: Insights From the National Cardiovascular Data Registry.
Ticagrelor is a P2Y12 receptor inhibitor with superior clinical efficacy compared with clopidogrel. However, it is associated with reduced efficacy when combined with a high-dose aspirin. Patients in the acute coronary treatment and intervention outcomes network (ACTION) Registry-Get With The Guidelines (GWTG) with acute myocardial infarction from October 2013 through December 2014 were included in the study (167 455 patients; 622 sites). We evaluated temporal trends in the prescription of P2Y12 inhibitors, and identified factors associated with ticagrelor use at discharge. Among patients discharged on ticagrelor and aspirin (21 262 patients), we evaluated the temporal trends and independent factors associated with high-dose aspirin prescription at discharge. Ticagrelor prescription at discharge increased significantly from 12% to 16.7% (P<0.0001). Decreases in prasugrel and clopidogrel use at discharge (15.7%-13.9% and 54.2%-51.1%, respectively, P<0.0001) were also observed. Independent factors associated with preferential ticagrelor prescription at discharge over clopidogrel included younger age, white race, home ticagrelor use, invasive management, and in-hospital re-infarction and stroke (P<0.0001 for all), whereas older age, female sex, prior stroke, home ticagrelor use, and in-hospital stroke (P<0.0001 for all) were associated with preferential ticagrelor prescription at discharge over prasugrel. High-dose aspirin was used in 3.1% of patients discharged on ticagrelor. Independent factors associated with high-dose aspirin prescription at discharge included home aspirin use, diabetes mellitus, previous myocardial infarction, previous coronary artery bypass graft, ST-segment-elevation myocardial infarction, cardiogenic shock, and geographic region (P=0.01). Our contemporary analysis shows a modest but significant increase in the use of ticagrelor and a high rate of adherence to the use of low-dose aspirin at discharge.


Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration.
Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of "primed" microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live Salmonella typhimurium at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with S. typhimurium resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as Grm1 and Grin2a, showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.


Superior mesenteric artery branch--jejunal artery aneurysm.
Visceral artery aneurysm (VAA) is a relatively uncommon disorder and it shows some vague symptoms. Therefore, the clinical diagnosis is difficult and these aneurysms are discovered and diagnosed only after rupture in many cases. This case report describes the history of a woman who had a superior mesenteric artery (SMA) branch aneurysm. A 62-year-old woman presented with fatigue and moderate to severe epigastric and mid-back pain. A computed tomography of the abdomen and pelvis demonstrated a partially thrombosed aneurysm (38×40 mm) rising from the jejunal branch of the SMA. The aneurysm which contains mural thrombus is resected, and a saphenous vein graft interposition is performed between the ends of the same jejuno-jejunal artery. The patient's recovery was unremarkable, and she was discharged on postoperative day 7. Rapid diagnosis, localization, and surgical or endovascular interventions are necessary to avoid devastating consequences in VAAs. Saphenous vein graft interposition is a good choice for surgical intervention for patients not suitable for endovascular treatment.


The MgB2-catalyzed growth of boron nitride nanotubes using B/MgO as a boron containing precursor.
With the development of preparation technology, obtaining boron nitride nanotubes (BNNTs) is no longer difficult, but it is still not easy to balance the quality and purity of the obtained products using existing methods. In this work, we investigated a previously reported MgB2 catalyst to explore the synthesis of BNNTs at a higher temperature in a conventional chemical vapor deposition (CVD) system from a classic B/MgO precursor. Various characterization methods showed the high activity of MgB2 at 1400 °C and the superiority of the as-grown BNNTs in terms of purity and quality. Further reference experiments and element characterization measurements were also performed to verify the role of MgB2 in the growth of the BNNTs, finding that B/MgO/MgB2 is a simple and efficient precursor.


Determination of the rates of appearance and loss of glucose transporters at the cell surface of rat adipose cells.
We have used an impermeant bis-mannose compound (2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-mannos+ ++- 4-yloxy)-2- propylamine; ATB-BMPA) to photolabel the glucose transporter isoforms GLUT4 and GLUT1 that are present in rat adipose cells. Plasma-membrane fractions and light-microsome membrane fractions were both labelled by ATB-BMPA. The labelling of GLUT4 in the plasma membrane fraction from insulin-treated cells was approximately 3-fold higher than that of basal cells and corresponded with a decrease in the labelling of the light-microsome fraction. In contrast with this, the cell-surface labelling of GLUT4 from insulin-treated intact adipose cells was increased approximately 15-fold above basal levels. In these adipose cell preparations, insulin stimulated glucose transport activity approximately 30-fold. Thus the cell-surface labelling, but not the labelling of membrane fractions, closely corresponded with the stimulation of transport. The remaining discrepancy may be due to an approx. 2-fold activation of GLUT4 intrinsic transport activity. We have studied the kinetics of trafficking of transporters and found the following. (1) Lowering the temperature to 18 degrees C increased basal glucose transport and levels of cell-surface glucose transporters by approximately 3-fold. This net increase in transporters probably occurs because the process of recruitment of transporters is less temperature-sensitive than the process involved in internalization of cell-surface transporters. (2) The time course for insulin stimulation of glucose transport activity occurred with a slight lag period of 47 s and a t 1/2 3.2 min. The time course of GLUT4 and GLUT1 appearance at the cell surface showed no lag and a t 1/2 of approximately 2.3 min for both isoforms. Thus at early times after insulin stimulation there was a discrepancy between transporter abundance and transport activity. The lag period in the stimulation of transport activity may represent the time required for the approximately 2-fold stimulation of transporter intrinsic activity. (3) The decrease in transport activity after insulin removal occurred with a very high activation energy of 159 kJ.mol-1. There was thus no significant decrease in transport or less of cell-surface transporters over 60 min at 18 degrees C. The decrease in transport activity occurred with a t1/2 of 9-11 min at 37 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS)


Protein deposition on contact lenses: the past, the present, and the future.
Proteins are a key component in body fluids and adhere to most biomaterials within seconds of their exposure. The tear film consists of more than 400 different proteins, ranging in size from 10 to 2360 kDa, with a net charge of pH 1-11. Protein deposition rates on poly-2-hydroxyethyl methacrylate (pHEMA) and silicone hydrogel soft contact lenses have been determined using a number of ex vivo and in vitro experiments. Ionic, high water pHEMA-based lenses attract the highest amount of tear film protein (1300 μg/lens), due to an electrostatic attraction between the material and positively charged lysozyme. All other types of pHEMA-based lenses deposit typically less than 100 μg/lens. Silicone hydrogel lenses attract less protein than pHEMA-based materials, with <10 μg/lens for non-ionic and up to 34 μg/lens for ionic materials. Despite the low protein rates on silicone hydrogel lenses, the percentage of denatured protein is typically higher than that seen on pHEMA-based lenses. Newer approaches incorporating phosphorylcholine, polyethers or hyaluronic acid into potential contact lens materials result in reduced protein deposition rates compared to current lens materials.


Comparison of BrdUrd and [3H]TdR incorporation to estimate cell proliferation, cell loss, and potential doubling time in tumor xenografts.
In this study, two different methods of estimating cell proliferation were compared: cell loss and potential growth rate of xenografted head and neck cancer grown in nude mice based on the detection of DNA incorporation of bromodeoxyuridine (BrdUrd) in one method, and [3H]thymidine ([3H]TdR) in the other. The 21-d-old xenografts were labelled in vivo, either with BrdUrd or [3H]TdR and excised at intervals during 65.5 h. In tumors containing BrdUrd, the percent labelling was measured in mid-S and mid-G1 phase windows of cytograms from bivariate DNA flow cytometry (FCM). In [3H]TdR-labelled tumors, the percent labelled mitoses (PLM) was determined by light microscopy evaluation of autoradiographs. With a computer program based on a theoretical model, the percent labelling versus time after injection was used to analyze cell cycle time, cell loss, tumor growth fraction, and potential doubling time. The values calculated from DNA incorporation with BrdUrd agreed well with those obtained from labelling with [3H]TdR, i.e., cell cycle time 2.3 vs. 2.4 d, and growth fraction 67 vs. 70%. The estimated potential doubling time was 3.1 d and cell loss factor 40% by both methods. Flow cytometry analysis of BrdUrd-labelling is considerably faster than the evaluation of [3H]TdR-labelling, and the present results provide further support for the BrdUrd labelling method as a promising alternative to the PLM method in cell cycle studies designed to evaluate the relevance of cell proliferative properties in relation to biological behavior in xenografted head and neck cancer.


Postmyelographic cauda equina syndrome in an asymptomatic acquired spinal stenosis of a young acromegalic.
Early postmyelographic cauda equina syndrome in an asymptomatic young acromegalic is presented. The patient was asymptomatic for more than 1 yr despite myelographic evidence of acquired spinal stenosis at the L2-L4 level. Radiographic and/or myelographic findings should be clinically correlated. It is postulated that, in acromegaly, the combined simultaneous bony apposition-remodeling resorption mechanism is involved in the spine as platyspondyly, hyperostosis of spinous processes and vertebral scalloping to counteract soft tissue hyperplasia within the spinal canal; entrapment myelopathy, cauda equina syndrome and/or radiculopathy are ascribed to a soft tissue edematous mechanism superimposed on congenital or degenerative spinal stenosis, traumatic or postoperative spondylolisthesis, postmyelographic and/or postoperative arachnoiditis and a traumatic swollen or protrused intervertebral disc.


Do oligodendrocytes mediate iron regulation in the human brain?
We used immunohistochemical studies to demonstrate that transferrin (the iron mobilization protein) and ferritin (the iron storage protein) are specifically localized in oligodendrocytes in gray and white matter of the human central nervous system. In addition, iron is also localized predominantly in oligodendrocytes. Oligodendrocytes have been well established as the cells responsible for myelin production in the central nervous system. The results of this study suggest that oligodendrocytes (or a subpopulation of oligodendrocytes) might have the additional function of mediating iron mobilization and storage in the central nervous system.


Characterization of seven low incidence blood group antigens carried by erythrocyte band 3 protein.
Recent studies have demonstrated that band 3 carries antigens of the Diego blood group system and have elucidated the molecular basis of several previously unassigned low incidence and high incidence antigens. Because the available serological data suggested that band 3 may carry additional low incidence blood group antigens, we screened band 3 genomic DNA encoding the membrane domain of band 3 for single-strand conformational polymorphisms. We found that the putative first ectoplasmic loop of band 3 carries blood group antigen ELO, 432 Arg-->Trp; the third putative loop harbors antigens Vga (Van Vugt), 555 Tyr-->His, BOW 561 Pro-->Ser, Wu (Wulfsberg), 565 Gly-->Ala, and Bpa (Bishop), 569 Asn-->Lys; and the putative fourth ectoplasmic loop carries antigens Hga (Hughes), 656 Arg-->Cys, and Moa (Moen), 656 Arg-->His. We studied erythrocytes from carriers of five of these blood group antigens. We found similar levels of reticulocyte mRNA corresponding to the two band 3 gene alleles, normal content and glycosylation of band 3 in the red blood cell membrane, and normal band 3-mediated sulfate influx into red blood cells, suggesting that the mutations do not have major effect on band 3 structure and function. In addition to elucidating the molecular basis of seven low incidence blood group antigens, these results help to create a more accurate structural model of band 3.


Association between sociodemographic and health factors and the practice of walking in a rural area.
The regular practice of walking can contribute to a better quality of life, reducing the risk of cardiovascular disease. To assess the association between sociodemographic and health factors related to adult practice of walking in the Brazilian rural context. Cross-sectional study of 567 adults. The outcome variable was the regular practice of walking (≥150 minutes per week) and the explanatory variables were sociodemographic factors, anthropometric measures, laboratory tests and self-perceived health. The chi-square test and Poisson regression were used in analysis, considering p ≤ 0.05. Only 34.7% of the population practices walking regularly. Women (PR 0.84, 95% CI 0.78-0.89), age of 31-45 years (OR 1.11, 95% CI 1.02-1.22, comparing to 18-30 years), and self-perception of poor/fair health (OR 0.90, 95% CI 0.84-0.97 comparing to people with great/good health) remained independently associated with regular practice of walking. Conclusion Age between 31 and 45 years and males were positively associated with walking and the perception of poor/fair health had negative association. These findings may suggest that public policies to encourage physical activity in urban areas should also be applied to rural areas.


Hybrid lipids, peptides, and lymphocytes: new era in type 1 diabetes research.
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β cells in islets of Langerhans. Many genetic and immunological insights into autoimmune disease pathogenesis were initially uncovered in the context of T1D and facilitated by preclinical studies using the nonobese diabetic (NOD) mouse model. Recently, the study of T1D has led to the discovery of fatty acid esters of hydroxyl fatty acids (FAHFAs), which are naturally occurring hybrid peptides that modulate inflammation and diabetes pathogenesis, and a hybrid lymphocyte that expresses both B and T cell receptors. Palmitic acid esters of hydroxy stearic acids (PAHSAs) are the most extensively studied FAHFA. In this issue of the JCI, Syed et al. have shown that PAHSAs both attenuate autoimmune responses and promote β cell survival in NOD mice. Given the lack of effective T1D therapies and the paucity of known side effects of PAHSAs, this lipid may have therapeutic potential for individuals at risk for or newly diagnosed with T1D.


Well-done meat intake, heterocyclic amine exposure, and cancer risk.
High intake of meat, particularly red and processed meat, has been associated with an increased risk of a number of common cancers such as breast, colorectum, and prostate in many epidemiological studies. Heterocyclic amines (HCAs) are a group of mutagenic compounds found in cooked meats, particularly well-done meats. HCAs are some of most potent mutagens detected using the Ames/salmonella tests and have been clearly shown to induce tumors in experimental animal models. Over the past 10 years, an increasing number of epidemiological studies have evaluated the association of well-done meat intake and meat carcinogen exposure with cancer risk. The results from these epidemiologic studies were evaluated and summarized in this review. The majority of these studies have shown that high intake of well-done meat and high exposure to meat carcinogens, particularly HCAs, may increase the risk of human cancer.


Helical Superstructure of Intermediate Filaments.
Intermediate filaments are the least explored among the large cytoskeletal elements. We show here that they display conformational anomalies in narrow microfluidic channels. Their unusual behavior can be understood as the consequence of a previously undetected, large-scale helically curved superstructure. Confinement in a channel orders the otherwise soft, strongly fluctuating helical filaments and enhances their structural correlations, giving rise to experimentally detectable, strongly oscillating tangent correlation functions. We propose an explanation for the detected intrinsic curving phenomenon-an elastic shape instability that we call autocoiling. The mechanism involves self-induced filament buckling via a surface stress located at the outside of the cross section. The results agree with ultrastructural findings and rationalize for the commonly observed looped intermediate filament shapes. Beyond curvature, explaining the molecular origin of the detected helical torsion remains an interesting challenge.


Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained drug delivery depots for local arterial wall biomanipulation.
Polymeric endoluminal paving is a process in which biodegradable polymers may be locally applied percutaneously to blood vessels as endoluminal liners, resurfacing or 'paving', the underlying vascular wall. Depending upon the type of polymer selected, endoluminal polymer layers may function as wall supports, barriers, therapeutic biomaterials or depots for local sustained drug delivery. In the original description of the paving process, that is solid paving, structural polymers were utilized. In this article a second form of paving--gel paving is described. In this process, hydrogel polymers are locally applied or polymerized on vascular endoluminal surfaces. Endoluminal hydrogel layers have been demonstrated to function as physical non-pharmacological barriers limiting cell and protein deposition and effectively reducing underlying arterial wall thrombogenicity. Hydrogel paving layers also provide a means for prolonged local arterial wall drug delivery. In this report an update on gel paving is provided. The overall process of polymeric endoluminal paving is initially reviewed. Gel paving and the rationale for this approach is described. Both thermoreversible as well as photopolymerizable PEG-lactide hydrogel paving systems are outlined. Recent experimental studies with gel paving examining polymer application, haemocompatability and endoluminal surface thromboprotection, effects on post-injury neointimal thickening and local drug delivery, are then reviewed. Finally, the role of gel paving in future approaches to vascular therapy is discussed.


[Overweight among adolescents from private schools in Fortaleza, CE, Brazil].
The purpose of the study was to identify cases of overweight among adolescents in private schools in Fortaleza, Brazil. We investigated 794 students between 12 and 17 years old from 12 private schools, in the months March to June and August-September 2007. The prevalence of overweight and obesity was 20% and 4%, respectively. Among the young people who watch TV while eat, the weight accumulated was higher and the cases of obesity was the double (p = 0, 000). About 28% of people who practiced regular physical activity were overweight (p <0, 001). In the fight against adolescent adiposity, to the nursing is primarily the preventive actions, because attenuate various pathological effects related to the accumulation of body weight.


Medical expulsive treatment in pediatric urolithiasis.
The frequency of stone disease in childhood ranges between 0.1-5 percent. Stone disease occurs as a result of enviromental, metabolic, anatomical, infectious and nutritional factors. Percutaneous nephrolitotomy, uretherorenoscopy, laparoscopic surgery, open surgery and extracorporeal shock wave lithothripsy are treatment alternatives for stone disease during childhood. However, these methods are not completely innocent. Some complications may occur after these procedures. These procedures are generally not cost- effective. Even invasive procedures have high success rates, so medical expulsive treatment modalities have become an alternative for a group of patients. Nonsteroidal anti- inflammatory drugs, antimuscarinic drugs, phospodiesterase type 5 inhibitors, steroids, calcium channel blockers and alpha blockers are treatment alterneatives used for this modality in the literature. The drug is chosen according to the location, size, and composition of the stone, recent technology, cost, surgeon's experience and surgeon's and the parents' preferences. In this review article the following topics will be discussed such as "Why medical expulsive treatment is needed during childhood? Which drug should be chosen for which stone type? How long should a treatment of urolithiasis last?


LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex.
Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.


Central origin of respiratory arrest in beta-blocker intoxication in rats.
Propranolol HCl (7.5 mg X kg-1), timolol maleate (7.0 mg X kg-1), and sotalol HCl (10 mg X kg-1) were administered intracerebroventricularly (icv) to spontaneously breathing (SB) rats. The respiratory rate declined until the rats all died from respiratory arrest. Artificial ventilation resulted in survival of the rats for a 3-hr observation period. Intravenous (iv) administration of the same doses of the three beta blockers to SB rats did not result in either respiratory depression or death. Except for a decrease in heart rate (HR) the hemodynamic and respiratory parameters remained almost constant during the 3-hr observation period after iv administration to SB rats. After icv administration to SB as well as to ventilated rats no significant differences could be observed in the initial decrease in HR in comparison with iv administration. In SB rats at the end of the experiments a further decrease in HR was observed which might be ascribed to hypoxia since it did not occur in ventilated rats. After icv administration of each drug to the ventilated rats, mean arterial blood pressure showed a significantly greater decrease at the end of the 3-hr observation period than after iv administration. Plasma concentrations of the three drugs were determined just before death after icv administration in SB rats. In the other two groups they were measured at mean survival time and at the end of the experimental period. The plasma concentrations showed that the route of administration rather than the concentration of the beta blocker in plasma determines the occurrence of respiratory arrest. It was concluded that an overdose of propranolol, timolol, or sotalol can cause a centrally mediated respiratory arrest. Furthermore, a central mechanism appears to be implicated in the decrease in blood pressure.


The phosphorylated membrane estrogen receptor and cytoplasmic signaling and apoptosis proteins in human breast cancer.
Estrogens play a central role in breast cancer development, and the estrogen receptor-alpha (ERalpha) remains the single most important predictor of breast cancer prognosis. Therefore, it is crucial to elucidate pathways that may contribute to ER signaling in clinical specimens. Using extracts of fresh invasive ERalpha-positive invasive breast carcinomas, ductal carcinoma in situ, and normal glandular breast tissue, the authors performed Western blot analyses of the membrane-bound ER, 1 of its phosphorylated isoforms, and cytosolic fractions from the same specimens, examining associated proteins (Akt/mitogen-activated protein kinase pathways). Western blot analysis and immunocapture for the apoptosis and survival factors Bcl-2 agonist of death (BAD)/Bcl-2 and BAD/Bcl-xL were also performed. To the authors' knowledge, this is the first study to report that ERalpha was phosphorylated in the plasma membrane fractions derived from patients' invasive breast carcinomas. This was associated with a predominance of phosphorylated BAD and a relative reduction in Bcl-2 compared with both normal tissue and ductal carcinoma in situ, although such studies in fresh tissue did not corroborate these findings. The authors also demonstrated that the BAD/Bcl-2 and BAD/Bcl-xL complexes characterized the invasive carcinoma state. A phosphorylated form of the membrane ER was found to characterize the invasive cancer state. This was associated with a reduction in BAD/Bcl-2 and BAD/Bcl-xl. These data implicate the membrane ERalpha as the in vivo receptor responsible for transcription-independent cellular responses to estrogens.


Generation of AAVS1 integrated doxycycline-inducible CRISPR-Prime Editor human induced pluripotent stem cell line.
Prime editing uses the Cas9 nickase fused to a reverse transcriptase to copy a DNA sequence into a specific locus from a 'prime editing' guide RNA (pegRNA), eliminating the need for double-stranded DNA breaks and donor DNA templates. To facilitate prime editing in human induced pluripotent stem cells (iPSCs), we integrated a doxycycline-inducible Prime Editor protein (PE2) into the AAVS1 genomic safe harbor locus. Prime editing of iPSCs resulted in precise insertion of three nucleotides in HEK3 locus with high efficiency, demonstrating the utility of this approach. This engineered cell line can be used to edit a single or multiple genomic loci by introducing a target-specific pegRNA for precise and effective genome editing to facilitate disease modeling and functional genetics studies.


Associations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas.
Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood. We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM(10)) was associated with SDB among persons 39 years of age and older. Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O(2) saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM(10) and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects). In summer, increases in RDI or percentage of sleep time at less than 90% O(2) saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM(10). Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature. Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.


Recent advances in myocardial protection using antegrade/retrograde blood cardioplegia.
This presentation details techniques of delivery of antegrade/retrograde blood cardioplegia to ensure its distribution to prevent ischemic damage during aortic clamping, and describes methods of using warm blood cardioplegia to "resuscitate" the heart when used to induce cardioplegia and "avoid reperfusion damage" when given just before aortic unclamping. A technique of rapid transatrial cannulation of the coronary sinus is described to permit safe, rapid, and simple use of retrograde cardioplegia and avoid right heart isolation. Theoretic objectives of these operative techniques are discussed, together with presentation of the specific methods of achieving the aforementioned goals of using blood cardioplegia for resuscitation, prevention, and avoidance of ischemic and reperfusion damage. The preliminary clinical experience with antegrade/retrograde cardioplegia is summarized, and these results have led to adoption of these techniques of blood cardioplegia as the preferred method of myocardial protection in all adult operations and in many pediatric cardiac procedures.


A prospective evaluation of survivorship of asymptomatic degenerative rotator cuff tears.
The purpose of this prospective study was to report the long-term risks of rotator cuff tear enlargement and symptom progression associated with degenerative asymptomatic tears. Subjects with an asymptomatic rotator cuff tear in one shoulder and pain due to rotator cuff disease in the contralateral shoulder enrolled as part of a prospective longitudinal study. Two hundred and twenty-four subjects (118 initial full-thickness tears, fifty-six initial partial-thickness tears, and fifty controls) were followed for a median of 5.1 years. Validated functional shoulder scores were calculated (visual analog pain scale, American Shoulder and Elbow Surgeons [ASES], and simple shoulder test [SST] scores). Subjects were followed annually with shoulder ultrasonography and clinical evaluations. Tear enlargement was seen in 49% of the shoulders, and the median time to enlargement was 2.8 years. The occurrence of tear-enlargement events was influenced by the severity of the final tear type, with enlargement of 61% of the full-thickness tears, 44% of the partial-thickness tears, and 14% of the controls (p < 0.05). Subject age and sex were not related to tear enlargement. One hundred subjects (46%) developed new pain. The final tear type was associated with a greater risk of pain development, with the new pain developing in 28% of the controls, 46% of the shoulders with a partial-thickness tear, and 50% of those with a full-thickness tear (p < 0.05). The presence of tear enlargement was associated with the onset of new pain (p < 0.05). Progressive degenerative changes of the supraspinatus muscle were associated with tear enlargement, with supraspinatus muscle degeneration increasing in 4% of the shoulders with a stable tear compared with 30% of the shoulders with tear enlargement (p < 0.05). Nine percent of the shoulders with a stable tear showed increased infraspinatus muscle degeneration compared with 28% of those in which the tear had enlarged (p = 0.07). This study demonstrates the progressive nature of degenerative rotator cuff disease. The risk of tear enlargement and progression of muscle degeneration is greater for shoulders with a full-thickness tear, and tear enlargement is associated with a greater risk of pain development across all tear types. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Therapeutic monoclonal antibodies.
Over a hundred years has passed since the discovery of the "magic bullet" serum therapy by Kitasato and Behring, the first ever therapeutic use of antibodies. More than 80 years later, the investigation of immunoglobulin structure and function and the development of cell and molecular biology introduced the production of monoclonal antibodies (MoAbs). In the 35 years since the first process for creating MoAbs was introduced, they have remained the centerpiece of the growing biotechnology and pharmaceutical industry. Herein, I review the history, development, and clinical settings of therapeutic MoAbs that have had a significant impact on life-saving medicine.


Single blastomere removal from murine embryos is associated with activation of matrix metalloproteinases and Janus kinase/signal transducers and activators of transcription pathways of placental inflammation.
Single blastomere removal from cleavage-stage embryos, a common procedure used in conjunction with preimplantation genetic diagnosis (PGD), may affect reproductive outcomes. We hypothesized that negative pregnancy outcomes associated with PGD may be due to impairment of placental signaling pathways. The goal of this study was to determine the molecular mechanisms through which placental signaling is deregulated by blastomere removal. Four-cell stage murine embryos produced by in vitro fertilization were subjected to removal of a single blastomere (biopsied) or to the same manipulations without the blastomere removal (controls). Placental tissues from term (18.5 day) pregnancies obtained after embryo transfer were tested for levels of nitrosative species, interleukin 6, signal transducers and activators of transcription (STAT) 1 and 3, suppressors of cytokine signaling (SOCS) 1, 2 and 3 and matrix metalloproteinases (MMP) 1, 2, 3 and 9. Significant increases in nitrosative stress (P < 0.05), phosphorylative activation of STAT1 (P < 0.05) but not STAT3, lower levels of the inhibitors SOCS2 (P < 0.01) and SOCS3 (P < 0.001) and activation of MMP9 (P < 0.001) were observed in placentas derived from biopsied embryos, compared with controls. Such effects could contribute to greater levels of premature membrane rupture, incorrect parturition, preterm birth and intrauterine growth restriction associated with PGD. This work has determined signaling mechanisms that may be responsible for blastomere removal effects on placental function, with the potential to become targets for improving obstetric and neonatal outcomes in assisted reproduction.


Complexation of As(III) by phosphonate ligands in aqueous fluids: Thermodynamic behavior, chemical binding forms and sequestering abilities.
In recent years, the contamination of water by arsenic reached alarming levels in many countries of the world, attracting the interest of many researchers engaged in testing methodologies able to remove this harmful pollutant. An important aspect that must be taken into consideration is the possibility to find arsenic in different chemical forms which could require different approaches for its removal. At this aim, a speciation analysis appears to be crucial for better understanding the behavior of arsenic species in aqueous solutions, especially in presence of compounds with marked chelating properties. Phosphonates can be identified as good sequestering agents and, at this purpose, this manuscript intends to investigate the interaction of As(III) with three phosphonic acids derived from nitrilotriacetic acid (NTA) by replacements of one (N-(Phosphonomethyl) iminodiacetic acid, NTAP), two (N,N-Bis-(phosphonomethyl) glycine, NTA2P) and three (Nitrilotri(methylphosphonic acid), NTA3P) carboxylic groups with the same number of phosphonate groups. An in-depth potentiometric and calorimetric investigation allowed to determine speciation models featured by simple ML, MLHi and ML(OH) species. A complete thermodynamic characterization of the systems is reported together with the definition of coordination mode by mass spectrometry measurements. On the light of the speciation models, the possibility of using these ligands in arsenic removal techniques was assessed by determining the pL0.5 (the concentration of ligand able to remove the 50% of metal ion present in trace). All ligands show a good sequestering ability, in particular under the conditions of fresh water, following the trend NTA3P > NTA2P > NTAP.


Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis.
Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I(2) = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I(2) = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I(2) = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I(2) = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I(2) = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I(2) = 0.0%) for first-degree family history of cancer. Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.


Empirical measurements of biomechanical anisotropy of the human vocal fold lamina propria.
The vocal folds are known to be mechanically anisotropic due to the microstructural arrangement of fibrous proteins such as collagen and elastin in the lamina propria. Even though this has been known for many years, the biomechanical anisotropic properties have rarely been experimentally studied. We propose that an indentation procedure can be used with uniaxial tension in order to obtain an estimate of the biomechanical anisotropy within a single specimen. Experiments were performed on the lamina propria of three male and three female human vocal folds dissected from excised larynges. Two experiments were conducted: each specimen was subjected to cyclic uniaxial tensile loading in the longitudinal (i.e., anterior-posterior) direction, and then to cyclic indentation loading in the transverse (i.e., medial-lateral) direction. The indentation experiment was modeled as contact on a transversely isotropic half-space using the Barnett-Lothe tensors. The longitudinal elastic modulus E(L) was computed from the tensile test, and the transverse elastic modulus E(T) and longitudinal shear modulus G(L) were obtained by inverse analysis of the indentation force-displacement response. It was discovered that the average of E(L) /E(T) was 14 for the vocal ligament and 39 for the vocal fold cover specimens. Also, the average of E(L)/G(L), a parameter important for models of phonation, was 28 for the vocal ligament and 54 for the vocal fold cover specimens. These measurements of anisotropy could contribute to more accurate models of fundamental frequency regulation and provide potentially better insights into the mechanics of vocal fold vibration.


Simultaneous allergen inactivation and detoxification of castor bean cake by treatment with calcium compounds.
Ricinus communis L. is of great economic importance due to the oil extracted from its seeds. Castor oil has been used for pharmaceutical and industrial applications, as a lubricant or coating agent, as a component of plastic products, as a fungicide or in the synthesis of biodiesel fuels. After oil extraction, a castor cake with a large amount of protein is obtained. However, this by-product cannot be used as animal feed due to the presence of toxic (ricin) and allergenic (2S albumin) proteins. Here, we propose two processes for detoxification and allergen inactivation of the castor cake. In addition, we establish a biological test to detect ricin and validate these detoxification processes. In this test, Vero cells were treated with ricin, and cell death was assessed by cell counting and measurement of lactate dehydrogenase activity. The limit of detection of the Vero cell assay was 10 ng/mL using a concentration of 1.6 x 10(5) cells/well. Solid-state fermentation (SSF) and treatment with calcium compounds were used as cake detoxification processes. For SSF, Aspergillus niger was grown using a castor cake as a substrate, and this cake was analyzed after 24, 48, 72, and 96 h of SSF. Ricin was eliminated after 24 h of SSF treatment. The cake was treated with 4 or 8% Ca(OH)2 or CaO, and both the toxicity and the allergenic properties were entirely abolished. A by-product free of toxicity and allergens was obtained.


The role of the right hemisphere in the interpretation of figurative aspects of language. A positron emission tomography activation study.
We investigated cerebral activity in six normal volunteers using PET to explore the hypothesis that the right hemisphere has a specific role in the interpretation of figurative aspects of language such as metaphors. We also mapped the anatomical structures involved in sentence comprehension. During regional cerebral blood flow measurement subjects were asked to perform three different linguistic tasks: (i) metaphorical comprehension; (ii) literal comprehension of sentences; and (iii) a lexical-decision task. We found that comprehension of sentences compared with the lexical-decision task, induced extensive activation in several regions of the left hemisphere, including the prefrontal and basal frontal cortex, the middle and inferior temporal gyri and temporal pole, the parietal cortex and the precuneus. Comprehension of metaphors was associated with similar activations in the left hemisphere, but in addition, a number of sites were activated in the right hemisphere: the prefrontal cortex, the middle temporal gyrus, the precuneus and the posterior cingulate. We conclude that the interpretation of language involves widespread distributed systems bilaterally with the right hemisphere having a special role in the appreciation of metaphors.


Histone trimethylation of the p53 gene by expression of a constitutively active prolactin receptor in prostate cancer cells.
Prolactin (PRL) is a pituitary polypeptide hormone characterized by multiple biological actions including stimulation of growth in the prostate, breast and ovarian epithelial cells. A sizable body of reports has presented evidences to indicate the involvement of PRL in the pathogenic process of cancers of the reproductive system, such as prostate and breast cancers. PRL exerts its effects by dimerizing its receptor (PRLR) on the plasma membrane, and initiating cellular Jak-Stat signal pathway. We have previously cloned from prostate cancer cells a natural variant of PRLR in which the S2 subdomain of the extracellular domain is missing (ΔS2). Our preliminary data showed that ΔS2 PRLR was able to dimerize and to constitutively activate the β-casein promoter (in the absence of its ligand, PRL) in breast and prostate epithelial cells. Enhancer of zeste homologue 2 (EZH2), an important histone-modifying enzyme, is able to trimethylate histone 3 on lysine 27 (H3K27Me3), consequently leading to gene silencing, especially silencing of tumor suppressor genes such as p53. We hypothesized that ΔS2 PRLR played an important pathogenic role in prostate cancer through, at least partly, alterations in the expression of EZH2 and the trimethylation of histone 3 on lysine 27. In the present study, overexpression of ΔS2 PRLR in prostate epithelial cells was achieved by infection with an adenoviral vector carrying the cDNA. The viable cell number overexpressing ΔS2 PRLR was assessed using MTS reagent. Western blot, chromatin immunoprecipitation (ChIP) assay and acid histone extraction were applied to detect expression of EZH2 as well as trimethylation of histone 3, respectively. In prostate epithelial cells, overexpression of ΔS2 PRLR increased the levels of EZH2 methyltransferase mRNA and protein, induced EZH2 methyltransferase recruitment to chromatin, increased the trimethylation of histone 3 on lysine 27, and decreased expression of the p53 gene. We concluded that ΔS2 PRLR plays an important pathogenic role in prostate cancer through epigenetic covalent modification leading to chromatin remodeling. Hypertrimethylation on H3K27 of the p53 gene promoter region due to elevated expression of ΔS2 PRLR by alternative splicing of the pre-mRNA in its full-length form might serve as a new mechanism underlying human prostate cancer.


Baseline data on Aedes aegypti populations in Santo Domingo, Dominican Republic.
Baseline field studies were conducted from April 1987 to July 1988 on Aedes aegypti in Santo Domingo, an endemic area for dengue fever. Premise, container and Breteau indices were measured in one treated area and 2 nearby control areas. These indices averaged 69.6, 46.3 and 142.1, respectively. The principal larval habitats of Ae. aegypti were 208-liter (55-gal) concrete-lined drums. The estimated daily adult production was approximately 60 per house. Adult mosquito populations were monitored using oviposition traps and by sweep net collections. There was no correlation between adult abundance and the larval indices. Monitoring the natural adult densities was more efficient for evaluating the impact of ULV malathion application than the use of standard bioassay procedures.


Clinical application of porcine small intestinal submucosa in the management of infected or potentially contaminated abdominal defects.
The repair of abdominal wall defects in potentially contaminated or grossly infected fields presents a difficult clinical problem. Polypropylene mesh is relatively contraindicated in these settings because of the potential for chronic infection. The alternatives to polypropylene include polyglactin mesh, which is not associated with chronic infection but is associated with a 100% recurrence of hernia. The ideal prosthetic for this patient group should be resistant to infection and ensure a low rate of hernia recurrence. We studied the use of small intestinal submucosa, which has been reported to be resistant to infection and incorporates into the fascia over 3 to 6 months, in 20 patients with ventral or inguinal hernias (18 ventral, 2 inguinal hernia) in the setting of bacterial contamination. The early postoperative complication rate was 50%. One patient with fasciitis had degradation of the small intestinal submucosa and loss of the bioprosthesis within 7 days. Other early complications included seroma (n=2), ileus (n=1), and wound infection (n=8). No patient experienced chronic infection. Mean follow up was 15.7 months and the rate of recurrence documented by CT or physical examination was 30%. We concluded the following: (1). small intestinal submucosa is an effective alternative bioprosthesis in the management of ventral/inguinal hernia when there is associated bacterial contamination; (2). human vs. pig immune response has not been seen in this patient population; (3). early graft failure due to overwhelming fascial infection was noted in one patient and may be a limitation of this technology in a minority of patients; and (4). early hernia recurrence is relatively low but long-term follow-up has not been completed.


Does energy consumption follow asymmetric behavior? An assessment of Ghana's energy sector dynamics.
The study answered the following questions: First, does energy evolves in different regimes by transitioning over a finite set of unobserved states? Second, does energy consumption follow an asymmetric behavior over "energy boom" and energy scarcity? and, Third, are there unobserved factors underpinning energy crisis? We employed Markov-switching dynamic regression to examine the asymmetric effect, NIPALS regression to examine energy determinants and neural network analysis for prediction. The neural network model suggests a 99% prediction of energy consumption by the predictor variables. It was evident that energy consumption evolves in two states by transitioning over a finite set of unobserved states. The 11.6% growth in energy consumption is expected to occur in 4.1 years while energy crisis is expected to last for 3.7 years. Technological advancement and the development of green energy through foreign direct investment are essential to improve energy sector portfolio.


Hair Aging in Different Races and Ethnicities.
BACKGROUND: Aging is an unavoidable biological process with many influencing factors, accounting for a multitude of visible manifestations on the hair as well as the skin. As the population ages while becoming more diverse, it is increasingly important to better understand the hair aging process. METHODS: A literature search was performed to review what is known about changes in hair structure over time, focusing on the differences in hair aging according to ethnic background. RESULTS: Sixty-nine publications were selected and information regarding hair structure, aging characteristics, and responses to extrinsic damage together with differences between races and ethnicities was collected. Hair-graying onset varies with race, with the average age for Caucasians being mid-thirties, that for Asians being late thirties, and that for Africans being mid-forties. Caucasians and Asians typically experience damage to the distal hair shaft, while African-Americans see damage occurring closer to the hair root. Postmenopausal changes include decreased anagen hairs in the frontal scalp, lower growth rates, and smaller hair diameters. CONCLUSION: There is a paucity of literature examining the characteristics of hair aging across all races. The unique characteristics of hair aging in different ethnicities provides information that will aid in a culturally sensitive approach and recommendations.


Policies, guidelines, and recommendations for MR imaging safety and patient management. SMRI Safety Committee.
The following are policies, guidelines, and recommendations from the Safety Committee of the Society for Magnetic Resonance Imaging (SMRI) concerning various issues related to magnetic resonance (MR) imaging safety and patient management. These policies, guidelines, and recommendations were developed to provide standardized and consistent information for use by health practitioners involved in clinical MR imaging.


Activation of the hypothalamic paraventricular nucleus by forebrain hypertonicity selectively increases tonic vasomotor sympathetic nerve activity.
We recently reported that mean arterial pressure (MAP) is maintained in water-deprived rats by an irregular tonic component of vasomotor sympathetic nerve activity (SNA) that is driven by neuronal activity in the hypothalamic paraventricular nucleus (PVN). To establish whether generation of tonic SNA requires time-dependent (i.e., hours or days of dehydration) neuroadaptive responses or can be abruptly generated by even acute circuit activation, forebrain sympathoexcitatory osmosensory inputs to PVN were stimulated by infusion (0.1 ml/min, 10 min) of hypertonic saline (HTS; 1.5 M NaCl) through an internal carotid artery (ICA). Whereas isotonic saline (ITS; 0.15 M NaCl) had no effect (n = 5), HTS increased (P < 0.001; n = 6) splanchnic SNA (sSNA), phrenic nerve activity (PNA), and MAP. Bilateral PVN injections of muscimol (n = 6) prevented HTS-evoked increases of integrated sSNA and PNA (P < 0.001) and attenuated the accompanying pressor response (P < 0.01). Blockade of PVN NMDA receptors with d-(2R)-amino-5-phosphonovaleric acid (AP5; n = 6) had similar effects. Analysis of respiratory rhythmic bursting of sSNA revealed that ICA HTS increased mean voltage (P < 0.001) without affecting the amplitude of inspiratory or expiratory bursts. Analysis of cardiac rhythmic sSNA likewise revealed that ICA HTS increased mean voltage. Cardiac rhythmic sSNA oscillation amplitude was also increased, which is consistent with activation of arterial baroreceptor during the accompanying pressor response. Increased mean sSNA voltage by HTS was blocked by prior PVN inhibition (muscimol) and blockade of PVN NMDA receptors (AP5). We conclude that even acute glutamatergic activation of PVN (i.e., by hypertonicity) is sufficient to selectively increase a tonic component of vasomotor SNA.


LipostarMSI: Comprehensive, Vendor-Neutral Software for Visualization, Data Analysis, and Automated Molecular Identification in Mass Spectrometry Imaging.
Mass Spectrometry Imaging (MSI) is an established and powerful MS technique that enables molecular mapping of tissues and cells finding widespread applications in academic, medical, and pharmaceutical industries. As both the applications and MSI technology have undergone rapid growth and improvement, the challenges associated both with analyzing large datasets and identifying the many detected molecular species have become apparent. The lack of readily available and comprehensive software covering all necessary data analysis steps has further compounded this challenge. To address this issue we developed LipostarMSI, comprehensive and vendor-neutral software for targeted and untargeted MSI data analysis. Through user-friendly implementation of image visualization and co-registration, univariate and multivariate image and spectral analysis, and for the first time, advanced lipid, metabolite, and drug metabolite (MetID) automated identification, LipostarMSI effectively streamlines biochemical interpretation of the data. Here, we introduce LipostarMSI and case studies demonstrating the versatility and many capabilities of the software.


Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.
The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MPhis converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.


sn-spMF: matrix factorization informs tissue-specific genetic regulation of gene expression.
Genetic regulation of gene expression, revealed by expression quantitative trait loci (eQTLs), exhibits complex patterns of tissue-specific effects. Characterization of these patterns may allow us to better understand mechanisms of gene regulation and disease etiology. We develop a constrained matrix factorization model, sn-spMF, to learn patterns of tissue-sharing and apply it to 49 human tissues from the Genotype-Tissue Expression (GTEx) project. The learned factors reflect tissues with known biological similarity and identify transcription factors that may mediate tissue-specific effects. sn-spMF, available at https://github.com/heyuan7676/ts_eQTLs , can be applied to learn biologically interpretable patterns of eQTL tissue-specificity and generate testable mechanistic hypotheses.


Early Infant Development and Intervention for Autism Spectrum Disorder.
The objective is to overview recent findings on early detection/diagnosis of autism spectrum disorders, as well as clinical trials of early interventions for toddlers at risk for/diagnosed with autism spectrum disorder. Prospective studies of infants at high risk of autism spectrum disorder have yielded significant advances in understanding early development in autism spectrum disorder. Findings from prospective studies indicate that abnormalities in social communication and repetitive behaviors emerge during the second year, whereas additional "prodromal features" (motor and sensory abnormalities) emerge in the first year. Subsequently, exciting progress has been made in establishing the efficacy of autism spectrum disorder-specific interventions for toddlers as young as 15 months. Finally, efforts occur to characterize autism spectrum disorder-specific characteristics in genetic syndromes with concurrent autism spectrum disorder symptomatology. Substantial progress in characterizing early developmental trajectories as well as the identification of specific behavioral markers has aided early detection. Work remains to ensure that research findings are translated into clinical practice for uptake in the health care system.


Advanced 2D image processing technique to predict hip fracture risk in an older population based on single DXA scans.
A new technique to enhance hip fracture risk prediction in older adults was presented and assessed. The new method dramatically improved prediction at high specificity levels using only a standard clinical diagnostic scan. This has the potential to be implemented in clinical practice to enhance patient fragility diagnosis. Diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) scans. However, studies have shown this to be insufficient to accurately predict hip fractures. Therefore, complementary methods are needed to enhance hip fracture risk prediction to identify vulnerable patients. Hip DXA scans were obtained for 192 subjects from the Canadian Multicenter Osteoporosis Study (CaMos), 50 of whom had experienced a hip fracture within 5 years of the scan. 2D statistical shape and appearance modeling was performed to account for the effect of the femur's geometry and BMD distribution on hip fracture risk. Statistical shape modeling (SSM), and statistical appearance modeling (SAM) were also used separately to predict the fracture risk based solely on the femur's geometry and BMD distribution, respectively. Combined with BMD, age, and body mass index (BMI), logistic regression was performed to estimate the fracture risk over the 5-year period. Using the new technique, hip fractures were correctly predicted in 78% of cases compared with 36% when using the T-score. The accuracy of the prediction was not greatly reduced when using SSM and SAM (78% and 74% correct, respectively). Various geometric and BMD distribution traits were identified in the fractured and non-fractured groups. 2D SSAM can dramatically improve hip fracture prediction at high specificity levels and estimate the year of the impending fracture using standard clinical images. This has the potential to be implemented in clinical practice to estimate hip fracture risk.


Active learning-based framework for optimal reaction mechanism selection from microkinetic modeling: a case study of electrocatalytic oxygen reduction reaction on carbon nanotubes.
The elucidation of complex electrochemical reaction mechanisms requires advanced models with many intermediate reaction steps, which are governed by a large number of parameters like reaction rate constants and charge transfer coefficients. Overcomplicated models introduce high uncertainty in the choice of the parameters and cannot be used to obtain meaningful insights on the reaction pathway. We describe a new framework of optimal reaction mechanism selection based on the mean-field microkinetic modeling approach (MF-MKM) and adaptive sampling of model parameters. The optimal model is selected to provide both the accurate fitting of experimental data within the experimental error and low uncertainty of model parameters choice. Generally, this approach can be applied for any complex heterogeneous electrochemical reaction. We use the "2e-" electrocatalytic oxygen reduction reaction (ORR) on carbon nanotubes (CNTs) as a representative example of a sufficiently complex reaction. Rotating disk electrode (RDE) experimental data for both ORR in O2-saturated 0.1 M KOH solution and hydrogen peroxide oxidation/reduction reaction (HPRR/HPOR) in Ar-purged 0.1 M KOH solution with different HO2- concentrations were used to show the dependence of the model parameters uniqueness on the completeness of the experimental dataset. It is demonstrated that the optimal reaction mechanism for ORR on CNT and available experimental data consists of O2 adsorption step on the electrode surface and effective step of two-electron reduction to HO2- combined with its desorption from the electrode. The low uncertainty of estimated model parameters is provided only within the 2-step model being applied to the full available experimental dataset. The assessment of elementary step mechanisms on electro-catalytic materials including carbon-based electrodes requires more diverse experimental data and/or higher precision of experimental measurements to facilitate more precise microkinetic modeling of more complex reaction mechanisms.


Secretion of bicarbonate by rat distal tubules in vivo. Modulation by overnight fasting.
We have performed microperfusion studies on distal tubule bicarbonate reabsorption (JtCO2) of fed and fasted rats to extend our previous observations of in vivo bicarbonate secretion and to resolve certain discrepancies between free-flow and microperfusion data. When rats are fasted overnight, as in previous free-flow studies, distal tubule microperfusion with a 28-mM tCO2 solution results in significant JtCO2 (53 +/- 6 pmol.min-1.mm-1) at normal flow and increases briskly (91 +/- 16 pmol.min-1.mm-1) with bicarbonate load. This response is not influenced by the addition of other normal tubular fluid constituents. However, when normally fed rats are used, as in our previous microperfusion studies, distal tubule JtCO2 is not different from zero when a 28-mM tCO2 solution is perfused at normal flow rates but becomes negative (-54 +/- 13 pmol.min-1.mm-1) at high flow rates, which indicates the existence of bicarbonate secretion against a concentration gradient. Alkali loading of fasted rats also elicits bicarbonate secretion at high flow. These results demonstrate for the first time that normal feeding or alkali loading can induce bicarbonate secretion in a mammalian nephron segment in vivo, and resolves previous discrepancies between free-flow and microperfusion data.


Hand-assisted laparoscopic surgery.
Hand-assisted laparoscopic surgery (HALS) has been proposed as a useful alternative to conventional open or laparoscopic surgery. However, most information is fragmented and comes from specific or selective indications. To assess the current situation of HALS, a general overview of the fields of application, results, and quality of the evidence of these results is necessary. Current English-language literature review. Case reports, series, and opinion articles on HALS. Evaluation of the type of study and results. Most of the articles are short case series. Only a few comparative or randomized comparative trials on HALS for splenectomy and colectomy have been published. Hand-assisted laparoscopic surgery seems to be a promising technique that has been applied with success in a wide range of digestive tract-related surgical procedures. The main role is to help in difficult cases before conversion is necessary or for training unskilled surgeons, and not as an alternative to pure laparoscopic surgery. However, not enough evidence-based data are available to know exactly the final outcome of this technique in general surgery. Prospective randomized trials with established open or laparoscopic procedures are lacking, and these trials are needed to support the final role of HALS.


Pre-Visit Digital Messaging Improves Patient-Reported Outcome Measure Participation Prior to the Orthopaedic Ambulatory Visit: Results from a Double-Blinded, Prospective, Randomized Controlled Trial.
Patient-reported outcome measures (PROMs) are metrics that assess physical health, mental health, pain, and satisfaction. However, PROM collection in orthopaedic clinics presents numerous logistical and financial challenges. These challenges are reduced when PROMs are completed before clinic encounters, relieving the workflow constraints of in-office PROM collection. The purpose of this study was to determine the efficacy of 3 different methods with respect to pre-visit electronic PROM completion. Consecutive adult orthopaedic patients with no previous PROM participation were enrolled. Patients who registered with the electronic medical record (EMR) patient portal (MyChart) and with active e-mail addresses were randomly assigned to 1 of 3 arms: control (no pre-visit messages), MyChart (EMR patient portal pre-visit messages), and e-mail (e-mail pre-visit messages). The primary outcome measure was pre-visit PROM completion rates in orthopaedic patients, and the secondary outcome measures were time to pre-visit PROM form completion and PROM form completion rates according to patient demographic characteristics. By default, the Patient-Reported Outcomes Measurement Information System (PROMIS) forms were available for completion through the portal by 7 days before scheduled visits. Pre-visit messages were sent 7 days prior to the scheduled visit except in the control group, with reminders sent 3 days prior if still not completed. The patients in each arm who completed all assigned forms were labeled as having total PROM completion, and those who completed at least 1 completed form were considered as having partial PROM completion. Multivariable logistic regression models were used to assess differences in PROM completion rates between study arms. Kruskal-Wallis tests were performed to compare the date of the form completion. A total of 291 patients were included. The pre-visit total completion rates for assigned PROMs were higher in the MyChart arm (49% of 97 patients; p = 0.005) and the e-mail arm (52% of 100 patients; p = 0.002) in comparison with the control arm (30% of 94 patients). Male patients were more likely than female patients to have partial pre-visit PROM completion (odds ratio [OR], 1.74; p = 0.03), and Caucasian patients were more likely to have partial pre-visit PROM completion than African American patients (OR, 2.28; p = 0.01). Orthopaedic patients receiving either e-mail or patient portal messages demonstrated higher pre-visit PROM completion rates. Pre-visit messaging appears to be a useful strategy for increasing PROM completion rates and limiting the clinical workflow strain imposed by in-clinic PROM administration. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Generalised demodicosis in a Friesian heifer from a zero-grazing unit.
A Friesian heifer with generalised skin lesions was slaughtered after unsuccessful treatment. It had thickened skin with lumps and nodules, with the severely affected parts thrown into folds over the eyelids, ears, most of the head, neck, legs and perineal area. The affected skin was soft and squamous in appearance. On postmortem examination, all the skin layers were affected and were 10-22 mm thick. There was also lymphadenopathy. Histological examination showed the presence of dermatitis characterised by follicular inflammation. Multiple follicular cysts with keratin squames and numerous demodectic mites were seen. Some mites had migrated to the peripheral lymph nodes causing eosinophilic lymphadenitis and panniculitis of the subcutis.


Cultural Values Influencing Immigrant Haitian Mothers' Attitudes Toward Human Papillomavirus Vaccination for Daughters.
Although research has shown that mothers significantly influence daughters' willingness to be vaccinated against the human papillomavirus (HPV), cultural factors influencing immigrant Haitian mothers' willingness to have adolescent daughters to be vaccinated are unknown. This is of concern as this population experiences disproportionately higher rates of HPV infection and related cervical cancers. This study identifies cultural beliefs influencing 31 immigrant Haitian mothers' willingness to vaccinate their daughters against HPV using semistructured interviews. Mothers had low levels of HPV and HPV vaccine knowledge, and desired more information. Concerns centered on cultural values regarding adolescent sexuality and HIV/AIDS stigmas specific to Haitian communities. If vaccination were recommended by a physician, mothers are more likely to have their daughters vaccinated. HPV vaccination uptake efforts targeting Haitian months should emphasize physician involvement and incorporate culturally relevant health concerns.


Influence of castration and of the kind of sympathomimetic drug used upon the reactivity of rat seminal vesicles.
An interdependence of the hormonal state of rodents and the genital muscle response to drugs was observed either on females or on males. Castration or castration followed by oestradiol treatment increased the responses of rat seminal vesicles to parasympathomimetic drugs. As, however, the influence of such procedures upon the responses to sympathomimetic drugs is controversial, the parameters pD2 (apparent affinity constant), alpha (intrinsic activity) and rho (relative responsiveness) of adrenaline, noradrenaline, methoxamine and phenylephrine on the seminal vesicles isolated from normal and castrated rats were determined. These parameters were shown to be different, depending not only of the hormonal state of the donor animals, but also of the drugs tested on each preparation. These facts must be considered in studies about sensitivity of rat seminal vesicles to sympathomimetic drugs.


Molecular mechanisms of FOXO1 in adipocyte differentiation.
Forkhead box-O1 (FOXO1) is a downstream target of AKT and plays crucial roles in cell cycle control, apoptosis, metabolism and adipocyte differentiation. It is thought that FOXO1 affects adipocyte differentiation by regulating lipogenesis and cell cycle. With the deepening in the understanding of this field, it is currently believed that FOXO1 translocation between nuclei and cytoplasm is involved in the regulation of FOXO1 activity, thus affecting adipocyte differentiation. Translocation of FOXO1 depends on its post-translational modifications and interactions with 14-3-3. Based on these modifications and interactions, FOXO1 could regulate lipogenesis through PPARγ and the adipocyte cell cycle through p21 and p27. In this review, we aim to provide a comprehensive FOXO1 regulation network in adipocyte differentiation by linking together distinct functions mentioned above to explain their effects on adipocyte differentiation and to emphasize the regulatory role of FOXO1. In addition, we also focus on the novel findings such as the use of miRNAs in FOXO1 regulation and highlight the improvable issues, such as RNA modifications, for future research in the field.


Surgical outcomes after radioactive 125I seed versus hookwire localization of non-palpable breast cancer: a multicentre randomized clinical trial.
Previous studies have suggested improved efficiency and patient outcomes with 125I seed compared with hookwire localization (HWL) in breast-conserving surgery, but high-level evidence of superior surgical outcomes is lacking. The aim of this multicentre pragmatic RCT was to compare re-excision and positive margin rates after localization using 125I seed or hookwire in women with non-palpable breast cancer. Between September 2013 and March 2018, women with non-palpable breast cancer eligible for breast-conserving surgery were assigned randomly to preoperative localization using 125I seeds or hookwires. Randomization was stratified by lesion type (pure ductal carcinoma in situ (DCIS) or other) and study site. Primary endpoints were rates of re-excision and margin positivity. Secondary endpoints were resection volumes and weights. A total of 690 women were randomized at eight sites; 659 women remained after withdrawal (125I seed, 327; HWL, 332). Mean age was 60.3 years in the 125I seed group and 60.7 years in the HWL group, with no difference between the groups in preoperative lesion size (mean 13.2 mm). Lesions were pure DCIS in 25.9 per cent. The most common radiological lesion types were masses (46.9 per cent) and calcifications (28.2 per cent). The localization modality was ultrasonography in 65.5 per cent and mammography in 33.7 per cent. The re-excision rate after 125I seed localization was significantly lower than for HWL (13.9 versus 18.9 per cent respectively; P = 0.019). There were no significant differences in positive margin rates, or in specimen weights and volumes. Re-excision rates after breast-conserving surgery were significantly lower after 125I seed localization compared with HWL. Registration number: ACTRN12613000655741 (http://www.ANZCTR.org.au/).


International Comparison of Patient Characteristics and Quality of Care for Ischemic Stroke: Analysis of the China National Stroke Registry and the American Heart Association Get With The Guidelines--Stroke Program.
Background Adherence to evidence-based guidelines is an important quality indicator; yet, there is lack of assessment of adherence to performance measures in acute ischemic stroke for most world regions. Methods and Results We analyzed 19 604 patients with acute ischemic stroke in the China National Stroke Registry and 194 876 patients in the Get With The Guidelines--Stroke registry in the United States from June 2012 to January 2013. Compared with their US counterparts, Chinese patients were younger, had a lower prevalence of comorbidities, and had similar median, lower mean, and less variability in National Institutes of Health Stroke Scale (median 4 [25th percentile-75th percentile, 2-7], mean 5.4±5.6 versus median 4 [1-10], mean 6.8±7.7). Chinese patients were more likely to experience delays from last known well to hospital arrival (median 1318 [330-3209] versus 644 [142-2055] minutes), less likely to receive thrombolytic therapy (2.5% versus 8.1%), and more likely to experience treatment delays (door-to-needle time median 95 [72-112] versus 62 [49-85] minutes). Adherence to early and discharge antithrombotics, smoking cessation counseling, and dysphagia screening were relatively high (eg >80%) in both countries. Large gaps existed between China and the United States with regard to the administration of thrombolytics within 3 hours (18.3% versus 83.6%), door-to-needle time ≤60 minutes (14.6% versus 48.0%), deep venous thrombosis prophylaxis (65.0% versus 97.8%), anticoagulation for atrial fibrillation (21.0% versus 94.4%), lipid treatment (66.3% versus 95.8%), and rehabilitation assessment (58.8% versus 97.4%). Conclusions We found significant differences in clinical characteristics and gaps in adherence for certain performance measures between China and the United States. Additional efforts are needed for continued improvements in acute stroke care and secondary prevention in both nations, especially China.


Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: A Practice Resource from the National Society of Genetic Counselors.
Polygenic scores (PGS) are primed for use in personalized risk assessments for common, complex conditions and population health screening. Although there is growing evidence supporting the clinical validity of these scores in certain diseases, presently, there is no consensus on best practices for constructing PGS or demonstrated clinical utility in practice. Despite these evidence gaps, individuals can access their PGS information through commercial entities, research programs, and clinical programs. This prompts the immediate need for educational resources for clinicians encountering PGS information in clinical practice. This practice resource is intended to increase genetic counselors' and other healthcare providers' understanding and comfort with PGS used in personalized risk assessments. Drawing on best practices in clinical genomics, we discuss the unique considerations for polygenic-based (1) testing, (2) clinical genetic counseling, and (3) translation to population health services. This practice resource outlines the emerging uses of PGS, as well as the critical limitations of this technology that need to be addressed before wide-scale implementation.


An altered-specificity mutation in a human POU domain demonstrates functional analogy between the POU-specific subdomain and phage lambda repressor.
The POU motif, conserved among a family of eukaryotic transcription factors, contains two DNA-binding domains: an N-terminal POU-specific domain (POUS) and a C-terminal homeodomain (POUHD). Surprisingly, POUS is similar in structure to the helix-turn-helix domains of bacteriophage repressor and Cro proteins. Such similarity predicts a common mechanism of DNA recognition. To test this prediction, we have studied the DNA-binding properties of the human Oct-2 POU domain by combined application of chemical synthesis and site-directed mutagenesis. The POUS footprint of DNA contacts, identified by use of modified bases, is analogous to those of bacteriophage repressor-operator complexes. Moreover, a loss-of-contact substitution in the putative POUS recognition alpha-helix leads to relaxed specificity at one position in the DNA target site. The implied side chain-base contact is identical to that of bacteriophage repressor and Cro proteins. These results establish a functional analogy between the POUS and prokaryotic helix-turn-helix elements and suggest that their DNA specificities may be governed by a shared set of rules.


Time-Resolved Luminescence Spectroelectrochemistry at Screen-Printed Electrodes: Following the Redox-Dependent Fluorescence of [Ru(bpy)3]2.
In this work, a compact instrument for time-resolved luminescence spectroelectrochemistry using low-cost disposable electrodes is reported. This instrument can be coupled with screen-printed electrodes via a specific cell and a reflection probe, which allows one to observe changes occurring at the electrode/solution interface. This approach allowed one to follow the fluorescence variation of electrofluorochromic species such as [Ru(bpy)3]2+ at screen-printed carbon electrodes. A strong correlation between the electrochemical processes and the fluorescence was found during potentiostatic or multipulsed amperometric measurements. A decrease of the fluorescence was observed when the [Ru(bpy)3]2+ was oxidized to [Ru(bpy)3]3+ and part of this fluorescence is recovered when [Ru(bpy)3]3+ was reduced to the initial species. Moreover, a significant increment of the fluorescence was found when the oxygen reduction reaction takes place, which also confirms its quenching effect. Finally, multipulsed amperometric detection was employed in order to obtain more information about the redox-dependent luminescence of [Ru(bpy)3]2+ finding a continuous quenching over time attributed to bleaching chlorine-based species.