Using a cessation-related outcome index to assess California's cessation progress at the population level.
The California Tobacco Control Program (CTCP) has employed strategies to change social norms around smoking in order to decrease the prevalence of smoking and tobacco-related diseases. Research is scarce on CTCP's impact on overall smoking cessation in California. Tobacco Use Supplement to the Current Population Survey (TUS-CPS) data from 1992-1993 to 2006-2007 was used to create a cessation-related outcome index (CROI), which was a summarised z score of the following determinants: plan to quit, quit attempt and recent quit rate for each of the 50 US states. CROI trends over the period of six separate TUS-CPSs were plotted for California and other comparison states, for 18-34 year olds and for those 35 years or older separately in the context of historical cigarette price z score trend. California had a consistently high CROI for both age groups. The CROI trend line increased moderately in California for both age groups despite a declining cigarette price z score trend. In contrast, other selected states with a declining cigarette price z score trend had a declining CROI trend for both age groups. The increase of CROI in California while cigarette price z score trend declined suggests that the implementation of CTCP, even without a significant direct cessation component, has had a profound impact on cessation outcomes.


Combined use of ion mobility and collision-induced dissociation to investigate the opening of disulfide bridges by electron-transfer dissociation in peptides bearing two disulfide bonds.
Disulfide bonds are post-translational modifications (PTMs) often found in peptides and proteins. They increase their stability toward enzymatic degradations and provide the structure and (consequently) the activity of such folded proteins. The characterization of disulfide patterns, i.e., the cysteine connectivity, is crucial to achieve a global picture of the active conformation of the protein of interest. Electron-transfer dissociation (ETD) constitutes a valuable tool to cleave the disulfide bonds in the gas phase, avoiding chemical reduction/alkylation in solution. To characterize the cysteine pairing, the present work proposes (i) to reduce by ETD one of the two disulfide bridges of model peptides, resulting in the opening of the cyclic structures, (ii) to separate the generated species by ion mobility, and (iii) to characterize the species using collision-induced dissociation (CID). Results of this strategy applied to several peptides show different behaviors depending on the connectivity. The loss of SH· radical species, observed for all the peptides, confirms the cleavage of the disulfides during the ETD process.


Do we really know the pharmacodynamics of anaesthetics used in newborns, infants and children? A review of the experimental and clinical data on neurodegeneration.
The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia, regardless of whether the patient is a newborn, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-pharmacodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and synaptogenesis) occurs during the fetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safety of general anaesthesia in humans. Prospective trials should continue being carried out, and anaesthesia and surgery, delayed if possible among the smallest patients. The simultaneous use of different anaesthetics with the same potential neurotoxicities should also be avoided, potentially in favour of regional anaesthesia techniques, in this group of patients.


Clinical utility of the Colorado Learning Difficulties Questionnaire.
Behavioral disorders are highly comorbid with childhood learning disabilities (LDs), and accurate identification of LDs is vital for guiding appropriate interventions. However, it is difficult to conduct comprehensive assessment of academic skills within the context of primary care visits, lending utility to screening of academic skills via informant reports. The current study evaluated the clinical utility of a parent-reported screening measure in identifying children with learning difficulties. Participants included 440 children (66.7% male), ages 5.25 to 17.83 years (mean = 10.32 years, SD = 3.06 years), referred for neuropsychological assessment. Academic difficulties were screened by parent report using the Colorado Learning Difficulties Questionnaire (CLDQ). Reading and math skills were assessed via individually administered academic achievement measures. Sensitivity, specificity, classification accuracy, and conditional probabilities were calculated to evaluate the efficacy of the CLDQ in predicting academic impairment. Correlations between the CLDQ reading scale and reading achievement measures ranged from -0.35 to -0.65 and from -0.24 to -0.46 between the CLDQ math scale and math achievement measures (all P < .01). Sensitivity was good for both reading and math scales, whereas specificity was low. Taking into account the high base rate of reading and math LDs within our sample, the conditional probability of true negatives (96.2% reading, 85.1% math) was higher than for true positives (40.5% reading, 37.9% math). Overall, the CLDQ may more accurately predict children without LDs than children with LDs. As such, the absence of parent-reported difficulties may be adequate to rule out an overt LD, whereas elevated scores likely indicate the need for more comprehensive assessment.


Trends in the incidence of digestive cancers in France between 1980 and 2005 and projections for the year 2010.
The aim of this study was to present estimates of national trends in the incidence of the most frequent digestive cancers over the period 1980-2005 and to provide projections up to 2010. World age-standardised estimates of national incidence were modelled using data from the French cancer registries and the incidence/mortality ratios observed in the area covered by the contributing registries, using an age-period-cohort model. The incidence of oesophageal cancers in men strongly decreased over time from 15.3 in 1980 to 7.9 per 100 000 in 2005, whereas the incidence in women slowly increased. A steadily decreasing trend in gastric cancer was found in both sexes. After a steady increase until 1995, the incidence of colorectal cancer stabilised in both sexes, with a slight decrease in men. In 2010, the projected incidence was 36.5 per 100 000 in men and 24.4 in women. The incidence of liver cancer showed the highest increase over time. In men, this increase was steeper until 1995 than later. The projected incidence in 2010 was 10.9 per 100 000 in men and 2.4 in women. The incidence of pancreatic cancer increased slowly between 1980 and 1990 and increased steeply after 1990, reaching an estimated 7.6 per 100 000 in men and 4.7 in women in 2005. This study on trends in the incidence of digestive cancers in France showed large changes between 1980 and 2010. The increase in the incidence of primary liver cancer and pancreatic cancer was striking. Colorectal cancer incidence is stabilising.


Utp23p is required for dissociation of snR30 small nucleolar RNP from preribosomal particles.
Yeast snR30 is an essential box H/ACA small nucleolar RNA (snoRNA) that promotes 18S rRNA processing through forming transient base-pairing interactions with the newly synthesized 35S pre-rRNA. By using a novel tandem RNA affinity selection approach, followed by coimmunoprecipitation and in vivo cross-linking experiments, we demonstrate that in addition to the four H/ACA core proteins, Cbf5p, Nhp2p, Nop10p and Gar1p, a fraction of snR30 specifically associates with the Utp23p and Kri1p nucleolar proteins. Depletion of Utp23p and Kri1p has no effect on the accumulation and recruitment of snR30 to the nascent pre-ribosomes. However, in the absence of Utp23p, the majority of snR30 accumulates in large pre-ribosomal particles. The retained snR30 is not base-paired with the 35S pre-rRNA, indicating that its aberrant tethering to nascent preribosomes is likely mediated by pre-ribosomal protein(s). Thus, Utp23p may promote conformational changes of the pre-ribosome, essential for snR30 release. Neither Utp23p nor Kri1p is required for recruitment of snR30 to the nascent pre-ribosome. On the contrary, depletion of snR30 prevents proper incorporation of both Utp23p and Kri1p into the 90S pre-ribosome containing the 35S pre-rRNA, indicating that snR30 plays a central role in the assembly of functionally active small subunit processome.


Management of chronic illness: voices of rural women.
The prevalence and cost of chronic illness globally and in the United States of America continue to escalate and the day-to-day management of these conditions presents a major challenge. The burden of chronic illness disproportionately affects vulnerable populations such as women and those living in rural areas. To add to the knowledge base of illness management by chronically ill rural women through examining their individual perceptions of the illness experience. The Women to Women project provided a nursing research-based computer intervention model for conducting support groups, providing health education, and fostering self-care, via personal computers and evaluated its effect on the women's psychosocial health. Fatigue and pain were the major physical symptoms that impacted the women's quality of life, with depression and stress being the primary emotions they experienced. The characteristics of humour, hope, and courage were key in their successful adaptation to living with chronic illness. The women's voices relate how they manage their illness responses and adaptation mechanisms. The data provide nurses with information to heighten their sensitivity to clients' day-to-day needs and experiences. It will assist them in their designing and planning of interventions that will enable clients to adapt and to have the best quality of life possible within the limitations of their chronic illnesses. The data are also important to nurses involved in rural research and theory development concerning self-management and adaptation to chronic illnesses.


Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study.
Sub-analysis of the fasudil post-marketing surveillance study compared the safety and efficacy of fasudil plus ozagrel to fasudil only. A total of 3690 patients received fasudil and 1138 received fasudil plus ozagrel between 1995 and 2000. The occurrence of adverse events, occurrence of low density areas associated with vasospasm on computed tomography, absence of symptomatic vasospasm, and poor clinical outcomes associated with vasospasm were compared between the fasudil and fasudil plus ozagrel groups. The pharmacokinetics of fasudil were assessed in 5 patients with subarachnoid hemorrhage. The drug interaction between fasudil and ozagrel was pharmacologically investigated in vitro and in vivo. The occurrence of adverse events and clinical outcomes were similar between the two groups. The occurrences of symptomatic vasospasm and low density areas were lower in the fasudil group than in the fasudil plus ozagrel group. The average trough value (8-hour value) of the fasudil active metabolite, hydroxyfasudil, was 50 nM. Fasudil showed no pharmacological interaction with ozagrel. The combination of fasudil plus ozagrel was well tolerated, but did not result in better efficacy than fasudil only.


Neat ionic liquids versus ionic liquid mixtures: a combination of experimental data and molecular simulation.
Simple mixtures of ionic liquids (IL-IL mixtures) can become a promising approach for the substitution of task-specific ILs. Such a concept was explored in this article by comparison of the thermophysical properties of neat 1-ethyl-3-methylimidazolium 2,2,2-trifluoromethylsulfonyl-N-cyanoamide, [C2mim][TFSAM], and equimolar mixtures of two structurally similar ILs having more common ions. Molecular dynamics (MD) simulations were additionally used to further highlight structural aspects of these systems at a molecular level.


Single-cell ELISA and flow cytometry as methods for highlighting potential neuronal and astrocytic toxicant specificity.
The timeline imposed by recent worldwide chemical legislation is not amenable to conventional in vivo toxicity testing, requiring the development of rapid, economical in vitro screening strategies which have acceptable predictive capacities. When acquiring regulatory neurotoxicity data, distinction on whether a toxic agent affects neurons and/or astrocytes is essential. This study evaluated neurofilament (NF) and glial fibrillary acidic protein (GFAP) directed single-cell (S-C) ELISA and flow cytometry as methods for distinguishing cell-specific cytoskeletal responses, using the established human NT2 neuronal/astrocytic (NT2.N/A) co-culture model and a range of neurotoxic (acrylamide, atropine, caffeine, chloroquine, nicotine) and non-neurotoxic (chloramphenicol, rifampicin, verapamil) test chemicals. NF and GFAP directed flow cytometry was able to identify several of the test chemicals as being specifically neurotoxic (chloroquine, nicotine) or astrocytoxic (atropine, chloramphenicol) via quantification of cell death in the NT2.N/A model at cytotoxic concentrations using the resazurin cytotoxicity assay. Those neurotoxicants with low associated cytotoxicity are the most significant in terms of potential hazard to the human nervous system. The NF and GFAP directed S-C ELISA data predominantly demonstrated the known neurotoxicants only to affect the neuronal and/or astrocytic cytoskeleton in the NT2.N/A cell model at concentrations below those affecting cell viability. This report concluded that NF and GFAP directed S-C ELISA and flow cytometric methods may prove to be valuable additions to an in vitro screening strategy for differentiating cytotoxicity from specific neuronal and/or astrocytic toxicity. Further work using the NT2.N/A model and a broader array of toxicants is appropriate in order to confirm the applicability of these methods.


Evaluation of graduate nursing students' information literacy self-efficacy and applied skills.
Maintaining evidence-based nursing practice requires information literacy (IL) skills that should be established prior to completing an undergraduate nursing degree. Based on Bandura's social cognitive theory, this cross-sectional descriptive correlational study assessed the perceived and applied IL skills of graduate nursing students from two family nurse practitioner (FNP) programs in the midwestern United States. Results showed that although the 26 newly admitted FNP students demonstrated a high level of confidence in their IL skills, the students did not perform well in the actual IL skills test. According to Bandura, the students' confidence in their IL knowledge should allow students to be engaged in course activities requiring IL skills. Nurse educators teaching in undergraduate or graduate programs are in key positions to incorporate IL experiences into class activities to allow for skill assessment and further practice. Further research is needed on nursing students' IL self-efficacy and performance.


Treatment of symptomatic oral mucositis with sodium hyaluronate and synthetic amino acid precursors of collagen in patients undergoing haematopoietic stem cell transplantation.
The purpose of the study is to evaluate the clinical effects of Mucosamin® (a spray preparation containing sodium hyaluronate combined with a pool of amino acids of precursor collagen, including L-Proline, L-Leucine, L-Lysine and glycine) on wound healing and pain management of oral mucositis after hematopoietic stem cell transplantation. The importance of professional dental hygiene by dental hygienist in reducing the severity of oral mucositis as unique therapy or in addition to therapy with Mucosamin® was also evaluated. One hundred thirty-seven patients undergoing hematopoietic stem cell transplantation were recruited in a case-control study and divided into 4 groups: Group A: professional oral hygiene + Mucosamin®; Group B: professional oral hygiene + standard treatment with chlorhexidine 0.20%;; Group C: only Mucosamin®; Group D: only standard treatment with chlorhexidine 0.20%. The following evaluations were made: WHO mucositis scale, OMAS mucositis scale, VAS, periodontal recording, days of mucositis. Comparing the groups at the onset of OM on WHO scale, it was observed that Group A grade 1 occurrence was more statistically significant than Group B (p= 0.03*); comparison between Group A and D showed a statistically significant difference in favour of Group A (p= 0.0002*). Also OMAS scale showed a statistically significant difference between groups who assumed Mucosamin, who developed lower OM grade (p = 0.001*). There was a statistically significant difference between group A compared with group B over the overall duration of OM (p = 0.02*), as well as between group A and group D (p=0.03*). According to the present study the combination of a careful debridement, correct oral hygiene during hospitalization and the use of Mucosamin® exponentially reduces the severity and duration of mucositis and consequently the discomfort of the patient. Moreover, it can be stated that the use of Mucosamin® also results in a reduction in the extent of chemotherapy lesions. Hyaluronic acid and amino acid-based sprays can be a valuable therapeutic aid in the treatment of mucositis.


Perceptions of paramedic educators on assessments used in the first year of a paramedic programme: a qualitative exploration.
In Ireland, there are currently three educational institutions (recognised institutions- RIs) providing paramedic programmes, accredited by the regulator, the Pre-Hospital Emergency Care Council (PHECC). Each RI assesses their students in-house, and in order to acquire a licence to practice, students must also pass summative assessments provided by PHECC. These assessments comprise multiple choice questions, short answer questions and skills assessments. The objective of this study was to explore the perceptions and experiences of paramedic educators of assessments used within their institution and by the regulator to provide insights that could inform the future design of paramedic assessments. A qualitative study with an interpretivist approach and purposive sampling strategy was performed. Semi-structured interviews were conducted with educators from one RI, across their three sites. Data were analysed using an inductive approach to thematic analysis. Four major themes were identified in the data: improving assessments by enhancing authenticity, modifying the current process of assessment, aligning the PHECC and RI examinations and opportunities to use assessment as learning. This study identifies perceived deficits and opportunities in the assessments currently used for paramedic students and ways in which these assessments could be improved. While participants were relatively content with their own RI assessments, they identified ways to improve both the RI and PHECC assessments. Modifying some of the current methods could be a useful first step. In particular, assessments used by PHECC could be improved by reflecting 'real-world' practice. The inclusion of additional assessment methods by PHECC, a continuous assessment process or devolvement of the entire assessment suite, to the RI/University has the potential to enhance assessments, particularly summative assessments, for paramedic students.


Hypotheses about sub-optimal hydration in the weeks before coronavirus disease (COVID-19) as a risk factor for dying from COVID-19.
To address urgent need for strategies to limit mortality from coronavirus disease 2019 (COVID-19), this review describes experimental, clinical and epidemiological evidence that suggests that chronic sub-optimal hydration in the weeks before infection might increase risk of COVID-19 mortality in multiple ways. Sub-optimal hydration is associated with key risk factors for COVID-19 mortality, including older age, male sex, race-ethnicity and chronic disease. Chronic hypertonicity, total body water deficit and/or hypovolemia cause multiple intracellular and/or physiologic adaptations that preferentially retain body water and favor positive total body water balance when challenged by infection. Via effects on serum/glucocorticoid-regulated kinase 1 (SGK1) signaling, aldosterone, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), aquaporin 5 (AQP5) and/or Na+/K+-ATPase, chronic sub-optimal hydration in the weeks before exposure to COVID-19 may conceivably result in: greater abundance of angiotensin converting enzyme 2 (ACE2) receptors in the lung, which increases likelihood of COVID-19 infection, lung epithelial cells which are pre-set for exaggerated immune response, increased capacity for capillary leakage of fluid into the airway space, and/or reduced capacity for both passive and active transport of fluid out of the airways. The hypothesized hydration effects suggest hypotheses regarding strategies for COVID-19 risk reduction, such as public health recommendations to increase intake of drinking water, hydration screening alongside COVID-19 testing, and treatment tailored to the pre-infection hydration condition. Hydration may link risk factors and pathways in a unified mechanism for COVID-19 mortality. Attention to hydration holds potential to reduce COVID-19 mortality and disparities via at least 5 pathways simultaneously.


[Proteins of mouse spermatogenic cells. II. Age differences at individual stages of differentiation].
The spermatogenic cells of the adult and young mice differ by the content of certain electrophoretic fractions of proteins and the activity of a number of enzymes (glucose-6-phosphate, sorbitol and pyruvate dehydrogenases). The expression of age differences changes in the process of differentiation. It is suggested that the differences found are of dual nature: they are due to both the "immaturity" of young animals and the age processes per se in adults; the role of the latter decreases as the differentiation proceeds.


Relationship Between Internal Load Indicators and Changes on Intermittent Performance After the Preseason in Professional Soccer Players.
The aim of this study was to examine the effects of accumulated internal training load (ITL) during the preseason (4 weeks) on changes in the intermittent performance, in a professional soccer team. Twelve professionals soccer players (Mean ± SD age: 27.7 ± 4.3 years; height: 177.1 ± 6.2 cm; body mass: 73.1 ± 5.2 kg; % body fat [Faulkner]: 10.2 ± 1.2) belonging to a Spanish second division team (2013-2014) participated in this study. The 30-15 intermittent fitness test was performed before and after the preseason, and the speed for the last period completed by each player was recorded (VIFT). During the preseason, the team alternated practice of training sessions (TRNs) with friendly matches (FMs). Session rating of perceived exertion (sRPE), heart rate (HR), and HR reserve were analyzed every TRN and FM to calculate ITL (ITL: sRPE-TL, Edward's-TL and Edward's-TLres). The players' VIFT substantially increased after the preseason period (20.1 ± 0.8 vs. 21.1 ± 0.8 km·h; effect size [ES] = 1.15 ± 0.25; almost certainly). The average value of sRPE throughout FMs was substantially greater than the value of the TRNs (7.4 ± 0.9 vs. 5.25 ± 0.2; ES = 2.31 ± 2.45; almost certainly). sRPE-TL, practice volume, and sum of RPE during the preseason were positively and largely correlated (r = 0.70-0.75) with changes on intermittent performance. No relationships were found between HR-derived measures of exercise load and changes on intermittent fitness. The present results suggest that practice volume and subjective measures of TL, related better than HR-based TL methods to changes on intermittent performance after the preseason, in professional soccer players.


Vehicle emissions during children's school commuting: impacts of education policy.
We explore how school policies influence the environmental impacts of school commutes. Our research is motivated by increased interest in school choice policies (in part because of the U.S. "No Child Left Behind" Act) and in reducing bus service to address recent budget shortfalls. Our analysis employs two samples of elementary-age children, age 5-12: a travel survey (n = 1246 respondents) and a school enrollment data set (n = 19,655 students). Multinomial logistic regression modeled the determinants of travel mode (automobile, school bus, and walking; n = 803 students meeting selection criteria). Travel distance has the single greatest effect on travel mode, though school choice, trip direction (to- or from-school), and grade play a role. Several policies were investigated quantitatively to predict the impact on school travel, vehicle emissions, and costs. We find that eliminating district-wide school choice (i.e., returning to a system with neighborhood schools only) would have significant impacts on transport modes and emissions, whereas in many cases proposed shifts in school choice and bus-provision policies would have only modest impacts. Policies such as school choice and school siting may conflict with the goal of increasing rates of active (i.e., nonmotorized) school commuting. Policies that curtail bus usage may reduce bus emissions but yield even larger increases in private-vehicle emissions. Our findings underscore the need to critically evaluate transportation-related environmental and health impacts of currently proposed changes in school policy.


Modeling the Effects of Onsite Wastewater Treatment Systems on Nitrate Loads Using SWAT in an Urban Watershed of Metropolitan Atlanta.
Onsite wastewater treatment systems (OWTSs) can be a source of nitrogen (N) pollution in both surface and ground waters. In metropolitan Atlanta, GA, >26% of homes are on OWTSs. In a previous article, we used the Soil Water Assessment Tool to model the effect of OWTSs on stream flow in the Big Haynes Creek Watershed in metropolitan Atlanta. The objective of this study was to estimate the effect of OWTSs, including failing systems, on nitrate as N (NO-N) load in the same watershed. Big Haynes Creek has a drainage area of 44 km with mainly urban land use (67%), and most of the homes use OWTSs. A USGS gauge station where stream flow was measured daily and NO-N concentrations were measured monthly was used as the outlet. The model was simulated for 12 yr. Overall, the model showed satisfactory daily stream flow and NO-N loads with Nash-Sutcliffe coefficients of 0.62 and 0.58 for the calibration period and 0.67 and 0.33 for the validation period at the outlet of the Big Haynes Watershed. Onsite wastewater treatment systems caused an average increase in NO-N load of 23% at the watershed scale and 29% at the outlet of a subbasin with the highest density of OWTSs. Failing OWTSs were estimated to be 1% of the total systems and did not have a large impact on stream flow or NO-N load. The NO-N load was 74% of the total N load in the watershed, indicating the important effect of OWTSs on stream loads in this urban watershed.


Global Inequities in COVID-19 Vaccination: Associated Factors and Tools to Measure Inequality.
Socioeconomic factors have been recognized by the WHO as determinants of health, and it is important to consider these factors in decision making to curb existing inequality in vaccination for SARS-CoV-2, which causes COVID-19. We aimed to determine whether there is a correlation between socioeconomic factors and vaccination worldwide and measure inequality. A study of secondary sources was carried out to assess inequality in vaccination against COVID-19 worldwide and its association with socioeconomic factors. For this assessment, 169 countries were chosen from January 2020 to March 2022 using LibreOffice and JASP 0.16.1.10. Several mathematical models and statistical tests were used, including a normality test, an analysis of frequencies and proportions, a Kruskal-Wallis test, Spearman's correlations, a Lorenz curve, a Concentration Index, and a slope. Correlations were found between socioeconomic factors and vaccination with one, two, and three doses. As the GDP showed correlations of 0.71 for one dose and 0.82 for three doses, we found that the greater the competitiveness of the countries, the higher the percentage of vaccinated individuals in their populations. According to the Concentration Index, there was greater inequality in vaccination with regard to receiving a higher number of doses, as reflected in the life expectancy indices of 0.16-0.19 and 0.50. The continent with the highest degree of inequality was Africa, and the continent with the lowest degree was America. South Americans were vaccinated with two doses at a rate of 6.19%/month, which was 4.3 times faster than Africans, with 72% of the population being vaccinated in South America, compared to only 16% in Africa. There is inequality in vaccination against COVID-19 with one, two, and three doses, which is associated with socioeconomic factors.


[Pain and painkillers. 3. Psychic component].
Psychic factors, for instance anxiety and the social and cultural environment, affect the tolerance for pain, amongst others due to an influence on the 'gate control' mechanism. Therefore psychopharmaca, which affect the brain, but also a placebo may be used to fight pain. Through three types to distinguish in learning, chronic pain may result in illness-behaviour.


Awareness of the response after feedback training for changes in heart rate and sudomotor laterality.
What is the relation between the ability to control visceral responding on a biofeedback task and the ability to report behaviors actually contributing to this performance? Subjects received biofeedback training for unidentified visceral responses and then gave written reports about what they had done to control the feedback displays. Independent judges were given these reports and, on the basis of knowledge about activities known to contribute to visceral activity, were asked to determine the visceral responses for which the subjects had been trained. The reports of subjects who succeeded at bidirectional control of heart rate (Experiment 1) or sudomotor laterality (Experiment 2) showed awareness of behaviors related to feedback as assessed by this procedure, whereas the reports of subjects who failed at bidirectional control did not. Subsequent experiments indicated that these results did not depend on a learning strategy that might have been specific to the initial studies. These findings call into question the view that people are unaware of what they have done to produce the response after training on biofeedback tasks. Earlier studies reporting lack of awareness in biofeedback are discussed in light of factors that affect the measurement of biofeedback learning and response awareness.


Can light make us bright? Effects of light on cognition and sleep.
Light elicits robust nonvisual effects on numerous physiological and behavioral variables, such as the human sleep-wake cycle and cognitive performance. Light effects crucially rely on properties such as dose, duration, timing, and wavelength. Recently, the use of methods such as fMRI to assess light effects on nonvisual brain responses has revealed how light can optimize brain function during specific cognitive tasks, especially in tasks of sustained attention. In this chapter, we address two main issues: how light impinges on cognition via consolidation of human sleep-wake cycles; and how light directly impacts on sleep and cognition, in particular in tasks of sustained attention. A thorough understanding of how light affects sleep and cognitive performance may help to improve light settings at home and at the workplace in order to improve well-being.


Effects of water chemistry on the chronic toxicity of lead to the cladoceran, Ceriodaphnia dubia.
As the first step toward parameterization of a chronic lead (Pb) biotic ligand model (BLM) for Ceriodaphnia dubia, 7-d toxicity tests were performed in waters modified to evaluate the influences of hardness, DOM (as Suwannee River NOM and Aldrich humic acid (HA)), pH (buffered with 4 mM MOPS) and alkalinity on the chronic toxicity of Pb. Calculated EC(20)s for the control base water test and each of the most extreme modified test waters were as follows in μg L(-1) Pb (95% confidence interval): base water control=45 (14-53), 5 mM CaSO(4)=22 (12-30), 32 mg L(-1) DOM=523 (388-573), 2.5 mM NaHCO(3)=73 (21-120) and pH 6.4 buffered with MOPS=3.9 μg L(-1) Pb (1-5). Results indicate that hardness does not protect against chronic toxicity of Pb to C. dubia, whereas HA does protect at the highest concentration tested (597 μM). Additionally, our findings suggest that low pH increases the chronic toxicity of Pb whereas increased alkalinity is protective. The findings reported herein support the need for a chronic Pb BLM as an alternative approach to hardness-based regulations.


Cardiac Fibrosis Alleviated by Exercise Training Is AMPK-Dependent.
Regular exercise can protect the heart against external stimuli, but the mechanism is not well understood. We determined the role of adenosine monophosphate-activated protein kinase (AMPK) in regulating swimming exercise-mediated cardiac protection against β-adrenergic receptor overstimulation with isoproterenol (ISO) in mice. Ten-week-old AMPKα2+/+ and AMPKα2-knockout (AMPKα2-/-) littermates were subjected to 4 weeks of swimming training (50 min daily, 6 days a week) or housed under sedentary conditions. The mice received daily subcutaneous injection of ISO (5 mg/kg/d), a nonselective β-adrenergic receptor agonist, during the last 2 weeks of swimming training. Swimming training alleviated ISO-induced cardiac fibrosis in AMPKα2+/+ mice but not AMPKα2-/- mice. Swimming training activated cardiac AMPK in AMPKα2+/+ mice. Furthermore, swimming training attenuated ISO-induced production of reactive oxygen species (ROS) and expression of NADPH oxidase and promoted the expression of antioxidant enzymes in AMPKα2+/+ mice but not AMPKα2-/- mice. In conclusion, swimming training attenuates ISO-induced cardiac fibrosis by inhibiting the NADPH oxidase-ROS pathway mediated by AMPK activation. Our findings provide a new mechanism for the cardioprotective effects of exercise.


Decreased expression of intelectin 1 in the human airway epithelium of smokers compared to nonsmokers.
Lectins are innate immune defense proteins that recognize bacterial cell wall components. Based on the knowledge that cigarette smoking is associated with an increased risk of infections, we hypothesized that cigarette smoking may modulate the expression of lectin genes in airway epithelium. Affymetrix microarrays were used to survey the expression of lectin genes in large airway epithelium from nine nonsmokers and 20 healthy smokers and in small airway epithelium from 13 nonsmokers and 20 healthy smokers. There were no changes (>2-fold change; p < 0.05) in lectin gene expression among healthy smokers compared with nonsmokers except for down-regulation of intelectin 1, a lectin that binds to galactofuranosyl residues in bacterial cell walls (large airway epithelium, p < 0.01; small airway epithelium, p < 0.01). This was confirmed by TaqMan RT-PCR in both large (p < 0.05) and small airway epithelium (p < 0.02). Immunohistochemistry assessment of airway biopsies demonstrated that intelectin 1 was expressed in secretory cells, while Western analysis confirmed the decreased expression of intelectin 1 in airway epithelium of healthy smokers compared with healthy nonsmokers (p < 0.02). Finally, compared with healthy nonsmokers, intelectin 1 expression was also decreased in small airway epithelium of smokers with lone emphysema and normal spirometry (n = 13, p < 0.01) and smokers with established chronic obstructive pulmonary disease (n = 14, p < 0.01). In the context that intelectin 1 plays a role in defense against bacteria, its down-regulation in response to cigarette smoking is another example of the immunomodulatory effects of smoking on the immune system and may contribute to the increase in susceptibility to infections observed in smokers.


Cognitive and behavioral development in maternal phenylketonuria offspring.
To assess cognitive and behavioral outcome in treated maternal phenylketonuria (PKU) offspring. In this prospective, longitudinal study, 228 children who were born to mothers with treated PKU or untreated mild hyperphenylalaninemia were compared with 70 control subjects at 7 years of age. Offspring cognitive outcome negatively correlated with the number of gestational weeks that elapsed until maternal metabolic control was achieved (r = -0.61). Behavioral outcome was similarly affected. Postnatal measurement of stimulation in the home was also related to offspring IQ. Children who are born to mothers who have PKU and attain metabolic control before or very early in pregnancy seem to begin life with undiminished potential. Delay in attainment of maternal metabolic control is associated with declines in offspring developmental outcome. The postnatal environment also significantly affects outcome. Interventions to improve dietary compliance before and throughout pregnancy as well as interventions to improve the postnatal home environment may reduce the risks associated with maternal PKU.


Computational spatiotemporal analysis identifies WAVE2 and cofilin as joint regulators of costimulation-mediated T cell actin dynamics.
Fluorescence microscopy is one of the most important tools in cell biology research because it provides spatial and temporal information to investigate regulatory systems inside cells. This technique can generate data in the form of signal intensities at thousands of positions resolved inside individual live cells. However, given extensive cell-to-cell variation, these data cannot be readily assembled into three- or four-dimensional maps of protein concentration that can be compared across different cells and conditions. We have developed a method to enable comparison of imaging data from many cells and applied it to investigate actin dynamics in T cell activation. Antigen recognition in T cells by the T cell receptor (TCR) is amplified by engagement of the costimulatory receptor CD28. We imaged actin and eight core actin regulators to generate over a thousand movies of T cells under conditions in which CD28 was either engaged or blocked in the context of a strong TCR signal. Our computational analysis showed that the primary effect of costimulation blockade was to decrease recruitment of the activator of actin nucleation WAVE2 (Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2) and the actin-severing protein cofilin to F-actin. Reconstitution of WAVE2 and cofilin activity restored the defect in actin signaling dynamics caused by costimulation blockade. Thus, we have developed and validated an approach to quantify protein distributions in time and space for the analysis of complex regulatory systems.


Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data.
We present here a framework for the study of molecular variation within a single species. Information on DNA haplotype divergence is incorporated into an analysis of variance format, derived from a matrix of squared-distances among all pairs of haplotypes. This analysis of molecular variance (AMOVA) produces estimates of variance components and F-statistic analogs, designated here as phi-statistics, reflecting the correlation of haplotypic diversity at different levels of hierarchical subdivision. The method is flexible enough to accommodate several alternative input matrices, corresponding to different types of molecular data, as well as different types of evolutionary assumptions, without modifying the basic structure of the analysis. The significance of the variance components and phi-statistics is tested using a permutational approach, eliminating the normality assumption that is conventional for analysis of variance but inappropriate for molecular data. Application of AMOVA to human mitochondrial DNA haplotype data shows that population subdivisions are better resolved when some measure of molecular differences among haplotypes is introduced into the analysis. At the intraspecific level, however, the additional information provided by knowing the exact phylogenetic relations among haplotypes or by a nonlinear translation of restriction-site change into nucleotide diversity does not significantly modify the inferred population genetic structure. Monte Carlo studies show that site sampling does not fundamentally affect the significance of the molecular variance components. The AMOVA treatment is easily extended in several different directions and it constitutes a coherent and flexible framework for the statistical analysis of molecular data.


Contribution of energy intake and tissue enzymatic profile to body weight gain in high-fat-fed rats.
The purpose of the current study was to examine the enzymatic profile [phosphofructokinase (PFK), beta-hydroxyacyl-CoA dehydrogenase (HADH), and citrate synthase (CS)] in gastrocnemius muscle, heart, and liver in rats allowed ad libitum access to a high-fat diet (HFD, 45% of kcal from corn oil). Male Wistar rats were fed a low-fat diet (LFD, 12% of kcal from corn oil) for a 2-wk baseline period after which some continued on the LFD and others were placed on the HFD. After 1 wk on the HFD, rats were categorized as obesity-resistant (OR), -intermediate (OI), or -prone (OP) on the basis of body weight gain (OR, lower tertile; OI, middle tertile; OP, upper tertile). At 1, 2, and 5 wk, rats from each group were killed (n = 9-14 from each group/time point) after a 24-h fast. At the end of the 5-wk dietary period, weight gain was 114.8 +/- 4.3 in LFD, 125.2 +/- 3.7 in OR, 147.1 +/- 4.1 in OI, and 173.7 +/- 3.5 g in OP rats (OP > OI > OR, LFD; P < 0.001). Energy intake was highly correlated with weight gain on the HFD at each time point (r > or = 0.72, P < 0.001). After 1 wk on the HFD, significant correlations between the ratio of PFK/HADH (an indication of the relative capacity for glycolysis vs. beta-oxidation, r = 0.4, P = 0.03) and HADH/CS (an indication of the capacity for beta-oxidation relative to total oxidative capacity, r = -0.56, P = 0.001) in the gastrocnemius muscle and weight gain were observed. At week 2, significant correlations between these ratios and weight gain were observed in the gastrocnemius, liver, and heart. In contrast, these ratios were not significantly correlated with weight gain at 5 wk. These results suggest that rats most susceptible to weight gain or a HFD are characterized by a continuous increase in energy intake (explaining approximately 50% of the variance in weight gain) and an early tissue enzymatic profile that favors carbohydrate over fat use.


Disease attributed to Mycobacterium chelonae in South African clawed frogs (Xenopus laevis).
The fast-growing nontuberculous mycobacterial species Mycobacterium chelonae was isolated from six captive South African clawed frogs (Xenopus laevis) with chronic weight loss and nonhealing ulcerative skin lesions. Three of the M. chelonae isolates were evaluated to confirm the species identification using polymerase chain reaction restriction analysis. Disease associated with M. chelonae is reported mainly in people and in fish. To our knowledge, this is the first report of disease associated with M. chelonae in a colony of captive Xenopus sp.


Modified Hyrax expander for the correction of upper midline deviation: a case report.
This article describes a case report of a patient treated by the modified version of the Hyrax rapid palatal expander described by Farronato et al. in 2009. This device can be utilized for the treatment of patients in mixed dentition who, due to the maxillary hypoplasia and to the premature exfoliation of some deciduous teeth, manifest a migration of the permanent incisors with a reduction or closure of the space for the permanent teeth substituting those previously exfoliated. This expander presents a vestibular arm for correcting maxillary asymmetric transverse discrepancies. The activation method, the therapeutic benefits as well as the clinical advantages are described. The use of this appliance allows to restore the correct transverse maxillary diameters, to regain space and at the same time to restore the symmetry of the midlines up to 5-6 mm. Moreover, a recovery of the arch length can be obtained, as demonstrated by the case report presented. The expander with vestibular arm represents an interceptive treatment which can reduce the duration of the orthodontic therapy with fixed appliances.


Malignancy estimation of Lung-RADS criteria for subsolid nodules on CT: accuracy of low and high risk spectrum when using NLST nodules.
Lung-RADS proposes malignancy probabilities for categories 2 (<1%) and 4B (>15%). The purpose of this study was to quantify and compare malignancy rates for Lung-RADS 2 and 4B subsolid nodules (SSNs) on a nodule base. We identified all baseline SSNs eligible for Lung-RADS 2 and 4B in the National Lung Screening Trial (NLST) database. Solid cores and nodule locations were annotated using in-house software. Malignant SSNs were identified by an experienced radiologist using NLST information. Malignancy rates and percentages of persistence were calculated. Of the Lung-RADS 2SSNs, 94.3% (1790/1897) could be located on chest CTs. Likewise, 95.1% (331/348) of part-solid nodules ≥6 mm in diameter could be located. Of these, 120 had a solid core ≥8 mm, corresponding to category 4B. Category 2 SSNs showed a malignancy rate of 2.5%, exceeding slightly the proposed rate of <1%. Category 4B SSNs showed a malignancy rate of 23.9%. In both categories one third of benign lesions were transient. Malignancy probabilities for Lung-RADS 2 and 4B generally match malignancy rates in SSNs. An option to include also category 2 SSNs for upgrade to 4X designed for suspicious nodules might be useful in the future. Integration of short-term follow-up to confirm persistence would prevent unnecessary invasive work-up in 4B SSNs. • Malignancy probabilities for Lung-RADS 2/4B generally match malignancy risks in SSNs. • Transient rate between low-risk Lung-RADS 2 and high-risk 4B lesions were similar. • Upgrade of highly suspicious Lung-RADS 2 SSNs to Lung-RADS 4X might be useful. • Up to one third of the benign high-risk Lung-RADS 4B lesions were transient. • Short-term follow-up confirming persistence would avoid unnecessary invasive work-up of 4B lesions.


Pesticide contamination drives adaptive genetic variation in the endemic mayfly Andesiops torrens within a semi-arid agricultural watershed of Chile.
Agrichemical contamination can provoke evolutionary responses in freshwater populations. It is a particularly relevant issue in semi-arid regions due to the sensitivity of endemic species to pollutants and to interactions with temperature stress. This paper investigates the presence of pesticides in rivers within a semi-arid agricultural watershed of Chile, testing for their effects on population genetic characteristics of the endemic mayfly Andesiops torrens (Insecta, Ephemeroptera). Pesticides were detected in sediment samples in ten out of the 30 sites analyzed throughout the upper part of the Limarí watershed. To study the evolutionary impact of such contamination on A. torrens, we used a genome-wide approach and analyzed 2056 single nucleotide polymorphisms (SNPs) loci in 551 individuals from all sites. Genetic differentiation was weak between populations, suggesting high gene flow across the study area. While we did not find evidence of pesticide effects on genetic diversity nor on population differentiation, the allele frequency of three outlier SNP loci correlated significantly with pesticide occurrence. Interrogation of genomic resources indicates that two of these SNPs are located within functional genes that encode for the low-density lipoprotein receptor-related protein 2 and Dumpy, both potentially involved in insect cuticle resistance processes. Such genomic signatures of local adaptation are indicative of past adverse effects of pesticide exposure on the locally adapted populations. Our results reveal that A. torrens is sensitive to pesticide exposure, but that a high gene flow may confer resilience to contamination. This research supports the contention that A. torrens is an ideal model organism to study evolutionary responses induced by pesticides on non-target, endemic species.


[Pseudoexfoliation syndrome. Clinical and statistical studies].
Between July 1, 1980 and December 31, 1982, out of 26 825 patients treated in both the outpatient and inpatient departments at the University Eye Clinic of Erlangen-Nürnberg, 107 (i.e., 0.4%) were found to have pseudo-exfoliation syndrome. In 51 cases only one eye was affected, in 56 cases both. Of these patients 49 were male and 58 female. They were between 54 and 89 years old, the average age being 73.2 years. In 61.3% of the cases the initial symptom was ocular hypertension. In about 75% the most important finding on slit-lamp examination, with the pupil undilated, was atrophy of the pupillary margin. A central disc was only seen in 39.3%, while the peripheral band was present in all cases. Fistulating operations had to be performed in 43 out of 100 cases diagnosed as having capsular glaucoma. This corresponds to 18.5% of all fistulating procedures performed for primary chronic open-angle glaucoma.


Features of the Opportunistic Behaviour of the Marine Bacterium Marinobacter algicola in the Microalga Ostreococcus tauri Phycosphere.
Although interactions between microalgae and bacteria are observed in both natural environment and the laboratory, the modalities of coexistence of bacteria inside microalgae phycospheres in laboratory cultures are mostly unknown. Here, we focused on well-controlled cultures of the model green picoalga Ostreococcus tauri and the most abundant member of its phycosphere, Marinobacter algicola. The prevalence of M. algicola in O. tauri cultures raises questions about how this bacterium maintains itself under laboratory conditions in the microalga culture. The results showed that M. algicola did not promote O. tauri growth in the absence of vitamin B12 while M. algicola depended on O. tauri to grow in synthetic medium, most likely to obtain organic carbon sources provided by the microalgae. M. algicola grew on a range of lipids, including triacylglycerols that are known to be produced by O. tauri in culture during abiotic stress. Genomic screening revealed the absence of genes of two particular modes of quorum-sensing in Marinobacter genomes which refutes the idea that these bacterial communication systems operate in this genus. To date, the 'opportunistic' behaviour of M. algicola in the laboratory is limited to several phytoplanktonic species including Chlorophyta such as O. tauri. This would indicate a preferential occurrence of M. algicola in association with these specific microalgae under optimum laboratory conditions.


Effects of hindlimb unloading on ex vivo growth and osteogenic/adipogenic potentials of bone marrow-derived mesenchymal stem cells in rats.
The goal of this study was to determine the effects of hindlimb unloading (HU) on the ex vivo growth and the osteogenic potential of mesenchymal stem cells (MSCs) from the femurs of rats. Microgravity was simulated by 28-day HU in male Sprague-Dawley (SD) rats, and the bone marrow (BM) was collected from hindlimb femurs of HU or control (CTL) rats. MSCs were isolated from BM and cultured for eight passages. Then MSCs at passages 2, 4, and 8 were induced for osteogenesis or adipogenesis. The results revealed that HU decreased the osteogenic potential of MSCs and also decreased the expression of osteoblast gene marker mRNAs in cells induced by osteogenic conditions. Meanwhile, the expression of Runx2 mRNA and the phosphorylation of ERK were also decreased. There were no significant differences of osteoblast gene marker and Runx2 mRNA expression between cells induced from different passages of MSCs in UH rats. Under adipogenic conditions, HU increased both the adipogenic potential of MSCs and the expression of adipocytic gene marker mRNAs in induced cells. HU also increased the expression of PPAR gamma 2 mRNA, but with no effect on the phosphorylation of p38MAPK. The adipogenic potential of MSCs and the expression of adipocytic gene marker mRNAs in induced cells decreased along with cell cultures under normal gravity. This suggests that the normal gravity during in vitro MSC culture and the centrifugal force produced during cell harvest after each passage could decrease the adipogenic potential of MSCs, but could not reverse the effect of HU on the osteogenic potential of MSCs.


Simulation-based mastery improves nursing skills in BSc nursing students: a quasi-experimental study.
Clinical education is an essential part of nursing education. Selected clinical teaching methods influence the quality of education. Simulation-based mastery learning has been used to improve clinical skills among nursing students and may provide a novel way to enhance nursing skills. This study aimed to assess the effect of simulation-based mastery learning on the clinical skills of undergraduate nursing students from 2017 to 2019. This quasi-experimental study was conducted with two groups (the control and intervention). A hundred and five students were selected by random convenience sampling, and written consent was obtained. The intervention group participated in a simulation-based mastery learning intervention, and the control group received no intervention except for traditional training. The students of both groups completed the demographic information questionnaire and the checklist before and after the intervention. The results were analyzed by SPSS version 21 and descriptive and inferential statistics. The results showed no significant differences between the two groups before the intervention (p> 0.05). In addition, students' performance in the intervention and control groups improved significantly at the post-test compared with the baseline (p< 0.05). Furthermore, the Cohen test implied that the simulation-based mastery model used by the intervention group was significantly more effective than the traditional training used by the control. These findings showed that mastery learning was more effective in improving clinical skills in undergraduate nursing students. The results suggest that other nursing and health programs can be developed by implementing a mastery-based learning model.


No Surprises: Training Robust Lung Nodule Detection for Low-Dose CT Scans by Augmenting With Adversarial Attacks.
Detecting malignant pulmonary nodules at an early stage can allow medical interventions which may increase the survival rate of lung cancer patients. Using computer vision techniques to detect nodules can improve the sensitivity and the speed of interpreting chest CT for lung cancer screening. Many studies have used CNNs to detect nodule candidates. Though such approaches have been shown to outperform the conventional image processing based methods regarding the detection accuracy, CNNs are also known to be limited to generalize on under-represented samples in the training set and prone to imperceptible noise perturbations. Such limitations can not be easily addressed by scaling up the dataset or the models. In this work, we propose to add adversarial synthetic nodules and adversarial attack samples to the training data to improve the generalization and the robustness of the lung nodule detection systems. To generate hard examples of nodules from a differentiable nodule synthesizer, we use projected gradient descent (PGD) to search the latent code within a bounded neighbourhood that would generate nodules to decrease the detector response. To make the network more robust to unanticipated noise perturbations, we use PGD to search for noise patterns that can trigger the network to give over-confident mistakes. By evaluating on two different benchmark datasets containing consensus annotations from three radiologists, we show that the proposed techniques can improve the detection performance on real CT data. To understand the limitations of both the conventional networks and the proposed augmented networks, we also perform stress-tests on the false positive reduction networks by feeding different types of artificially produced patches. We show that the augmented networks are more robust to both under-represented nodules as well as resistant to noise perturbations.


An emancipatory study of contemporary nursing practice.
Changes in health care facilities have created the necessity for individual nurses to change, eg, change jobs, pursue additional education, become independent entrepreneurs. There is a shortage of nurses that places stress on those who remain to care for an increasing number of persons with too few resources. The purposes of this study were to explore nurses' perceptions of the circumstances of their work lives and to describe the processes by which they can create change in these circumstances. The methodology was an emancipatory design combining tenets of critical inquiry and feminist research. The method used was a dialectical process of reflection and action (praxis). Three diverse groups of nurses met weekly over 6-10 weeks. Using the group process method, each group reflected on, discussed, and analyzed the phenomenon of practicing nursing today. The outcome of an emancipatory study is reflected in the power of the process. The group interaction increased awareness, promoted reflection on the status quo, and energized the groups to derive possible solutions to changing that status quo. It is not the solutions themselves that are as relevant as is the obvious cogency of the process to achieve individual and group emancipation. Six codifications reflected the themes that emerged and 5 processes for exploring untested feasibilities for change were identified. The participants perceived themselves more as subjects in their history than objects to be manipulated, capable of transforming a rather dismal situation of nursing practice into one that was critical, creative, and freer from constraints. The implication of this study is that nurses are encouraged to adopt and adapt this process of group interaction because of its demonstrated credibility to empower and validate the role that nurses have to derive and implement solutions to change their unsatisfactory status quo.


On the non-hormonal control of the termination of regeneration.
Simultaneous amputation at three different anterior and three posterior levels in the earthworm Eisenia foetida did not produce any measurable effect on the number of segments regenerated posteriorly compared to controls with intact heads. In every group, the number of segments formed depended only on the level of the posterior cut, declining by ten every time the level of the posterior cut was moved ten segments further from the head end. Repeated anterior amputation to prevent regeneration of the brain and subpharyngeal ganglia was without effect. No consistent differences were observed in the anterior neurosecretory cells either at the start or the end of regeneration. These results are discussed in relation to the "progress zone theory," the limited clonal cell life theory, and the theory of "sequential cumulative inhibition." It is concluded that the information determining the number of segments regenerated posteriorly resides in the tissues adjacent to the cut surface.


PIKfyve Deficiency in Myeloid Cells Impairs Lysosomal Homeostasis in Macrophages and Promotes Systemic Inflammation in Mice.
Macrophages are professional phagocytes that are essential for host defense and tissue homeostasis. Proper membrane trafficking and degradative functions of the endolysosomal system are known to be critical for the function of these cells. We have found that PIKfyve, the kinase that synthesizes the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate, is an essential regulator of lysosomal biogenesis and degradative functions in macrophages. Genetically engineered mice lacking PIKfyve in their myeloid cells (PIKfyvefl/fl LysM-Cre) develop diffuse tissue infiltration of foamy macrophages, hepatosplenomegaly, and systemic inflammation. PIKfyve loss in macrophages causes enlarged endolysosomal compartments and impairs the lysosomal degradative function. Moreover, PIKfyve deficiency increases the cellular levels of lysosomal proteins. Although PIKfyve deficiency reduced the activation of mTORC1 pathway and was associated with increased cleavage of TFEB proteins, this does not translate into transcriptional activation of lysosomal genes, suggesting that PIKfyve modulates the abundance of lysosomal proteins by affecting the degradation of these proteins. Our study shows that PIKfyve modulation of lysosomal degradative activity and protein expression is essential to maintain lysosomal homeostasis in macrophages.


Assessing suicidal youth with antisocial, borderline, or narcissistic personality disorder.
This paper has 3 objectives. First, we review the epidemiologic evidence for the association between suicidal behaviour and suicide in individuals diagnosed with antisocial, borderline, or narcissistic personality disorder. Second, we examine whether any potentially modifiable risk factors are associated with these diagnoses, based on existing empirical evidence. Last, we discuss clinical approaches to assessing youth with antisocial, borderline, or narcissistic personality disorder presenting at risk for suicide. We reviewed the English-language literature for the last 12 years (from January 1, 1991, to December 31, 2002), using as search terms the names of the 3 disorders, as well as the key words suicide, suicidal behaviour, youth, and adolescents. Patients with antisocial or borderline personality disorder are likely to be at increased risk for suicidal behaviour when they demonstrate such comorbid disorders as major depressive episodes or substance abuse disorders, when they experience recent negative life events, or when they have a history of childhood sexual abuse. For patients with antisocial personality disorder, the risk of violence has to be judged in addition to the risk of suicide or self-harm. For patients with borderline personality disorder, interventions are determined by differentiating acute-on-chronic from chronic risk of suicidal behaviour. Finally, patients with narcissistic personality disorder can be at high risk for suicide during periods when they are not suffering from clinical depression. These episodes can seem to be unpredictable.


Newborn feeding recommendations and practices increase the risk of development of overweight and obesity.
The prevalence of obesity among infants less than 2 years of age has increased by more than 60% over the last three decades. Obese infants and toddlers are at an increased risk for staying overweight into adolescence and adulthood. Metabolic programming has been demonstrated in animal models whereby early life feeding habits result in life-long changes in hormone balance and metabolism. Our study explores if newborn over-nutrition on the first day of life (DOL1) is associated with risk for future overweight and obesity in childhood. Retrospective chart data was collected for full term formula-fed infants born between January 2008 and December 2012 who continued care at the same institution. Data included the volume of formula (ml) consumed on DOL1 as well, as subsequent yearly BMI measures from well child checkups (WCC). Overfeeding was categorized as any feed greater than or equal to 30 ml on any of the first seven feeds while controlling for birth weight. The final data set included 1106 infants (547 male; 559 female). 1023 of the 1106 newborns (93%) were overfed at least once during DOL1, while 789 of 1106 (71%) were overfed 3 or more times during their first 7 feeds. After adjusting for birth weight, infants who were overfed 5 of the first 7 feeds were 5 times as likely to be overweight or obese at their 4th year well child check-up (p < 0.05) compared to children not overfed. Infants who were overfed on all 7 of their first 7 feeds were 7 times more likely to be overweight or obese at their 4th year WCC (p = 0.017). Infants overfed on DOL1 were significantly more likely to be overweight or obese at their 4th year WCC, compared to infants not overfed on their first day of life. Newborn families may benefit from counseling regarding age-appropriate volumes of formula during this critical time period. Future studies will aim to look at effect of implementation of smaller feeding bottle size on reducing overfeeding practices and future risk of overweight and obesity.


Regulation of Biomolecular-Motor-Driven Cargo Transport by Microtubules under Mechanical Stress.
Mechanical stress on cells has profound influences on biological processes, such as cell shape regulation, the formation of tissue patterns, and development. Recently, mechanosensing properties of the microtubule, an important cytoskeletal component, have drawn attention. In this work, we studied cargo transport by dynein, a microtubule-associated motor protein, along microtubules deformed under mechanical stress. We reveal that the microtubule deformation took place as a response to the applied stress and that the deformation of microtubules facilitated the transport of dynein-driven quantum dots. This finding will provide opportunities to explore the role of microtubules as molecular mechanotransducers in cellular processes.


Possible link of different slow calcium signals generated by membrane potential and hormones to differential gene expression in cultured muscle cells.
The study of fluorescent calcium signals from cultured rat myotubes has provided interesting results in the past few years. Both K+ depolarization and tetanic electrical stimulation were shown to produce slow Ca2+ signals, unrelated to contraction and associated to regulation of gene expression in cultured rat myotubes. We studied the effect of IGF-I, insulin and testosterone on intracellular Ca2+ in cultured muscle cells. Insulin produced a fast (< 1 s) and transient [Ca2+] increase lasting less than 10 s. IGF-I induced a transient [Ca2+] increase, reaching a fluorescence peak 6 s after stimulus, to return to basal values after 60 s. Testosterone induced delayed (35 s) and long lasting (100-200 s) signals, frequently associated with oscillations. IGF-I, testosterone and electrical stimulation-induced Ca2+ signals were shown to be dependent on IP3 production. All of these Ca2+ signals were blocked by inhibitors of the IP3 pathway. On the other hand, insulin-induced Ca2+ increase was dependent on ryanodine receptors and blocked by either nifedipine or ryanodine. The different intracellular Ca2+ patterns produced by electrical stimulation, testosterone, IGF-I and insulin, may help to understand the role of intracellular calcium kinetics in the regulation of gene expression by various stimuli in skeletal muscle cells.


Effects of a Concurrent Working Memory Task on Speech Acoustics in Parkinson's Disease.
The purpose of this study was to determine the effect of a concurrent working memory task on acoustic measures of speech in individuals with Parkinson's disease (PD). Individuals with PD and age- and sex-matched controls performed a speaking task with and without a Stroop-like concurrent working memory task. Cepstral peak prominence, low-to-high spectral energy ratio, fundamental frequency (fo) standard deviation, articulation rate, pause duration, articulatory-acoustic vowel space, relative fo, mean voice onset time (VOT), and VOT variability were calculated for each condition. Mixed-model analyses of variance were performed to determine the effects of group, condition (presence of the concurrent working memory task), and their interaction on the acoustic measures. All measures except for VOT variability, mean pause duration, and relative fo offset differed between people with and without PD. Cepstral peak prominence, articulation rate, and relative fo offset differed as a function of condition. However, no measures indicated disparate effects of condition as a function of group. Although differentially impactful on limb motor function in PD, here a concurrent working memory task was not found to be differentially disruptive to speech acoustics in PD. https://doi.org/10.23641/asha.24759648.


VH3 gene usage in neutralizing human antibodies specific for the Entamoeba histolytica Gal/GalNAc lectin heavy subunit.
A combinatorial human immunoglobulin gene library was constructed from peripheral lymphocytes of an asymptomatic Entamoeba histolytica cyst passer and screened for the production of Fab antibody to the parasite. One of the Fab clones, CP33, recognized the 260-kDa galactose- and N-acetyl-D-galactosamine (Gal/GalNAc)-specific lectin of E. histolytica. By shuffling the heavy and light chains of CP33 with the heavy and light chains of two libraries derived from the cyst passer and a liver abscess patient, 18 additional clones were obtained. Sequence analysis of the heavy-chain genes, including CP33-H, revealed that all the nearest V-segment germ lines belonged to the VH3 family (VH3-21, VH3-30, VH3-48, and VH3-53), but the levels of homology were only 85 to 95%. The closest D-segment germ line was D2-2 or D6-6, and for the J-segment the closest germ line was JH4b or JH6b. On the other hand, all the light-chain genes, including CP33-L, belonged to the V kappa 1 family, in which the closest V kappa germ line gene was 02/012 or L5, with the J kappa 1, J kappa 2, J kappa 4, or J kappa 5 segment. CP33 and three other Fabs obtained by light-chain shuffling were purified and analyzed further. All of these Fabs recognized the cysteine-rich domain of the 170-kDa heavy subunit of the Gal/GalNAc lectin. Preincubation of E. histolytica trophozoites with these Fabs significantly inhibited amebic adherence to Chinese hamster ovary cells and also inhibited erythrophagocytosis. The ability of the neutralizing antibodies to block erythrophagocytosis for the first time implicates the lectin in phagocytosis and VH3 antibodies in defense against parasitic infections. These results demonstrate the utility of a combinatorial human immunoglobulin gene library for identifying and characterizing neutralizing antibodies from humans with amebiasis.


MicroRNA regulation in blood cells of renal transplanted patients with interstitial fibrosis/tubular atrophy and antibody-mediated rejection.
Interstitial fibrosis/tubular atrophy (IFTA) is associated with reduced allograft survival, whereas antibody-mediated rejection (ABMR) is the major cause for renal allograft failure. To identify specific microRNAs and their regulation involved in these processes, total RNA from blood cells of 16 kidney transplanted (KTx) patients with ABMR, stable graft function (SGF) and with T-cell mediated rejection (TCMR) was isolated. MicroRNA expression was determined by high-throughput sequencing. Differentially expressed candidate microRNAs were analyzed with RT-PCR in patients with SGF (n = 53), urinary tract infection (UTI) (n = 17), borderline rejection (BL) (n = 19), TCMR (n = 40), ABMR (n = 22) and IFTA (n = 30). From the 301 detected microRNAs, 64 were significantly regulated between the three cohorts. Selected candidate microRNAs miR-223-3p, miR-424-3p and miR-145-5p distinguished TCMR and ABMR from SGF, but not from other pathologies. Most importantly, miR-145-5p expression in IFTA patients was significantly downregulated and displayed a high diagnostic accuracy compared to SGF alone (AUC = 0.891) and compared to SGF, UTI, BL, TCMR and ABMR patients combined (AUC = 0.835), which was verified by cross-validation. The identification of miR-145-5p as IFTA specific marker in blood constitutes the basis for evaluating this potentially diagnostic microRNA as biomarker in studies including high numbers of patients and different pathologies and also the further analysis of fibrosis causing etiologies after kidney transplantation.


HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal.
Post-transcriptional gene silencing (PTGS) is a sequence-specific RNA degradation mechanism that is widespread in eukaryotic organisms. It is often associated with methylation of the transcribed region of the silenced gene and with accumulation of small RNAs (21 to 25 nucleotides) homologous to the silenced gene. In plants, PTGS can be triggered locally and then spread throughout the organism via a mobile signal that can cross a graft junction. Previously, we showed that the helper component-proteinase (HC-Pro) of plant potyviruses suppresses PTGS. Here, we report that plants in which PTGS has been suppressed by HC-Pro fail to accumulate the small RNAs associated with silencing. However, the transgene locus of these plants remains methylated. Grafting experiments indicate that HC-Pro prevents the plant from responding to the mobile silencing signal but does not eliminate its ability to produce or send the signal. These results demonstrate that HC-Pro functions downstream of transgene methylation and the mobile signal at a step preceding accumulation of the small RNAs.


Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.
Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the clinical potential for squalamine, this agent was evaluated in nu/nu mouse xenograft models using the chemoresistant MV-522 human non-small cell lung carcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination with either cisplatin or paclitaxel plus carboplatin. Squalamine alone produced a modest MV-522 tumor growth inhibition (TGI) and yielded a TGI with cisplatin that was better than cisplatin alone. Squalamine also significantly enhanced the activity of paclitaxel/carboplatin combination therapy in the MV-522 tumor model. Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD human neuroblastoma xenograft. Xenograft tumor shrinkage was seen for the MV-522 tumor in combination treatments including squalamine, whereas no tumor shrinkage was seen when squalamine was omitted from the treatment regimen. To gain a greater understanding of the mechanism by which squalamine inhibited tumor growth in the xenograft studies, in vitro experiments were carried out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine. Squalamine treatment was found to retard two cellular events necessary for angiogenesis, inducing disorganization of F-actin stress fibers and causing a concomitant reduction of detectable cell the surface molecular endothelial cadherin (VE-cadherin). We propose that the augmentation by squalamine of cytotoxicity from platinum-based therapies is attributable to interference by squalamine with the ability of stimuli to promote endothelial cell movement and cell-cell communication necessary for growth of new blood vessels in xenografts after chemotherapeutic injury to the tumor.


Neurologic Complications of Cancer Immunotherapy.
Immunotherapeutic approaches have revolutionized cancer treatment with immune checkpoint inhibitors and adoptive T-cell therapy now approved to treat a variety of solid and hematologic malignancies. This article summarizes the distinctive neurologic side effects of these therapies as well as their management. Neurologic immune-related adverse events are rare but potentially serious complications of immune checkpoint inhibitors. Both peripheral and central nervous system disorders have been described, often necessitating a pause or cessation of immunotherapy. Immune effector cell-associated neurotoxicity syndrome is a potentially serious complication of chimeric antigen receptor T-cell therapy. While symptoms may be mild and self-limited, delirium, encephalopathy, seizures, focal neurologic deficits, and fulminant cerebral edema can be seen. Close neurologic monitoring is imperative. The mainstay of treatment for neurologic complications includes high-dose corticosteroids, although other immunomodulatory strategies may be used in severe or refractory cases. The spectrum of neurologic complications of cancer immunotherapy is broad, encompassing both central and peripheral nervous system disorders, indolent as well as fulminant clinical presentations, and wide-ranging severity with variable response to treatment. Early identification and multidisciplinary management are crucial to balance neurologic recovery and antitumor control.


[Interneuronal relationships in the basolateral amygdala of cats trained for choice in the quality of food reinforcement].
The alimentary instrumental conditioned bar-pressing reflex was elaborated in cats by the method of "active choice" of either short-delayed reinforcement with bread-meat mixture of delayed more valuable reinforcement with meat. The animals differed in behavior strategy: some animals preferred bar-pressing with the long delay (the so-called "self-control" group), other animals pressed the bar with short delay (the so-called "impulsive" group). The multiunit activity in the basolateral amygdala was recorded with chronically implanted nichrome microelectrodes. The interactions between the spike trains of the neighbouring neurons selected from the multiunit activity were evaluated by means of statistical crosscorrelation analysis. It was shown that the number of correlations between the discharges of neurons was significantly higher in the "impulsive" cats. In both groups the number of cross-correlations was maximal in cases of a difficult choice, i.e., during the omission of the conditioned bar-pressing response. In "impulsive" cats the number of interneuronal correlations was highest with the latencies in the range of 0-30 msec. We suggest that the basolateral amygdala is involved in the system of structures which determine the individual-typological characteristics of animals.


Role of IL-33-ST2 pathway in regulating inflammation: current evidence and future perspectives.
Interleukin (IL)-33 is an alarmin of the IL-1 superfamily localized to the nucleus of expressing cells, such as endothelial cells, epithelial cells, and fibroblasts. In response to cellular damage or stress, IL-33 is released and activates innate immune responses in some immune and structural cells via its receptor interleukin-1 receptor like-1 (IL-1RL1 or ST2). Recently, IL-33 has become a hot topic of research because of its role in pulmonary inflammation. The IL-33-ST2 signaling pathway plays a pro-inflammatory role by activating the type 2 inflammatory response, producing type 2 cytokines and chemokines. Elevated levels of IL-33 and ST2 have been observed in chronic pulmonary obstructive disease (COPD). Notably, IL-33 is present in COPD induced by cigarette smoke or acute inflammations. The role of IL-33 in sepsis is becoming increasingly prominent, and understanding its significance in the treatment of sepsis associated with high mortality is critical. In addition to its pro-inflammatory effects, the IL-33-ST2 axis appears to play a role in bacterial clearance and tissue repair. In this review, we focused on the role of the IL-33-ST2 axis in sepsis, asthma, and COPD and summarized the therapeutic targets associated with this axis, providing a basis for future treatment.


Sinonasal Tumors With Neuroepithelial Differentiation (Olfactory Carcinoma): Delineation of Their Pathologic and Clinical Features With Insights into Their Relationship to Olfactory Neuroblastoma and Sinonasal Carcinoma.
Olfactory carcinoma is one of many names applied to sinonasal malignancies with histologic similarity to olfactory neuroblastoma (ONB) but cytokeratin expression or gland formation. It is unclear whether these neuroepithelial tumors represent a unified category and if they are separate from ONB and currently-recognized sinonasal carcinomas. This study aims to explore their clinicopathologic characteristics based on a large collective experience. A total of 53 sinonasal tumors with neuroepithelial differentiation were identified affecting 41 men and 12 women, median age 47 years (range: 12 to 82 y). The vast majority arose in the superior nasal cavity and presented at the high Kadish-Morita stage. Frequent histologic findings included (1) lobulated and solid growth, (2) rosettes and/or neurofibrillary stroma, (3) high-grade cytology, (4) complex, often ciliated glands, (5) nonfocal pancytokeratin expression, (6) neuroendocrine pos+itivity, and (7) variable S100-positive sustentacular cells. Twelve patients with available follow-up (48%) developed progressive disease at a median 8 months (range: 0 to 114 mo to progression), and 7 (28%) died of disease. Despite disparate historical terminology, neuroepithelial differentiation is a recurrent and recognizable histologic pattern that is associated with aggressive behavior in sinonasal tumors. While tumors with this phenotype may originate from olfactory mucosa, well-developed epithelial features warrant separation from conventional ONB and neural elements distinguish them from most sinonasal carcinomas. Although their full histogenesis remains uncertain and some heterogeneity may exist, we propose that this pattern is sufficiently distinctive to merit separate recognition as olfactory carcinoma. Use of consistent nomenclature may facilitate greater recognition of tumors with this phenotype and understanding of their pathogenesis and classification.


Disaggregating race and ethnicity in chronic health conditions: implications for public health social work.
This study examines the ethnic subgroup variation in chronic health by comparing self-reports of chronic conditions across diverse ethnic subgroups of Asian American (Vietnamese, Filipino, Chinese), Latino American (Cuban, Portuguese, Mexican), and African Caribbean (Haitian, Jamaican, Trinidadian/Tobagonian) respondents. This analysis utilizes linked data from the Collaborative Psychiatric Epidemiology Surveys (CPES). Logistic regression revealed significant subgroup differences in reports of chronic respiratory, cardiovascular, and pain conditions across nine ethnic subgroups masked by racial categorization. Findings suggest that precautions must be taken by public health social workers as there may be far more ethnic heterogeneity than is apparent among broad racial categories.


Funding Peyronie's disease: funding sources for primary research literature.
The objective was to describe funding sources and publication trends for the primary literature on Peyronie's disease (PD), including direct industry research support. A search of EMBASE, PubMed, Scopus, and Web of Science was performed to identify articles published from 2006 to 2018. Articles not published in English, reviews, case reports, editorials, guidelines, and meta-analysis were excluded from analysis. Data collected included year and journal of publication, major focus, and funding sources. The US Federal Open Payments database was searched for direct industry research payments to authors. Four hundred thirty-seven articles met criteria. The median number of yearly publications was 31. The most frequent publications were Journal of Sexual Medicine (25.6%), Urology (8.9%), BJU International (7.3%), and Journal of Urology (5.7%). Plaque excision/grafting was the most common topic (16.5%) followed by pathophysiology (15.3%), and intralesional therapy (14.9%). Only 15.1% (n = 66) of articles had a funding source with only 2.3% (n = 10) articles receiving any National Institutes of Health (NIH) funding. In total, 4.1% (n = 18) of the articles were industry funded, 61.1% (n = 11) of these from Xiaflex manufacturer Endo/Auxilium. Remaining articles appeared self-funded. There were 1524 unique authors and just 13 received any direct industry funds, totaling US$718,426. Most PD research is self-funded with only a small percentage from NIH or industry.


Insights from genomic microarrays into structural chromosome rearrangements.
Array-based comparative genomic hybridization allows high-resolution screening of copy number abnormalities in the genome, and becomes an increasingly important tool to detect deletions and duplications in tumor and post-natal cytogenetics. Here we illustrate that genomic arrays can also provide novel clues regarding the structural basis of chromosome rearrangement, including instability and mechanisms of formation of ring chromosomes. We also showed that array results might impact the recurrence risks for relatives of affected individuals. Our data indicate that chromosome rearrangements frequently involve more breaks than current cytogenetic models assume.


Hyphal induction in the human fungal pathogen Candida albicans reveals a characteristic wall protein profile.
The ability of Candida albicans to switch from yeast to hyphal growth is essential for its virulence. The walls and especially the covalently attached wall proteins are involved in the primary host-pathogen interactions. Three hyphal induction methods were compared, based on fetal calf serum, the amino sugar N-acetylglucosamine (GlcNAc) and the mammalian cell culture medium Iscove's modified Dulbecco's medium (IMDM). GlcNAc and IMDM were preferred, allowing stable hyphal growth over a prolonged period without significant reversion to yeast growth and with high biomass yields. We employed Fourier transform-MS combined with a (15)N-metabolically labelled reference culture as internal standard for relative quantification of changes in the wall proteome upon hyphal induction. A total of 21 wall proteins were quantified. Our induction methods triggered a similar response characterized by (i) a category of wall proteins showing strongly increased incorporation levels (Als3, Hwp2, Hyr1, Plb5 and Sod5), (ii) another category with strongly decreased levels (Rhd3, Sod4 and Ywp1) and (iii) a third one enriched for carbohydrate-active enzymes (including Cht2, Crh11, Mp65, Pga4, Phr1, Phr2 and Utr2) and showing only a limited response. This is, to our knowledge, the first systematic, quantitative analysis of the changes in the wall proteome of C. albicans upon hyphal induction. Finally, we propose new wall-protein-derived candidates for vaccine development.


Lung transcriptomic clock predicts premature aging in cigarette smoke-exposed mice.
Lung aging is characterized by a number of structural alterations including fibrosis, chronic inflammation and the alteration of inflammatory cell composition. Chronic exposure to cigarette smoke (CS) is known to induce similar alterations and may contribute to premature lung aging. Additionally, aging and CS exposure are associated with transcriptional alterations in the lung. The current work aims to explore the interaction between age- and CS- associated transcriptomic perturbations and develop a transcriptomic clock able to predict the biological age and the impact of external factors on lung aging. Our investigations revealed a substantial overlap between transcriptomic response to CS exposure and age-related transcriptomic alterations in the murine lung. Of particular interest is the strong upregulation of immunoglobulin genes with increased age and in response to CS exposure, indicating an important implication of B-cells in lung inflammation associated with aging and smoking. Furthermore, we used a machine learning approach based on Lasso regression to build a transcriptomic age model that can accurately predict chronological age in untreated mice and the deviations associated with certain exposures. Interestingly, CS-exposed-mice were predicted to be prematurely aged in contrast to mice exposed to fresh air or to heated tobacco products (HTPs). The accelerated aging rate associated with CS was reversed upon smoking cessation or switching to HTPs. Additionally, our model was able to predict premature aging associated with thoracic irradiation from an independent public dataset. Aging and CS exposure share common transcriptional alteration patterns in the murine lung. The massive upregulation of B-cell restricted genes during these processes shed light on the contribution of cell composition and particularly immune cells to the measured transcriptomic signal. Through machine learning approach, we show that gene expression changes can be used to accurately monitor the biological age and the modulations associated with certain exposures. Our findings also suggest that the premature lung aging is reversible upon the reduction of harmful exposures.


Expression of the class A macrophage scavenger receptor on specific subpopulations of murine dendritic cells limits their endotoxin response.
Dendritic cells (DC) function at the interface of innate and acquired immunity and are uniquely sensitive to specific stimuli. Pattern recognition receptors (PRR) on these cells are critically important because of their ability to recognise and initiate responses to conserved microbial-associated molecular signatures. With the exception of Toll-like receptors (TLR), we know relatively little about the specific distribution of other PRR amongst populations of DC. Here, we describe the expression of the murine class A macrophage scavenger receptor (SR-A) and show that it is restricted to specific subpopulations of bone marrow-derived and splenic DC. Importantly, we demonstrate that the receptor significantly alters the response of DC to endotoxin. In contrast to the activities of other PRR that have so far been examined, uniquely SR-A limits the maturation response; SR-A-/- cells display enhanced CD40 expression and TNF-alpha production. We discuss the potential contributions of SR-A to DC biology in the context of the known multiple activities of this receptor.


Biosensors for Detection of Biochemical Markers Relevant to Osteoarthritis.
This systematic review aimed to assess the advantages of biosensors in detecting biomarkers for the early diagnosis of osteoarthritis (OA). OA is the most prevalent musculoskeletal disease and is a leading cause of disability and pain worldwide. The diagnosis of OA could be performed through clinical examinations and imaging only during the late stages of the disease. Biomarkers could be used for the diagnosis of the disease in the very early stages. Biosensors could detect biomarkers with high accuracy and low costs. This paper focuses on the biosensors mainly adopted to detect OA markers (electrochemical, optical, Quartz crystal microbalance, molecular and wearable biosensors). A comprehensive search on PubMed, Cochrane, CINAHL and Embase databases was conducted from the inception to November 2020. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used to improve the reporting of the review. The Methodological Index for Non-Randomized Studies (MINORS) was used for quality assessment. From a total amount of 1086 studies identified, only 19 articles were eligible for this study. The main advantages of the biosensors reported were accuracy, limited cost and ease of use, compared to traditional methods (ELISA). Otherwise, due to the lack of data and the low level of evidence of the papers included, it was impossible to find significant results. Therefore, further high-quality studies are required.


[Concentration of circulating immune complexes in the blood in clinical and experimental epileptic seizures].
The levels of circulating immune complexes (CIC) in the peripheral blood were studied in 31 epileptic patients and 30 rabbits which served as an experimental model of the development of the epileptic process. CIC levels in the blood serum were measured by means of polyethylene glycol precipitation followed by measurement of optic density by a spectrophotometer. Elevated concentrations of CIC in the patients' blood were observed in the period of the epileptic status and during a series of epileptic attacks, as well as in experimental animal during epileptic attacks and in the period preceding their development. Blood analysis made at different periods after controlling the attacks showed gradual normalization of the levels of CIC. The role of CIC in the development and maintenance of epileptic seizures is discussed.


In the hunt for the "sultans of smack:" dope, gangsters and the construction of the Turkish deep state.
This article traces the development and evolution of the Turkish heroin trade against the backdrop of the Republic of Turkey's long transition from imperial core to nation-state. In taking up heroin's relationship to modern Turkey, I would like to specifically explore the meaning and manifestations of what many inside and outside of academia have called the "deep state." Heroin, I argue, was and is one of the most vital enablers of the factional "deep state" rivalries that compete for power in Ankara, adding a steady violent dimension to local and national politics.


Clinically applied anthropology: concepts for the family physician.
The incorporation of the sociobehavioral sciences into the teaching and practice of medicine has been a hallmark of family practice. The strong ecological orientation that family medicine shares with anthropology provides a unifying framework for incorporating anthropological concepts and techniques into clinical family practice. This paper presents an ecologically oriented framework for organizing and integrating individual, family (primary group), neighborhood (community), and societal level variables. Core anthropological concepts are presented within the context of this framework. The application of this approach is illustrated using case material derived from a five-year multidisciplinary experience in teaching these concepts to family practice residents.


Discrimination and instructional comprehension: guided discretion, racial bias, and the death penalty.
This study links two previously unrelated lines of research: the lack of comprehension of capital penalty-phase jury instructions and discriminatory death sentencing. Jury-eligible subjects were randomly assigned to view one of four versions of a simulated capital penalty trial in which the race of defendant (Black or White) and the race of victim (Black or White) were varied orthogonally. Dependent measures included a sentencing verdict (life without the possibility of parole or the death penalty), ratings of penalty phase evidence, and a test of instructional comprehension. Results indicated that instructional comprehension was poor overall and that, although Black defendants were treated only slightly more punitively than White defendants in general, discriminatory effects were concentrated among participants whose comprehension was poorest. In addition, the use of penalty phase evidence differed as a function of race of defendant and whether the participant sentenced the defendant to life or death. The study suggest that racially biased and capricious death sentencing may be in part caused or exacerbated by the inability to comprehend penalty phase instructions.


Evaluating lysine requirements of nursery pigs fed low protein diets with different sources of nonessential amino acids.
The Lys requirement of nursery pigs may be dependent on the source of nonessential AA (NEAA) nitrogen or the source of Lys itself. However, little peer-reviewed data examines these phenomena. The objectives of these experiments were to determine if the Lys requirement of pigs is altered when 1) low protein diets are supplemented with different sources of NEAA nitrogen or 2) Lys is supplied as a crystalline source instead of intact protein such as soybean meal (SBM). Two 14-d experiments were conducted using 450 (Exp. 1) and 540 (Exp. 2) pigs (PIC C22/C29 × 337). There were 10 treatments in each experiment, each aligned as a 2 × 5 factorial. In Exp. 1, there were 2 sources of NEAA (l-Gln + l-Gly or l-Gly + l-Ala + l-Pro + l-His) and 5 levels of Lys (1.2, 1.3, 1.4, 1.5, and 1.6%). In Exp. 2, there were 2 sources of proteins providing additional Lys (l-Lys HCl or SBM) and the same 5 levels of Lys. Following weaning at 18 to 22 d of age, pigs were fed a common starter diet for 5 d postweaning followed by a 14-d treatment period. Pigs were weighed and feed disappearance determined on d 0, 7, and 14 of the experiment. Data were analyzed using the MIXED and NLIN procedures of SAS (SAS Inst., Cary, NC). In Exp. 1, increasing CP and Lys resulted in a quadratic increase (P < 0.05) in ADG and a linear improvement (P < 0.05) in G:F during the 14-d treatment period. Breakpoint regression analyses revealed that optimum ADG was obtained at 1.36% Lys, while optimum G:F was obtained at 1.45% Lys. The source of NEAA did not affect (P > 0.10) growth performance during the treatment period. In Exp. 2, both ADG and G:F increased linearly (P < 0.05) with increasing Lys. Optimal ADG was obtained at 1.47% Lys, but the breakpoint for optimum G:F was above tested levels. Source of Lys did not affect (P > 0.10) ADG, but pigs fed additional Lys from crystalline sources had improved (P < 0.05) G:F than those fed additional Lys from intact protein at 1.50% Lys; however, the analyzed Lys values at this level differ. Overall, these data show that the standardized ileal digestibility Lys requirement of pigs is not altered when low protein diets are supplemented with different sources of NEAA nitrogen. Feed efficiency appears to be maximized when additional Lys is supplied by l-Lys HCl instead of SBM, but more research is needed to confirm this phenomenon.