Cardiovascular disease risk factor profiles of 263,356 older Australians according to region of birth and acculturation, with a focus on migrants born in Asia.
Risk factors for cardiovascular disease (CVD), such as obesity, diabetes, hypertension and physical inactivity, are common in Australia, but the prevalence varies according to cultural background. We examined the relationship between region of birth, measures of acculturation, and CVD risk profiles in immigrant, compared to Australian-born, older Australians. Cross-sectional data from 263,356 participants aged 45 and over joining the population-based 45 and Up Study cohort from 2006-2008 were used. Prevalence ratios for CVD risk factors in Australian- versus overseas-born participants were calculated using modified Poisson regression, adjusting for age, sex and socioeconomic factors and focusing on Asian migrants. The association between time resident in Australia and age at migration and CVD risk factors in Asian migrants was also examined. Migrants from Northeast (n = 3,213) and Southeast Asia (n = 3,942) had lower levels of overweight/obesity, physical activity and female smoking than Australian-born participants (n = 199,356), although differences in prevalence of overweight/obesity were sensitive to body-mass-index cut-offs used. Compared to Australian-born participants, migrants from Northeast Asia were 20-30% less likely, and from Southeast Asia 10-20% more likely, to report being treated for hypertension and/or hypercholesterolaemia; Southeast Asian migrants were 40-60% more likely to report diabetes. Northeast Asian-born individuals were less likely than Australian-born to have 3 or more CVD risk factors. Diabetes, treated hypertension and hypercholesterolaemia occurred at relatively low average body-mass-index in Southeast Asian migrants. The CVD risk factor profiles of migrants tended to approximate those of Australian-born with increasing acculturation, in both favourable (e.g., increased physical activity) and unfavourable directions (e.g., increased female smoking). Minimizing CVD risk in migrant populations may be achieved through efforts to retain the healthy facets of the traditional lifestyle, such as a normal body mass index and low prevalence of smoking in women, in addition to adopting healthy aspects of the host country lifestyle, such as increased physical activity.


[Phosphorylation of endogenous proteins of bovine retina rod outer segments].
The components of bovine rod outer segments (ROS) and water-soluble extracts of ROS were separated by SDS-electrophoresis after incubation with [gamma-32P]ATP or [gamma-32P]GTP at different experimental conditions. After that gels were autoradiographed to reveal the phosphorylated intermediates. Our results suggest, that ROS contains the following protein kinase systems: 1) water-soluble cAMP-dependent protein kinases, that uses ATP, but not GTP, and phosphorylates the water-soluble 30 000 molecular weight protein; 2) protein kinase that uses GTP (probably, ATP also) and phosphorylates the 20 000 molecular weight protein in light-adapted ROS; 3) water-soluble cyclic nucleotide- and Ca2+-independent protein kinase that uses ATP rather than GTP and phosphorylates the water-soluble 70 000 molecular weight protein. The concentrations of phosphorylated intermediates in bovine ROS are estimated.


Redox-tuning of oxidizing disulfide oxidoreductase generates a potent disulfide isomerase.
Oxidative folding of extracellular proteins is pivotal for the biogenesis of bacterial virulence factors. Escherichia coli DsbA catalyzes disulfide bond formation in extracellular proteins and in multicomponent architectures on the cell surface. The present study assessed the significance of the redox properties of DsbA by exploiting the plaque-forming ability of bacteriophage M13, which specifically recognizes F-pili during infection of the host cell. A library of mutant dsbA genes was constructed by randomizing the dipeptide XX sequence in the active-site redox motif CXXC and then screened for mutants that altered plaque yield and appearance. In total, 24 dsbA mutant alleles produced substantially different degrees of complementation, and one mutant dsbA gene that encodes a CDIC sequence produced over 40-fold more clear plaques than wild type dsbA. The redox potential of purified DsbA [CDIC] was -172 mV, representing a less-oxidizing catalysis than the wild type DsbA (-122 mV), but one that is closer to yeast protein disulfide isomerase (-175 mV). DsbA [CDIC] exhibited a greater ability to refold fully denatured glutathionylated ribonuclease A than the wild type enzyme and a DsbA [CRIC] mutant, which has the same redox potential of -172 mV. Homology modeling and molecular dynamics simulation suggest that the CDIC mutant may have an enlarged substrate-binding cleft near the redox center, which confers kinetic advantages when acting on protein substrates.


[Diagnosis of constipation: a systematic review].
To diagnose constipation accurately in self-reported constipated patients is very important not to miss organic disease and prevent therapeutic abuse. To investigate the etiology of functional constipation is also important to determine the therapeutic modality of constipation. In this systemic review, the clinical usefulness of symptom evaluation, diagnostic tests to rule out organic and systemic disease, and functional tests to discriminate underlying pathophysiology in the diagnosis of constipation were discussed. No specific symptoms or tests were available to predict organic versus functional constipation or differentiate slow transit constipation versus evacuation disorder. Therefore, collaborative studies are necessary to determine the pathophysiology of this disorder.


Chemotherapy in alveolar soft part sarcomas. What do we know?
Alveolar soft part sarcoma (ASPS) is a rare tumour. Published series about treatment and outcome are scarce. Conclusive data about the response to chemotherapy are not available. The aim of this study was to analyse the efficacy of palliative chemotherapeutic treatment options and the incidence and mode of presentation of brain metastases. We retrospectively analysed our own sarcoma data-base and reviewed the literature. From our registry containing 757 patients, we identified 8 patients with ASPS. From the literature, 47 cases of adult patients and 13 children with sufficient data about chemotherapy were identified. Response to first-line chemotherapy in 68 patients was: complete remission (CR) 4%, partial remission (PR) 3%, stable disease (SD) 41%, progressive disease (PD) 51%. 285 patients with stage IV disease were evaluable for the analysis of metastatic sites. The incidence of brain metastases was 30.5% (87/285). Brain metastases were detected at a median interval of 48 months (range 0-396 months) after the primary diagnosis. Median survival after the diagnosis of brain metastases was 12 months. The median survival for patients with stage IV disease treated by chemotherapy was 36+ months (range 10-132 months) (31 patients evaluable) with a median follow-up of 46 months (range 10-135 months). ASPS shows a high incidence of brain metastases, at least 3 times higher than that of other soft tissue sarcomas. Chemotherapeutic regimens used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. Staging investigations for ASPS should routinely include imaging of the brain. ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. New targets for specific biologically-directed therapies need to be developed.


Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.


Exact Equality and Successor Function: Two Key Concepts on the Path towards understanding Exact Numbers.
Humans possess two nonverbal systems capable of representing numbers, both limited in their representational power: the first one represents numbers in an approximate fashion, and the second one conveys information about small numbers only. Conception of exact large numbers has therefore been thought to arise from the manipulation of exact numerical symbols. Here, we focus on two fundamental properties of the exact numbers as prerequisites to the concept of exact numbers: the fact that all numbers can be generated by a successor function, and the fact that equality between numbers can be defined in an exact fashion. We discuss some recent findings assessing how speakers of Mundurucu (an Amazonian language), and young western children (3-4 years old) understand these fundamental properties of numbers.


Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels.
c-Myc is a predominantly nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.


Heterogeneity of Specific CD4+ and CD8+ T Cells Stimulated by CMV pp65 and IE1 Antigens.
Characterization of human cytomegalovirus-specific T cells (CMV-T) is of critical importance for their potential use in adoptive immunotherapy after allogeneic hematopoietic stem cell transplantation. Background frequencies of CMV-T in peripheral blood mononuclear cells (PBMCs) of CMV-seropositive healthy subjects are usually very low, hence the requirement for prolonged culture time and multiple stimulations to expand them. The evaluation of the end-culture specificity and composition has sometimes been neglected or difficult to assess in these settings. We explored the identity and the functionality of pp65-specific and IE1-specific T cells, enriched in short-term cultures from PBMCs. Antigen-specific T cells were further isolated by IFN-γ capture system and/or CD154 microbeads. Frequency of IE1-specific cytotoxic T cells in PBMCs secreting IFN-γ was higher compared with the pp65-specific one, whereas the latter cell types showed a higher median CD107a degranulation. Cell viability, rate of CMV-T increase, and multicytokine secretion profile after epitope-specific short-term cultures were heterogenous. T cells were mainly of late effector stages but they significantly dropped off upon CMV rechallenge with peptide pools. In parallel, CMV-T expansion was accompanied by a significant increase of cytotoxic naive/memory stem cells (CTLs), whereas the CD4 counterpart significantly increased only upon stimulation with IE1. Outcome was variable and showed donor and epitope dependency. Differences in human leukocyte antigen and epitope dominance and variability in the relative number of CD3 effector cells and IFN-γ/CD154 expression among healthy donors could reflect the observed individual CMV-specific cellular immunity. This heterogeneity raises points to be considered when approaching adoptive immunotherapy.


Extracellular vesicles from hiPSC-NSCs can prevent peripheral inflammation-induced cognitive dysfunction with inflammasome inhibition and improved neurogenesis in the hippocampus.
Extracellular vesicles (EVs) released by human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) are enriched with miRNAs and proteins capable of mediating robust antiinflammatory activity. The lack of tumorigenic and immunogenic properties and ability to permeate the entire brain to incorporate into microglia following intranasal (IN) administrations makes them an attractive biologic for curtailing chronic neuroinflammation in neurodegenerative disorders. We tested the hypothesis that IN administrations of hiPSC-NSC-EVs can alleviate chronic neuroinflammation and cognitive impairments induced by the peripheral lipopolysaccharide (LPS) challenge. Adult male, C57BL/6J mice received intraperitoneal injections of LPS (0.75 mg/kg) for seven consecutive days. Then, the mice received either vehicle (VEH) or hiPSC-NSC-EVs (~ 10 × 109 EVs/administration, thrice over 6 days). A month later, mice in all groups were investigated for cognitive function with behavioral tests and euthanized for histological and biochemical studies. Mice receiving VEH after LPS displayed deficits in associative recognition memory, temporal pattern processing, and pattern separation. Such impairments were associated with an increased incidence of activated microglia presenting NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasomes, elevated levels of NLRP3 inflammasome mediators and end products, and decreased neurogenesis in the hippocampus. In contrast, the various cognitive measures in mice receiving hiPSC-NSC-EVs after LPS were closer to naive mice. Significantly, these mice displayed diminished microglial activation, NLRP3 inflammasomes, proinflammatory cytokines, and a level of neurogenesis matching age-matched naïve controls. Thus, IN administrations of hiPSC-NSC-EVs are an efficacious approach to reducing chronic neuroinflammation-induced cognitive impairments.


Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle's cell, and poorly differentiated human thyroid carcinoma.
Expression of the invasion/metastasis suppressor, E-cadherin, is diminished or lost in thyroid carcinomas. Yet, mutational inactivation of E-cadherin is rare. Herein, we show that this loss is associated with hypermethylation of the E-cadherin 5' CpG island in a panel of human thyroid cancer cell lines. This aberrant methylation is evident in 83% of papillary thyroid carcinoma, 11% of follicular thyroid carcinoma, 40% of Hurthle's cell carcinoma, and 21% of poorly differentiated thyroid carcinomas. Contrary to previous reports, the majority of these poorly differentiated thyroid carcinomas express E-cadherin, but often within the cytoplasm rather than at the cell surface. Together, our data indicate that the invasion/metastasis suppressor function of E-cadherin is frequently compromised in human papillary, Hurthle's cell, and poorly differentiated thyroid carcinoma by epigenetic and biochemical events.


Label-free in vitro toxicity and uptake assessment of citrate stabilised gold nanoparticles in three cell lines.
Reliable in vitro toxicity testing is needed prior to the commencement of in vivo testing necessary for hazard identification and risk assessment of nanoparticles. In this study, the cytotoxicity and uptake of 14 nm and 20 nm citrate stabilised gold nanoparticles (AuNPs) in the bronchial epithelial cell line BEAS-2B, the Chinese hamster ovary cell line CHO, and the human embryonic kidney cell line HEK 293 were investigated. Cytotoxicity of the AuNPs was assessed via traditional XTT-, LDH-, and ATP-based assays, followed by cell impedance studies. Dark-field imaging and hyperspectral imaging were used to confirm the uptake of AuNPs into the cells. Interference of the AuNPs with the XTT- and ATP-based assays was overcome through the use of cell impedance technology. AuNPs were shown to be relatively non-toxic using this methodology; nevertheless CHO cells were the most sensitive cell type with 20 nm AuNPs having the highest toxicity. Uptake of both 14 nm and 20 nm AuNPs was observed in all cell lines in a time- and cell type-dependent manner. Using the cell impedance and dark-field hyperspectral imaging technologies, it was possible to study the toxicity of AuNPs in different cell lines and show that these cells could internalize AuNPs with their subsequent intracellular aggregation. It was also possible to show that this toxicity would not correlate with the level of uptake but it would correlate with cell-type and the size of the AuNPs. Therefore, these two label-free methodologies used in this study are suitable for in vitro studies on the effects of AuNPs, and could present themselves as appropriate and valuable methodologies for future nanoparticle toxicity and uptake studies.


Host-parasitoid extinction and colonization in a fragmented prairie landscape.
Few field studies of natural populations have examined the factors influencing local extinctions and colonization of empty habitat patches for a prey species and its predator. In this study, I carried out a census of planthopper (Prokelisia crocea; Hemiptera: Delphacidae) and egg parasitoid (Anagrus columbi; Hymenoptera: Mymaridae) incidence and densities in 147 host-plant patches (Spartina pectinata; Poaceae) over seven planthopper generations in a tall-grass prairie landscape. For both species, the likelihood of going extinct in a patch was related to a number of patch-specific variables: density, temporal variability in density, proportion of hosts parasitized (planthopper only), host-plant density, patch size, patch isolation, and composition of the surrounding matrix. Colonization likelihood was related only to the physical attributes of the patch. There was high patch turnover in this prairie landscape. On average, planthoppers went extinct in 23% of the patches and A. columbi went extinct in 51% of the patches in each generation. For the planthopper, extinction likelihood increased with a decrease in patch size and the proportion of the matrix composed of mudflat. Parasitism of eggs had no effect on the extinction likelihood of local P. crocea populations, suggesting that A. columbi may not play a major role in the patch dynamics of its host. The likelihood of extinction for A. columbi was dependent on factors that spanned three trophic levels. An increase in plant density, decrease in host density and decrease in parasitoid density all increased the likelihood of A. columbi extinction within a patch. The dependency on multiple trophic levels may explain the higher extinction risk for the parasitoid than its host. A. columbi extinction was also affected by the matrix habitat surrounding the patch--the effect was the opposite of that for P. crocea. Finally, vacant patches were colonized at rates of 53% and 34% per generation for the planthopper and parasitoid, respectively. For both species, colonization probabilities decreased with an increase in patch isolation. High host densities in a patch also favored high rates of colonization by A. columbi. I discuss how anthropogenic changes to the prairie landscape can affect the metapopulation dynamics and persistence time of this host-parasitoid interaction.


Spatial frequency spectrum of the x-ray scatter distribution in CBCT projections.
X-ray scatter is a source of significant image quality loss in cone-beam computed tomography (CBCT). The use of Monte Carlo (MC) simulations separating primary and scattered photons has allowed the structure and nature of the scatter distribution in CBCT to become better elucidated. This work seeks to quantify the structure and determine a suitable basis function for the scatter distribution by examining its spectral components using Fourier analysis. The scatter distribution projection data were simulated using a CBCT MC model based on the EGSnrc code. CBCT projection data, with separated primary and scatter signal, were generated for a 30.6 cm diameter water cylinder [single angle projection with varying axis-to-detector distance (ADD) and bowtie filters] and two anthropomorphic phantoms (head and pelvis, 360 projections sampled every 1°, with and without a compensator). The Fourier transform of the resulting scatter distributions was computed and analyzed both qualitatively and quantitatively. A novel metric called the scatter frequency width (SFW) is introduced to determine the scatter distribution's frequency content. The frequency content results are used to determine a set basis functions, consisting of low-frequency sine and cosine functions, to fit and denoise the scatter distribution generated from MC simulations using a reduced number of photons and projections. The signal recovery is implemented using Fourier filtering (low-pass Butterworth filter) and interpolation. Estimates of the scatter distribution are used to correct and reconstruct simulated projections. The spatial and angular frequencies are contained within a maximum frequency of 0.1 cm(-1) and 7/(2π) rad(-1) for the imaging scenarios examined, with these values varying depending on the object and imaging setup (e.g., ADD and compensator). These data indicate spatial and angular sampling every 5 cm and π/7 rad (~25°) can be used to properly capture the scatter distribution, with reduced sampling possible depending on the imaging scenario. Using a low-pass Butterworth filter, tuned with the SFW values, to denoise the scatter projection data generated from MC simulations using 10(6) photons resulted in an error reduction of greater than 85% for the estimating scatter in single and multiple projections. Analysis showed that the use of a compensator helped reduce the error in estimating the scatter distribution from limited photon simulations by more than 37% when compared to the case without a compensator for the head and pelvis phantoms. Reconstructions of simulated head phantom projections corrected by the filtered and interpolated scatter estimates showed improvements in overall image quality. The spatial frequency content of the scatter distribution in CBCT is found to be contained within the low frequency domain. The frequency content is modulated both by object and imaging parameters (ADD and compensator). The low-frequency nature of the scatter distribution allows for a limited set of sine and cosine basis functions to be used to accurately represent the scatter signal in the presence of noise and reduced data sampling decreasing MC based scatter estimation time. Compensator induced modulation of the scatter distribution reduces the frequency content and improves the fitting results.


Electrocatalytic Urea Synthesis via N2 Dimerization and Universal Descriptor.
Electrocatalytic urea synthesis through N2 + CO2 coreduction and C-N coupling is a promising and sustainable alternative to harsh industrial processes. Despite considerable efforts, limited progress has been made due to the challenges of breaking inert N≡N bonds for C-N coupling, competing side reactions, and the absence of theoretical principles guiding catalyst design. In this study, we propose a mechanism for highly electrocatalytic urea synthesis using two adsorbed N2 molecules and CO as nitrogen and carbon sources, respectively. This mechanism circumvents the challenging step of N≡N bond breaking and selective CO2 to CO reduction, as the free CO molecule inserts into dimerized *N2 and binds concurrently with two N atoms, forming a specific urea precursor *NNCONN* with both thermodynamic and kinetic feasibility. Through the proposed mechanism, Ti2@C4N3 and V2@C4N3 are identified as highly active catalysts for electrocatalytic urea formation, exhibiting low onset potentials of -0.741 and -0.738 V, respectively. Importantly, taking transition metal atoms anchored on porous graphite-like carbonitride (TM2@C4N3) as prototypes, we introduce a simple descriptor, namely, effective d electron number (Φ), to quantitatively describe the structure-activity relationships for urea formation. This descriptor incorporates inherent atomic properties of the catalyst, such as the number of d electrons, the electronegativity of the metal atoms, and the generalized electronegativity of the substrate atoms, making it potentially applicable to other urea catalysts. Our work advances the comprehension of mechanisms and provides a universal guiding principle for catalyst design in urea electrochemical synthesis.


In minimal access surgery.
The pediatrician must be cognizant of the extensive applications of endoscopic surgery in the pediatric patient. The ability to provide either outpatient surgery or short-stay surgery appears to be cost-effective and appropriate state-of-the-art medical care. As the array of surgical instruments continues to evolve, new and innovative endoscopic procedures will become increasingly available.


Drug samples in family medicine teaching units: a cross-sectional descriptive study: Part 1: drug sample management policies and the relationship between the pharmaceutical industry and residents in Quebec.
To determine the existence and the level of health care professional (HCP) knowledge of local policies regarding drug sample use and the relationship between residents and the pharmaceutical industry in academic primary health care settings. Descriptive cross-sectional survey. Health care providers were invited to complete a self-administered questionnaire on drug sample use between February and December 2013. Managers of drug samples were also asked to complete a specific questionnaire on drug sample management and policies and an inventory log sheet. Data about the existence of written policies were validated with health and social services centre (HSCC) directors or pharmacy departments and family medicine teaching unit (FMTU) directors between February and June 2014. All 42 FMTUs in Quebec. All HCPs in the FMTUs authorized to hand out drug samples (practising physicians, residents, pharmacists, and nurses). Dispensers were defined as those who reported using drug samples. Managers were defined as HCPs or staff members who managed drug samples. Existence of written policies on drug sample use in HSCCs and FMTUs; whether FMTUs applied the HSCC policies if they existed; whether dispensers were aware of the existence of the policies; and whether policies on the relationships between residents and pharmaceutical companies existed. Among the 42 FMTUs, 33 (79%) kept drug samples. Of these, 30% (10 of 33) did not have policies about drug samples in the FMTU or in the HSCC. A total of 67% (579 of 859) of HCPs from these FMTUs reported using drug samples. Most dispensers did not know if a policy existed in their FMTU (n = 297; 51%) or their HSCC (n = 420; 73%). Eleven (26%) of the 42 FMTU directors reported having a policy regarding relationships between residents and the pharmaceutical industry. Most drug sample dispensers were not aware whether such a policy existed (n = 310; 54%). Many FMTUs did not have policies regarding drug samples or relationships between residents and the pharmaceutical industry. Variation in use and management of drug samples and the lack of knowledge of HCPs about the existence of policies point to the need to implement uniform policies in all FMTUs in Quebec.


Polydrug Use During Pregnancy and Preterm Birth in a Low-Income, Multiethnic Birth Cohort, Boston, 1998-2018.
The opioid epidemic in the United States increasingly affects women of reproductive age and has resulted in a rise in concurrent polydrug use. The objective of this study was to investigate the effect of this polydrug use on preterm birth in a multiethnic birth cohort. We analyzed data from 8261 mothers enrolled in the Boston Birth Cohort from 1998 to 2018 in Boston, Massachusetts. We grouped substances used during pregnancy based on their primary effects (stimulant or depressant) and assessed independent and combined associations with smoking on preterm birth. Of 8261 mothers, 131 used stimulant drugs and 193 used depressant drugs during pregnancy. The preterm birth rate was 27.5% (2271 of 8261) in the sample. Mothers who smoked had 35% increased odds of preterm birth across adjusted models. Mothers who used stimulant drugs without smoking were not at increased risk of preterm delivery compared with mothers who used neither (odds ratio [OR] = 0.69; 95% confidence interval [CI], 0.19-1.98), whereas mothers who used depressant drugs without smoking had more than twice the odds of having preterm delivery (OR = 2.31; 95% CI, 1.19-4.44), and infants were at risk of a 1-week reduction in gestational age (OR = -1.05; 95% CI, -2.07 to -0.03). Concurrently smoking and using depressant drugs was associated with increased odds of preterm birth (OR = 1.83; 95% CI, 1.28-2.61), as was concurrently smoking and using stimulant drugs (OR = 1.73; 95% CI, 1.14-2.59). Using stimulant drugs and depressant drugs during pregnancy is a risk factor for preterm birth. The individual and combined effects of using these drugs with smoking must be considered together to reduce the risk of preterm birth in the United States.


Pedagogical Orientations and Evolving Responsibilities of Technological Universities: A Literature Review of the History of Engineering Education.
Current societal changes and challenges demand a broader role of technological universities, thus opening the question of how their role evolved over time and how to frame their current responsibility. In response to urgent calls for debating and redefining the identity of contemporary technological universities, this paper has two aims. The first aim is to identify the key characteristics and orientations marking the development of technological universities, as recorded in the history of engineering education. The second aim is to articulate the responsibility of contemporary technological universities given their different orientations and characteristics. For this, we first provide a non-systematic literature review of the key pedagogical orientations of technological universities, grounded in the history of engineering education. The five major orientations of technological universities presented in the paper are technical, economic, social, political, and ecological. We then use this historical survey to articulate the responsibilities of contemporary technological universities reflecting the different orientations. Technological universities can promote and foster the development of scientific, professional, civic, legal, or intra- and inter- generational responsibility. We argue that responsibility is not specific to any particular orientation, such that the concept is broadened to complement each orientation or mix of orientations of a technological university. Our contribution thus serves as a call for technological universities to self-reflect on their mission and identity, by offering a lens for identifying the orientations they currently foster and making explicit the responsibility arising from their current orientation or the ones they strive to cultivate.


Species-specific identification and differentiation of Arcobacter, Helicobacter and Campylobacter by full-spectral matrix-associated laser desorption/ionization time of flight mass spectrometry analysis.
Rapid and reliable identification of Arcobacter and Helicobacter species, and their distinction from phenotypically similar Campylobacter species, has become increasingly important, since many of them are now recognized as human and/or animal pathogens. Matrix-associated laser desorption/ionization-time of flight (MALDI-TOF) MS has been shown to be a rapid and sensitive method for characterization of micro-organisms. In this study, we therefore established a reference database of selected Arcobacter, Helicobacter and Campylobacter species for MALDI-TOF MS identification. Besides the species with significance as food-borne pathogens - Arcobacter butzleri, Helicobacter pullorum, Campylobacter jejuni and Campylobacter coli - several other members of these genera were included in the reference library to determine the species specificity of the designed MALDI Biotyper reference database library. Strains that made up the reference database library were grown on Columbia agar, and yielded reproducible and unique mass spectra profiles, which were compared with the Bruker Biotyper database, version 2. The database was used to identify 144 clinical isolates using whole spectral profiles. Furthermore, reproducibility of MALDI-TOF MS results was evaluated with respect to age and/or storage of bacteria and different growth media. It was found that correct identification could be obtained even if the bacteria were stored at room temperature or at 4 degrees C up to 9 days before being tested. In addition, bacteria were correctly identified when grown on Campylosel agar; however, they were not when grown on modified charcoal cefoperazone deoxycholate agar. These results indicate that MALDI-TOF MS fingerprinting is a fast and reliable method for the identification of Arcobacter and Helicobacter species, and their distinction from phenotypically similar Campylobacter species, with applications in clinical diagnostics.


Environmental tobacco smoke may induce early lung damage in healthy male adolescents.
Childhood exposure to environmental tobacco smoke (ETS) adversely affects dynamic spirometric indexes as a result of combined early life (including in utero) and current exposure to parental smoking. The aim of our study was to investigate the effect of ETS on lung function and to identify the most sensitive functional parameter for evaluating lung damage. Cross-sectional survey. Health survey on secondary school children. Eighty adolescents boys (mean age +/- SD, 16 +/- 1 years) classified in three groups: 21 smokers, 30 nonsmokers, and 29 passive smokers. Standardized questionnaire on the smoking habits of the subjects and their parents; assay of urinary cotinine level and measurement of the cotinine/creatine ratio (CCR); and lung function tests, including measurements of lung volumes, spirometric dynamic parameters, and the single-breath diffusing capacity of the lung for carbon monoxide (DLCO). Passive smokers presented a higher residual volume than nonsmokers, and a lower maximal expiratory flow at 25% of FVC (MEF(25)) and DLCO. Passive smokers whose mothers had smoked during pregnancy had significantly lower MEF(25) percentage, DLCO, carbon monoxide transfer coefficient, and diffusion capacity of the alveolar-capillary membrane (DM) values than did passive smokers whose mothers had given up smoking during pregnancy. Nevertheless, the MEF(25) and DM values of subjects with mothers who had given up smoking during pregnancy were lower than those observed in nonsmokers (p < 0.05), suggesting a negative effect of passive smoking independent of the mother's smoking habit during pregnancy. A statistically significant, negative correlation was found between CCR and DLCO in smokers (r = - 0.63, p < 0.01) and in passive smokers (r = - 0.91, p < 0.001), but not in nonsmokers (r = 0.26, p = not significant), suggesting a dose-effect relationship. Current exposure to ETS in healthy male adolescents is associated with lung function impairment independently of the effects of maternal smoking during pregnancy. More information may be obtained from determining static lung volumes and DLCO.


Pyramidal Cell Subtypes and Their Synaptic Connections in Layer 5 of Rat Frontal Cortex.
The frontal cortical areas make a coordinated response that generates appropriate behavior commands, using individual local circuits with corticostriatal and corticocortical connections in longer time scales than sensory areas. In secondary motor cortex (M2), situated between the prefrontal and primary motor areas, major subtypes of layer 5 corticostriatal cells are crossed-corticostriatal (CCS) cells innervating both sides of striatum, and corticopontine (CPn) cells projecting to the ipsilateral striatum and pontine nuclei. CCS cells innervate CPn cells unidirectionally: the former are therefore hierarchically higher than the latter among L5 corticostriatal cells. CCS cells project directly to both frontal and nonfrontal areas. On the other hand, CPn cells innervate the thalamus and layer 1a of frontal areas, where thalamic fibers relaying basal ganglia outputs are distributed. Thus, CCS cells can make activities of frontal areas in concert with those of nonfrontal area using corticocortical loops, whereas CPn cells are more involved in closed corticostriatal loops than CCS cells. Since reciprocal connections between CPn cells with facilitatory synapses may be related to persistent activity, CPn cells play a key role of longer time constant processes in corticostriatal as well as in corticocortical loops between the frontal areas.


Evaluation of older persons in the ambulatory setting.
This report provides a comprehensive description of an established outpatient geriatric consultation service. The basic objectives of the service are to promote health and to prevent or minimize disability. The consultation service uses a multidisciplinary team with core participants from medicine, nursing, and social work and is based in a setting where a wide range of specialty consultants and ancillary services are available. A detailed description of 131 individuals who received geriatric consultations during a one-year period is provided. Despite a substantial burden of disability, most older persons after the consultation process were able to continue living in their own preferred setting. The degree to which the geriatric consultation service contributed to these favorable outcomes is currently being evaluated through a randomized clinical trial.


Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age.
Alterations in DNA methylation have been proposed to create a field cancerization state in the colon, where molecular alterations that predispose cells to transformation occur in histologically normal tissue. However, our understanding of the role of DNA methylation in field cancerization is limited by an incomplete characterization of the methylation state of the normal colon. In order to determine the colon's normal methylation state, we extracted DNA from normal colon biopsies from the rectum, sigmoid, transverse, and ascending colon and assessed the methylation status of the DNA by pyrosequencing candidate loci as well as with HumanMethylation450 arrays. We found that methylation levels of repetitive elements LINE-1 and SAT-α showed minimal variability throughout the colon in contrast to other loci. Promoter methylation of EVL was highest in the rectum and progressively lower in the proximal segments, whereas ESR1 methylation was higher in older individuals. Genome-wide methylation analysis of normal DNA revealed 8388, 82, and 93 differentially methylated loci that distinguished right from left colon, males from females, and older vs. younger individuals, respectively. Although variability in methylation between biopsies and among different colon segments was minimal for repetitive elements, analyses of specific cancer-related genes as well as a genome-wide methylation analysis demonstrated differential methylation based on colon location, individual age, and gender. These studies advance our knowledge regarding the variation of DNA methylation in the normal colon, a prerequisite for future studies aimed at understanding methylation differences indicative of a colon field effect.


Medicare readmission rates showed meaningful decline in 2012.
Descriptive analysis of 30-day, all-cause hospital readmission rate patterns from 2007-2012. Medicare FFS beneficiaries experiencing at least one acute inpatient hospital stay. Using Chronic Condition Data Warehouse claims, we estimate unadjusted, monthly, readmission rates for the nation, within the Dartmouth Hospital Referral Regions (HRR), and compare participating and non-participating hospitals in the Partnership for Patients (P4P) program (overall and by number of inpatient beds at each facility). From 2007 through 2011, the national 30-day, all-cause, hospital readmission rate averaged 19 percent. During calendar year 2012, the readmission rate averaged 18.4 percent. Of the 306 HRRs, rates in 166 HRRs fell by between 1 and 5 percent, while rates dropped by more than 5 percent in 73 HRRs, with the largest reduction in Longview, Texas. Rates increased by more than 1 percent in only 30 HRRs, with the largest increase in Bloomington, Illinois. Readmission rates at hospitals participating in the P4P program have been, on average, consistently lower than the rates at non-participating hospitals within all size categories except for the very smallest and largest hospitals, but rates at both participant and non-participant hospitals fell in 2012. Although claims data are not yet final for 2012, our analysis indicates that hospital readmission rates for all Medicare FFS beneficiaries dropped noticeably during the year. The reasons behind the apparent reduction are not yet clear and merit further investigation.


A Change-Management Approach to Closing Care Gaps in a Federally Qualified Health Center: A Rural Kentucky Case Study.
Effective organizational change requires intentional planning. We applied Kotter's 8-Step Process for Leading Change model in understanding and evaluating how a federally qualified health center in rural Kentucky implemented a significant organizational change - a proactive office encounter (POE) model - to improve preventive care service delivery, close care gaps, and reduce health disparities among its patients. We completed qualitative interviews with 21 clinic personnel (eg, administrators, physicians, support staff, care coordinators) who were directly involved with POE implementation. We found evidence of steps 1 through 7 of Kotter's 8 steps of change in the POE implementation process. Step 8, anchoring new approaches in the organizational culture, was an area for improvement. Change-management models, such as Kotter's 8-Step Process for Leading Change, provide a systematic guide for health clinics to implement sustainable organizational change aimed at improving patient health outcomes.


Raising the issue of DNAR orders in vascular surgery patients.
The Tracey Report has recently raised the status of Do Not Attempt Cardio Pulmonary Resuscitation (DNACPR) orders in the hospital setting.[1] Guidelines are in place both nationally and locally to provide advice to clinicians on when to discuss DNACPR, and the approach to be taken. There was concern that on a busy regional vascular surgery unit, discussion of resuscitation status was not regular practice. Consequently, some patients were at risk of being inappropriately resuscitated, particularly out of hours. The North Bristol Somerset and Gloucester DNAR decision tree[2] was the tool used to decide whether a patient should have a documented discussion and/or a DNACPR form completed. We correlated the outcome of the decision tree with the presence of a DNACPR form or documented resuscitation discussion. Baseline measurements from all vascular inpatients on the vascular surgery unit demonstrated that only 27% had a DNACPR form or documented discussion in concordance with the DNACPR Decision Tree outcome. The aim of this project was to increase the proportion of patients with concordance of the DNACPR decision tree outcome with documented discussion or DNACPR form. The following three simple interventions raised concordance from 27% to 64% of patients on the vascular surgery unit. 1. Including resuscitation status of each patient as a column in the doctors daily handover. 2. Posters in staff only areas to highlight the meaning of DNACPR and raise awareness of the DNACPR decision tree. 3. Educational meeting surrounding DNACPR with the vascular surgery consultants, led by a care of the elderly consultant . This project has highlighted how raising awareness around DNACPR increases discussion amongst the clinical team surrounding resuscitation status of a patient. Consequently, this enables discussion to be had with patient and their family.


Efficacy of SCH 39304 in treatment of experimental invasive aspergillosis.
The efficacy of SCH 39304 (SCH) against Aspergillus fumigatus was assessed with an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with SCH at 10 or 15 mg/kg of body weight per day was begun 24 h after lethal challenge and compared with therapy with amphotericin B at 1.5 mg/kg/day. Compared with untreated controls, SCH reduced mortality and also reduced the tissue burden of A. fumigatus 100- to 1,000-fold in liver, kidney, and lung tissues. SCH at 15 mg/kg/day and amphotericin B eliminated A. fumigatus in liver, kidney, and lung tissues. In addition, both dosages of SCH significantly eliminated the organism from brain tissues, compared with controls. Both SCH and amphotericin B decreased or eliminated circulating aspergillus antigen. These results show that new azoles can be as effective as amphotericin B in eradicating the organism from tissues and offer promise in improving the treatment of invasive aspergillosis.


Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas.
The pharmacologic treatment of schizophrenia and bipolar disorder leaves much to be desired. Repurposed drugs, which are approved for other medical conditions, represent an underutilized therapeutic resource for patients who have not responded to other drugs. Using experience gained from a decade of repurposed drug studies by the Stanley Medical Research Institute and search of the literature, we have identified nine such drugs for which there is some evidence of efficacy for schizophrenia and/or bipolar disorder. These include: aspirin; celecoxib; estrogen/raloxifene; folate; minocycline; mirtazapine; omega-3 fatty acids; pramipexole; and, pregnenolone. The evidence of efficacy is reviewed for each drug. Because there is little or no financial incentive for pharmaceutical companies to promote such drugs, there is a paucity of definitive trials, and these drugs are less widely known than they deserve to be. Biomarker studies should also be carried out to identify subgroups of patients who do respond to these drugs.


Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone.
The effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on morphine-induced analgesia, tolerance and dependence was investigated by administering alpha-MSH by intracerebroventricular (i.c.v.) injection to mice 15 min before morphine administration. alpha-MSH antagonized morphine-induced analgesia at doses lower than that necessary to demonstrate hyperalgesia. Pretreatment of mice with 100 mg/kg of morphine sulfate s.c. did not increase the ED50 of morphine in alpha-MSH-treated mice to the same degree as that of control mice. Furthermore, the increase in naloxone potency due to morphine pretreatment, which was used as an indicator of tolerance development, was inhibited by alpha-MSH. The ED50 of naloxone needed to induce withdrawal jumping in dependent mice was increased by alpha-MSH administered 15 min before morphine, but not when alpha-MSH was administered 15 min before naloxone. alpha-MSH did not alter whole-brain levels of morphine. Naloxone (1.0 mg/kg), administered i.p. 15 min before alpha-MSH, did not alter the antagonism by alpha-MSH of morphine-induced analgesia, tolerance or dependence. Furthermore, alpha-MSH did not change the affinity of opioid receptors for etorphine or the maximal number of binding sites, but alpha-MSH did exhibit a very weak affinity for opioid receptors. These results indicate that alpha-MSH antagonized the actions of morphine but this antagonism did not appear to be mediated through an interaction with opioid receptors.


[Oesophageal cancer: multidisciplinary approach].
Despite recent progresses, the prognosis of oesophageal cancer is still bad, mostly because of frequent late diagnosis. In early cases, radical surgery alone is able to cure 60-70% of the patients. In locally-advanced cases, on the other hand, surgical results are considerably worse and combined therapies are contemplated. In these cases, neoadjuvant therapy (induction chemotherapy followed by radiotherapy and surgical resection) is often proposed, but without formal proof of superiority. These combined therapies are heavy for the patient and complex for the team. They can only be decided and managed in the frame of intensive multidisciplinary collaboration. Future progresses will come at the same time from larger studies and from the efforts of the medical community towards earlier diagnosis of this disease.


Identification of a microtubule-associated motor protein essential for dendritic differentiation.
The quintessential feature of the dendritic microtubule array is its nonuniform pattern of polarity orientation. During the development of the dendrite, a population of plus end-distal microtubules first appears, and these microtubules are subsequently joined by a population of oppositely oriented microtubules. Studies from our laboratory indicate that the latter microtubules are intercalated within the microtubule array by their specific transport from the cell body of the neuron during a critical stage in development (Sharp, D.J., W. Yu, and P.W. Baas. 1995. J. Cell Biol. 130:93- 104). In addition, we have established that the mitotic motor protein termed CHO1/MKLP1 has the appropriate properties to transport microtubules in this manner (Sharp, D.J., R. Kuriyama, and P.W. Baas. 1996. J. Neurosci. 16:4370-4375). In the present study we have sought to determine whether CHO1/MKLP1 continues to be expressed in terminally postmitotic neurons and whether it is required for the establishment of the dendritic microtubule array. In situ hybridization analyses reveal that CHO1/MKLP1 is expressed in postmitotic cultured rat sympathetic and hippocampal neurons. Immunofluorescence analyses indicate that the motor is absent from axons but is enriched in developing dendrites, where it appears as discrete patches associated with the microtubule array. Treatment of the neurons with antisense oligonucleotides to CHO1/MKLP1 suppresses dendritic differentiation, presumably by inhibiting the establishment of their nonuniform microtubule polarity pattern. We conclude that CHO1/MKLP1 transports microtubules from the cell body into the developing dendrite with their minus ends leading, thereby establishing the nonuniform microtubule polarity pattern of the dendrite.


Automated Text-Based Symptom Monitoring With Rapid Clinician Triage for Patients With Cancer and Suspected or Confirmed COVID-19.
Patients with cancer are at greater risk of developing severe symptoms from COVID-19 than the general population. We developed and tested an automated text-based remote symptom-monitoring program to facilitate early detection of worsening symptoms and rapid assessment for patients with cancer and suspected or confirmed COVID-19. We conducted a feasibility study of Cancer COVID Watch, an automated COVID-19 symptom-monitoring program with oncology nurse practitioner (NP)-led triage among patients with cancer between April 23 and June 30, 2020. Twenty-six patients with cancer and suspected or confirmed COVID-19 were enrolled. Enrolled patients received twice daily automated text messages over 14 days that asked "How are you feeling compared to 12 hours ago? Better, worse, or the same?" and, if worse, "Is it harder than usual for you to breathe?" Patients who responded worse and yes were contacted within 1 hour by an oncology NP. Mean age of patients was 62.5 years. Seventeen (65%) were female, 10 (38%) Black, and 15 (58%) White. Twenty-five (96%) patients responded to ≥ 1 symptom check-in, and overall response rate was 78%. Four (15%) patients were escalated to the triage line: one was advised to present to the emergency department (ED), and three were managed in the outpatient setting. Median time from escalation to triage call was 11.5 minutes. Four (15%) patients presented to the ED without first escalating their care via our program. Participant satisfaction was high (Net Promoter Score: 100, n = 4). Implementation of an intensive remote symptom monitoring and rapid NP triage program for outpatients with cancer and suspected or confirmed COVID-19 infection is possible. Similar tools may facilitate more rapid triage for patients with cancer in future pandemics.


Leflunomide or methotrexate for juvenile rheumatoid arthritis.
We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial. Patients 3 to 17 years of age received leflunomide or methotrexate for 16 weeks in a double-dummy, blinded fashion, followed by a 32-week blinded extension. The rates of American College of Rheumatology Pediatric 30 percent responses (ACR Pedi 30) and the Percent Improvement Index were assessed at baseline and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension study. Of 94 patients randomized, 86 completed 16 weeks of treatment, 70 of whom entered the extension study. At week 16, more patients in the methotrexate group than in the leflunomide group had an ACR Pedi 30 response (89 percent vs. 68 percent, P=0.02), whereas the values for the Percent Improvement Index did not differ significantly (-52.87 percent vs. -44.41 percent, P=0.18). In both groups, the improvements achieved at week 16 were maintained at week 48. The most common adverse events in both groups included gastrointestinal symptoms, headache, and nasopharyngeal symptoms. Aminotransferase elevations were more frequent with methotrexate than with leflunomide during the initial study and the extension study. In patients with polyarticular juvenile rheumatoid arthritis, methotrexate and leflunomide both resulted in high rates of clinical improvement, but the rate was slightly greater for methotrexate. At the doses used in this study, methotrexate was more effective than leflunomide.


Iodine-131 monitoring in sewage plant outflow.
Three different hospital sites (Oxford, Sutton and Guildford) have performed sampling of their local sewage plant outflow to determine levels of radioactivity resulting from iodine-131 patients undergoing radionuclide therapies. It was found that a maximum of 20% of activity discharged from the hospitals was present in the sewage plant final effluent channel. This is significantly below the level predicted by mathematical models in current use. The results further show that abatement systems to reduce public exposure are unlikely to be warranted at hospital sites.


Real-time rotation vectors.
Rotation vectors are a useful way of describing eye position without reference to arbitrary axes of rotation since any eye position can be reached from the reference position by rotation about a single axis. A real-time display of rotation vectors would not only help to acquire more reliable data, but would also widen the range of possible eye movement experiments. We describe a novel PC based data acquisition and analysis system which calculates and displays rotation vectors, velocity vectors and Listing's plane in real-time using voltages obtained from a two field coil system. The system was implemented using LabVIEW and optimised using Code Interface Nodes. Off-line processing can be sped up by varying parameters that indicate the amount of available RAM. During processing Listing's plane data can be rotated horizontally, vertically and torsionally. A computer controlled laser target changes position randomly every half second and so the targets are evenly spread, producing an appropriate range of eye positions which are used to calculate Listing's plane.


Personalised perioperative care by e-health after intermediate-grade abdominal surgery: a multicentre, single-blind, randomised, placebo-controlled trial.
Instructing and guiding patients after surgery is essential for successful recovery. However, the time that health-care professionals can spend with their patients postoperatively has been reduced because of efficiency-driven, shortened hospital stays. We evaluated the effect of a personalised e-health-care programme on return to normal activities after surgery. A multicentre, single-blind, randomised controlled trial was done at seven teaching hospitals in the Netherlands. Patients aged 18-75 years who were scheduled for laparoscopic cholecystectomy, inguinal hernia surgery, or laparoscopic adnexal surgery for a benign indication were recruited. An independent researcher randomly allocated participants to either the intervention or control group using computer-based randomisation lists, with stratification by sex, type of surgery, and hospital. Participants in the intervention group had access to a perioperative, personalised, e-health-care programme, which managed recovery expectations and provided postoperative guidance tailored to the patient. The control group received usual care and access to a placebo website containing standard general recovery advice. Participants were unaware of the study hypothesis and were asked to complete questionnaires at five timepoints during the 6-month period after surgery. The primary outcome was time between surgery and return to normal activities, measured using personalised patient-reported outcome measures. Intention-to-treat and per-protocol analyses were done. This trial is registered in the Netherlands National Trial Register, number NTR4699. Between Aug 24, 2015, and Aug 12, 2016, 344 participants were enrolled and randomly allocated to either the intervention (n=173) or control (n=171) group. 14 participants (4%) were lost to follow-up, with 330 participants included in the primary outcome analysis. Median time until return to normal activities was 21 days (95% CI 17-25) in the intervention group and 26 days (20-32) in the control group (hazard ratio 1·38, 95% CI 1·09-1·73; p=0·007). Complications did not differ between groups. A personalised e-health intervention after abdominal surgery speeds up the return to normal activities compared with usual care. Implementation of this e-health programme is recommended in patients undergoing intermediate-grade abdominal, gynaecological, or general surgical procedures. ZonMw.


Informatics and quantitative analysis in biological imaging.
Biological imaging is now a quantitative technique for probing cellular structure and dynamics and is increasingly used for cell-based screens. However, the bioinformatics tools required for hypothesis-driven analysis of digital images are still immature. We are developing the Open Microscopy Environment (OME) as an informatics solution for the storage and analysis of optical microscope image data. OME aims to automate image analysis, modeling, and mining of large sets of images and specifies a flexible data model, a relational database, and an XML-encoded file standard that is usable by potentially any software tool. With this design, OME provides a first step toward biological image informatics.


Phospholipase A2 of Microbiota as Pathogenetic Determinant to Induce Inflammatory States in Ulcerative Colitis: Therapeutic Implications of Phospholipase A2 Inhibitors.
Attack by commensal microbiota is one component of induction of inflammatory episodes in ulcerative colitis (UC). In UC, the mucus layer is intrinsically devoid of phosphatidylcholine (PC) resulting in low hydrophobicity which facilitates bacterial invasion. Colonic ectophospholipase-carrying bacterial strains are likely candidates to further thinning the PC mucus barrier and to precipitate inflammatory episodes. To evaluate the effect of phospholipase A2 (PLA2) inhibitors on inflammation in a genetic UC mouse model. As PLA2 inhibitor, we applied the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) or as control 5% Tween 80 by oral gavage to intestine-specific kindlin 2 knockout mice. Luminal UDCA-LPE reduced the PLA2 activity in stool by 36 ± 8%. Concomitantly no inflammatory phenotype was observed when compared to kindlin 2(-/-) mice not treated with UDCA-LPE. The improvement was documented in regard to stool consistency, calprotectin levels in stool, and macroscopic/endoscopic as well as histologic features of the mucosa. The pattern of colonic microbiota distribution obtained in the UC phenotype mice was reversed by UDCA-LPE to the control mice pattern. The inhibition of the bacterial ectophospholipase A2 activity improves mucosal inflammation in a genetic mouse model of UC. It is assumed that the remaining mucus PC shield is better preserved when luminal PLA2 is suppressed.


Serum Amyloid A-Mediated Inflammasome Activation of Microglial Cells in Cerebral Ischemia.
Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1β (IL-1β), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1β induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1β. N-acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1β by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes.SIGNIFICANCE STATEMENT In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1β release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.


Arthrography and arthrotomy of the knee in sports injuries.
A total of 266 patients with injuries to the knee sustained during sports activities were managed by arthroscopy and/or arthrotomy. All of them received systemic examination and a standard battery of knee stability tests. Fifty-three were examined by arthrography and all underwent arthrotomy for surgical correction of the lesion diagnosed by both clinical examination and arthrography. Our study showed that clinical examination could give an accurate clinical diagnosis in 88.35% of cases and arthrography in 76.89%. No complication from arthrography was found. Injury occurred most commonly between 21 and 30 years of age and was more common to the right knee than the left. The sport in which most injuries occurred was football.


Effectiveness of Trainings of General Practitioners on Antibiotic Stewardship: Methods of a Pragmatic Quasi-Experimental Study in a Controlled Before-After Design in South-East-Lower Saxony, Germany (WASA).
Introduction: Antibiotic resistance is a serious threat to global public health. It reduces the effectiveness of treatments for serious bacterial infections and thus increases the risk of fatal outcomes. Antibiotic prescriptions are often not in line with clinical evidence-based guidelines. The process of emergence of resistant bacteria can be slowed down by adherence to guidelines. Yet this adherence seems to be lacking in primary health care. Methods and Analysis: This pragmatic quasi-experimental study using a controlled before-after design was carried out in South-East-Lower Saxony in 2018-2020. The voluntary attendance of interactive trainings with condensed presentation of current guidelines for general practitioners (GP) on antibiotic management for urinary and respiratory tract infections is regarded as intervention. Those GP not attending the trainings constitute the control group. Data were collected via questionnaires; routine health records are provided by a statutory health insurance. The primary outcome is the proportion of (guideline-based) prescriptions in relation to the relevant ICD-10 codes as well as daily defined doses and the difference in proportion of certain prescriptions according to guidelines before and after the intervention as compared to the control group. Further outcomes are among others the subjectively perceived risk of antibiotic resistance and the attitude toward the guidelines. The questionnaires to assess this are based on theory of planned behavior (TPB) and health action process approach (HAPA). Variations over time and effects caused by measures other than WASA (Wirksamkeit von Antibiotika-Schulungen in der niedergelassenen Aerzteschaft-Effectiveness of antibiotic management training in the primary health care sector) training are taken into account by including the control group and applying interrupted time series analysis. Ethics and Dissemination: The study protocol and the data protection concept respectively were reviewed and approved by the Ethics Committee of the Hannover Medical School and the Federal Commissioner for Data Protection and Freedom of Information. Trial Registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013951, identifier DRKS00013951.


Knowledge, Attitudes, and Beliefs of Prenursing and Nursing Students About Sexual Assault.
Sexual assault has been identified as a major public health problem in the United States, yet little research has been done regarding nursing students' knowledge, attitudes, and beliefs about sexual assault. Lack of knowledge, or victim-blaming attitudes held by healthcare providers can be problematic for the care of the sexual assault victim, leaving them feeling upset and distressed after the healthcare encounter. Prenursing and nursing students were surveyed about their knowledge, attitudes, and beliefs about sexual assault. A knowledge test, the Illinois Rape Myth Acceptance scale, and the Attitudes Toward Rape Victims scale were utilized in the survey; 297 students completed the survey. Results indicate that rape myth acceptance is lower for nursing students in their last semester of college than in the prenursing group; and that last-semester nursing students held less victim-blaming attitudes toward rape victims than prenursing students. The knowledge test highlights problem areas that need to be addressed by nursing education to improve the care of sexual assault patients.


Augmented Reality Guided Needle Biopsy of Soft Tissue: A Pilot Study.
Percutaneous biopsies are popular for extracting suspicious tissue formations (primarily for cancer diagnosis purposes) due to the: relatively low cost, minimal invasiveness, quick procedure times, and low risk for the patient. Despite the advantages provided by percutaneous biopsies, poor needle and tumor visualization is a problem that can result in the clinicians classifying the tumor as benign when it was malignant (false negative). The system developed by the authors aims to address the concern of poor needle and tumor visualization through two virtualization setups. This system is designed to track and visualize the needle and tumor in three-dimensional space using an electromagnetic tracking system. User trials were conducted in which the 10 participants, who were not medically trained, performed a total of 6 tests, each guiding the biopsy needle to the desired location. The users guided the biopsy needle to the desired point on an artificial spherical tumor (diameters of 30, 20, and 10 mm) using the 3D augmented reality (AR) overlay for three trials and a projection on a second monitor (TV) for the other three trials. From the randomized trials, it was found that the participants were able to guide the needle tip 6.5 ± 3.3 mm away from the desired position with an angle deviation of 1.96 ± 1.10° in the AR trials, compared to values of 4.5 ± 2.3 mm and 2.70 ± 1.67° in the TV trials. The results indicate that for simple stationary surgical procedures, an AR display is non-inferior a TV display.


Estradiol induces physical association of neuronal nitric oxide synthase with NMDA receptor and promotes nitric oxide formation via estrogen receptor activation in primary neuronal cultures.
Estrogens and nitric oxide (NO) exert wide-ranging effects on brain function. Recent evidence suggested that one important mechanism for the regulation of NO production may reside in the differential coupling of the calcium-activated neuronal NO synthase (nNOS) to glutamate NMDA receptor channels harboring NR2B subunits by the scaffolding protein post-synaptic density-95 (PSD-95), and that estrogens promote the formation of this ternary complex. Here, we demonstrate that 30-min estradiol-treatment triggers the production of NO by physically and functionally coupling NMDA receptors to nNOS in primary neurons of the rat preoptic region in vitro. The ability of estradiol to activate neuronal NO signaling in preoptic neurons and to promote changes in protein-protein interactions is blocked by ICI 182,780, an estrogen receptor antagonist. In addition, blockade of NMDA receptor NR2B subunit activity with ifenprodil or disruption of PSD-95 synthesis in preoptic neurons by treatment with an anti-sense oligodeoxynucleotide inhibited the estradiol-promoted stimulation of NO release in cultured preoptic neurons. Thus, estrogen receptor-mediated stimulation of the nNOS/PSD-95/NMDA receptor complex assembly is likely to be a critical component of the signaling process by which estradiol facilitates coupling of glutamatergic fluxes for NO production in neurons.


[Effect of autophagy on expression of neutrophil programmed death ligand-1 in mice with sepsis].
To investigate the effect and mechanism of autophagy on the expression of neutrophil programmed death ligand-1 (PD-L1) in mice with sepsis. (1) In vivo experiment: male C57BL/6 mice aged 6-8 weeks were divided into sham operation group (Sham group), cecum ligation and perforation (CLP) group, and rapamycin (RAP)+CLP group by random number table with 10 mice in each group. The sepsis model was reproduced by CLP, and the cecum and perforation were not ligated in Sham group, and other operations were the same as CLP group. The mice in RAP+CLP group were intraperitoneally injected with autophagy agonist RAP 4 mg×kg-1×d-1 7 days before modeling, while the mice in Sham group and CLP group were not treated. Lung, liver, spleen and pancreas tissues were harvested for immunohistochemical staining 4 days after the operation, and the infiltration of neutrophils in various organs was observed under light microscope. Meanwhile, the expressions of immunosuppressive molecule PD-L1 and autophagy marker microtubule-associated protein 1 light chain 3 (LC3) in lung neutrophils were determined by immunofluorescence staining. (2) In vitro experiment: mouse bone marrow neutrophils were extracted and re-suspended to 1×1010/L, and they were divided into blank control group (without any treatment), RAP control group (RAP 100 μmol/L), autophagy inhibitor Bafilomycin A1 (Baf) control group (Baf 10 μmol/L), lipopolysaccharide (LPS) stimulation group (LPS 1 mg /L), RAP+LPS group, and Baf+LPS group. The latter two groups were pretreated with 100 μmol/L RAP or 10 μmol/L Baf 30 minutes before LPS stimulation, respectively. The expression of PD-L1 mRNA of neutrophils was determined by reverse transcription-polymerase chain reaction (RT-PCR) at 0, 4, 12 hours after LPS stimulation. At the same time, the expressions of PD-L1, LC3 and p62 at the protein level were determined by Western Blot. (1) In vivo experiment: according to immunohistochemical experiments, a large amount of infiltration of neutrophils in lung, liver, spleen and pancreas was found at 4 hours after CLP. In the immunofluorescence, with the time extension after CLP, the positive expression of LC3 in the lung tissue showed a decreased tendency, and PD-L1 expression was significantly increased. RAP pretreatment could promote the expression of LC3 and reduce the expression of PD-L1 in CLP mice. (2) In vitro experiment: in terms of mRNA levels, with the extension of LPS stimulation time, the expression of PD-L1 mRNA in mouse neutrophils was increased continuously, and peaked at 12 hours, it was significantly higher than that in the blank control group (2-ΔΔCT: 72.2±10.0 vs. 13.0±0.8, P < 0.01). Compared with LPS stimulation group, the expression of PD-L1 mRNA in RAP+LPS group was significantly down-regulated [12-hour PD-L1 mRNA (2-ΔΔCT): 47.4±7.3 vs. 72.2±10.0, P < 0.01]. In Baf+LPS group, PD-L1 mRNA expression was significantly up-regulated as compared with that in LPS stimulation group [12-hour PD-L1 mRNA (2-ΔΔCT): 109.1±7.4 vs. 72.2±10.0, P < 0.01]. At the protein levels, at 4 hours after LPS stimulation, the positive expressions of PD-L1, LC3 and p62 were increased significantly as compared with those in the blank control group, and PD-L1 and p62 were increased continuously with time. Compared with the LPS stimulation group, the expressions of PD-L1 and p62 in the RAP+LPS group were significantly down-regulated, while the expression of LC3 was continually increased, indicating that the level of autophagy was increased, and autophagy was circulated smoothly. On the contrary, the expressions of PD-L1, LC3 and p62 in the Baf+LPS group were significantly up-regulated, indicating that the binding of autophagy and lysosome was blocked, and autophagy was not smooth. In sepsis, the infiltration of neutrophils in all organs increased, and the expression of PD-L1 of neutrophils in lungs was increased significantly, while the expression level of autophagy was decreased. The expression of PD-L1 stimulated by LPS can be inhibited by autophagy agonists, and promoted by autophagy inhibitors. PD-L1 has a negative regulatory effect on sepsis. It can reduce the expression of PD-L1 molecule in sepsis by targeting autophagy, so as to improve sepsis.


The phylogeny of the Schistosomatidae based on three genes with emphasis on the interrelationships of Schistosoma Weinland, 1858.
Schistosomes are digenean flukes, parasitic of birds, mammals and crocodiles. The family Schistosomatidae contains species of considerable medical and veterinary importance, which cause the disease schistosomiasis. Previous studies, both morphological and molecular, which have provided a good deal of information on the phylogenetics of this group, have been limited in the number of species investigated or the type or extent of molecular data used. This paper presents the most comprehensive phylogeny to date, based on the sequences of 3 genes, complete ribosomal small subunit rRNA and large ribosomal subunit rRNA, and mitochondrial cytochrome oxidase 1, sequenced from 30 taxa including at least 1 representative from 10 of the 13 known genera of the Schistosomatidae and 17 of the 20 recognized Schistosoma species. The phylogeny is examined using morphological characters, intermediate and definitive host associations and biogeography. Theories as to the origins and spread of Schistosoma are also explored. The principal findings are that Ornithobilharzia and Austrobilharzia form a sister group to the Schistosoma; mammalian schistosomes appear paraphyletic and 2 Trichobilharzia species, T. ocellata and T. szidati, seem to be synonymous. The position of Orientobilharzia within the Schistosoma is confirmed, as is an Asian origin for the Schistosoma, followed by subsequent dispersal through India and Africa.


A practical assessment of magnetic resonance diffusion-perfusion mismatch in acute stroke: observer variation and outcome.
MR diffusion/perfusion mismatch may help identify patients for acute stroke treatment, but mixed results from clinical trials suggest that further evaluation of the mismatch concept is required. To work effectively, mismatch should predict prognosis on arrival at hospital. We assessed mismatch duration and associations with functional outcome in acute stroke. We recruited consecutive patients with acute stroke, recorded baseline clinical variables, performed MR diffusion and perfusion imaging and assessed 3-month functional outcome. We assessed practicalities, agreement between mismatch on mean transit time (MTT) or cerebral blood flow (CBF) maps, visually and with lesion volume, and the relationship of each to functional outcome. Of 82 patients starting imaging, 14 (17%) failed perfusion imaging. Overall, 42% had mismatch (56% at <6 h; 41% at 12-24 h; 23% at 24-48 h). Agreement for mismatch by visual versus volume assessment was fair using MTT (kappa 0.59, 95% CI 0.34-0.84) but poor using CBF (kappa 0.24, 95% CI 0.01-0.48). Mismatch by either definition was not associated with functional outcome, even when the analysis was restricted to just those with mismatch. Visual estimation is a reasonable proxy for mismatch volume on MTT but not CBF. Perfusion is more difficult for acute stroke patients than diffusion imaging. Mismatch is present in many patients beyond 12 h after stroke. Mismatch alone does not distinguish patients with good and poor prognosis; both can do well or poorly. Other factors, e.g. reperfusion, may influence outcome more strongly, even in patients without mismatch.


Primary prevention of diabetes mellitus type 2 and cardiovascular diseases using a cognitive behavior program aimed at lifestyle changes in people at risk: Design of a randomized controlled trial.
The number of people with cardiovascular disease (CVD) and diabetes mellitus type 2 (T2DM) is growing rapidly. To a large extend, this increase is due to lifestyle-dependent risk factors, such as overweight, reduced physical activity, and an unhealthy diet. Changing these risk factors has the potential to postpone or prevent the development of T2DM and CVD. It is hypothesized that a cognitive behavioral program (CBP), focused in particular on motivation and self-management in persons who are at high risk for CVD and/or T2DM, will improve their lifestyle behavior and, as a result, will reduce their risk of developing T2DM and CVD. 12,000 inhabitants, 30-50 years of age living in several municipalities in the semi-rural region of West-Friesland will receive an invitation from their general practitioner (n = 13) to measure their own waist circumference with a tape measure. People with abdominal obesity (male waist >/= 102 cm, female waist >or= 88 cm) will be invited to participate in the second step of the screening which includes blood pressure, a blood sample and anthropometric measurements. T2DM and CVD risk scores will then be calculated according to the ARIC and the SCORE formulae, respectively. People with a score that indicates a high risk of developing T2DM and/or CVD will then be randomly assigned to the intervention group (n = 300) or the control group (n = 300).Participants in the intervention group will follow a CBP aimed at modifying their dietary behavior, physical activity, and smoking behavior. The counseling methods that will be used are motivational interviewing (MI) and problem solving treatment (PST), which focus in particular on intrinsic motivation for change and self-management of problems of the participants. The CBP will be provided by trained nurse practitioners in the participant's general practice, and will consists of a maximum of six individual sessions of 30 minutes, followed by 3-monthly booster sessions by phone. Participants in the control group will receive brochures containing health guidelines regarding physical activity and diet, and how to stop smoking. The primary outcome measures will be changes in T2DM and CVD risk scores. Secondary outcome measures will be changes in lifestyle behavior and cost-effectiveness and cost-utility ratios. All relevant direct and indirect costs will be measured, and there will be a follow-up of 24 months. Changing behaviors is difficult, requires time, considerable effort and motivation. Combining the two counseling methods MI and PST, followed by booster sessions may result in sustained behavioral change. Current Controlled Trials ISRCTN59358434.


The reliability of intermittent ECG sampling in arrhythmia detection.
Although intermittent ECG sampling is a commonly used method for arrhythmia detection there are no controlled studies of its efficiency. In the present study a continuous ECG was recorded for three hours in 52 patients with ventricular tachyarrhythmias. All ECGs were interpreted minute to minute to get the true arrhythmia content. Intermittent ECG samples were simulated by analyzing the first two and first five minutes of every 15 minutes in the ECG material. Two minute long ECG samples were also used every 30 minutes. The 15 and 30 minute long periods were classified as containing arrhythmias or not according to the arrhythmia content of the samples. These findings were subsequently compared with the true arrhythmia content. The arrhythmia detection rate depends on the sampling time and true arrhythmia occurrence. The distribution of arrhythmias within the periods was also of importance. With a five minute long ECG sample about 80% of the intervals containing any type of ventricular tachyarrhythmia will be detected. This is reduced to about 50% when one minute long ECG strips are used. Infrequent types of VPCs such as R on T or ventricular tachycardia are very poorly detected also when sampling as much as one-third of the total time. The study also included a comparison between the results obtained from the clinical material and the results obtained by the use of computerized arrhythmia models. It is concluded that intermittent ECG sampling besides a low detection rate for infrequent arrhythmias and short ECG samples, also brings a risk of underestimating or overemphasizing the arrhythmia occurrence depending on a periodic type of arrhythmia distribution among the patients. These factors make intermittent ECG sampling an unsuitable method for evaluating antiarrhythmic drugs.


Clinical, pathologic, and serologic features of an epizootic of mousepox in Minnesota.
An epizootic of mousepox in two colonies of mice was described. Clinical signs, morbidity and mortality rates, and necropsy lesions were substantially influenced by husbandry practices, intercurrent diseases (Sendai pneumonia, mouse hepatitis virus), and total body x-irradiation. In one colony, 54 mice were necropsied; 19 mice had cutaneous or visceral lesions of mousepox although none had combined visceral and cutaneous lesions. In the other colony, 20 mice were necropsied, and 10 mice had cutaneous lesions; none had visceral lesions. Sera from 24 mice with the cutaneous form of the disease had no demonstrable HI antibody titer. Experimental mice injected with spleen/liver homogenates from infected colony mice developed typical visceral lesions with numerous poxvirus profiles on electron micrographs and positive HI titers. Mice immunized with vaccinia virus were not susceptible to the disease.


Mesolimbic and striatal dopamine receptor supersensitivity: prophylactic and reversal effects of L-prolyl-L-leucyl-glycinamide (PLG).
Functional supersensitivity of mesolimbic and striatal dopamine receptors has been suggested to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. Using the rodent model of chronic administration of the neuroleptic haloperidol, we investigated the possible desensitizing effects of a tripeptide structurally unrelated to dopamine agonists, L-prolyl-L-leucyl-glycinamide (PLG) on mesolimbic and striatal dopaminergic receptor supersensitivity. Administration of PLG either prior to or after chronic haloperidol, inhibited the supersensitivity of dopamine receptors. The results have implications for pharmacological intervention in preventing tardive dyskinesia and relapse psychosis of schizophrenia.


Intergenerational issues regarding nuclear power, nuclear waste, and nuclear weapons.
Nuclear power, nuclear waste, and nuclear weapons raise substantial public concern in many countries. While new support for nuclear power can be found in arguments concerning greenhouse gases and global warming, the long-term existence of radioactive waste has led to requirements for 10,000-year isolation. Some of the support for such requirements is based on intergenerational equity arguments. This, however, places a very high value on lives far in the future. An alternative is to use discounting, as is applied to other resource applications. Nuclear weapons, even though being dismantled by the major nations, are growing in number due to the increase in the number of countries possessing these weapons of mass destruction. This is an unfortunate legacy for future generations.


Can current models explain the lack of liver complications in Y-90 microsphere therapy?
Normal liver complications have not been observed in Y-90 microsphere therapy of hepatic tumors [selective internal radiation (SIR)], despite clinical studies reporting estimated absorbed doses to normal liver between 100 and 150 Gy. The purpose of the study was to see whether predictions of normal tissue complication probability (NTCP) models for liver based on clinical data from external beam therapy are consistent with clinical results of SIR. Liver NTCP was calculated using a parallel architecture model and normal liver dose-volume histograms that have been proposed for SIR. A parallel model including internal functional subunit structure is also proposed. Dose rate effects are incorporated. A criterion for comparing model calculations with clinical data is presented. For the parallel architecture model, the predicted NTCP is sensitive to the dose distribution in normal liver and to the model parameters, particularly the repair time. With reasonable assumptions about the microsphere distribution, the parallel model with parameters deduced from external beam therapy outcome analysis is consistent with the observed lack of liver complications. Inclusion of FSU structure widens the range of assumptions under which consistency is found. The parallel model can be consistent with the clinically observed lack of liver complications in SIR. More information about the activity distribution and the radiobiology of normal liver under conditions typical of microsphere therapy should be sought.


Alcohol policy enforcement and changes in student drinking rates in a statewide public college system: a follow-up study.
Heavy alcohol use among U.S. college students is a major contributor to young adult morbidity and mortality. The aim of this study was to examine whether college alcohol policy enforcement levels predict changes in student drinking and related behaviors in a state system of public colleges and universities, following a system-wide change to a stricter policy. Students and administrators at 11 Massachusetts public colleges/universities completed surveys in 1999 (N of students = 1252), one year after the policy change, and again in 2001 (N = 1074). We calculated policy enforcement scores for each school based on the reports of deans of students, campus security chiefs, and students, and examined the correlations between perceived enforcement levels and the change in student drinking rates over the subsequent two year period, after weighting the 2001 data to adjust for demographic changes in the student body. Overall rates of any past-30-days drinking, heavy episodic drinking, and usual heavy drinking among past-30-days drinkers were all lower in 2001 compared to 1999. School-level analyses (N = 11) found deans' baseline reports of stricter enforcement were strongly correlated with subsequent declines in heavy episodic drinking (Pearson's r = -0.73, p = 0.011). Moreover, consistently high enforcement levels across time, as reported by deans, were associated with greater declines in heavy episodic drinking. Such relationships were not found for students' and security chiefs' reports of enforcement. Marijuana use did not rise during this period of decline in heavy drinking. Study findings suggest that stronger enforcement of a stricter alcohol policy may be associated with reductions in student heavy drinking rates over time. An aggressive enforcement stance by deans may be an important element of an effective college alcohol policy.


Neurophysiological aspects of the toxicity of organic solvents.
Symptoms after long-term exposure to organic solvents are nonspecific, and for both medical and insurance purposes objective demonstration of toxic damage would be desirable at the earliest possible stage of beginning disease. Axonopathy does not dramatically decrease nerve conduction velocities; however, epidemiologic studies may reveal slower conduction velocities, especially in the distal nerve segments, among workers exposed to organic solvents. Among patients with solvent poisoning abnormally slow nerve conduction velocities are detected. Electromyography reveals denervation activity in early axonopathy; loss of motor units is detectable at a later stage. Hexacarbons, eg, n-hexane, have caused changes in visual evoked potentials, namely, prolonged latencies and decreased amplitudes, probably due to axonal lesions within the central nervous system. Electroencephalography (EEG) has been applied in studies of individual patients or patient groups and in epidemiologic approaches. Among patients actual abnormalities, mainly diffuse or local slow wave abnormalities, are frequent. In epidemiologic studies the frequency of abnormal EEG findings is related to overall exposure levels in the studied populations.


Attention-Guided Deep Neural Network With Multi-Scale Feature Fusion for Liver Vessel Segmentation.
Liver vessel segmentation is fast becoming a key instrument in the diagnosis and surgical planning of liver diseases. In clinical practice, liver vessels are normally manual annotated by clinicians on each slice of CT images, which is extremely laborious. Several deep learning methods exist for liver vessel segmentation, however, promoting the performance of segmentation remains a major challenge due to the large variations and complex structure of liver vessels. Previous methods mainly using existing UNet architecture, but not all features of the encoder are useful for segmentation and some even cause interferences. To overcome this problem, we propose a novel deep neural network for liver vessel segmentation, called LVSNet, which employs special designs to obtain the accurate structure of the liver vessel. Specifically, we design Attention-Guided Concatenation (AGC) module to adaptively select the useful context features from low-level features guided by high-level features. The proposed AGC module focuses on capturing rich complemented information to obtain more details. In addition, we introduce an innovative multi-scale fusion block by constructing hierarchical residual-like connections within one single residual block, which is of great importance for effectively linking the local blood vessel fragments together. Furthermore, we construct a new dataset containing 40 thin thickness cases (0.625 mm) which consist of CT volumes and annotated vessels. To evaluate the effectiveness of the method with minor vessels, we also propose an automatic stratification method to split major and minor liver vessels. Extensive experimental results demonstrate that the proposed LVSNet outperforms previous methods on liver vessel segmentation datasets. Additionally, we conduct a series of ablation studies that comprehensively support the superiority of the underlying concepts.


Surveillance for bacterial diarrhea and antimicrobial resistance in rural western Kenya, 1997-2003.
Diarrhea is a major cause of preventable illness in sub-Saharan Africa. Although most cases of bacterial gastroenteritis do not require antimicrobial treatment, antimicrobial use is widespread. We examined the bacterial causes of diarrhea and monitored antimicrobial susceptibilities of isolates through clinic-based surveillance in a rural Kenyan community. From May 1997 through April 2003, diarrheal stool samples from persons presenting to 4 sentinel health centers were cultured by standard techniques for routine bacterial enteric pathogens, for which antimicrobial susceptibilities were determined. A random subset of specimens was also evaluated for diarrheagenic Escherichia coli. Among stool specimens from 3445 persons, 1092 (32%) yielded at least 1 bacterial pathogen. Shigella species was most commonly isolated (responsible for 16% of all illnesses; 54% of isolates were Shigella flexneri). Campylobacter species and diarrheagenic E. coli predominated among children aged <5 years and were progressively replaced by Shigella species with increasing age. With the exception of Campylobacter species, susceptibility to the antimicrobials used most widely in the community was low: <40% for all isolates tested and <25% for Shigella species. Most persons were treated with an antimicrobial to which their isolate was resistant. Susceptibility to specific antimicrobials was inversely proportional to the frequency with which they were prescribed. The utility of available antimicrobials for treating bacterial diarrhea in rural western Kenya is substantially limited by reduced susceptibility. More judicious use of appropriate antimicrobials is warranted. Efforts to prevent illness through provision of clean water, improved hygiene, and vaccine development should be strengthened.


The IGF1 Receptor Is Involved in Follicle-Stimulating Hormone Signaling in Porcine Neonatal Sertoli Cells.
Experimental evidence has shown that the IGF1 receptor (IGF1R) is involved in testicular development during embryogenesis. More recently, data gathered from mice granulosa cells and zebrafish spermatogonia suggest that IGF1R has a role in Follicle-stimulating hormone (FSH) signaling. No evidence has been reported on this matter in Sertoli cells (SCs) so far. The aim of the study was to evaluate the role, if any, of the IGF1R in FSH signaling in SCs. The effects of FSH exposure on myosin-phosphatase 1 (MYPT1), ERK 1/2, AKT308, AKT473, c-Jun N-terminal kinase (JNK) phosphorylation and on anti-Müllerian hormone (AMH), inhibin B and FSH receptor (FSHR) mRNA levels were assessed with and without the IGF1R inhibitor NVP-AEW541 in purified and functional porcine neonatal SCs. Pre-treatment with NVP-AEW541 inhibited the FSH-induced MYPT1 and ERK 1/2 phosphorylation, decreased the FSH-dependent Protein kinase B (AKT)308 phosphorylation, but did not affect the FSH-induced AKT473 and JNK phosphorylation rate. It also interfered with the FSH-induced AMH and FSHR down-regulation. No influence was observed on the FSH-stimulated Inhibin B gene expression. Conclusion. These findings support the role of theIGF1R in FSH signaling in porcine SCs. The possible influence of IGF1 stimulation on the FSH-mediated effects on SCs should be further explored.


Management of cystic diseases of the pancreas.
Pancreatic cysts are challenging to the gastroenterologist. Detection rate is increasing and neither criteria for a definitive diagnosis, nor a validated surveillance strategy is available. Pancreatic endosonography with or without sampling is necessary in most of the cases. However this technique requires expertise and is not widely available. While some cysts have a malignant potential or already malign at the diagnosis, most are benign and remain so for decades. We are going to review the existing data on this controversial subject.


Affective norms of 875 Spanish words for five discrete emotional categories and two emotional dimensions.
In the present study, we introduce affective norms for a new set of Spanish words, the Madrid Affective Database for Spanish (MADS), that were scored on two emotional dimensions (valence and arousal) and on five discrete emotional categories (happiness, anger, sadness, fear, and disgust), as well as on concreteness, by 660 Spanish native speakers. Measures of several objective psycholinguistic variables--grammatical class, word frequency, number of letters, and number of syllables--for the words are also included. We observed high split-half reliabilities for every emotional variable and a strong quadratic relationship between valence and arousal. Additional analyses revealed several associations between the affective dimensions and discrete emotions, as well as with some psycholinguistic variables. This new corpus complements and extends prior databases in Spanish and allows for designing new experiments investigating the influence of affective content in language processing under both dimensional and discrete theoretical conceptions of emotion. These norms can be downloaded as supplemental materials for this article from www.dropbox.com/s/o6dpw3irk6utfhy/Hinojosa%20et%20al_Supplementary%20materials.xlsx?dl=0 .