The impact of expertise on brain computer interface based salient image retrieval.
Autonomous decision making modules in computer vision application allow recognition and classification of different objects, persons, and events in images and video sequences and also make it possible to classify different sensor readings (e.g. images) according to their scientific saliencies. In this paper, we propose a new approach to create the training set for these algorithms by retrieving salient images using electroencephalogram (EEG) and brain computer interface (BCI) and rapid image presentation. To this end, two groups of subjects, namely, expert and novice subjects were asked to participate in our experiments. We show that a relatively high retrieval accuracy can be achieved for most of the subjects. Furthermore, to assess the impact of expertise on the retrieval process, we study their EEG signals separately and show that there is a clear difference in their brainwaves while observing salient images.


Fetal trans-apical stent delivery into the pulmonary artery: prospects for prenatal heart-valve implantation.
The purpose of this study was to assess the technical feasibility of a fetal trans-apical stent delivery into the pulmonary artery using a novel hybrid-intervention technique as a possible route for prenatal minimally invasive heart-valve-implantation approaches. Pregnant Pre-Alp sheep between 122 and 128 days' gestation (n = 3) underwent a midline laparotomy. The fetus was left in utero or partially externalized and its chest was opened via a left-sided minithoracotomy. The fetal heart was cannulated and a guide wire was introduced through the ductus arteriosus into the aorta. A 14-French delivery system was then mounted onto the guide wire and advanced to the landing zone in the pulmonary artery, where the stent was deployed. The position of the stent was confirmed using echocardiography, angiography as well as computed tomography. The trans-apical implantation was successful in all animals. However, at necropsy in one animal, the stent was found to partly occlude one of the pulmonary valvular leaflets. Bleeding at the antero-apical incision occurred in all animals but could be managed without fetal demise. No fetal cardiopulmonary bypass was performed. In all animals, contrast angiography displayed normal perfusion of the pulmonary vasculature as well as the ductus arteriosus. Our study demonstrates the principal technical feasibility of a prenatal stent delivery into the pulmonary artery using a novel trans-apical hybrid-intervention technique. This approach demonstrates the first step towards possible future minimally invasive prenatal heart-valve-implantation procedures.


The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory.
The anaphase promoting complex (APC) or cyclosome is a multisubunit E3 ubiquitin ligase. Cdc20 (fizzy (fzy)) or p55CDC, and Cdh1 (Hct1, srw1 or fizzy-related 1 (fzr1)) encode two adaptor proteins that bring substrates to the APC. Both APC-Cdc20 and APC-Cdh1 have been implicated in the control of mitosis through mediating ubiquitination of mitotic regulators, such as cyclin B1 and securin. However, the importance of Cdh1 function in vivo and whether its function is redundant with that of Cdc20 are unclear. Here we have analysed mice lacking Cdh1. We show that Cdh1 is essential for placental development and that its deficiency causes early lethality. Cdhl-deficient mouse embryonic fibroblasts (MEFs) entered replicative senescence prematurely because of stabilization of Ets2 and subsequent activation of p6(Ink4a) expression. These results have uncovered an unexpected role of the APC in maintaining replicative lifespan of MEFs. Further, Cdh1 heterozygous mice show defects in late-phase long-term potentiation (L-LTP) in the hippocampus and are deficient in contextual fear-conditioning, suggesting that Cdh1 has a role in learning and memory.


Estimation of cadmium load from soybeans and soy-based foods for vegetarians.
Soybeans, as legumes, belong among food items that contribute most to the dietary intake of the heavy metal cadmium (Cd). The consumption of soy-based foods may contribute significantly to Cd intake in vegetarians as probably the most frequent consumers of these foods. In this research, the weekly dietary intake of Cd from soy-based foods was investigated in 119 participants (including vegetarians, vegans, and non-vegetarians) in the Czech Republic by means of a semi-quantitative food frequency questionnaire (SFFQ) with personal assistance and the measurement of body weight. Cd content in soy-based foods available on the market was determined by means of atomic absorption spectrometry after microwave digestion. Tofu, as the most frequently consumed food item in the vegetarian/vegan group, contributed most to the total dietary Cd intake. It contained 7.6 ± 0.1 μg Cd/kg, while the highest Cd content was observed in tempeh (18.1 ± 0.4 μg/kg). The highest mean dietary Cd intake per week from soy-based foods was 0.4 μg/kg b.w. and was found in the vegan group. The consumption of soy-based foods was the lowest in the non-vegetarian group as was the dietary intake of Cd, which was 0.04 μg/kg b.w. per week.


Plasma and brain angiotensin concentrations associated with water response behavior in the desert anuran, Scaphiopus couchii under natural conditions in the field.
Terrestrial amphibians obtain water by absorption across a specialized region of the ventral skin and exhibit a behavior, the water absorption response (WR) to place that region in contact with moist surfaces. Spadefoot toads (Scaphiopus couchii) spend dry months of the year in burrows, then emerge during brief periods of summer rainfall and seek water sources for rehydration and reproduction. We tested the hypothesis that these toads have changes in plasma and/or central angiotensin concentrations that are associated with seasonal emergence and WR behavior. Immunoreactive concentrations of combined angiotensin II and III (ir-ANG) were measured in plasma samples and microdissected regions of brain tissue taken from toads moving across the road or toads showing WR behavior in shallow puddles on the road. Plasma ir-ANG concentrations were not significantly different between these groups, but were significantly higher in the periventricular region of the hypothalamus in toads showing WR behavior. Concentrations in other brain regions, while highly variable among individuals, were not different between groups. Within the context of the natural history of a specialized desert toad, these results support the hypothesis that ir-ANG is associated with WR behavior in spadefoot toads in a manner analogous to oral drinking exhibited by other vertebrate clades.


Relative Association of Multi-Level Supportive Environments on Poor Health among Older Adults.
Background: The aging of the United States population poses significant challenges to American healthcare and informal caregiving systems. Additional research is needed to understand how health promotion programs and policies based on a socio-ecological perspective impact the health and well-being of older persons. The purpose of this study was to investigate personal characteristics and supportive environments associated with poor health among older individuals aged 65 and over. Methods: This study used a cross-sectional design and was guided by a conceptual framework developed by the authors to depict the relationship between personal characteristics and environments associated with poor health status. Environment types included in this study were family, home, financial, neighborhood, and healthcare. The sample was comprised of 1319 adults aged 65 years and older residing in Central Texas. From a random selection of households, participants were administered a mail-based survey created by a community collaborative effort. Descriptive statistics and three binary logistic regression models were fitted to examine associations with poor health status (i.e., physical, mental, and combined physical/mental). Results: Two personal characteristics (number of chronic conditions and educational level) were consistently related (p < 0.05) to health outcomes. Supportive family, home, financial, neighborhood, and health care environmental factors were shown to be related (p < 0.05) to various aspects of physical or mental health outcomes. Conclusions: Multidimensional factors including personal characteristics and protective environments are related to health status among older individuals. The unique roles of each environment can help inform public health interventions to create and enhance support for older adults to engage in healthful activities and improve their physical and mental health.


Audiovisual informed consent process in vaccine trials: Experience from North India.
Audiovisual (AV) recording of the informed consent process in a clinical or vaccine trial to document the consent process of participants (especially from vulnerable populations), ensures preservation of their rights and well-being. This paper describes the AV consent process during a phase III rotavirus vaccine trial among healthy infants in Chandigarh and examines its effects. Out of 155 parents/guardians of participating infants who were contacted to be a part of the study, 50 were reluctant to participate in the study trial (not necessarily in the AV consenting process). Among 105 parents/guardians of participating infants who expressed initial willingness to participate in the trial, all agreed to undergo the AV consenting process; and 100 finally consented to participate and were enrolled in the study. So, the participation rate was 64.5% (100/155) among those who were contacted, and 95.2% (100/105) among those who underwent AV consenting process. AV recordings of these 100 patient representatives were transcribed and later translated into English for a thematic analysis of the text. A total of 105 queries were raised by 55 participants. All queries were patiently listened to and addressed, allaying most fears, especially those related to adverse events following intervention. The AV process ensured transparency and accountability of the investigators, responsive referral mechanism in case of adverse events, building an initial rapport with the participant, complete vaccination of the trial subjects, and provision for free private care consultation depending upon the willingness of the parents. These benefits of the AV consent process might have led to a higher participation rate.


Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop.
This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.


Effect of empirical versus definitive antimicrobial selection on postoperative complications in dogs and cats undergoing total ear canal ablation with lateral bulla osteotomy: 120 cases (2009-2019).
To evaluate dogs and cats undergoing total ear canal ablation with lateral bulla osteotomy (TECA-LBO), document antimicrobial choices, and determine relationships associated with infection-related and neurologic postoperative complications. 107 client-owned dogs and 13 client-owned cats that underwent TECA-LBO. A retrospective analysis of medicals records of dogs and cats with TECA-LBO from 2 veterinary hospitals with postoperative data for at least 6 months was performed. All information associated with the TECA-LBO surgery including follow-up was recorded. Logistic regression analyses were performed and corrected using a false discovery rate to identify significance between antimicrobial administration and other perioperative variables and the outcomes of short- and long-term neurologic and infection-related complications, need for revision surgery, and euthanasia due to recurrence of infection-related signs. Intraoperative cultures were performed in 111 animals, and 95 (85.5%) had bacterial growth, with Staphylococcus spp most commonly isolated. Revision surgeries due to infection-related signs occurred in 13 of 120 (10.8%) patients. If intraoperative bacterial cultures were positive and antimicrobials were administered within 1 month of surgery, patients were 85.8% less likely to exhibit infection-related complications, whereas patients not administered antimicrobials were 10.3 times as likely to require a revision surgery. Longer durations of postoperative antimicrobial administration were associated with revision surgery and euthanasia due to infection-related signs. Administration of systemic antimicrobials within the first postoperative month may be necessary to prevent complications when intraoperative cultures exhibit bacterial growth and plays a role in the successful outcome of TECA-LBO.


Pre- and postsynaptic properties of glutamatergic transmission in the immature inhibitory MNTB-LSO pathway.
The lateral superior olive (LSO) integrates excitatory inputs driven by sound arriving at the ipsilateral ear with inhibitory inputs driven by sound arriving at the contralateral ear in order to compute interaural intensity differences needed for localizing high-frequency sound sources. Specific mechanisms necessary for developmental refinement of the inhibitory projection, which arises from the medial nucleus of the trapezoid body (MNTB), have only been partially deciphered. The demonstration that immature MNTB-LSO synapses release glutamate has led to a model in which early glutamate neurotransmission plays a major role in inhibitory plasticity. We used whole cell electrophysiology in acute auditory brain stem slices of neonatal rats to examine glutamatergic transmission in the developing MNTB-LSO pathway. Unexpectedly, AMPA receptor (AMPAR)-mediated responses were prevalent at the earliest ages. We found a salient developmental profile for NMDA receptor (NMDAR) activation, described both by the proportion of total glutamate current and by current durations, and we found evidence for distinct release probabilities for GABA/glycine and glutamate in the MNTB-LSO pathway. The developmental profile of NMDAR is consistent with the possibility that the inhibitory MNTB-LSO pathway experiences a sensitive period, driven by cochlear activity and mediated by GluN2B-containing NMDARs, between postnatal days 3 and 9. Differing neurotransmitter release probabilities could allow the synapse to switch between GABA/glycinergic transmission and mixed glutamate/GABA/glycinergic transmission in response to changing patterns of spiking activity.


Laparoscopic appendectomy for acute appendicitis: Is this a feasible option for developing countries?
The role of laparoscopic appendectomy is still not well defined in the literature. This study was conducted to evaluate the feasibility of laparoscopic appendectomy at a university hospital in a developing country. Patients undergoing laparoscopic appendectomy (LA) from August 2002 to August 2006 were identified. For each case, a control was selected from patients undergoing open appendectomy (OA) during the same year by systematic sampling. The groups were compared in terms of duration of surgery, requirement of narcotic analgesia, length of hospital stay, postoperative complications and the overall cost for each patient. A total of 68 patients underwent laparoscopic appendectomy during the study period. Median duration of surgery was 82 minutes in LA group and 70 minutes in OA group (P < 0.001). Forty-five patients in LA group and 64 in OA group required narcotic analgesia (P 0.001). Median length of hospital stay (P = 0.672) and postoperative complications (P = 0.779) were comparable in both groups. Median cost of hospital stay was Pakistani Rupees (PKR) 47121/in LA group and PKR 39318/in OA group, the difference being significant (P = 0.001). Laparoscopic appendectomy is feasible in developing countries with similar postoperative outcome and less requirement of narcotic analgesia. The duration of surgery and overall cost were significantly higher and efforts should be made to develop expertise and reduce operative time with resultant decrease in cost. Development of standardized protocols for discharge of patients from the hospital after LA may further reduce the cost and benefit patients in developing countries.


Mechanical load on the ventilatory muscles during an incremental cycle ergometer test.
An incremental cycle ergometer test performed with a total of 40 healthy subjects (25 male, 15 female) was used to study the mechanical load on the ventilatory muscles. The parameters for the mechanical load on the ventilatory muscles are the time integral of the oesophageal pressure and the mean oesophageal pressure change per time unit (dPoe/dTI) of each breathing manoeuvre. The pressure-time integral is the area delimited by the oesophageal pressure trace and the inspiratory time axis. It is expressed as a fraction of the product of the subject's maximum oesophageal pressure (Poe(max)) and total breath cycle duration (TTOT). This parameter is called oesophageal tension time index (TTIoe). The relationship between minute ventilation and these two parameters during ergometer test showed gender-specific variations because of the differences between men and women as to anthropometric data, lung function parameters and maximum ventilatory muscle strength. Moreover, the dPoe/dTI values significantly depend on the breathing frequency. The present study has provided evidence that, in general, the TTIoe and dPoe/dTI values in terms of a specific minute ventilation (VE) are higher in women than in men. Parameters for the mechanical load on the ventilatory muscles regarding the level of pressure to be generated as well as the duration and velocity of muscle contraction should therefore also allow for the gender of the patients.


Online Mendelian Inheritance in Man (OMIM) as a knowledgebase for human developmental disorders.
In this review, we summarize the current genetic information on human developmental disorders found in Online Mendelian Inheritance in Man (OMIM). The OMIM catalogues human phenotypes and genotypes and relevant mouse models. Among the more than 11005 genetic disorders and loci, we found at least 1231 human conditions with known gene mutationsffWe searched for human developmental disorders that present with structural defects during the perinatal period, and identified 162 such entries. We classified these entries by phenotypic features (e.g., skeletal dysplasias, axis and laterality defects, or eye disorders) and by the type of gene mutated (e.g., genes coding for transcription factors, structural proteins, enzymes, or receptors). Thirty-eight entries have allelic variants with gene mutations causing different functional consequences, thereby altering their interactions with modifying genes. Thirty-two entries show genetic heterogeneity due to either functional redundancy of more than one gene or genes that interact in common developmental pathways. Although many different types of genes are mutated in developmental disorders, we found that the disease genes are transcription factors in 49 entries. Mouse models are available for many of the human conditions, with the majority of these mutants being secondary to null mutations. These data allow us to begin to elucidate the complex developmental pathways involved in the molecular pathogenesis of human malformations.


Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy.
Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.


Importance of magnesium depletion with hypofunction of the biological clock in the pathophysiology of headhaches with photophobia, sudden infant death and some clinical forms of multiple sclerosis.
Mg depletion is a type of Mg deficit due to a dysregulation of the Mg status. It cannot be corrected through nutritional supplementation only, but requires the most specific correction of the dysregulating mechanism. Among those, Biological Clock (BC) dysrhythmias are to be considered. The aim of this study is to analyze the clinical forms of Mg depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary with homeostatic response [reactive Photophobia (Pphi] to light neurostimulating effects [Nervous Hyper Excitability (NHE)]. The symptomatology is mainly diurnal and observed during fair weather (Spring,Summer). The elective marker of hBC is represented by a decrease in melatonin and in its metabolites in various fluids. The clinical forms of NHE due to Mg depletion with hBC are central and peripheral. The central forms associate anxiety, headaches and dyssomnia. The peripheral manifestations are neuromuscular: photosensitive epilepsia mainly. Three chronopathological forms of Mg depletion with hBC have been highlighted: 1. Headaches with Pphi: mainly migraine; 2. Sudden Infant Death Syndrome (SIDS); 3. Multiple Sclerosis (MS).- Headaches with Pphi, migraine particularly. These cephalalgias are diurnal with Pphi and are aggravated during the fair seasons (particularly during midnight sun-summer). Migraine is their typical form with its dishabituation to visual stimuli and its occipital cortex hyperexcitability. Comorbidity with anxiety is frequent. In 2/3 of the cases, it appears first.- SIDS might be linked to an impaired maturation of both photoendocrine system and brown adipose tissue. MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons. They have been underestimated because they disagree with the dogma of the << latitude gradient >>, presently questioned. Comorbidities with anxiety and migraine are frequent.hBC may be treated by using darkness therapy with a balanced Mg status. Absolute light deprivation should only be used only in acute indications and is time-limited. Partial substitutive therapy and chromatotherapy have not been validated yet and are still uncertain.


Peptide microarray-based identification of Mycobacterium tuberculosis epitope binding to HLA-DRB1*0101, DRB1*1501, and DRB1*0401.
A more effective vaccine against Mycobacterium tuberculosis is needed, and a number of M. tuberculosis vaccine candidates are currently in preclinical or clinical phase I and II studies. One of the strategies to select M. tuberculosis (protein) targets to elicit a CD8(+) or CD4(+) T-cell response is to gauge the binding of candidate peptides to major histocompatibility complex (MHC) class I or class II molecules, a prerequisite for successful peptide presentation and to expand antigen-specific T cells. We scanned 61 proteins from the M. tuberculosis proteome for potential MHC class II-presented epitopes that could serve as targets for CD4(+) T-cell responses. We constructed a peptide microarray consisting of 7,466 unique peptides derived from 61 M. tuberculosis proteins. The peptides were 15-mers overlapping by 12 amino acids. Soluble recombinant DRB1*0101 (DR1), DRB1*1501 (DR2), and DRB1*0401 (DR4) monomers were used to gauge binding to individual peptide species. Out of 7,466 peptides, 1,282, 674, and 1,854 peptides formed stable complexes with HLA-DR1, -DR2, and -DR4, respectively. Five hundred forty-four peptides bound to all three MHC class II molecules, 609 bound to only two, and 756 bound to only a single MHC class II molecule. This allowed us to rank M. tuberculosis proteins by epitope density. M. tuberculosis proteins contained "hot spots," i.e., regions with enriched MHC class II binding epitopes. Two hundred twenty-two peptides that formed MHC class II-peptide complexes had previously been described as exclusively recognized by IgG in sera from patients with active pulmonary tuberculosis, but not in sera from healthy individuals, suggesting that these peptides serve as B-cell and CD4(+) T-cell epitopes. This work helps to identify not only M. tuberculosis peptides with immunogenic potential, but also the most immunogenic proteins. This information is useful for vaccine design and the development of future tools to explore immune responses to M. tuberculosis.


Structural dissection and high-throughput screening of mannosylglycerate synthase.
The enzymatic transfer of activated mannose yields mannosides in glycoconjugates and oligo- and polysaccharides. Yet, despite its biological necessity, the mechanism by which glycosyltransferases recognize mannose and catalyze its transfer to acceptor molecules is poorly understood. Here, we report broad high-throughput screening and kinetic analyses of both natural and synthetic substrates of Rhodothermus marinus mannosylglycerate synthase (MGS), which catalyzes the formation of the stress protectant 2-O-alpha-D-mannosyl glycerate. The sequence of MGS indicates that it is at the cusp of inverting and retaining transferases. The structures of apo MGS and complexes with donor and acceptor molecules, including GDP-mannose, combined with mutagenesis of the binding and catalytic sites, unveil the mannosyl transfer center. Nucleotide specificity is as important in GDP-D-mannose recognition as the nature of the donor sugar.


Redox balance is key to explaining full vs. partial switching to low-yield metabolism.
Low-yield metabolism is a puzzling phenomenon in many unicellular and multicellular organisms. In abundance of glucose, many cells use a highly wasteful fermentation pathway despite the availability of a high-yield pathway, producing many ATP molecules per glucose, e.g., oxidative phosphorylation. Some of these organisms, including the lactic acid bacterium Lactococcus lactis, downregulate their high-yield pathway in favor of the low-yield pathway. Other organisms, including Escherichia coli do not reduce the flux through the high-yield pathway, employing the low-yield pathway in parallel with a fully active high-yield pathway. For what reasons do some species use the high-yield and low-yield pathways concurrently and what makes others downregulate the high-yield pathway? A classic rationale for metabolic fermentation is overflow metabolism. Because the throughput of metabolic pathways is limited, influx of glucose exceeding the pathway's throughput capacity is thought to be redirected into an alternative, low-yield pathway. This overflow metabolism rationale suggests that cells would only use fermentation once the high-yield pathway runs at maximum rate, but it cannot explain why cells would decrease the flux through the high-yield pathway. Using flux balance analysis with molecular crowding (FBAwMC), a recent extension to flux balance analysis (FBA) that assumes that the total flux through the metabolic network is limited, we investigate the differences between Saccharomyces cerevisiae and L. lactis that downregulate the high-yield pathway at increasing glucose concentrations, and E. coli, which keeps the high-yield pathway functioning at maximal rate. FBAwMC correctly predicts the metabolic switching mode in these three organisms, suggesting that metabolic network architecture is responsible for differences in metabolic switching mode. Based on our analysis, we expect gradual, "overflow-like" switching behavior in organisms that have an additional energy-yielding pathway that does not consume NADH (e.g., acetate production in E. coli). Flux decrease through the high-yield pathway is expected in organisms in which the high-yield and low-yield pathways compete for NADH. In support of this analysis, a simplified model of metabolic switching suggests that the extra energy generated during acetate production produces an additional optimal growth mode that smoothens the metabolic switch in E. coli. Maintaining redox balance is key to explaining why some microbes decrease the flux through the high-yield pathway, while other microbes use "overflow-like" low-yield metabolism.


Evidence that glucagon acts on the liver to decrease mitochondrial calcium stores.
1. Mitochondria isolated from rats treated with glucagon for 60 min or lives perfused in the presence of glucagon for 10 min exhibited lower rates of 45Ca2+ exchange than did control mitochondria when this was measured under steady-state conditions in the presence of Mg2+, ATP, Pi and 0.13 microM- or 0.16 microM-free Ca2+ at pH 7.4 and at 25 degrees C or 37 degrees C. Under these conditions no significant difference in the rates of Ruthenium Red-induced 45Ca2+ efflux was observed. These results contrast with earlier work in which mitochondria isolated from glucagon-treated livers were shown to exhibit faster rates of Ca2+ uptake [Yamazaki (1975) J. Biol. Chem. 250, 7924-7930] and slower rates of spontaneous Ca2+ efflux [Hughes & Barritt (1978) Biochem. J. 176, 295-304] when these parameters were measured under different incubation conditions, including supra-physiological concentrations of free Ca2+ and the absence of added Mg2+ and ATP. 2. Perfusion of livers with glucagon before the addition of adrenaline or the Ca2+-selective ionophore A23187, to release Ca2+ from intracellular stores, decreased the amount of Ca2+ released by these agents. 3. Incubation of isolated hepatocytes in the presence of glucagon at 1.3 mM extracellular Ca2+ induced a small decrease in the plateau of the 45Ca2+-exchange curve obtained under steady-state conditions. 4. It is concluded that the actions of glucagon on liver mitochondrial Ca2+ transporters lead to a decrease, rather than an increase, in mitochondrial Ca2+ stores in the intact cell.


Hexagonal class representation for fingerprinting and facile comparison of petroleomic samples.
Because of the high complexity of petroleomic-type samples, there is a need for efficient ways of visualizing and interpreting the resulting data in mass spectrometry-based petroleomics. Over the years, several graphing approaches have become widespread, yet they mostly deal with a particular subset of compounds detected within a given sample. Here, we present an alternative and complementary sample visualization method, the hexagonal class representation, based on relative abundance vs compound classes plot. The representation can be used to "fingerprint" a petroleomic-type sample, provide a simple means of sample comparison, as well as allow for a fast overview and detection of any compound of interest based on its elemental composition and chemical properties.


A review of co-morbidity between infectious and chronic disease in Sub Saharan Africa: TB and diabetes mellitus, HIV and metabolic syndrome, and the impact of globalization.
Africa is facing a rapidly growing chronic non-communicable disease burden whilst at the same time experiencing continual high rates of infectious disease. It is well known that some infections increase the risk of certain chronic diseases and the converse. With an increasing dual burden of disease in Sub Saharan Africa the associations between diseases and our understanding of them will become of increased public health importance. In this review we explore the relationships reported between tuberculosis and diabetes mellitus, human immunodeficiency virus, its treatment and metabolic risk. We aimed to address the important issues surrounding these associations within a Sub Saharan African setting and to describe the impact of globalization upon them. Diabetes has been associated with a 3-fold incident risk of tuberculosis and it is hypothesised that tuberculosis may also increase the risk of developing diabetes. During co-morbid presentation of tuberculosis and diabetes both tuberculosis and diabetes outcomes are reported to worsen. Antiretroviral therapy for HIV has been associated with an increased risk of developing metabolic syndrome and HIV has been linked with an increased risk of developing both diabetes and cardiovascular disease. Globalization is clearly related to an increased risk of diabetes and cardiovascular disease. It may be exerting other negative and positive impacts upon infectious and chronic non-communicable disease associations but at present reporting upon these is sparse. The impact of these co-morbidities in Sub Saharan Africa is likely to be large. An increasing prevalence of diabetes may hinder efforts at tuberculosis control, increasing the number of susceptible individuals in populations where tuberculosis is endemic, and making successful treatment harder. Roll out of anti-retroviral treatment coverage within Sub Saharan Africa is an essential response to the HIV epidemic however it is likely to lead to a growing number of individuals suffering adverse metabolic consequences. One of the impacts of globalization is to create environments that increase both diabetes and cardiovascular risk but further work is needed to elucidate other potential impacts. Research is also needed to develop effective approaches to reducing the frequency and health impact of the co-morbidities described here.


Impact of intrauterine tobacco exposure on fetal telomere length.
We sought to investigate whether maternal smoking during pregnancy affects telomere length of the fetus. Pregnant women were recruited on hospital admission at delivery. A self-report questionnaire and salivary cotinine test were used to confirm tobacco exposure. Neonatal umbilical cord blood samples were collected, and genomic DNA was isolated from cord blood leukocytes and was analyzed for fetal telomere length based on quantitative polymerase chain reaction. A ratio of relative telomere length was determined by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare the telomere length of active, passive, and nonsmokers. Bootstrap and analysis of variance statistical methods were used to evaluate the relationship between prenatal smoking status and fetal telomere length. Of the 86 women who were included in this study, approximately 69.8% of the participants were covered by Medicaid, and 55.8% of the participants were black or Hispanic. The overall mean T/S ratio was 0.8608 ± 1.0442. We noted an inverse relationship between smoking and fetal telomere length in a dose-response pattern (T/S ratio of nonsmokers that was more than passive smokers that was more than active smokers). Telomere length was significantly different for each pairwise comparison, and the greatest difference was between active and nonsmokers. Our results provide the first evidence to demonstrate a positive association between shortened fetal telomere length and smoking during pregnancy. Our findings suggest the possibility of early intrauterine programming for accelerated aging that is the result of tobacco exposure.


The effects of a home-based exercise program on physical function in frail older adults.
Exercise has been shown to improve physical function in frail older adults; however, the effects of exercise may vary with degree of frailty, the format and intensity of the exercise intervention, and level of supervision. This cohort study describes the effects of participation in a 6-week home-based exercise program on measures of physical function as well as exercise-related beliefs, including exercise self-efficacy and outcomes expectation, in frail older adults. Participants were 72 frail older adults who participated in a 6-week home-based exercise program supervised by graduate physical therapy students. Individualized home-based exercises targeted strength, flexibility, balance, gait, and cardiovascular fitness. Physical function was measured at baseline and after completion of the 6-week exercise program using the Functional Fitness Test (Biceps Curl, Chair Stand, 8-Foot Up and Go) and velocity on a 4-m walk. Measures of exercise-related beliefs included the Self-Rated Abilities for Health Practices Scale and Exercise Outcome Expectations. Participation in the 6-week home-based exercise program was associated with improvements in measures of physical function, including an average increase of 3 repetitions (35%) on the biceps curl, 2.4 repetitions (59%) on the chair stand, and an average increase of 0.17 m/s (33%) in gait velocity. Average decrease in Timed Up and Go test scores was 5.7 seconds (26%). Scores for exercise-related beliefs also improved (self-efficacy average increase was 7 points [40%], and average increase in outcome expectations was 3 [47%]). A supervised 6-week, multidimensional home-based exercise program was safe and associated with improvements in physical and exercise-related belief outcome measures in this cohort study of frail older adults.


Measurement of urinary cauxin in geriatric cats with variable plasma creatinine concentrations and proteinuria and evaluation of urine cauxin-to-creatinine concentration ratio as a predictor of developing azotemia.
To evaluate urine cauxin immunoreactivity in geriatric cats with variable plasma creatinine concentrations and proteinuria and to assess urinary cauxin-to-creatinine concentration ratio (UC/C) as a predictor of developing azotemia. 188 client-owned geriatric (>or= 9 years of age) cats. A direct immunoassay was developed and validated for the quantification of urinary cauxin relative to a standard curve generated from a urine sample with high cauxin immunoreactivity. Relationships among UC/C, plasma creatinine concentration, and proteinuria were assessed. Nonazotemic cats were recruited and followed for 12 months. Urinary cauxin-to-creatinine concentration ratio was evaluated as a predictor of development of azotemia in these cats. No relationship was evident between UC/C and plasma creatinine concentration. A weak positive correlation was identified between UC/C and urine protein-to-creatinine concentration ratio (r = 0.212). At entry to the longitudinal study, those cats that later developed azotemia had a UC/C that was significantly higher than in those remaining nonazotemic after 12 months. The UC/C did not vary with severity of azotemia but appeared contributory to the feline urinary proteome. High UC/C values were predictive of the geriatric cats in our study developing azotemia. However, it seems unlikely that UC/C will provide additional information about the measurement of urine protein-to-creatinine concentration ratio as a biomarker for the development of azotemia in cats.


Vitamin E analogues: a new class of inducers of apoptosis with selective anti-cancer effects.
In spite of unrelenting effort, the net incidence of neoplastic diseases appears not to have been curbed. While some types of cancer have been suppressed significantly, others are either stagnating or on the increase. Therefore, the need for a cure is imperative, in particularly a drug or combination of drugs that would be selective for malignant cells, i.e. with as low secondary toxicity as possible. Recent data strongly suggest that analogues of vitamin E, epitomised by the most studied alpha-tocopheryl succinate (alpha-TOS), may meet the need for the coveted drugs with a selective anti-neoplastic effect. The reasons for this optimism are reviewed in this article.


Carotid surgery versus medical therapy in asymptomatic carotid stenosis. The CASANOVA Study Group.
The CASANOVA study (Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin) is a multicenter trial in 410 patients with asymptomatic stenosis (50-90%) of the internal carotid artery who were randomized after angiography. In group A, 206 patients with unilateral and bilateral stenosis had surgery unilaterally or bilaterally, respectively. In group B, 160 patients with unilateral stenosis had no initial surgery, whereas those with bilateral stenosis had surgery on the more affected side. Patients were operated on during the 3-year follow-up period if one of the following events occurred: development of a stenosis exceeding 90%; development of a bilateral internal carotid artery stenosis greater than 50% (operation on the more affected side); transient ischemic attack in the region supplied by the internal carotid artery, together with a stenosis of this artery greater than 50%; development of an internal carotid stenosis greater than 50% contralateral to the operated side or restenosis greater than 50% in group A. All patients were treated with 330 mg acetylsalicylic acid and 75 mg dipyridamole three times daily. The minimal follow-up was 3 years. End points were ischemic neurologic deficit exceeding 24 hours or death due to surgery or stroke. Altogether, 334 carotid endarterectomies were performed. Complications of angiography and operation (6.9%) were included. Statistical analysis found no significant difference in the number of neurologic deficits and deaths between the two groups. Carotid endarterectomy for asymptomatic patients with a stenosis of the internal carotid artery of less than 90% is not recommended at this time except as part of a controlled clinical trial. However, cases of higher grade stenosis (greater than 90%) were excluded from this study and were referred for operation. No conclusion can be rendered regarding the potential benefit of endarterectomy in these higher risk categories.


Serologic prevalence of amoeba-associated microorganisms in intensive care unit pneumonia patients.
Patients admitted to intensive care units are frequently exposed to pathogenic microorganisms present in their environment. Exposure to these microbes may lead to the development of hospital-acquired infections that complicate the illness and may be fatal. Amoeba-associated microorganisms (AAMs) are frequently isolated from hospital water networks and are reported to be associated to cases of community and hospital-acquired pneumonia. We used a multiplexed immunofluorescence assay to test for the presence of antibodies against AAMs in sera of intensive care unit (ICU) pneumonia patients and compared to patients at the admission to the ICU (controls). Our results show that some AAMs may be more frequently detected in patients who had hospital-acquired pneumonia than in controls, whereas other AAMs are ubiquitously detected. However, ICU patients seem to exhibit increasing immune response to AAMs when the ICU stay is prolonged. Moreover, concomitant antibodies responses against seven different microorganisms (5 Rhizobiales, Balneatrix alpica, and Mimivirus) were observed in the serum of patients that had a prolonged ICU stay. Our work partially confirms the results of previous studies, which show that ICU patients would be exposed to water amoeba-associated microorganisms, and provides information about the magnitude of AAM infection in ICU patients, especially patients that have a prolonged ICU stay. However, the incidence of this exposure on the development of pneumonia remains to assess.


Silent mutations in the phenylalanine hydroxylase gene as an aid to the diagnosis of phenylketonuria.
Direct sequencing of the phenylalanine hydroxylase (PAH) gene indicated the existence of silent mutations in codons 232, 245, and 385, linked to specific RFLP haplotypes in several Caucasian populations, namely Germans, Bulgarians, Italians, Turks, and Lithuanians. All three mutations create a new restriction site and can be easily detected on PCR amplified DNA. The usefulness of the silent mutations for diagnostic purposes depends on the haplotype distribution in the target population. The combined analysis of these markers and one or two PKU mutations forms a simple panel of diagnostic tests with full informativeness in a large proportion of PKU families, which helps to avoid the problems of genetic heterogeneity and of prenatal genomic Southern blot analysis.


Gaps in COPD Guidelines of Low- and Middle-Income Countries: A Systematic Scoping Review.
Guidelines are critical for facilitating cost-effective COPD care. Development and implementation in low-and middle-income countries (LMICs) is challenging. To guide future strategy, an overview of current global COPD guidelines is required. We systematically reviewed national COPD guidelines, focusing on worldwide availability and identification of potential development, content, context, and quality gaps that may hamper effective implementation. Scoping review of national COPD management guidelines. We assessed: (1) global guideline coverage; (2) guideline information (authors, target audience, dissemination plans); (3) content (prevention, diagnosis, treatments); (4) ethical, legal, and socio-economic aspects; and (5) compliance with the eight Institute of Medicine (IOM) guideline standards. LMICs guidelines were compared with those from high-income countries (HICs). Of the 61 national COPD guidelines identified, 30 were from LMICs. Guidelines did not cover 1.93 billion (30.2%) people living in LMICs, whereas only 0.02 billion (1.9%) in HICs were without national guidelines. Compared with HICs, LMIC guidelines targeted fewer health-care professional groups and less often addressed case finding and co-morbidities. More than 90% of all guidelines included smoking cessation advice. Air pollution reduction strategies were less frequently mentioned in both LMICs (47%) and HICs (42%). LMIC guidelines fulfilled on average 3.37 (42%) of IOM standards, compared with 5.29 (66%) in HICs (P < .05). LMICs scored significantly lower compared with HICs regarding conflicts of interest management, updates, articulation of recommendations, and funding transparency (all, P < .05). Several development, content, context, and quality gaps exist in COPD guidelines from LMICs that may hamper effective implementation. Overall, COPD guidelines in LMICs should be more widely available and should be transparently developed and updated. Guidelines may be further enhanced by better inclusion of local risk factors, case findings, and co-morbidity management, preferably tailored to available financial and staff resources.


[Organizational socialization in the first three years of nursing profession: strategies to decrease turnover intention].
In the first years of nursing profession, new-graduate nurses' turnover intention is a relevant issue due to both the tangible and intangible costs it generates to health care organizations, such as selection and recruitment costs, ward team burden in the onboarding process and the possibility to enhance ward team stability in order to provide an effective and safe nusing care. Organizational socialization is the main factor involved in these dynamics of turnover intention in the first years of nursing profession. This study aims to identify the main factors involved in the organizational socialization process to reduce turnover intention in the first 3 years of nursing profession. 101 new-graduate nurses have been enrolled within the first three years of nursing profession. They have been stratified looking at tenure and years in nursing. Organizational Socialization Inventory scale has been used to assess the onboarding process and 4 items to assess turnover intention. Turnover intention is of 23% in the first year in nursing, and it's over the 26% starting from the second year. The onboarding process explains over the 26% of the variance in turnover intention, and over the 36% in the sub-sample with a stable tenure. Unstable tenured nurses prefer to acquire those competences useful to perform their work, while stable tenure nurses aim to search for professional growth opportunities and integration in the ward-team, in order to reduce turnover intention. Turnover intention is relevant in the first three years of nursing profession. According to the different tenure, different strategies are necessary to plan an effective onboarding process and enhance nursing retention.


Petroleum ether extract of Cissus quadrangularis (Linn.) enhances bone marrow mesenchymal stem cell proliferation and facilitates osteoblastogenesis.
To evaluate the effects of the petroleum ether extract of Cissus quadrangularis on the proliferation rate of bone marrow mesenchymal stem cells, the differentiation of marrow mesenchymal stem cells into osteoblasts (osteoblastogenesis) and extracellular matrix calcification. This study also aimed to determine the additive effect of osteogenic media and Cissus quadrangularis on proliferation, differentiation and calcification. MSCs were cultured in media with or without Cissus quadrangularis for 4 weeks and were then stained for alkaline phosphatase. Extracellular matrix calcification was confirmed by Von Kossa staining. marrow mesenchymal stem cells cultures in control media and osteogenic media supplemented with Cissus quadrangularis extract (100, 200, 300 microg/mL) were also subjected to a cell proliferation assay (MTT). Treatment with 100, 200 or 300 microg/mL petroleum ether extract of Cissus quadrangularis enhanced the differentiation of marrow mesenchymal stem cells into ALP-positive osteoblasts and increased extracellular matrix calcification. Treatment with 300 microg/mL petroleum ether extract of Cissus quadrangularis also enhanced the proliferation rate of the marrow mesenchymal stem cells. Cells grown in osteogenic media containing Cissus quadrangularis exhibited higher proliferation, differentiation and calcification rates than did control cells. The results suggest that Cissus quadrangularis stimulates osteoblastogenesis and can be used as preventive/ alternative natural medicine for bone diseases such as osteoporosis.


Comparison of the antimicrobial activity of Ulmo honey from Chile and Manuka honey against methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.
Honey has previously been shown to have wound healing and antimicrobial properties, but this is dependent on the type of honey, geographical location and flower from which the final product is derived. We tested the antimicrobial activity of a Chilean honey made by Apis mellifera (honeybee) originating from the Ulmo tree (Eucryphia cordifolia), against selected strains of bacteria. Ulmo 90 honey was compared with manuka UMF 25+ (Comvita) honey and a laboratory synthesised (artificial) honey. An agar well diffusion assay and a 96 well minimum inhibitory concentration (MIC) spectrophotometric-based assay were used to assess antimicrobial activity against five strains of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa. Initial screening with the agar diffusion assay demonstrated that Ulmo 90 honey had greater antibacterial activity against all MRSA isolates tested than manuka honey and similar activity against E. coli and P. aeruginosa. The MIC assay, showed that a lower MIC was observed with Ulmo 90 honey (3.1% - 6.3% v/v) than with manuka honey (12.5% v/v) for all five MRSA isolates. For the E. coli and Pseudomonas strains equivalent MICs were observed (12.5% v/v). The MIC for artificial honey was 50% v/v. The minimum bactericidal concentration for all isolates tested for Ulmo 90 honey was identical to the MIC. Unlike manuka honey, Ulmo 90 honey activity is largely due to hydrogen peroxide production. Due to its high antimicrobial activity, Ulmo 90 may warrant further investigation as a possible alternative therapy for wound healing.


Iron-sulfur world in aerobic and hyperthermoacidophilic archaea Sulfolobus.
The general importance of the Fe-S cluster prosthetic groups in biology is primarily attributable to specific features of iron and sulfur chemistry, and the assembly and interplay of the Fe-S cluster core with the surrounding protein is the key to in-depth understanding of the underlying mechanisms. In the aerobic and thermoacidophilic archaea, zinc-containing ferredoxin is abundant in the cytoplasm, functioning as a key electron carrier, and many Fe-S enzymes are produced to participate in the central metabolic and energetic pathways. De novo formation of intracellular Fe-S clusters does not occur spontaneously but most likely requires the operation of a SufBCD complex of the SUF machinery, which is the only Fe-S cluster biosynthesis system conserved in these archaea. In this paper, a brief introduction to the buildup and maintenance of the intracellular Fe-S world in aerobic and hyperthermoacidophilic crenarchaeotes, mainly Sulfolobus, is given in the biochemical, genetic, and evolutionary context.


Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats.
Locus coeruleus neurons in brain slices prepared from neonatal rats have rhythmic oscillations in membrane potential at frequencies ranging from 0.3 to 3 Hz. Recordings from pairs of neurons separated by 50-300 microns showed that this oscillatory activity was synchronized at ages less than 24 d. Slices cut from rats 24-27 d old showed rhythmic activity which was only partially synchronous between cell pairs, but full synchrony could be restored by superfusion with tetraethylammonium (2 mM) and/or barium (2 mM). No synchronous rhythmic activity was observed between neurons in slices from rats 40 d old, even in the presence of tetraethylammonium and barium. In those cells in which rhythmic potential oscillations were synchronous, action potentials occurring in one cell were not observed in the second cell. Electrotonic coupling was directly demonstrated between 41% of neurons (12 of 29 pairs) in slices from rats less than 10 d old but not in tissue from older rats (4 pairs). The input resistance of neurons from neonatal rats (less than 15 d old) was about half (81 M omega) that measured under identical conditions from neurons from adult rats (213 M omega). The electrotonic potential in cells from rats less than 15 d old was best fit by a double exponential, whereas that from adults was best fit by a single exponential. The results demonstrate that significant electrical coupling occurs among locus coeruleus neurons from neonatal rats; this appears to decline with age. The coupling serves as a low-pass filter and causes the synchronized occurrence of membrane potential oscillations. Such a rhythmic background activity within the entire nucleus may be important for the widespread trophic role of the noradrenergic neurons during development.


Molecularly imprinted solid phase extraction of fluconazole from pharmaceutical formulations.
This work encompasses a direct and coherent strategy to synthesise a molecularly imprinted polymer (MIP) capable of extracting fluconazole from its sample. The MIP was successfully prepared from methacrylic acid (functional monomer), ethyleneglycoldimethacrylate (crosslinker) and acetonitrile (porogenic solvent) in the presence of fluconazole as the template molecule through a non-covalent approach. The non-imprinted polymer (NIP) was prepared following the same synthetic scheme, but in the absence of the template. The data obtained from scanning electronic microscopy, infrared spectroscopy, thermogravimetric and nitrogen Brunauer-Emmett-Teller plot helped to elucidate the structural as well as the morphological characteristics of the MIP and NIP. The application of MIP as a sorbent was demonstrated by packing it in solid phase extraction cartridges to extract fluconazole from commercial capsule samples through an offline analytical procedure. The quantification of fluconazole was accomplished through UPLC-MS, which resulted in LOD≤1.63×10(-10) mM. Furthermore, a high percentage recovery of 91±10% (n=9) was obtained. The ability of the MIP for selective recognition of fluconazole was evaluated by comparison with the structural analogues, miconazole, tioconazole and secnidazole, resulting in percentage recoveries of 51, 35 and 32%, respectively.


Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice.
Purpose Guidelines generally do not recommend oral antimicrobials for prophylaxis against chemotherapy-related infections in patients with solid tumors. Evidence on antimicrobial prophylaxis use, and associated chemotherapy-related infection risk, in US clinical practice is limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. Study population included adults who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for non-Hodgkin's lymphoma. For each subject, the first chemotherapy course was characterized, and within the first course, each chemotherapy cycle and chemotherapy-related infection episode was identified. Use of prophylaxis with oral antimicrobials and colony-stimulating factors in each cycle also was identified. Results A total of 7116 (22% of all) non-metastatic breast cancer, 1833 (15%) non-metastatic colorectal cancer, 1999 (15%) non-metastatic lung cancer, and 1949 (21%) non-Hodgkin's lymphoma patients received antimicrobial prophylaxis in ≥1 cycle. Mean number of antimicrobial prophylaxis cycles during the course among these patients was typically <2, with little difference across cancers and chemotherapy regimens. Fluoroquinolones were the most commonly received class of antimicrobials, accounting for 20%-50% all antimicrobials administered. Among subjects who received first-cycle antimicrobial prophylaxis, chemotherapy-related infection risk in that cycle ranged from 3% to 6% across cancer types. Among patients who received first-cycle antimicrobial prophylaxis and developed chemotherapy-related infections, 38%-67% required inpatient care. Chemotherapy-related infection risk in subsequent cycles with antimicrobial prophylaxis was comparable. Conclusion The results of this study suggest that use of antimicrobial prophylaxis during myelosuppressive chemotherapy is far from uncommon in clinical practice. The results also suggest that an important minority of cancer chemotherapy patients receiving antimicrobial prophylaxis still develop serious infection requiring hospitalization.


Teesside coronary survey: an epidemiological study of acute attacks of myocardial infarction.
A 12-month epidemiological survey of attacks of acute myocardial infarction was carried out in a large urban population. The incidence and mortality at all ages and in both sexes were examined. Altogether, 1938 attacks were diagnosed--an overall incidence of 4-89 per 1000 population. The 28-day fatality rate was 50-5%. A third of the patients were treated at home and these patients had a lower fatality rate than those in hospital, a difference that could not be attributed to age, sex, or severity of attack. Half of the deaths that were witnessed occurred suddenly and a further 21% occurred within the next two hours. The median time to patients coming under care was about three hours. As used at present, coronary care units are unlikely to improve fatality rates. Future advances in treatment must take place outside hospital and will require re-education of the public and the general practitioner.


Aspartate-27 and glutamate-473 are involved in catalysis by Zymomonas mobilis pyruvate decarboxylase.
Zymomonas mobilis pyruvate decarboxylase (EC 126.96.36.199) was subjected to site-directed mutagenesis at two acidic residues near the thiamin diphosphate cofactor in the active site. Asp-27 was changed to Glu or Asn, and Glu-473 was mutated to Asp (E473D) or Gln (E473Q). Each mutant protein was purified to near-homogeneity, and the kinetic and cofactor-binding properties were compared with those of the wild-type protein. Despite the very conservative nature of these alterations, all mutants had a very low, but measurable, specific activity ranging from 0.025% (E473Q) to 0.173% (E473D) of the wild type. With the exception of E473Q, the mutants showed small decreases in the affinity for thiamin diphosphate, and binding of the second cofactor (Mg2+) was also weakened somewhat. With E473Q, both cofactors seemed to be very tightly bound so that they were not removed by the treatment that was effective for the wild-type enzyme and other mutant forms. All mutants showed minor changes in the Km for substrate, but these alterations did not account for the low activities. These low specific activities, accompanied by little change in the Km for pyruvate, are consistent with a quantitative model of the catalytic cycle in which the main effect of the mutations is to slow the decarboxylation step with a minor change in the rate constant for pyruvate binding.


A New ELISA Using the ANANAS Technology Showing High Sensitivity to diagnose the Bovine Rhinotracheitis from Individual Sera to Pooled Milk.
Diagnostic tests for veterinary surveillance programs should be efficient, easy to use and, possibly, economical. In this context, classic Enzyme linked ImmunoSorbent Assay (ELISA) remains the most common analytical platform employed for serological analyses. The analysis of pooled samples instead of individual ones is a common procedure that permits to certify, with one single test, entire herds as "disease-free". However, diagnostic tests for pooled samples need to be particularly sensitive, especially when the levels of disease markers are low, as in the case of anti-BoHV1 antibodies in milk as markers of Infectious Bovine Rhinotracheitis (IBR) disease. The avidin-nucleic-acid-nanoassembly (ANANAS) is a novel kind of signal amplification platform for immunodiagnostics based on colloidal poly-avidin nanoparticles that, using model analytes, was shown to strongly increase ELISA test performance as compared to monomeric avidin. Here, for the first time, we applied the ANANAS reagent integration in a real diagnostic context. The monoclonal 1G10 anti-bovine IgG1 antibody was biotinylated and integrated with the ANANAS reagents for indirect IBR diagnosis from pooled milk mimicking tank samples from herds with IBR prevalence between 1 to 8%. The sensitivity and specificity of the ANANAS integrated method was compared to that of a classic test based on the same 1G10 antibody directly linked to horseradish peroxidase, and a commercial IDEXX kit recently introduced in the market. ANANAS integration increased by 5-fold the sensitivity of the 1G10 mAb-based conventional ELISA without loosing specificity. When compared to the commercial kit, the 1G10-ANANAS integrated method was capable to detect the presence of anti-BHV1 antibodies from bulk milk of gE antibody positive animals with 2-fold higher sensitivity and similar specificity. The results demonstrate the potentials of this new amplification technology, which permits improving current classic ELISA sensitivity limits without the need for new hardware investments.


Regulation of the insulin-Akt signaling pathway and glycolysis during dehydration stress in the African clawed frog Xenopus laevis.
Estivation is an adaptive stress response utilized by some amphibians during periods of drought in the summer season. In this study, we examine the regulation of the insulin signaling cascade and glycolysis pathway in the African clawed frog Xenopus laevis during the dehydration stress induced state of estivation. We show that in the brain and heart of X. laevis, dehydration reduces the phosphorylation of the insulin growth factor-1 receptor (IGF-1R), and this is followed by similar reductions in the phosphorylation of the Akt and mechanistic target of rapamycin (mTOR) kinase. Interestingly, phosphorylation levels of IGF-1R and mTOR were not affected in the kidney, and phosphorylation levels of P70S6K and the ribosomal S6 protein were elevated during dehydration stress. Animals under estivation are also susceptible to periods of hypoxia, suggesting that glycolysis may also be affected. We observed that protein levels of many glycolytic enzymes remained unchanged during dehydration; however, the hypoxia response factor-1 alpha (HIF-1α) protein was elevated by greater than twofold in the heart during dehydration. Overall, we provide evidence that shows that the insulin signaling pathway in X. laevis is regulated in a tissue-specific manner during dehydration stress and suggests an important role for this signaling cascade in mediating the estivation response.


An on-chip microfluidic pressure regulator that facilitates reproducible loading of cells and hydrogels into microphysiological system platforms.
Coculturing multiple cell types together in 3-dimensional (3D) cultures better mimics the in vivo microphysiological environment, and has become widely adopted in recent years with the development of organ-on-chip systems. However, a bottleneck in set-up of these devices arises as a result of the delivery of the gel into the microfluidic chip being sensitive to pressure fluctuations, making gel confinement at a specific region challenging, especially when manual operation is performed. In this paper, we present a novel design of an on-chip regulator module with pressure-releasing safety microvalves that can facilitate stable gel delivery into designated microchannel regions while maintaining well-controlled, non-bursting gel interfaces. This pressure regulator design can be integrated into different microfluidic chip designs and is compatible with a wide variety of gel injection apparatuses operated automatically or manually at different flow rates. The sensitivity and working range of this pressure regulator can be adjusted by changing the width of its pressure releasing safety microvalve design. The effectiveness of the design is validated by its incorporation into a microfluidic platform we have developed for generating 3D vascularized micro-organs (VMOs). Reproducible gel loading is demonstrated for both an automatic syringe pump and a manually-operated micropipettor. This design allows for rapid and reproducible loading of hydrogels into microfluidic devices without the risk of bursting gel-air interfaces.


Rac1 mediates the osteoclast gains-in-function induced by haploinsufficiency of Nf1.
Neurofibromatosis type I (NF1) is a congenital disorder resulting from loss-of-function of the tumor suppressor gene, NF1, a GTPase-activating protein for p21ras. Fifty percent of NF1 patients have osseous manifestations including a high incidence of osteoporosis. Osteoclasts are specialized macrophage/monocyte lineage-derived cells that resorb bone and NF1 haploinsufficient osteoclasts have abnormal Ras-dependent bone resorption. Ras-regulated functions are in part mediated via the activation of small Rho family of GTPases including the Rac-GTPases. In the present study, we demonstrate that the Rho-GTPase Rac1 is a crucial Ras-mediated effector in Nf1 haploinsufficient (+/-) osteoclasts. Nf1+/- mice were intercrossed with conditional Rac1(flox/flox)Mxcre+ (Rac1-/-) mice to generate Nf1+/-; Rac1-/- mice. Genetic disruption of Rac1 restored the pathological increase in osteoclast progenitor cells in Nf1+/- mice and was sufficient to correct the increased Nf1+/- osteoclast motility and osteoclast belt formation, an f-actin structure observed in mature osteoclasts critical for bone resorption and lytic activity. Finally, we demonstrate that Nf1+/-; Rac1-/- osteoclasts have normalized Erk activation compared with Nf1+/- osteoclasts, a biochemical function critical for osteoclast formation, actin organization and motility. Collectively, these data demonstrate that Rac1 critically contributes to increased osteoclast function induced by haploinsufficiency of Nf1 and implicate Rac1 as a rational therapeutic target for osteoporosis.


Hyperbaric Oxygen Sensitizes Anoxic Pseudomonas aeruginosa Biofilm to Ciprofloxacin.
Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm, which is subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes. The exact mechanisms affecting the antibiotic susceptibility of biofilms remain unclear, but accumulating evidence suggests that the efficacy of several bactericidal antibiotics is enhanced by stimulation of aerobic respiration of pathogens, while lack of O2 increases their tolerance. In fact, the bactericidal effect of several antibiotics depends on active aerobic metabolism activity and the endogenous formation of reactive O2 radicals (ROS). In this study, we aimed to apply hyperbaric oxygen treatment (HBOT) to sensitize anoxic P. aeruginosa agarose biofilms established to mimic situations with intense O2 consumption by the host response in the cystic fibrosis (CF) lung. Application of HBOT resulted in enhanced bactericidal activity of ciprofloxacin at clinically relevant durations and was accompanied by indications of restored aerobic respiration, involvement of endogenous lethal oxidative stress, and increased bacterial growth. The findings highlight that oxygenation by HBOT improves the bactericidal activity of ciprofloxacin on P. aeruginosa biofilm and suggest that bacterial biofilms are sensitized to antibiotics by supplying hyperbaric O2.


Role of Choline in the Modulation of Degenerative Processes: In Vivo and In Vitro Studies.
The purpose of the present study was to examine the nutraceutical potential of choline as an added value to its well-known brain nutrient role. Several toxicity, antitoxicity, genotoxicity, antigenotoxicity, and longevity endpoints were checked in the somatic mutation and recombination test in in vivo Drosophila animal model. Cytotoxicity in human leukemia-60 cell line (HL-60) promyelocytic and NIH3T3 mouse fibroblast cells, proapoptotic DNA fragmentation, comet assay, methylation status, and macroautophagy (MA) activity were tested in in vitro assays. Choline is not only safe but it is also able to protect against the DNA damage caused by an oxidative genotoxin. Moreover, it improves the life extension in the animal model. The in vitro results show that it is able to exhibit genetic damage against leukemia HL-60 cells. Single-strand breaks in DNA are observed at the molecular level in treatments with choline, although only a significant hypermethylation on the long interspersed elements-1 and a hypomethylation on the satellite-alpha DNA repetitive DNA sequences of HL-60 cells at the lowest concentration (0.447 mM) were observed. Besides, choline decreased MA at the lower assayed concentration and the MA response to topoisomerase inhibitor (etoposide) is maintained in the presence of treatment with 0.22 mM choline. Taking into account the hopeful results obtained in the in vivo and in vitro assays, choline could be proposed as a substance with an important nutraceutical value for different purposes.


PDZK1: I. a major scaffolder in brush borders of proximal tubular cells.
In proximal tubular cells, PDZK1 (NaPi-Cap1) has been implicated in apical expression of the Na+-dependent phosphate cotransporter (NaPi-IIa) via interaction with its C-terminus. PDZK1 represents a multidomain protein consisting of four PDZ domains and thus is believed to have a broader specificity besides NaPi-IIa. We subjected single PDZ domains derived from PDZK1 either to yeast two-hybrid screens or yeast trap assays. Different pull-down assays and blot overlays were applied to corroborate the PDZK1-mediated interactions in vitro. Co-localization of interacting proteins with PDZK1 in proximal tubular cells was assessed by immunohistochemistry. In the yeast screens, the most abundant candidate protein to interact with PDZK1 was the membrane-associated protein of 17 kD (MAP17). Besides MAP17, C-terminal parts of following transporters were also identified: NaPi-IIa, solute carrier SLC17A1 (NaPi-I), Na+/H+ exchanger (NHE-3), organic cation transporter (OCTN1), chloride-formate exchanger (CFEX), and urate-anion exchanger (URAT1). In addition, other regulatory factors were found among the clones, such as a protein kinase A (PKA)-anchoring protein (D-AKAP2) and N+/H+ exchanger regulator factor (NHERF-1). All interactions of itemized proteins with PDZK1 were affirmed by in vitro techniques. Apart from PDZK1, strong in vitro interactions of NHERF-1 were also observed with the solute transporters (excluding MAP17) and D-AKAP2. All identified proteins were immunolocalized in proximal tubular cells, wherein all membrane proteins co-localized with PDZK1 in brush borders. We hypothesize that PDZK1 and NHERF-1 establish an extended network beneath the apical membrane to which membrane proteins and regulatory components are anchored.


Perceptions of legislation relating to the sharing of genomic biobank results with donors-a survey of BBMRI-ERIC biobanks.
Biobanks accumulate huge amounts of research findings, including participants' genomic data. Increasingly this leads to biobanks receiving research results that could be of clinical significance to biobank participants. The EU Horizon 2020 Project 'Genetics Clinic of the Future' surveyed European biobanks' perceptions of the legal and regulatory requirements for communicating individual research results to donors. The goal was to gain background knowledge for possible future guidelines, especially relating to the consent process. The Survey was implemented using a web-based Webropol tool. The questionnaire was sent at the end of 2015 to 351 European biobanks in 13 countries that are members of BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium). Seventy-two biobanks responded to the survey, representing each of the 13 BBMRI Member States. Respondents were mainly individuals responsible for the governance of biobanks. The replies indicate that the majority of the respondents thought that their national legislation allowed them to contact participants to communicate results, and that research participants had the right to request their results. However, respondents' understanding of their national legislation varied even within member states. Our results indicate that legislation applied to biobanks in many countries may be scattered and difficult to interpret. In BBMRI-ERIC, there is an ongoing discussion about the need for European recommendations on sharing genomic biobank results with donors, which may pave the way for more coherent global guidelines. Our results form a basis for this work.


Inhibition of the renin-angiotensin-aldosterone system: is there room for dual blockade in the cardiorenal continuum?
Antagonism of renin-angiotensin-aldosterone system is exerted through angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, renin inhibitors and mineralocorticoid receptor antagonists. These drugs have been successfully tested in numerous trials and in different clinical settings. The original indications of renin-angiotensin-aldosterone system blockers have progressively expanded from the advanced stages to the earlier stages of cardiorenal continuum. To optimize the degree of blockade of renin-angiotensin-aldosterone system, dose uptitrations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists or the use of a dual blockade, initially identified with the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, have been proposed. The data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study do not support this specific dual blockade approach. However, the dual blockade of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists with direct renin inhibitors is currently under investigation while that based on an aldosterone blocker with any of the previous three drugs requires more evidence beyond heart failure. In this review, we revisited potential advantages of dual blockade of renin-angiotensin-aldosterone system in arterial hypertension and diabetes.


Medical methods for mid-trimester termination of pregnancy.
With the improvement of ultrasound technology, the likelihood of detection of major fetal structural anomalies in mid-pregnancy has increased considerably. Upon the detection of serious anomalies, women typically are offered the option of pregnancy termination. Additionally, there are still many reasons other than fetal anomalies why women seek abortion in the mid-trimester. To compare different methods of second trimester medical termination of pregnancy for their efficacy and side-effects. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, Popline and reference lists of retrieved papers and other sources. All randomised controlled trials (RCTs) examining medical regimens for termination of pregnancy of a singleton living fetus between 12-28 weeks' gestation were analysed. The outcome measures were the induction to abortion interval, abortion rate within 24 hours, need for surgical evacuation, blood loss, uterine rupture, pain, and side-effects.Trials including >20% fetal death, multiple pregnancies, previous uterine scars and regimens which involved cervical preparation were excluded. Two authors selected the trials and three authors extracted data. Fourty RCTs were included, addressing various agents for pregnancy termination and methods of administration. When used alone, misoprostol was an effective inductive agent, though it appeared to be more effective in combination with mifepristone. However, the evidence from RCTs is limited.Misoprostol was preferably administered vaginally, although among multiparous women sublingual administration appeared equally effective. A range of doses of vaginally administered misoprostol has been used. No randomised trials comparing doses of misoprostol were identified; however low doses of misoprostol appear to be associated with fewer side-effects while moderate doses appear to be more efficient in completing abortion. Four RCTs showed that the induction to abortion interval with 3-hourly vaginal administration of prostaglandins is shorter than 6-hourly administration without an increase in side-effects.Many studies reported the need for surgical evacuation. Indications for surgical evacuation include retained products of the placenta and heavy vaginal bleeding. Fewer women required surgical evacuation when misoprostol was administrated vaginally compared with women receiving intra-amniotical PGF(2a) . Mild, self-limiting diarrhoea was more common among women who received misoprostol compared to other agents. Medical abortion in the second trimester using the combination of mifepristone and misoprostol appeared to have the highest efficacy and shortest abortion time interval. Where mifepristone is not available, misoprostol alone is a reasonable alternative. The optimal route for administering misoprostol is vaginally, preferably using tablets at 3-hourly intervals. Apart from pain, the side-effects of vaginal misoprostol are usually mild and self limiting. Conclusions from this review are limited by the gestational age ranges and variable medical regimens, including dosing, administrative routes and intervals of medication, of the included trials.


The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.
We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.


What do we get for our money? Cost-effectiveness of adding contingency management.
To assess the relative cost-effectiveness of lower versus higher cost prize-based contingency management (CM) treatments for cocaine abuse. Cost-effectiveness analyses based on resource utilization, unit costs and outcomes from a previous CM efficacy trial. Two community-based treatment centers. Patients (n = 120) enrolled in out-patient treatment for cocaine abuse. Random assignment to one of three 12-week treatment conditions: standard treatment (STD) alone or two variants of STD combined with prize based CM. In CM, drawing for prizes was available to those submitting drug-free urine samples and completing goal-related activities. There were two levels of pay-out (referred to as $80 versus $240) based on the potential value of prizes won. Costs per participant associated with counseling utilization, urine and breathalyzer testing, and operation of the prize-drawing procedure were derived from a survey conducted at 16 clinics that had participated in CM studies. The three measures of effectiveness were: (1) longest duration of consecutive abstinence; (2) percentage completing treatment; and (3) percentage of samples drug-free. The higher magnitude CM produced outcomes at a lower per unit cost than did the lower magnitude prize CM treatment. This was the case for all three outcome measures examined and held across various assumptions in the sensitivity analysis. Cost-effectiveness analyses can inform policy decisions regarding selection of one treatment model over another. Decisions on adoption of new evidence-based treatments would be aided by more information on society's willingness to pay for incremental gains in effectiveness.


Non-biological methods for phosphorus and nitrogen removal from wastewater: A gap analysis of reinvented-toilet technologies with respect to ISO 30500.
The aims of the Reinvent the Toilet Challenge (RTTC) include creation of an off-the-grid sanitation system with operating costs of less than US$0.05 per user per day. Because of the small scale at which many reinvented toilets (RT) are intended to operate, non-biological treatment has been generally favored. The RTTC has already instigated notable technological advances in non-sewered sanitation systems (NSSS). However, increasingly stringent liquid effluent standards for N and P could limit the deployment of current RT in real-world scenarios, despite the urgent need for these systems. The newly adopted ISO 30500 standards for water reuse in NSSS dictate minimal use of chemical/biological additives, while at the same time requiring a 70% and 80% reduction in total nitrogen and phosphorus, respectively. This document provides a brief overview of the mature and emerging technologies for N and P (specifically ammonia/ammonium and orthophosphate) removal from wastewater. At present, the dearth of nutrient removal methods proven to be effective at small scales is a significant barrier to meeting ISO 30500 standards. Closing the gap between RTs and ISO 30500 will require significant investments in basic R&D of emerging technologies for non-biological N and P remediation and/or increased reliance on biological processes. Adaptation of existing nutrient-removal technologies to small-scale NSSS is a viable option that merits additional investigation.


Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis.
Dietary consumption of food supplements has been found to modulate skin functions and can therefore be useful in the treatment of skin aging. However, there is only a limited number of clinical studies supporting these claims. In this double-blind, placebo-controlled study, the effectiveness of the specific bioactive collagen peptide (BCP) VERISOL® on eye wrinkle formation and stimulation of procollagen I, elastin and fibrillin biosynthesis in the skin was assessed. A hundred and fourteen women aged 45-65 years were randomized to receive 2.5 g of BCP or placebo, once daily for 8 weeks, with 57 subjects being allocated to each treatment group. Skin wrinkles were objectively measured in all subjects, before starting the treatment, after 4 and 8 weeks as well as 4 weeks after the last intake (4-week regression phase). A subgroup was established for suction blister biopsies analyzing procollagen I, elastin and fibrillin at the beginning of the treatment and after 8 weeks of intake. The ingestion of the specific BCP used in this study promoted a statistically significant reduction of eye wrinkle volume (p < 0.05) in comparison to the placebo group after 4 and 8 weeks (20%) of intake. Moreover a positive long-lasting effect was observed 4 weeks after the last BCP administration (p < 0.05). Additionally, after 8 weeks of intake a statistically significantly higher content of procollagen type I (65%) and elastin (18%) in the BCP-treated volunteers compared to the placebo-treated patients was detected. For fibrillin, a 6% increase could be determined after BCP treatment compared to the placebo, but this effect failed to reach the level of statistical significance. In conclusion, our findings demonstrate that the oral intake of specific bioactive collagen peptides (Verisol®) reduced skin wrinkles and had positive effects on dermal matrix synthesis.


Error reduction and performance improvement in the emergency department through formal teamwork training: evaluation results of the MedTeams project.
To evaluate the effectiveness of training and institutionalizing teamwork behaviors, drawn from aviation crew resource management (CRM) programs, on emergency department (ED) staff organized into caregiver teams. Nine teaching and community hospital EDs. A prospective multicenter evaluation using a quasi-experimental, untreated control group design with one pretest and two posttests of the Emergency Team Coordination Course (ETCC). The experimental group, comprised of 684 physicians, nurses, and technicians, received the ETCC and implemented formal teamwork structures and processes. Assessments occurred prior to training, and at intervals of four and eight months after training. Three outcome constructs were evaluated: team behavior, ED performance, and attitudes and opinions. Trained observers rated ED staff team behaviors and made observations of clinical errors, a measure of ED performance. Staff and patients in the EDs completed surveys measuring attitudes and opinions. Hospital EDs were the units of analysis for the seven outcome measures. Prior to aggregating data at the hospital level, scale properties of surveys and event-related observations were evaluated at the respondent or case level. A statistically significant improvement in quality of team behaviors was shown between the experimental and control groups following training (p = .012). Subjective workload was not affected by the intervention (p = .668). The clinical error rate significantly decreased from 30.9 percent to 4.4 percent in the experimental group (p = .039). In the experimental group, the ED staffs' attitudes toward teamwork increased (p = .047) and staff assessments of institutional support showed a significant increase (p = .040). Our findings point to the effectiveness of formal teamwork training for improving team behaviors, reducing errors, and improving staff attitudes among the ETCC-trained hospitals.


Beta-adrenergic mechanism of insulin-induced adrenocorticotropin release from the anterior pituitary.
Intraperitoneal administration of insulin to control rats and to rats with pituitary stalk transections or with lesions of the median eminence resulted in increased plasma adrenocorticotropin (ACTH) levels. The insulin-induced stimulation of ACTH release was blocked in both the control and lesioned animals by prior treatment with either the beta-adrenergic antagonist propranolol or the glucocorticoid analog dexamethasone. The direct application of insulin to primary cultures of the anterior pituitary did not evoke ACTH release or affect the maximal ability of corticotropin-releasing factor or epinephrine to stimulate ACTH secretion. The results suggest that insulin stimulates ACTH release by a mechanism in which catecholamines of peripheral origin act directly on the anterior pituitary.


Spatially distinct functions of Clb2 in the DNA damage response.
In budding yeast four mitotic cyclins (Clb1-4) cooperate in a partially redundant manner to bring about M-phase specific events, including the apical isotropic switch that ends polarized bud growth initiated at bud emergence. How exactly this morphogenetic transition is regulated by mitotic CDKs remains poorly understood. We have taken advantage of the isotropic bud growth that prevails in cells responding to DNA damage to unravel the contribution of mitotic cyclins in this cellular context. We find that clb2∆, in contrast to the other mitotic cyclin mutants, inappropriately respond to the presence of DNA damage. This aberrant response is characterized by a Cdc42- and Bni1-dependent but Cln-independent resumption of polarized bud growth after a brief period of actin depolarization. Biochemical and genetic evidence is presented that formally excludes the possibility of indirect effects due for instance to unrestrained APC activity, untimely mitotic exit or Swe1-mediated CDK inhibition. Importantly, our data demonstrate that in order to maintain the characteristic dumbbell arrest phenotype upon checkpoint activation Clb2 needs to be efficiently exported into the cytoplasm. We propose that the inhibition of mitotic cyclin destruction by the DNA damage checkpoint pathway leads to a buildup of Clb2 in the cytoplasm where this cyclin can stabilize the apical isotropic switch throughout a G 2/M checkpoint arrest. Our study also unveils an essential role of nuclear Clb2 in both survival and adaptation to the DNA damage checkpoint, illustrating a spatially distinct dual function of this mitotic cyclin in the response to DNA damage.


Training and competence assessment in GI endoscopy: a systematic review.
Training procedural skills in GI endoscopy once focused on threshold numbers. As threshold numbers poorly reflect individual competence, the focus gradually shifts towards a more individual approach. Tools to assess and document individual learning progress are being developed and incorporated in dedicated training curricula. However, there is a lack of consensus and training guidelines differ worldwide, which reflects uncertainties on optimal set-up of a training programme. The primary aim of this systematic review was to evaluate the currently available literature for the use of training and assessment methods in GI endoscopy. Second, we aimed to identify the role of simulator-based training as well as the value of continuous competence assessment in patient-based training. Third, we aimed to propose a structured training curriculum based on the presented evidence. A literature search was carried out in the available medical and educational literature databases. The results were systematically reviewed and studies were included using a predefined protocol with independent assessment by two reviewers and a final consensus round. The literature search yielded 5846 studies. Ninety-four relevant studies on simulators, assessment methods, learning curves and training programmes for GI endoscopy met the inclusion criteria. Twenty-seven studies on simulator validation were included. Good validity was demonstrated for four simulators. Twenty-three studies reported on simulator training and learning curves, including 17 randomised control trials. Increased performance on a virtual reality (VR) simulator was shown in all studies. Improved performance in patient-based assessment was demonstrated in 14 studies. Four studies reported on the use of simulators for assessment of competence levels. Current simulators lack the discriminative power to determine competence levels in patient-based endoscopy. Eight out of 14 studies on colonoscopy, endoscopic retrograde cholangiopancreatography and endosonography reported on learning curves in patient-based endoscopy and proved the value of this approach for measuring performance. Ten studies explored the numbers needed to gain competence, but the proposed thresholds varied widely between them. Five out of nine studies describing the development and evaluation of assessment tools for GI endoscopy provided insight into the performance of endoscopists. Five out of seven studies proved that intense training programmes result in good performance. The use of validated VR simulators in the early training setting accelerates the learning of practical skills. Learning curves are valuable for the continuous assessment of performance and are more relevant than threshold numbers. Future research will strengthen these conclusions by evaluating simulation-based as well as patient-based training in GI endoscopy. A complete curriculum with the assessment of competence throughout training needs to be developed for all GI endoscopy procedures.


Strengthening Health Systems for Chronic Care: Leveraging HIV Programs to Support Diabetes Services in Ethiopia and Swaziland.
The scale-up of HIV services in sub-Saharan Africa has catalyzed the development of highly effective chronic care systems. The strategies, systems, and tools developed to support life-long HIV care and treatment are locally owned contextually appropriate resources, many of which could be adapted to support continuity care for noncommunicable chronic diseases (NCD), such as diabetes mellitus (DM). We conducted two proof-of-concept studies to further the understanding of the status of NCD programs and the feasibility and effectiveness of adapting HIV program-related tools and systems for patients with DM. In Swaziland, a rapid assessment illustrated gaps in the approaches used to support DM services at 15 health facilities, despite the existence of chronic care systems at HIV clinics in the same hospitals, health centers, and clinics. In Ethiopia, a pilot study found similar gaps in DM services at baseline and illustrated the potential to rapidly improve the quality of care and treatment for DM by adapting HIV-specific policies, systems, and tools.