Spontaneous and radiation-induced genomic instability in human cell lines differing in cellular TP53 status.
Structural chromosomal rearrangements are commonly observed in tumor karyotypes and in radiation-induced genomic instability. Here we report the effects of TP53 deficiency on karyotypic stability before and after irradiation using related cells and clones differing in cellular TP53 status. The parental cell line, TK6, is a TP53 wild-type human B-lymphoblastoid line with a highly stable karyotype. In the two TK6 derivatives used here, TP53 has been inactivated by biochemical means (expression of HPV16 E6; TK6-5E) or genetic means (allelic inactivation; NH32). Biochemical inactivation of TP53 (TK6-5E) had little effect on the spontaneous karyotype, whereas allelic inactivation of TP53 (NH32) resulted in a modest increase in spontaneous karyotypic instability. After 2 Gy gamma irradiation, the number of unstable clones derived from TP53-deficient cells was significantly elevated compared to the TP53 wild-type counterpart. Extensively destabilized clones were common after irradiation in the set of clones derived from NH32 cells, and one was observed in the set of TK6-5E clones; however, they were never observed in TK6-derived clones. In two of the irradiated NH32 clones, whole chromosomes or chromosome bands were preferentially involved in alterations. These results suggest that genomic instability may differ both quantitatively and qualitatively as a consequence of altered TP53 expression. Some of the results showing repeated and preferential chromosome involvement in aberrations support a model in which instability may be driven by cis mechanisms.


Understanding the structural and dynamic consequences of DNA epigenetic modifications: computational insights into cytosine methylation and hydroxymethylation.
We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.


Situating Nutri-Ethics at the Junction of Nutrigenomics and Nutriproteomics in Postgenomics Medicine.
Food has societal, economic, medical and ethical implications, being fundamental for life. It plays an important role also in sports medicine, since a healthy diet is an important part of an athlete's training. Nutrigenomics and nutriproteomics are emerging as a result of a convergence of nutritional, genomics and proteomics knowledge strands in the postgenomics era. These fields of inquiry present an opportunity for the design of customized diets potentially able to counterbalance the extant obesity epidemic and remedy metabolic diseases, among others. They are noteworthy for sport medicine as well since they could provide athletes with crucial information for personalized training and nutrition, in order to achieve the best results possible and express one's own potential. But they could also be used as a form of personalized doping, thus constituting an advancement of "classical nutrition-based doping" (i.e., the use of nutraceuticals, stimulants and supplements). However, nutrigenomics (or nutriproteomics)-based nutritional doping is different from the first-generation doping because it is specifically tailored to the genomics and proteomics makeup of the athlete, although their effectiveness remain to be discerned in future systematic studies. Against this scientific background, ethical issues of nutrigenomics and nutriproteomics are discussed in the present paper with emphasis on the current limitations and the dizzying potentials of the omics data-intensive research for science and society. Additionally, I discuss the need to communicate uncertainty as a fundamental construct and intrinsic part of postgenomics personalized medicine, not to forget the gaps regarding the lack of adequate governance, and issues over providing a proper nutritional education to athletes as onus of the international sports organizations. "Let food be your medicine, and medicine be your food"Hippocrates.


The faunal drugstore: animal-based remedies used in traditional medicines in Latin America.
Zootherapy is the treatment of human ailments with remedies made from animals and their products. Despite its prevalence in traditional medical practices worldwide, research on this phenomenon has often been neglected in comparison to medicinal plant research. This review discusses some related aspects of the use of animal-based remedies in Latin America, identifies those species used as folk remedies, and discusses the implications of zootherapy for public health and biological conservation. The review of literature revealed that at least 584 animal species, distributed in 13 taxonomic categories, have been used in traditional medicine in region. The number of medicinal species catalogued was quite expansive and demonstrates the importance of zootherapy as an alternative mode of therapy in Latin America. Nevertheless, this number is certainly underestimated since the number of studies on the theme are very limited. Animals provide the raw materials for remedies prescribed clinically and are also used in the form of amulets and charms in magic-religious rituals and ceremonies. Zootherapeutic resources were used to treat different diseases. The medicinal fauna is largely based on wild animals, including some endangered species. Besides being influenced by cultural aspects, the relations between humans and biodiversity in the form of zootherapeutic practices are conditioned by the social and economic relations between humans themselves. Further ethnopharmacological studies are necessary to increase our understanding of the links between traditional uses of faunistic resources and conservation biology, public health policies, sustainable management of natural resources and bio-prospecting.


Supportive Care and eHealth: A Narrative Review of Technologies, Interventions, and Opportunities for Optimizing Care in Patients With Cancer.
Cancer can be distressing for patients and families. eHealth interventions have the potential to lessen this distress by creating opportunities for providing supportive care resources to patients at home. This article reviews supportive care eHealth interventions in cancer and emerging opportunities to optimize these interventions for diverse populations across the cancer trajectory. A narrative literature review was conducted to evaluate eHealth supportive care for patients with cancer, including effective interventions, accessibility and interactivity issues, patient-reported outcomes, and strategies to improve care for older adults. To ensure that patients with cancer and their family members benefit from supportive care eHealth interventions, nurses need to understand how to leverage such interventions to improve care.


Unprogrammed deworming in the Kibera slum, Nairobi: implications for control of soil-transmitted helminthiases.
Programs for control of soil-transmitted helminth (STH) infections are increasingly evaluating national mass drug administration (MDA) interventions. However, "unprogrammed deworming" (receipt of deworming drugs outside of nationally-run STH control programs) occurs frequently. Failure to account for these activities may compromise evaluations of MDA effectiveness. We used a cross-sectional study design to evaluate STH infection and unprogrammed deworming among infants (aged 6-11 months), preschool-aged children (PSAC, aged 1-4 years), and school-aged children (SAC, aged 5-14 years) in Kibera, Kenya, an informal settlement not currently receiving nationally-run MDA for STH. STH infection was assessed by triplicate Kato-Katz. We asked heads of households with randomly-selected children about past-year receipt and source(s) of deworming drugs. Local non-governmental organizations (NGOs) and school staff participating in school-based deworming were interviewed to collect information on drug coverage. Of 679 children (18 infants, 184 PSAC, and 477 SAC) evaluated, 377 (55%) reported receiving at least one unprogrammed deworming treatment during the past year. PSAC primarily received treatments from chemists (48.3%) or healthcare centers (37.7%); SAC most commonly received treatments at school (55.0%). Four NGOs reported past-year deworming activities at 47 of >150 schools attended by children in our study area. Past-year deworming was negatively associated with any-STH infection (34.8% vs 45.4%, p = 0.005). SAC whose most recent deworming medication was sourced from a chemist were more often infected with Trichuris (38.0%) than those who received their most recent treatment from a health center (17.3%) or school (23.1%) (p = 0.05). Unprogrammed deworming was received by more than half of children in our study area, from multiple sources. Both individual-level treatment and unprogrammed preventive chemotherapy may serve an important public health function, particularly in the absence of programmed deworming; however, they may also lead to an overestimation of programmed MDA effectiveness. A standardized, validated tool is needed to assess unprogrammed deworming.


Genetic and evolutionary correlates of fine-scale recombination rate variation in Drosophila persimilis.
Recombination is fundamental to meiosis in many species and generates variation on which natural selection can act, yet fine-scale linkage maps are cumbersome to construct. We generated a fine-scale map of recombination rates across two major chromosomes in Drosophila persimilis using 181 SNP markers spanning two of five major chromosome arms. Using this map, we report significant fine-scale heterogeneity of local recombination rates. However, we also observed "recombinational neighborhoods," where adjacent intervals had similar recombination rates after excluding regions near the centromere and telomere. We further found significant positive associations of fine-scale recombination rate with repetitive element abundance and a 13-bp sequence motif known to associate with human recombination rates. We noted strong crossover interference extending 5-7 Mb from the initial crossover event. Further, we observed that fine-scale recombination rates in D. persimilis are strongly correlated with those obtained from a comparable study of its sister species, D. pseudoobscura. We documented a significant relationship between recombination rates and intron nucleotide sequence diversity within species, but no relationship between recombination rate and intron divergence between species. These results are consistent with selection models (hitchhiking and background selection) rather than mutagenic recombination models for explaining the relationship of recombination with nucleotide diversity within species. Finally, we found significant correlations between recombination rate and GC content, supporting both GC-biased gene conversion (BGC) models and selection-driven codon bias models. Overall, this genome-enabled map of fine-scale recombination rates allowed us to confirm findings of broader-scale studies and identify multiple novel features that merit further investigation.


Management of intracranial tuberculous mass lesions: how long should we treat for?
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis ( M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.


Clozapine versus typical neuroleptic medication for schizophrenia.
Long-term drug treatment of schizophrenia with typical antipsychotics has limitations: 25 to 33% of patients have illnesses that are treatment-resistant. Clozapine is an antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment. To evaluate the effects of clozapine compared with typical antipsychotic drugs in people with schizophrenia. For the current update of this review (March 2006) we searched the Cochrane Schizophrenia Group Trials Register. All relevant randomised clinical trials (RCTs). We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. We have included 42 trials (3950 participants) in this review. Twenty-eight of the included studies are less than 13 weeks in duration, and, overall, trials were at significant risk of bias. We found no significant difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at the end of the study. Clinical improvements were seen more frequently in those taking clozapine (n=1119, 14 RCTs, RR 0.72 CI 0.7 to 0.8, NNT 6 CI 5 to 8). Also, participants given clozapine had fewer relapses than those on typical antipsychotic drugs (n=1303, RR 0.62 CI 0.5 to 0.8, NNT 21 CI 15 to 49). BPRS scores showed a greater reduction of symptoms in clozapine-treated patients, (n=1145, 16 RCTs, WMD -4.22 CI -5.4 to -3.1), although the data were heterogeneous (Chi(2) 0.0001, I(2) 66%). Short-term data from the SANS negative symptom scores favoured clozapine (n=196, 5 RCTs, WMD -5.92 CI -7.8 to -4.1). We found clozapine to be more acceptable in long-term treatment than conventional antipsychotic drugs (n=982, 16 RCTs, RR 0.60 CI 0.5 to 0.7, NNT 15 CI 12 to 20). Blood problems occurred more frequently in participants receiving clozapine (3.2%) compared with those given typical antipsychotics (0%) (n=1031, 13 RCTs, RR 7.09 CI 2.0 to 25.6). Clozapine participants experienced more drowsiness, hypersalivation, or temperature increase, than those given conventional neuroleptics. However, clozapine patients experienced fewer motor adverse effects (n=1433, 18 RCTs, RR 0.58 CI 0.5 to 0.7, NNT 5 CI 4 to 6).The clinical effects of clozapine were more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. Thirty-four per cent of treatment-resistant participants had a clinical improvement with clozapine treatment. Clozapine may be more effective in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse, than typical antipsychotic drugs - but data are weak and prone to bias. Participants were more satisfied with clozapine treatment than with typical neuroleptic treatment. The clinical effect of clozapine, however, is, at least in the short term, not reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The short-term benefits of clozapine have to be weighed against the risk of adverse effects. Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle-age.The existing trials have largely neglected to assess the views of participants and their families on clozapine. More community-based long-term randomised trials are needed to evaluate the efficacy of clozapine on global and social functioning as trials in special groups such as people with learning disabilities.


Inhibitory Control of Spanish-Speaking Language-Minority Preschool Children: Measurement and Association With Language, Literacy, and Math Skills.
Children's self-regulation, including components of executive function such as inhibitory control, is related concurrently and longitudinally with elementary school children's reading and math abilities. Although several recent studies have examined links between preschool children's self-regulation or executive function and their academic skill development, few included large numbers of Spanish-speaking language-minority children. Among the fastest growing segments of the U.S. school-age population, many of these children are at significant risk of academic difficulties. We examined the relations between inhibitory control and academic skills in a sample containing a large number of Spanish-speaking preschoolers. Overall, the children demonstrated substantial academic risk based on preschool-entry vocabulary scores in the below-average range. Children completed assessments of language, literacy, and math skills in English and Spanish, when appropriate, at the start and end of their preschool year, along with a measure of inhibitory control, the Head-Toes-Knees-Shoulders task, which was administered at the start of the preschool year in the child's dominant conversational language. Scores on this last measure were lower for children for whom it was administered in Spanish. For both English and Spanish outcomes, those scores were significantly and uniquely associated with higher scores on measures of phonological awareness and math skills but not vocabulary or print knowledge skills.


Outcomes after laparoscopic adrenalectomy.
Laparoscopic adrenalectomy (LA) has become the standard of care for many conditions requiring removal of the adrenal gland. Previous studies on outcomes after LA have had limitations. This report describes the 30-day morbidity and mortality rates after LA and analyzes factors affecting operative time, hospital length of stay (LOS), and postoperative morbidity. Patients undergoing LA in 2007 and 2008 were identified from the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP). Using multivariate analysis of variance (ANOVA) and logistic regression, 52 demographic/comorbidity variables were analyzed to ascertain factors affecting operative time, LOS, and morbidity. The mean age of the 988 patients was 53.5 ± 13.7 years, and 60% of the patients were women. The mean body mass index (BMI) of the patients was 31.8 ± 7.9 kg/m(2). The 30-day morbidity and mortality rates were 6.8% and 0.5%, respectively. The mean and median operative times were 146.7 ± 66.8 min and 134 min, respectively. The mean and median hospital stays were 2.6 ± 3.1 days and 2 days, respectively. Compared with independent status, totally dependent functional status was associated with a 9.5-day increase in LOS (P = 0.0006) and an increased risk for postoperative morbidity (odds ratio [OR], 14.7; 95% confidence interval [CI], 2.4-91.9; P < 0.0001). Peripheral vascular disease (OR, 7.3; 95% CI, 1.7-31.7; P = 0.008) also was associated with increased 30-day morbidity. Neurologic and respiratory comorbidities were associated with increased LOS (P < 0.05). American Society of Anesthesiology (ASA) class 4 patients had a longer operative time than ASA class 1 patients (P = 0.002). The morbidity and mortality rates after LA are low. Dependent functional status and peripheral vascular disease predispose to postoperative morbidity. Dependent status, higher ASA class, and respiratory and neurologic comorbidities are associated with longer operative time and LOS.


Ethics and the care of critically ill infants and children. American Academy of Pediatrics Committee on Bioethics.
The ability to provide life support to ill children who, not long ago, would have died despite medicine's best efforts challenges pediatricians and families to address profound moral questions. Our society has been divided about extending the life of some patients, especially newborns and older infants with severe disabilities. The American Academy of Pediatrics (AAP) supports individualized decision making about life-sustaining medical treatment for all children, regardless of age. These decisions should be jointly made by physicians and parents, unless good reasons require invoking established child protective services to contravene parental authority. At this time, resource allocation (rationing) decisions about which children should receive intensive care resources should be made clear and explicit in public policy, rather than be made at the bedside.


Microsatellite standardization and evaluation of genotyping error in a large multi-partner research programme for conservation of Atlantic salmon (Salmo salar L.).
Microsatellite genotyping is a common DNA characterization technique in population, ecological and evolutionary genetics research. Since different alleles are sized relative to internal size-standards, different laboratories must calibrate and standardize allelic designations when exchanging data. This interchange of microsatellite data can often prove problematic. Here, 16 microsatellite loci were calibrated and standardized for the Atlantic salmon, Salmo salar, across 12 laboratories. Although inconsistencies were observed, particularly due to differences between migration of DNA fragments and actual allelic size ('size shifts'), inter-laboratory calibration was successful. Standardization also allowed an assessment of the degree and partitioning of genotyping error. Notably, the global allelic error rate was reduced from 0.05 ± 0.01 prior to calibration to 0.01 ± 0.002 post-calibration. Most errors were found to occur during analysis (i.e. when size-calling alleles; the mean proportion of all errors that were analytical errors across loci was 0.58 after calibration). No evidence was found of an association between the degree of error and allelic size range of a locus, number of alleles, nor repeat type, nor was there evidence that genotyping errors were more prevalent when a laboratory analyzed samples outside of the usual geographic area they encounter. The microsatellite calibration between laboratories presented here will be especially important for genetic assignment of marine-caught Atlantic salmon, enabling analysis of marine mortality, a major factor in the observed declines of this highly valued species.


Development of an Objective Structured Clinical Examination as a Component of Assessment for Initial Board Certification in Anesthesiology.
With its first administration of an Objective Structured Clinical Examination (OSCE) in 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate this type of assessment into its high-stakes certification examination system. The fundamental rationale for the ABA's introduction of the OSCE is to include an assessment that allows candidates for board certification to demonstrate what they actually "do" in domains relevant to clinical practice. Inherent in this rationale is that the OSCE will capture competencies not well assessed in the current written and oral examinations-competencies that will allow the ABA to judge whether a candidate meets the standards expected for board certification more properly. This special article describes the ABA's journey from initial conceptualization through first administration of the OSCE, including the format of the OSCE, the process for scenario development, the standardized patient program that supports OSCE administration, examiner training, scoring, and future assessment of reliability, validity, and impact of the OSCE. This information will be beneficial to both those involved in the initial certification process, such as residency graduate candidates and program directors, and others contemplating the use of high-stakes summative OSCE assessments.


Extract of ice plant (Mesembryanthemum crystallinum) ameliorates hyperglycemia and modulates the gut microbiota composition in type 2 diabetic Goto-Kakizaki rats.
Ice plant (Mesembryanthemum crystallinum) extract (IPE) is a rich source of d-pinitol, which is widely known to have potential anti-diabetic effects. In the present study, response surface methodology (RSM) was used to optimize d-pinitol extraction conditions with the Box-Behnken design. We then evaluated the anti-diabetic effects properties of IPE that was extracted under optimized conditions (53 °C, 119 min extraction time, and 1 : 11 dilution) in type 2 diabetic Goto-Kakizaki (GK) rats. IPE (400 mg kg-1 day-1) effectively controlled the increased fasting blood glucose level (decreased by 45% vs. GK-control rats) and impaired glucose tolerance (decreased area under curve (AUC) of glucose values by 24%, p < 0.05 vs. GK-control rats) after eight weeks of treatment. Furthermore, IPE significantly improved pancreatic islet morphology, β-cell survival, and insulin secretion in diabetic rats, thus contributing to the antihyperglycemic effect. Finally, prebiotic effects of IPE on gut microbiota were observed and included increased abundance of the beneficial bacteria Bacteroidales_S24-7 and Ruminococcaceae_UCG-014 and decreased abundance of Treponema_2 and Lactobacillus. Overall, IPE has a substantial effect on attenuating hyperglycemia and modulating gut microbiota composition in diabetic GK rats. Therefore, IPE might be a promising functional food for the prevention of diabetes.


Unveiling (-)-Englerin A as a Modulator of L-Type Calcium Channels.
The voltage-dependent L-type Ca(2+) channel was identified as a macromolecular target for (-)-englerin A. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-Englerin A features high substructure dissimilarity to known ligands for voltage-dependent Ca(2+) channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations. Experimental confirmation of this hitherto unknown macromolecular target expands the bioactivity space for this natural product and corroborates the effectiveness of chemocentric computational methods for prioritizing target-based screens and identifying binding counterparts of complex natural products.


Black grain mycetoma caused by Leptosphaeria tompkinsii.
Leptosphaeria tompkinsii is a dematiaceous fungus which is rarely reported as an agent of black-grain mycetoma. We present a case involving a mycetoma of the hand of a former farmer from Mali, West Africa, who has been a resident in France for 27 years. The patient was successfully treated with surgery and the use of oral itraconazole for 6 months. Species identification was based on sexual reproductive structures observed on potato-carrot agar media and the use of internal transcribed spacer sequencing.


mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that participates in at least two distinct multiprotein complexes, mTORC1 and mTORC2 . These complexes play important roles in the regulation of cell growth, proliferation, survival, and metabolism. mTORC2 is a hydrophobic motif kinase for the cell-survival protein Akt/PKB and, here, we identify mSin1 as a component of mTORC2 but not mTORC1. mSin1 is necessary for the assembly of mTORC2 and for its capacity to phosphorylate Akt/PKB. Alternative splicing generates at least five isoforms of the mSin1 protein , three of which assemble into mTORC2 to generate three distinct mTORC2s. Even though all mTORC2s can phosphorylate Akt/PKB in vitro, insulin regulates the activity of only two of them. Thus, we propose that cells contain several mTORC2 flavors that may phosphorylate Akt/PKB in response to different signals.


The two fACEs of the tissue renin-angiotensin systems: implication in cardiovascular diseases.
The implication of the renin-angiotensin system (RAS) in the regulation of the cardiovascular system has been well known for many years. Accordingly, many pharmaceutical inhibitors have been developed to treat several pathologies, like hypertension and heart failure, and angiotensin converting enzyme (ACE) became one of the major target in the treatment of these cardiovascular diseases. In the last decade however, it has become apparent that the classical view of the RAS was not quite accurate. For instance, ACE has been shown to work not only by generating angiotensin-II but also by interacting with receptors outside the renin-angiotensin system. Moreover, it has been shown that many local RAS are present in different tissues, such as the heart, brain, kidney and vasculature. However, in the past, it was impossible to determine the role of these local systems as they were pharmacologically indistinguishable from the systemic RAS. Hence, in recent years, the development of transgenic animals has allowed us to determine that these local systems are implicated in the roles that had been originally attributed exclusively to the systemic action of the RAS. However, with almost 30% of the medicated hypertensive patients harboring an uncontrolled blood pressure, a need for new drugs and new targets appears necessary. With the new century came the discovery of a new homolog of ACE, called ACE2, and early studies suggest that it may play a pivotal role in the RAS by controlling the balance between the vasoconstrictor effects of angiotensin-II and the vasodilatory properties of the angiotensin(1-7) peptide. Like ACE, ACE2 appears to hydrolyze peptides not related with the RAS and the enzyme has also been identified as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Although the tissue localization of ACE2 was originally though to be very restricted, new studies have emerged showing a more widespread distribution. Therefore, the whole dynamics of the RAS has to be re-evaluated in light of this new information. In this review, we will compare the structures, distributions and properties of ACE and its new homologue in the context of cardiovascular function, focusing on the autocrine/paracrine cardiac and brain renin-angiotensin systems and we will present recent data from the literature and our laboratory offering a new perspective on this potential target for the treatment of cardiovascular diseases.


Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium.
The change of dietary habits in Western societies, including reduced consumption of fiber, is linked to alterations in gut microbial ecology. Nevertheless, mechanistic connections between diet-induced microbiota changes that affect colonization resistance and enteric pathogen susceptibility are still emerging. We sought to investigate how a diet devoid of soluble plant fibers impacts the structure and function of a conventional gut microbiota in specific-pathogen-free (SPF) mice and how such changes alter susceptibility to a rodent enteric pathogen. We show that absence of dietary fiber intake leads to shifts in the abundances of specific taxa, microbiome-mediated erosion of the colonic mucus barrier, a reduction of intestinal barrier-promoting short-chain fatty acids, and increases in markers of mucosal barrier integrity disruption. Importantly, our results highlight that these low-fiber diet-induced changes in the gut microbial ecology collectively contribute to a lethal colitis by the mucosal pathogen Citrobacter rodentium, which is used as a mouse model for enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Our study indicates that modern, low-fiber Western-style diets might make individuals more prone to infection by enteric pathogens via the disruption of mucosal barrier integrity by diet-driven changes in the gut microbiota, illustrating possible implications for EPEC and EHEC infections.


The role of the dorsal lip in the induction of heart mesoderm in Xenopus laevis.
We have examined the tissue interactions responsible for the expression of heart-forming potency during gastrulation. By comparing the specification of different regions of the marginal zone, we show that heart-forming potency is expressed only in explants containing both the dorsal lip of the blastopore and deep mesoderm between 30 degrees and 45 degrees lateral to the dorsal midline. Embryos from which both of these 30 degrees-45 degrees dorsolateral regions have been removed undergo heart formation in two thirds of cases, as long as the dorsal lip is left intact. If the dorsal lip is removed along with the 30 degrees-45 degrees regions, heart formation does not occur. These results indicate that the dorsolateral deep mesoderm must interact with the dorsal lip in order to express heart-forming potency. Transplantation of the dorsal lip into the ventral marginal zone of host embryos results in the formation of a secondary axis; in over half of cases, this secondary axis includes a heart derived from the host mesoderm. These findings suggest that the establishment of heart mesoderm is initiated by a dorsalizing signal from the dorsal lip of the blastopore.


Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease.
Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.


Molecularly imprinted solid-phase extraction for the selective determination of bromhexine in human serum and urine with high performance liquid chromatography.
In this work, a novel method is described for the determination of bromhexine in biological fluids using molecularly imprinted solid-phase extraction as the sample cleanup technique combined with high performance liquid chromatography (HPLC). The water-compatible molecularly imprinted polymers (MIPs) were prepared using methacrylic acid as functional monomer, ethylene glycol dimethacrylate as cross-linker, chloroform as porogen and bromhexine as the template molecule. The novel imprinted polymer was used as a solid-phase extraction sorbent for the extraction of bromhexine from human serum and urine. Various parameters affecting the extraction efficiency of the polymer have been evaluated. The optimal conditions for molecularly imprinted solid-phase extraction (MISPE) consisted of conditioning 1 mL methanol and 1 mL of deionized water at neutral pH, loading of 5 mL of the water sample (25 microg L(-1)) at pH 6.0, washing using 2 mL acetonitrile/acetone (1/4, v/v) and elution with 3x 1 mL methanol/acetic acid (10/1, v/v). The MIP selectivity was evaluated by checking several substances with similar molecular structures to that of bromhexine. Results from the HPLC analyses showed that the calibration curve of bromhexine using MIP from human serum and urine is linear in the ranges of 0.5-100 and 1.5-100 microg L(-1) with good precisions (3.3% and 2.8% for 5.0 microg L(-1)), respectively. The recoveries for serum and urine samples were higher than 92%.


Nanoleakage types and potential implications: evidence from unfilled and filled adhesives with the same resin composition.
To compare nanoleakage patterns of an unfilled (OS; One-Step), a 6 wt% spherical silica-filled (OSs; One-Step Plus) and a 15 wt% glass-filled (OSg) version of a two-step, acetone-based self-priming adhesive. Permeability of bonded dentin treated with OS and OSs was also examined. Deep, coronal dentin from extracted third molars were etched and bonded using these adhesives. One-mm thick sections were immersed in 50 wt% ammoniacal silver nitrate (pH 9.5) for 24 hours. Unstained, undemineralized sections were examined by TEM. The permeability of dentin bonded with OS and OSs were investigated at 20 cm of H2O hydrostatic pressure and compared with the osmotic conductance determined with 4.8 M CaCl2 at zero hydrostatic pressure. Composite-dentin beams bonded with OS, OSs and OSg that were fractured after microtensile bond testing were examined by SEM. Two types of nanoleakage patterns were recognized along the resin-dentin interfaces. The reticular type consisted of discontinuous islands of silver deposits and was exclusively seen in hybrid layers. The spotted type consisted of isolated silver grains and was evident throughout the hybrid and adhesive layers in OS. These two patterns were seen to variable extents in the two filled adhesive versions OSs and OSg and their distribution was independent of one another. OS and OSs bonded dentin were permeable to fluid filtration. However, part of this fluid movement was due to the permeability of the adhesive layer, as demonstrated by osmotic fluid conductance in the absence of hydrostatic pressure. Fractographic analysis revealed denuded collagen fibrils within fractured hybrid layers that were indicative of incomplete resin infiltration.


Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition.
DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer. We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inversely correlated to the degree of DNA methylation. We found these candidate genes to be differentially methylated in normal lung tissue versus non-small cell lung cancer tumors, and segregated by histologic and tumor subtypes. We used gene set enrichment analysis of the genes ranked by the degree of correlation between gene expression and DNA methylation to identify gene sets involved in cellular migration and metastasis. Our unsupervised hierarchical clustering of the candidate genes segregated cell lines according to the epithelial-to-mesenchymal transition phenotype. Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. Greater numbers of genes were methylated in the mesenchymal cells and their expressions were upregulated by 5-azacytidine treatment. Methylation of the candidate genes was associated with erlotinib resistance in wild-type EGFR cell lines. The expression profiles of the candidate genes were associated with 8-week disease control in patients with wild-type EGFR who had unresectable non-small cell lung cancer treated with erlotinib, but not in patients treated with sorafenib. Our results demonstrate that the underlying biology of genes regulated by DNA methylation may have predictive value in lung cancer that can be exploited therapeutically.


Detection of malarial byproduct hemozoin utilizing its unique scattering properties.
The scattering characteristics of the malaria byproduct hemozoin, including its scattering distribution and depolarization, are modeled using Discrete Dipole Approximation (DDA) and compared to those of healthy red blood cells. Scattering (or dark-field) spectroscopy and imaging are used to identify hemozoin in fresh rodent blood samples. A new detection method is proposed and demonstrated using dark-field in conjunction with cross-polarization imaging and spectroscopy. SNRs greater than 50:1 are achieved for hemozoin in fresh blood without the addition of stains or reagents. The potential of such a detection system is discussed.


SU-E-T-604: Inter Planner Dosimetric Variations in IMRT.
To study inter-planner variations in IMRT dosimetry with identical dose prescription in IMRT optimization for estimation of quality of treatment plans by using dose volume histogram (DVH). Five treatment planners: p1, p2, p3, p4 and p5 with Eclipse TPS and Varian accelerator were chosen. The 3D data sets including PTV and OAR of a prostate case was sent with instructions for beam orientations, energy and dose-volume constraints. Each planner performed the treatment planning process with inhomogeneity corrections by using the same dose constraints. DVH and isodose distributions were compared to examine the inter-planner variations. There were large variations in the IMRT plans reflected by the DVH among the planners even with identical dose constraints in IMRT optimization. Clinically constraint#1 (D95-V95) dose criteria could be considered as the most important one. Two planners did not meet the criteria, whereas planner 4 met all of the dose criteria for PTV and OARs. The inter-planner variations in PTV as large as 20% were found in this study. Every time optimization is performed even with the same constraints, the DVH output was significantly different due to the differences in constraint weights. There exists a significant inter planner variation for all cases studied indicating that even for the same constraints the outcome cannot be guaranteed to be identical due to cost function convergence. It seems feasible to control the over-dosage for all planners. However we see large deviations in plans with respect to different constraints. Planner 4 met all the dose criteria for PTV and OARs indicating that it is possible to plan and meet all the dose criteria. This approach could be used as gold standard.


Sleep Quality, Fatigue, and Health-Related Quality of Life in Patients on Initial Peritoneal Dialysis and Multiple Modalities after Two Years: A Prospective Study.
The purpose of this study was to investigate changes in sleep quality, fatigue, mental health, and health-related quality of life (HRQoL) over a two-year period among patients undergoing peritoneal dialysis treatment at home. We further explored the extent to which sleep quality, fatigue, and mental health predicted health-related quality of life outcomes. This prospective study included 55 patients. Sleep parameters changed over two years, independently of treatment. Sleep variables at baseline, to some extent, predicted sleep quality after two years. Daytime sleepiness can be a long-term problem. Findings indicate improvements in nocturnal sleep over a two-year time period, independently of dialysis treatment. In contrast, fatigue remained unchanged over the same time period. Transplantation seems to generally benefit the outcome of HRQoL. Strategies to improve sleep and HRQoL may include systematic risk factor modification and efforts to optimise symptomatic treatment.


Optimization of Extraction of Cycloalliin from Garlic (Allium sativum L.) by Using Principal Components Analysis.
In this study, we report the optimal extraction conditions for obtaining organosulfur compounds, such as cycloalliin, from garlic by using principal component analysis (PCA). Extraction variables including temperature (40~80°C), time (0.5~12 h), and pH (4~12) were investigated for the highest cycloalliin yields. The cycloalliin yield (5.5 mmol/mL) at pH 10 was enhanced by ~40% relative to those (~3.9 mmol/mL) at pH 4 and pH 6. The cycloalliin level at 80°C showed the highest yield among the tested temperatures (5.05 mmol/mL). Prolonged extraction times also increased cycloalliin yield; the yield after 12 h was enhanced ~2-fold (4 mmol/mL) compared to the control. Isoalliin and cycloalliin levels were inversely correlated, whereas a direct correlation between polyphenol and cycloalliin levels was observed. In storage for 30 days, garlic stored at 60°C (11 mmol/mL) showed higher levels of cycloalliin and polyphenols than those at 40°C, with the maximum cycloalliin level (13 mmol/mL) on day 15. Based on the PCA analysis, the isoalliin level depended on the extraction time, while cycloalliin amounts were influenced not only by extraction time, but also by pH and temperature. Taken together, extraction of garlic at 80°C, with an incubation time of 12 h, at pH 10 afforded the maximum yield of cycloalliin.


NADH fluorescence as a photobiological metric in 5-aminolevlinic acid (ALA)-photodynamic therapy.
Photodynamic therapy (PDT) dosimetry is complex as many factors are involved and varied interdependently. Monitoring the biological consequence of PDT such as cell death is the most direct approach to assess treatment efficacy. In this study, we performed 5-aminolevlinic acid (ALA)-PDT in vitro to induce different cell death modes (i.e., slight cell cytotoxicity, apoptosis, and necrosis) by a fixed fluence rate of 10 mW/cm(2) and varied fluences (1, 2, and 6 J/cm(2)). Time course measurements of cell viability, caspase-3 activity, and DNA fragmentation were conducted to determine the mode of cell death. We demonstrated that NADH fluorescence lifetime together with NADH fluorescence intensity permit us to detect apoptosis and differentiate it from necrosis. This feature will be unique in the use of optimizing apoptosis-favored treatments such as metronomic PDT.


Dietary Protein Intake and Distribution Patterns of Well-Trained Dutch Athletes.
Dietary protein intake should be optimized in all athletes to ensure proper recovery and enhance the skeletal muscle adaptive response to exercise training. In addition to total protein intake, the use of specific proteincontaining food sources and the distribution of protein throughout the day are relevant for optimizing protein intake in athletes. In the present study, we examined the daily intake and distribution of various proteincontaining food sources in a large cohort of strength, endurance and team-sport athletes. Well-trained male (n=327) and female (n=226) athletes completed multiple web-based 24-hr dietary recalls over a 2-4 wk period. Total energy intake, the contribution of animal- and plant-based proteins to daily protein intake, and protein intake at six eating moments were determined. Daily protein intake averaged 108±33 and 90±24 g in men and women, respectively, which corresponded to relative intakes of 1.5±0.4 and 1.4±0.4 g/kg. Dietary protein intake was correlated with total energy intake in strength (r=0.71, p <.001), endurance (r=0.79, p <.001) and team-sport (r=0.77, p <.001) athletes. Animal and plant-based sources of protein intake was 57% and 43%, respectively. The distribution of protein intake was 19% (19±8 g) at breakfast, 24% (25±13 g) at lunch and 38% (38±15 g) at dinner. Protein intake was below the recommended 20 g for 58% of athletes at breakfast, 36% at lunch and 8% at dinner. In summary, this survey of athletes revealed they habitually consume > 1.2 g protein/kg/d, but the distribution throughout the day may be suboptimal to maximize the skeletal muscle adaptive response to training.


Euthanasia and other end-of-life decisions: a mortality follow-back study in Belgium.
This study compares prevalence and types of medical end-of-life decisions between the Dutch-speaking and French-speaking communities of Belgium. This is the first nationwide study that can make these comparisons and the first measurement after implementation of the euthanasia law (2002). We performed a mortality follow-back study in 2005-2006. Data were collected via the nationwide Sentinel Network of General Practitioners, an epidemiological surveillance system representative of all Belgian GPs.Weekly, all GPs reported the medical end-of-life decisions among all non-sudden deaths of patients in their practice. We compared the northern Dutch-speaking (60%) and southern French-speaking communities (40%) controlling for population differences. We analysed 1690 non-sudden deaths. An end-of-life decision with possible life-shortening effect was made in 50% of patients in the Dutch-speaking community and 41% of patients in the French-speaking community (OR 1.4; 95%CI, 1.2 to 1.8). Continuous deep sedation until death occurred in 8% and 15% respectively (OR 0.5; 95%CI, 0.4 to 0.7). Community differences regarding the prevalence of euthanasia or physician-assisted suicide were not significant.Community differences were more present among home/care home than among hospital deaths: non-treatment decisions with explicit life-shortening intention were made more often in the Dutch-speaking than in the French-speaking community settings (OR 2.2; 95%CI, 1.2 to 3.9); while continuous deep sedation occurred less often in the Dutch-speaking community settings (OR 0.5; 95%CI, 0.3 to 0.9). Even though legal and general healthcare systems are the same for the whole country, there are considerable variations between the communities in type and prevalence of certain end-of-life decisions, even after controlling for population differences.


Genetic analysis of a successful repatriation programme: giant Galápagos tortoises.
As natural populations of endangered species dwindle to precarious levels, remaining members are sometimes brought into captivity, allowed to breed and their offspring returned to the natural habitat. One goal of such repatriation programmes is to retain as much of the genetic variation of the species as possible. A taxon of giant Galápagos tortoises on the island of Española has been the subject of a captive breeding-repatriation programme for 33 years. Core breeders, consisting of 12 females and three males, have produced more than 1200 offspring that have been released on Española where in situ reproduction has recently been observed. Using microsatellite DNA markers, we have determined the maternity and paternity of 132 repatriated offspring. Contributions of the breeders are highly skewed. This has led to a further loss of genetic variation that is detrimental to the long-term survival of the population. Modifications to the breeding programme could alleviate this problem.


Common variants for atrial fibrillation: results from genome-wide association studies.
Atrial fibrillation (AF) affects more than 5 million people worldwide; however, none of the anti-arrhythmic drugs available now are entirely optimal in terms of efficacy and safety. A better understanding of the molecular mechanism of AF will facilitate the process of finding new strategies to prevent AF. As the non-familial AF is the major form of AF, identifying common variants for AF in these populations by genome-wide association studies will definitely accelerate this process. This review summarizes the recently identified common AF variants on 4q25, 16q22, and 1q21 and discusses their implications for the clinic.


Anatomy of the lateral intermuscular septum of the arm and its relationships to the radial nerve and its proximal branches. Laboratory investigation.
Other than very simple descriptions of the existence of the lateral intermuscular septum (LIS), the literature offers almost nothing about its detailed anatomy, relationships to the radial nerve, and proximal branches. To further elucidate its morphological characteristics, the present cadaveric study was performed. The lateral arm was bilaterally dissected from 25 adult fixed cadavers (50 sides). Specifically, a detailed evaluation of the LIS was made, and this structure's attachments and relationships to the radial nerve were analyzed and measured. In addition to the previously described muscles arising from the LIS, the authors identified the extensor carpi radialis brevis muscles as partially arising from this structure. The deep and posterior portion of the deltoid tendon was confluent with the superior aspect of the LIS. The mean thickness of the LIS was 1.0 mm. Distally, the LIS attached strongly to the lateral epicondyle of the humerus and became confluent with the annular ligament encircling the head of the radius. The distal attachment of the LIS was confluent with the capsule of the elbow joint. All radial nerves traveled through a defect (mean diameter 1 cm) in the LIS. With traction on the nerve from proximal and distal to this defect, there was free excursion. In 85% of the specimens, however, the posterior antebrachial cutaneous nerve traveled through a tunnel within the LIS and pierced the septum at a mean of 5 cm proximal to the lateral epicondyle. The lower lateral brachial cutaneous nerve proximally pierced the LIS near its origin, occurring a mean of 3.2 cm distal to the LIS's origin from the humerus. To the authors' knowledge, the details regarding the LIS and its relationships to the radial nerve have not been reported. Such information may be of use to surgeons who operate in this region, for example, during neural repair or entrapment procedures.


A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria.
Trials testing the RTS,S candidate malaria vaccine and radiation-attenuated sporozoites (RAS) have shown that protective immunity against malaria can be induced and that an effective vaccine is not out of reach. However, longer-term protection and higher protection rates are required to eradicate malaria from the endemic regions. It implies that there is still a need to explore new vaccine strategies. Lentiviral vectors are very potent at inducing strong immunological memory. However their integrative status challenges their safety profile. Eliminating the integration step obviates the risk of insertional oncogenesis. Providing they confer sterile immunity, nonintegrative lentiviral vectors (NILV) hold promise as mass pediatric vaccine by meeting high safety standards. In this study, we have assessed the protective efficacy of NILV against malaria in a robust pre-clinical model. Mice were immunized with NILV encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP) and challenged with sporozoites one month later. In two independent protective efficacy studies, 50% (37.5-62.5) of the animals were fully protected (p = 0.0072 and p = 0.0008 respectively when compared to naive mice). The remaining mice with detectable parasitized red blood cells exhibited a prolonged patency and reduced parasitemia. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization (p = 0.0042). Post-challenge CD8+ T cells to CSP, in contrast to anti-CSP antibodies, were associated with protection (r = -0.6615 and p = 0.0004 between the frequency of IFN-g secreting specific T cells in spleen and parasitemia). However, while NILV and RAS immunizations elicited comparable immunity to CSP, only RAS conferred 100% of sterile protection. Given that a better protection can be anticipated from a multi-antigen vaccine and an optimized vector design, NILV appear as a promising malaria vaccine.


Racial/Ethnic Differences in Drug- and Alcohol-Related Arrest Outcomes in a Southwest County From 2009 to 2018.
Objectives. To estimate the association between race/ethnicity and drug- and alcohol-related arrest outcomes.Methods. We used multinomial logistic regression and general estimating equations to estimate the association between race/ethnicity and arrest outcomes in 36 073 drug- and alcohol-related arrests obtained from administrative records in a Southwest US county from 2009 to 2018. Results were stratified by charge type.Results. Among misdemeanor drug- and alcohol-related arrests, American Indian/Alaska Native (AI/AN; adjusted odds ratio [AOR] = 3.60; 95% confidence interval [CI] = 3.32, 3.90), Latino (AOR = 1.53; 95% CI = 1.35, 1.73), and Black persons (AOR = 1.28; 95% CI = 1.05, 1.55) were more likely than White persons to be booked into jail as opposed to cited and released. AI/AN (AOR = 10.77; 95% CI = 9.40, 12.35), Latino (AOR = 2.63; 95% CI = 2.12, 3.28), and Black persons (AOR = 1.84; 95% CI = 1.19, 2.84) also were more likely than White persons to be convicted and serve time for their misdemeanor charges. Results were similar for felony drug- and alcohol-related arrests aggregated and stratified.Conclusions. Our results suggest that race/ethnicity is associated with outcomes in drug-related arrests and that overrepresentation of racial/ethnic minorities in the criminal justice system cannot be attributed to greater use of drugs and alcohol in general.


miR-431 Promotes Metastasis of Pancreatic Neuroendocrine Tumors by Targeting DAB2 Interacting Protein, a Ras GTPase Activating Protein Tumor Suppressor.
The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR-431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR-431 contributes to metastasis of PNETs. Herein, we show that miR-431 overexpression activates Ras/extracellular signal-regulated kinase (Erk) signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR-431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR-431. A Ras GTPase activating protein tumor suppressor (RasGAP), DAB2 interacting protein (DAB2IP), was discovered as an miR-431 target. Overexpression of DAB2IP's rat homolog, but not its mutant defective in Ras GTPase activating protein activity, reverses miR-431's effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR-431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR-431 may be targeted to manage metastatic PNETs.


Changing expectancies: cognitive mechanisms and context effects.
This article presents the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, organized by Reinout W. Wiers and Mark D. Wood. The symposium combined two topics of recent interest in studies of alcohol expectancies: cognitive mechanisms in expectancy challenge studies, and context-related changes of expectancies. With increasing recognition of the substantial role played by alcohol expectancies in drinking, investigators have begun to develop and evaluate expectancy challenge procedures as a potentially promising new prevention strategy. The two major issues addressed in the symposium were whether expectancy challenges result in changes in expectancies that mediate intervention (outcome relations), and the influence of simulated bar environments ("bar labs," in which challenges are usually done) on expectancies. The presentations were (1) An introduction, by Jack Darkes; (2) Investigating the utility of alcohol expectancy challenge with heavy drinking college students, by Mark D. Wood; (3) Effects of an expectancy challenge on implicit and explicit expectancies and drinking, by Reinout W. Wiers; (4) Effects of graphic feedback and simulated bar assessments on alcohol expectancies and consumption, by William R. Corbin; (5) Implicit alcohol associations and context, by Barry T Jones; and (6) A discussion by Kenneth J. Sher, who pointed out that it is important not only to study changes of expectancies in the paradigm of an expectancy challenge but also to consider the role of changing expectancies in natural development and in treatments not explicitly aimed at changing expectancies.


The effects of collagen peptide supplementation on body composition, collagen synthesis, and recovery from joint injury and exercise: a systematic review.
Collagen peptide supplementation (COL), in conjunction with exercise, may be beneficial for the management of degenerative bone and joint disorders. This is likely due to stimulatory effects of COL and exercise on the extracellular matrix of connective tissues, improving structure and load-bearing capabilities. This systematic review aims to evaluate the current literature available on the combined impact of COL and exercise. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a literature search of three electronic databases-PubMed, Web of Science and CINAHL-was conducted in June 2020. Fifteen randomised controlled trials were selected after screening 856 articles. The study populations included 12 studies in recreational athletes, 2 studies in elderly participants and 1 in untrained pre-menopausal women. Study outcomes were categorised into four topics: (i) joint pain and recovery from joint injuries, (ii) body composition, (iii) muscle soreness and recovery from exercise, and (iv) muscle protein synthesis (MPS) and collagen synthesis. The results indicated that COL is most beneficial in improving joint functionality and reducing joint pain. Certain improvements in body composition, strength and muscle recovery were present. Collagen synthesis rates were elevated with 15 g/day COL but did not have a significant impact on MPS when compared to isonitrogenous higher quality protein sources. Exact mechanisms for these adaptations are unclear, with future research using larger sample sizes, elite athletes, female participants and more precise outcome measures such as muscle biopsies and magnetic imagery.


Cyclodipeptide synthases: a promising biotechnological tool for the synthesis of diverse 2,5-diketopiperazines.
Covering: Up to mid-2019 Cyclodipeptide synthases (CDPSs) catalyse the formation of cyclodipeptides using aminoacylated-tRNA as substrates. The recent characterization of large sets of CDPSs has revealed that they can produce highly diverse products, and therefore have great potential for use in the production of different 2,5-diketopiperazines (2,5-DKPs). Sequence similarity networks (SSNs) are presented as a new, efficient way of classifying CDPSs by specificity and identifying new CDPS likely to display novel specificities. Several strategies for further increasing the diversity accessible with these enzymes are discussed here, including the incorporation of non-canonical amino acids by CDPSs and use of the remarkable diversity of 2,5-DKP-tailoring enzymes discovered in recent years.


Is manipulation of mood a critical component of cognitive bias modification procedures?
This paper investigates whether changes in mood state are an important component of cognitive bias modification (CBM) procedures. In a novel CBM procedure participants read either positive or negative statements relating to social issues for 5 min. Interpretation bias was measured by means of a scrambled sentence test, which was presented both before and after the CBM procedure. Participants who read the positive statements made more positive resolutions to the scrambled sentences, while participants who read the negative statements made more negative resolutions. Thus, the appropriate positive and negative interpretative biases were induced by the CBM procedure. However, significant mood changes also occurred following CBM. In Experiment 2, a musical mood induction procedure was presented with depressing or elating music. As before, a scrambled sentence test was presented both before and after the musical mood induction. Mood changed in accordance with the valence of the music to the same extent as with CBM. Critically however, performance on the scrambled sentence task did not change for both groups. This demonstrates that a change in mood state is not sufficient for a change in cognitive bias to occur.


New visual acuity chart for patients with macular hole.
To evaluate the usefulness of a new multiple-letter visual acuity chart (MLAC) for the measurement of visual acuity in patients with macular hole. Visual acuity was measured using a standard visual acuity chart (Landolt rings, also referred to as C's) and with the MLAC in normal subjects and in patients with a cataract or a macular hole. The MLAC has 14 plates (45 x 45 cm), and on one plate, many Landolt C's were printed with the gaps pointing in the same direction and all of one size. The sizes of the letters and gaps were made to give equivalent visual acuities of 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.5, and 2.0. The spacing between the letters was 33.3% of the diameter of the C's. Each chart projected many C's onto the macular area (5 degrees x 5 degrees ), which permitted the measurement of visual acuity at an extrafoveal point without the patient having to search for the extrafoveal point with the best acuity. There was no difference in the acuity measurement determined with the standard chart and the MLAC in normal subjects and patients with cataracts. Twelve of 16 patients with open macular hole, however, demonstrated higher acuity measurement (more than two lines) on the MLAC than on the standard chart. The improvement of visual acuity measurement after successful macular hole surgery was significantly less with the MLAC than with the standard chart. Our results suggest that the standard acuity chart, when administered before surgery, underestimates the patient's potential visual acuity after surgery, whereas the MLAC provides a better estimate of the patient's postoperative acuity. The MLAC can be a useful tool for measuring visual acuity in patients with macular hole.


Age-related cognitive decline is accelerated in alcohol use disorder.
This study aimed to examine potential cognitive impairments in patients with alcohol use disorder (AUD), and explore the factors affecting them. We recruited 97 inpatients with AUD, showing superficially normal cognitive function (mini-mental state examination score ≥24) for this study. We assessed cognitive function after a 4-week post-abstinence period using the Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J). Relationships between BACS-J subcategory/composite raw scores and Z-scores (deviation from standard data in healthy Japanese) and background factors such as age, sex, education, smoking status, mini-mental state examination score, body mass index, systolic blood pressure, severity of depression, alcohol consumption, and laboratory findings were analyzed. Multiple regression analysis showed that the age (p < 0.001) and total bilirubin level (p = 0.014) were worsening factors for the BACS-J composite raw score, whereas education (p < 0.001) was a protective factor. An inverse correlation was apparent between the age and the composite Z-score of the BACS-J (r = -0.431, p < 0.001). Receiver operating characteristic (ROC) analysis identified 53 years as the cutoff age for predicting more than -2SD cognitive decline from the normal standard, with a high negative predictive value (95%). Patients with AUD aged ≥53 years showed more pronounced impairments in verbal memory, working memory, verbal fluency, and attention than those younger than 53 years (p < 0.05). These findings clearly demonstrate accelerated age-related cognitive decline in patients with AUD, especially those aged ≥53 years, suggesting the necessity of early intervention in patients with AUD to prevent progressive cognitive impairment and preserve their quality of life.


Comparison of high dose ivermectin and diethylcarbamazine for activity against bancroftian filariasis in Haiti.
This three-phase study was designed to compare high dose ivermectin with a standard diethylcarbamazine (DEC) regimen for patient tolerability, potential to kill adult filaria, and duration of microfilarial suppression in 30 Haitian subjects with Wuchereria bancrofti microfilaremia. All were first given a 1-mg oral dose of ivermectin (phase 1) to reduce microfilaria densities. Participants were randomized into three groups: Group 1 received DEC (6mg/kg per day for 12 days), Group 2 received 200 mcg/kg of ivermectin, and Group 3 received 400 mcg/kg of ivermectin (200 mcg/kg per day for 2 days). All drug regimens were well tolerated with few adverse reactions. Most reactions occurred during phase I and consisted primarily of headache, fever, and myalgia. At the end of phase 1, 27 of 30 (90%) patients were microfilaria negative. During phase 2, four of the six men receiving DEC developed scrotal reactions suggesting killing adult worms; no such reactions were noted in 10 men receiving ivermectin (p less than 0.05). At one-year follow up (phase 3), all treatment groups had less than 10% return to pretreatment microfilaria levels. The mean percent of baseline microfilaria counts were for Group 1, 0.9% (range 0-5%); Group 2, 8.2% (range 0-31%); and Group 3, 3.8% (range 0-25%). Seven individuals in Group 1 were microfilaria-negative, while only one and three individuals were microfilaria-negative in Groups 2 and 3, respectively. These results suggest that DEC causes more damage to the adult worms and greater reduction in microfilaria densities than ivermectin, but that high doses of ivermectin may suppress microfilaremia in lymphatic filariasis for periods much longer than previously reported.


The attentive brain: insights from developmental cognitive neuroscience.
Visual attention functions as a filter to select environmental information for learning and memory, making it the first step in the eventual cascade of thought and action systems. Here, we review studies of typical and atypical visual attention development and explain how they offer insights into the mechanisms of adult visual attention. We detail interactions between visual processing and visual attention, as well as the contribution of visual attention to memory. Finally, we discuss genetic mechanisms underlying attention disorders and how attention may be modified by training.


Atrial Fibrillation and Mortality in Critically Ill Patients: A Retrospective Study.
Although atrial fibrillation is common in critically ill patients, no large studies on its impact on patient mortality in general intensive care units have been done. To evaluate the association between atrial fibrillation and hospital mortality in critically ill patients. In a retrospective cohort study, critically ill patients who had atrial fibrillation during a 2-year period were compared with patients who did not. The primary outcome was death during the hospital stay. Secondary outcomes were duration of mechanical ventilation and lengths of stay in the intensive care unit and hospital. Among a total of 2018 first-time admissions to the intensive care unit during the study period, 421 patients (20.9%) had atrial fibrillation. Patients with atrial fibrillation had higher mortality, significantly longer duration of mechanical ventilation, and longer stays in the intensive care unit and in the hospital than did patients without this cardiac arrhythmia. However, multiple logistic regression analysis indicated that atrial fibrillation was not independently associated with a higher risk for death. Atrial fibrillation may not be independently associated with hospital mortality.


An analysis of the geographic variation in cancer incidence and its determinants in Ontario.
Cancer incidence data for the Ontario Public Health Units in 1980-91 were examined to investigate regional patterns and the existence of outlier values after adjustment for known risk factors. Candidate risk factors were derived from the Ontario Health Survey and the census. Weighted regressions were fit to the data, and the spatial pattern of the residuals was analyzed. The number of outlier data points with significant elevations or reductions in risk was close to that expected by chance. They were dispersed geographically, and occurred in a variety of cancer types. We conclude that, in general, most of the geographic variation in cancer risk can be associated with variation in known risk factors, and that there appear to be no broad regional effects remaining after adjustment for these factors. A few cancer sites provide limited evidence of regional effects that may warrant further investigation.


Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.
A cohort of 1792 human immunodeficiency virus (HIV)-positive and 2970 HIV-negative South African miners was observed for 12 months starting in February 1998. All-cause hospitalizations and deaths were significantly associated with HIV infection (respective unadjusted incidence rate ratios, 2.9 and 9.2; respective 95% confidence intervals, 2.5-3.4 and 5.5-16.0). Tuberculosis (TB), bacterial pneumonia, cryptococcosis, and trauma were the major causes of admission for HIV-positive patients, whereas Pneumocystis carinii pneumonia was an uncommon cause (respective admission rates, 8.5, 6.9, 2.2, 6.0, and 0.53 admissions per 100 person-years). Enteritis, bronchitis, urinary tract infections, and soft-tissue infections were also significantly associated with HIV infection. Cryptococcosis caused 44% of deaths among HIV-positive patients. Trauma was the main hazard for HIV-negative men, causing 42% of admissions and 60% of deaths. A broad range of infectious conditions is significantly associated with HIV infection in South African miners. Identification and implementation of effective prophylactic regimens are urgently needed.


Control the source: Source memory for semantic, spatial and self-related items in patients with LIFG lesions.
Patients with multimodal semantic deficits following stroke ('semantic aphasia') have largely intact knowledge, yet difficulty controlling conceptual retrieval to suit the circumstances. Although conceptual representations are thought to be largely distinct from episodic representations of recent events, controlled retrieval processes may overlap across semantic and episodic memory domains. We investigated this possibility by examining item familiarity and source memory for recent events in semantic aphasia following infarcts affecting left inferior frontal gyrus. We tested the hypothesis that the nature of impairment in episodic judgements reflects the need for control over retrieval: item familiarity might be relatively intact, given it is driven by strong cues (re-presentation of the item), while source recollection might be more impaired since this task involves resolving competition between several potential sources. This pattern was observed most strongly when the degree of competition between sources was higher, i.e., when non-meaningful sources had similar perceptual features, and existing knowledge was incongruent with the source. In contrast, when (i) spatial location acted as a strong cue for retrieval; (ii) existing knowledge was congruent with episodic memory and (iii) distinctiveness of sources was increased by means of self-referential processing, source memory reached normal levels. These findings confirm the association between deregulated control of semantic and episodic memory in patients with semantic aphasia and delineate circumstances that ameliorate or aggravate these deficits.


Concise review: Therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis.
Currently, the most effective therapy for acute liver failure and advanced cirrhosis is liver transplantation. However, this procedure has several limitations, including lack of donors, surgical complications, immunological suppression, and high medical costs. The alternative approaches that circumvent the use of a whole liver, such as stem cell transplantation, have been suggested as an effective alternate therapy for hepatic diseases. Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal cells, are self-renewing cells that can be found in almost all postnatal organs and tissues, including liver. During the past decade, great progress has been made in the field of MSC-dependent liver regeneration and immunomodulation. Because of their potential for differentiation into hepatocytes as well as their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of acute liver failure and cirrhosis. In this concise review, we have summarized therapeutic potential of MSCs in the treatment of acute liver failure and cirrhosis, emphasizing their regenerative and immunomodulatory characteristics after engraftment in the liver. We have also presented several outstanding problems including conflicting data regarding MSCs engraftment in the liver and unwanted mesenchymal lineage differentiation in vivo which limits MSC therapy as a mainstream treatment approach for liver regeneration. It can be concluded that efficient and safe MSC-based therapy for acute and chronic liver failure remains a challenging issue that requires more investigation and continuous cooperation between clinicians, researchers, and patients.


Cross-cultural and site-based influences on demographic, well-being, and social network predictors of risk perception in hazard and disaster settings in Ecuador and Mexico: predictors of risk perception in hazard and disaster settings in Ecuador and Mexico.
Although virtually all comparative research about risk perception focuses on which hazards are of concern to people in different culture groups, much can be gained by focusing on predictors of levels of risk perception in various countries and places. In this case, we examine standard and novel predictors of risk perception in seven sites among communities affected by a flood in Mexico (one site) and volcanic eruptions in Mexico (one site) and Ecuador (five sites). We conducted more than 450 interviews with questions about how people feel at the time (after the disaster) regarding what happened in the past, their current concerns, and their expectations for the future. We explore how aspects of the context in which people live have an effect on how strongly people perceive natural hazards in relationship with demographic, well-being, and social network factors. Generally, our research indicates that levels of risk perception for past, present, and future aspects of a specific hazard are similar across these two countries and seven sites. However, these contexts produced different predictors of risk perception-in other words, there was little overlap between sites in the variables that predicted the past, present, or future aspects of risk perception in each site. Generally, current stress was related to perception of past danger of an event in the Mexican sites, but not in Ecuador; network variables were mainly important for perception of past danger (rather than future or present danger), although specific network correlates varied from site to site across the countries.


Carbon speciation in ash, residual waste and contaminated soil by thermal and chemical analyses.
Carbon in waste can occur as inorganic (IC), organic (OC) and elemental carbon (EC) each having distinct chemical properties and possible environmental effects. In this study, carbon speciation was performed using thermogravimetric analysis (TGA), chemical degradation tests and the standard total organic carbon (TOC) measurement procedures in three types of waste materials (bottom ash, residual waste and contaminated soil). Over 50% of the total carbon (TC) in all studied materials (72% in ash and residual waste, and 59% in soil) was biologically non-reactive or EC as determined by thermogravimetric analyses. The speciation of TOC by chemical degradation also showed a presence of a non-degradable C fraction in all materials (60% of TOC in ash, 30% in residual waste and 13% in soil), though in smaller amounts than those determined by TGA. In principle, chemical degradation method can give an indication of the presence of potentially inert C in various waste materials, while TGA is a more precise technique for C speciation, given that waste-specific method adjustments are made. The standard TOC measurement yields exaggerated estimates of organic carbon and may therefore overestimate the potential environmental impacts (e.g. landfill gas generation) of waste materials in a landfill environment.


Oliver Heaviside's electromagnetic theory.
The year 2018 marks the 125th anniversary of the first of three published volumes on electromagnetic theory by the eminent Victorian electrical engineer, physicist and mathematician, Oliver Heaviside FRS. This commemorative issue of Philosophical Transactions of the Royal Society A celebrates the publication of this work by collecting papers on a broad spectrum across the field of electromagnetic theory, including innovative research papers interspersed between historical perspectives and relevant reviews. Heaviside was a remarkable man, an original thinker with brilliant mathematical powers and physical insight who made many significant contributions in his fields of interest, though he is remembered primarily for his 'step function', commonly used today in many branches of physics, mathematics and engineering. Here, we celebrate the man and his work by illustrating his major contributions and highlighting his great success in solving some of the great telegraphic engineering problems of the Victorian era, in part due to his development and detailed understanding of the governing electromagnetic theory. We celebrate his Electromagnetic theory: three volumes of insights, techniques and understanding from mathematical, physical and engineering perspectives-as dictated by J. C. Maxwell FRS, but interpreted, reformulated and expanded by Heaviside to advance the art and science of electrical engineering beyond all expectations.This article is part of the theme issue 'Celebrating 125 years of Oliver Heaviside's 'Electromagnetic Theory''.


Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab.
To assess the effects of intravitreal ranibizumab therapy on intraocular pressure (IOP) and retinal nerve fiber (RNFL) thickness. Forty-nine eyes of 49 patients with neovascular age-related macular degeneration (AMD) treated with intravitreal ranibizumab injections and 27 fellow eyes not requiring treatment were followed for 1 year. RNFL thickness, as measured by Fourier domain optical coherence tomography, and IOP were determined pre- and postinjection. After 12 months, the mean number of injections received was 4.8 ± 1.6. The incidence of IOP elevations (>5 mm Hg over baseline) observed at the time of injection was 0.4%. Baseline RNFL thickness was 105.7 ± 12.2 μm in the treatment group compared with 101.8 ± 11.6 μm in the control group (P = 0.176). At the end of follow-up, significant RNFL thinning was noted in the treatment group (100.2 ± 11.0 μm, P < 0.001), whereas no differences were found in the control group (100.5 ± 10.8 μm, P = 0.477). Intravitreal ranibizumab injections used to treat AMD caused a significant change in RNFL thickness after 12 months of follow-up.


Patient crossover and potentially avoidable repeat computed tomography exams across a health information exchange.
The purpose of this study was to measure the number of repeat computed tomography (CT) scans performed across an established health information exchange (HIE) in New York City. The long-term objective is to build an HIE-based duplicate CT alerting system to reduce potentially avoidable duplicate CTs. This retrospective cohort analysis was based on HIE CT study records performed between March 2009 and July 2012. The number of CTs performed, the total number of patients receiving CTs, and the hospital locations where CTs were performed for each unique patient were calculated. Using a previously described process established by one of the authors, hospital-specific proprietary CT codes were mapped to the Logical Observation Identifiers Names and Codes (LOINC®) standard terminology for inter-site comparison. The number of locations where there was a repeated CT performed with the same LOINC code was then calculated for each unique patient. There were 717 231 CTs performed on 349 321 patients. Of these patients, 339 821 had all of their imaging studies performed at a single location, accounting for 668 938 CTs. Of these, 9500 patients had 48 293 CTs performed at more than one location. Of these, 6284 patients had 24 978 CTs with the same LOINC code performed at multiple locations. The median time between studies with the same LOINC code was 232 days (range of 0 to 1227); however, 1327 were performed within 7 days and 5000 within 30 days. A small proportion (3%) of our cohort had CTs performed at more than one location, however this represents a large number of scans (48 293). A noteworthy portion of these CTs (51.7%) shared the same LOINC code and may represent potentially avoidable studies, especially those done within a short time frame. This represents an addressable issue, and future HIE-based alerts could be utilized to reduce potentially avoidable CT scans.


Rituximab Use in the Management of Childhood Nephrotic Syndrome.
Childhood nephrotic syndrome is a challenging and often persistent renal disorder, and its incidence varies between different ethnicities and regions. Corticosteroids have been the main treatment for decades and are effective in most children with idiopathic NS, although 10-15% of these children become steroid resistant. Furthermore, some initially steroid sensitive children follow a steroid dependent or frequently relapsing course and are therefore at increased risk for developing steroid toxicity. In such children, alternative immunosuppressive medications are used to induce and/or maintain remission of NS. One such drug, rituximab, is a monoclonal antibody directed against the B lymphocyte CD20 marker which induces depletion of B cells, and has shown promising results in the management of NS in children. In this review, we summarize recent studies on the efficacy and safety of rituximab in the different types of childhood nephrotic syndrome, the known and potential mechanisms of action of rituximab, its possible complications and side effects, and the available and potential biomarkers of rituximab activity.


N-methyl-D-aspartate and vasopressin activate distinct voltage-dependent inward currents in facial motoneurones.
Facial motoneurones of the rat respond to arginine vasopressin by generating a voltage-dependent inward current which is sodium-dependent and is resistant to tetrodotoxin. In the present study, we have investigated the action of N-methyl-D-aspartate (NMDA) on these same neurones. We have obtained single-electrode voltage-clamp recordings from brainstem slices of newborn rats. In a majority of vasopressin-sensitive facial motoneurones, NMDA induced an inward current. This action was direct, was concentration-related and could be suppressed by the specific competitive antagonist D-2-amino-5-phosphopentanoic acid (D-AP5). The NMDA-evoked current increased in amplitude as the neuronal membrane was depolarized. It could be blocked by the noncompetitive antagonist MK-801. It was potentiated following removal of extracellular magnesium, and was attenuated or suppressed when the external magnesium concentration was increased from 1 to 10 mM. By contrast, none of these treatments affected the vasopressin-induced current. These results show that facial motoneurones in the rat possess functional NMDA receptors and indicate that NMDA and vasopressin affect the bioelectrical properties of these neurones by turning on distinct voltage-dependent inward currents.


Causal effect models for realistic individualized treatment and intention to treat rules.
Marginal structural models (MSM) are an important class of models in causal inference. Given a longitudinal data structure observed on a sample of n independent and identically distributed experimental units, MSM model the counterfactual outcome distribution corresponding with a static treatment intervention, conditional on user-supplied baseline covariates. Identification of a static treatment regimen-specific outcome distribution based on observational data requires, beyond the standard sequential randomization assumption, the assumption that each experimental unit has positive probability of following the static treatment regimen. The latter assumption is called the experimental treatment assignment (ETA) assumption, and is parameter-specific. In many studies the ETA is violated because some of the static treatment interventions to be compared cannot be followed by all experimental units, due either to baseline characteristics or to the occurrence of certain events over time. For example, the development of adverse effects or contraindications can force a subject to stop an assigned treatment regimen.In this article we propose causal effect models for a user-supplied set of realistic individualized treatment rules. Realistic individualized treatment rules are defined as treatment rules which always map into the set of possible treatment options. Thus, causal effect models for realistic treatment rules do not rely on the ETA assumption and are fully identifiable from the data. Further, these models can be chosen to generalize marginal structural models for static treatment interventions. The estimating function methodology of Robins and Rotnitzky (1992) (analogue to its application in Murphy, et. al. (2001) for a single treatment rule) provides us with the corresponding locally efficient double robust inverse probability of treatment weighted estimator.In addition, we define causal effect models for "intention-to-treat" regimens. The proposed intention-to-treat interventions enforce a static intervention until the time point at which the next treatment does not belong to the set of possible treatment options, at which point the intervention is stopped. We provide locally efficient estimators of such intention-to-treat causal effects.


Human-specific regulation of alpha 2-6-linked sialic acids.
Many microbial pathogens and toxins recognize animal cells via cell surface sialic acids (Sias) that are alpha 2-3- or alpha 2-8-linked to the underlying glycan chain. Human influenza A/B viruses are unusual in preferring alpha 2-6-linked Sias, undergoing a switch from alpha 2-3 linkage preference during adaptation from animals to humans. This correlates with the expression of alpha 2-6-linked Sias on ciliated human airway epithelial target cells and of alpha 2-3-linked Sias on secreted soluble airway mucins, which are unable to inhibit virus binding. Given several known differences in Sia biology between humans and apes, we asked whether this pattern of airway epithelial Sia linkages is also human-specific. Indeed, we show that since the last common ancestor with apes, humans underwent a concerted bidirectional switch in alpha 2-6-linked Sia expression between airway epithelial cell surfaces and secreted mucins. This can explain why the chimpanzee appears relatively resistant to experimental infection with human Influenza viruses. Other tissues showed additional examples of human-specific increases or decreases in alpha 2-6-linked Sia expression and only one example of a change specific to certain great apes. Furthermore, while human and great ape leukocytes both express alpha 2-6-linked Sias, only human erythrocytes have markedly up-regulated expression. These cell type-specific changes in alpha 2-6-Sia expression during human evolution represent another example of a human-specific change in Sia biology. Because the data set involves multiple great apes, we can also conclude that Sia linkage expression patterns can be conserved during millions of years of evolution within some vertebrate taxa while undergoing sudden major changes in other closely related ones.


Prevalence of erectile dysfunction in male survivors of cancer: a systematic review and meta-analysis of cross-sectional studies.
Prevalence of erectile dysfunction (ED) in male survivors of cancer across cancer types has not been systematically analysed. To estimate the prevalence of ED in all types of cancer and identify characteristics associated with ED in survivors of cancer. Systematic review and meta-analysis (MA) of cross-sectional studies. MEDLINE, CINAHL, PsycINFO, and EMBASE were searched, targeting reports published from inception to 1 February 2020. All retrospective or prospective studies reporting prevalence of ED in male patients with cancer and using a validated tool for detection of ED were included. A random-effects MA model was used to pool prevalence of ED as absolute estimates at three different stages, that is, 'healthy', 'at diagnosis', and 'after treatment'. A univariate MA regression including the three-level group variable as the only independent variable was used to assess the difference in ED prevalence across the three groups. Further MAs were conducted for studies involving patients at diagnosis and after treatment, and statistical inferences were made with setting for multiple testing controlling for a false discovery rate (FDR) <0.05. In total, 1301 studies were assessed for inclusion. Of these, 141 were potentially eligible and subsequently scrutinised in full text. Finally, 43 studies were included with a total of 13 148 participants. Overall, pooled data of the included studies showed an ED prevalence of 40.72% (95% confidence interval [CI] = 31.80 to 50.29) in patients with cancer, with prevalences of 28.60% (95% CI = 12.10 to 53.83) at time of diagnosis and 42.70% (95% CI = 32.97 to 53.03) after treatment, with significant difference between these two stages and across cancer locations, controlling for an FDR <0.05. Erectile dysfunction was particularly high in male survivors of cancer and was associated with cancer treatment, cancer site, and age.


What are the indications for bariatric surgery?
No studies evaluate the commonly used indications for bariatric surgery. Consensus guidelines suggest that the surgical treatment of obesity should be reserved for patients with a body-mass index (BMI) >40 kg/m(2) or with BMI >35 kg/m(2) and 1 or more significant comorbid conditions, when less invasive methods of weight loss have failed and the patient is at high risk for obesity-associated morbidity and mortality (strength of recommendation: C, based on consensus guidelines).