DivulgaMicro : A Brazilian Initiative To Empower Early-Career Scientists with Science Communication Skills.
Communication is fundamental in science. Among scientists, communication skills are required to write a comprehensible scientific manuscript or to prepare an attractive oral presentation. In addition, the ability to communicate successfully with the nonscientific community has been increasingly appreciated, as it represents the most effective way to promote popular scientific literacy. Nevertheless, students majoring in sciencerelated courses are not trained specifically for these purposes, and improving communication skills usually depends on tips and advice given by peers. To this end, we have launched DivulgaMicro, an initiative that aims to enhance science communication among early-career scientists in Brazil. DivulgaMicro relies on two major cornerstones: providing online resources via a dedicated website (www.divulgamicro.com.br/index.html) and promoting onsite workshops in universities located in different macro regions of the country. On the website, people can access a collection of fun activities designed to teach scientific concepts to a general audience, along with tips and news regarding public outreach events in Brazil. In the month following its launch, our website had 1,026 visitors from 10 different countries besides Brazil. Regarding the workshops, six were offered during 2018, with nearly 600 attendees. In the course, scientists are presented best practices for scientific writing and oral presentations, as well as techniques to improve communication with lay audiences, such as the use of storytelling structure and analogies. There is a high demand for science communication resources in Brazil, attesting to the importance of initiatives such as DivulgaMicro in our country.


Pain, fatigue and well-being one to five years after lung transplantation - a nationwide cross-sectional study.
Little is known about persistent pain after lung transplantation. Therefore, the aim was to present a multidimensional assessment of self-reported pain 1-5 years after lung transplantation and its relationship with fatigue and transplant-specific well-being. This nationwide, cross-sectional cohort study is part of the self-management after thoracic transplantation study. A total of 117 lung recipients, all White, who were due for their annual follow-up at one (n = 35), two (n = 28), three (n = 23), four (n = 20) and 5 years (n = 11) after lung transplantation were included. We used three instruments; the Pain-O-Meter (POM), which provides information about pain intensity, sensation, location and duration, the MFI-19 fatigue instrument and the Organ Transplant Symptom and Well-being Instrument (OTSWI). Permission to carry out this study was granted by the Regional Ethical Review Board in southern Sweden (D-nr 2014-124). The prevalence of pain was 51% after 1 year, 68% after 2 years, 69.5% after 3 years, 75% after 4 years and 54.5% after 5 years. Women experienced more pain than men. Lung recipients with pain reported lower well-being and higher symptom distress but were not more fatigued than those without pain. The limitations of this study are due to the cross-sectional design. The recruitment of patients during the study period was probably affected by the different conditions regarding staffing at the outpatient lung transplant clinic in the two thoracic transplant centres in Sweden. The slightly different approach to the care of these patients in the pre, peri and postoperative setting contributes to the heterogeneity of the study population. Chronic bodily pain up to 5 years after lung transplantation reduces perceived well-being. Lung recipients with pain report higher symptom distress than those without pain.


European Portuguese Adaptation of Glasgow Content of Thoughts Inventory (GCTI): Psychometric Characterization in Higher Education Students.
Persistent cognitive activity is an important factor in disturbing sleep-onset both during bedtime and when attempting to get back to sleep after nocturnal awakenings. One of the most specific self-report measures designed to assess this feature is the Glasgow Content of Thoughts Inventory (GCTI). In this study, we investigated the preliminary psychometric properties of GCTI in a large sample of higher education European Portuguese students (N = 2995). Our results suggest that there is evidence of good internal consistency (α = 0.93) and validity indicators. Moreover, we found an interpretable factorial structure comprising 5 correlated factors that needs to be confirmed in future studies. The European Portuguese version of the GCTI appears to be a reliable and valid instrument for measurement of sleep-onset disturbing cognitions.


Determination of the InvE binding site required for expression of IpaB of the Shigella sonnei virulence plasmid: involvement of a ParB boxA-like sequence.
The InvE protein positively regulates the expression of virulence genes ipaBCD in Shigella sonnei. The InvE has significant homology with ParB of plasmid P1, which is known as a plasmid partitioning factor with DNA binding ability. Although the DNA binding activity of InvE has been predicted, it is not known whether the DNA binding activity is necessary for type III secretion system-associated gene expression. In this study, we determined the transcription start site of the icsB-ipaBCD operon (ipa operon) and constructed a series of deletions of the icsB promoter region in the Escherichia coli K-12 background. The deletion study revealed that an 86-bp region upstream of the icsB transcription start site was essential for expression of the ipa operon, where the ParB binding motif (ParB BoxA-like sequence) was observed. Purified glutathione S-transferase-InvE fusion protein bound directly to the -93 to -54 region (designating the icsB transcription start site as nucleotide +1) containing the ParB BoxA-like sequence. These results indicated that InvE bound directly to the promoter region.


Immunizing effect of vaccinia virus expressing the nucleoprotein of rinderpest virus on systemic rinderpest virus infection in rabbits.
A recombinant vaccinia virus (RVV) expressing the nucleoprotein (NP) of rinderpest virus (RPV) was examined in rabbits for the involvement of the NP protein in protection from the RPV infection. Despite their production of anti-NP antibody, the RVV-immunized rabbits succumbed to the RPV challenge, although there was a slight delay in the onset of disease after the low-dose challenge. On the other hand, the animals immunized with RVV expressing the hemagglutinin (H) protein of the RPV were completely protected. These results indicate that the NP protein might be not so effective as the H protein for the protection against viremic and systemic infection with RPV.


Engineered exosomes delivering specific tumor-suppressive RNAi attenuate oral cancer progression.
Exosomes are involved in a wide range of biological processes in human cells. Considerable evidence suggests that engineered exosomes (eExosomes) containing therapeutic agents can attenuate the oncogenic activity of human cancer cells. Despite its biomedical relevance, no information has been available for oral squamous cell carcinoma (OSCC), and therefore the development of specific OSCC-targeting eExosomes (octExosomes) is urgently needed. We demonstrated that exosomes from normal fibroblasts transfected with Epstein-Barr Virus Induced-3 (EBI3) cDNA were electroporated with siRNA of lymphocyte cytoplasmic protein 1 (LCP1), as octExosomes, and a series of experiments were performed to evaluate the loading specificity/effectiveness and their anti-oral cancer cell activities after administration of octExosomes. These experiments revealed that octExosomes were stable, effective for transferring siLCP1 into OSCC cells and LCP1 was downregulated in OSCC cells with octExosomes as compared with their counterparts, leading to a significant tumor-suppressive effect in vitro and in vivo. Here we report the development of a new valuable tool for inhibiting tumor cells. By engineering exosomes, siLCP1 was transferred to specifically suppress oncogenic activity of OSCC cells. Inhibition of other types of human malignant cells merits further study.


Phytotherapeutics against Alzheimer's Disease: Mechanism, Molecular Targets and Challenges for Drug Development.
Alzheimer's disease is inflating worldwide and is combatted by only a few approved drugs. At best, these drugs treat symptomatic conditions by targeting cholinesterase and N-methyl- D-aspartate receptors. Most of the clinical trials in progress are focused on developing disease-modifying agents that aim at single targets. The 'one drug-one target' approach is failing in the case of Alzheimer's disease due to its labyrinth etiopathogenesis. Traditional medicinal systems like Ayurveda use a holistic approach encompassing the legion of medicinal plants exhibiting multimodal activity. Recent advances in high-throughput technologies have catapulted the research in the arena of Ayurveda, specifically in identifying plants with potent anti-Alzheimer's disease properties and their phytochemical characterization. Nonetheless, clinical trials of very few herbal medicines are in progress. This review is a compendium of Indian plants and ayurvedic medicines against Alzheimer's disease and their paraphernalia. A record of 230 plants that are found in India with anti-Alzheimer's disease potential and about 500 phytochemicals from medicinal plants have been solicited with the hope of exploring the unexplored. Further, the molecular targets of phytochemicals isolated from commonly used medicinal plants, such as Acorus calamus, Bacopa monnieri, Convolvulus pluricaulis, Tinospora cordifolia and Withania somnifera, have been reviewed with respect to their multidimensional property, such as antioxidant, anti-inflammation, anti-aggregation, synaptic plasticity modulation, cognition, and memory-enhancing activity. In addition, the strengths and challenges in ayurvedic medicine that limit its use as mainstream therapy are discussed, and a framework for the development of herbal medicine has been proposed.


Transcriptional pause, arrest and termination sites for RNA polymerase II in mammalian N- and c-myc genes.
Using either highly purified RNA polymerase II (pol II) elongation complexes assembled on oligo(dC)-tailed templates or promoter-initiated (extract-generated) pol II elongation complexes, the precise 3" ends of transcripts produced during transcription in vitro at several human c- and N- myc pause, arrest and termination sites were determined. Despite a low overall similarity between the entire c- and N- myc first exon sequences, many positions of pol II pausing, arrest or termination occurred within short regions of related sequence shared between the c- and N- myc templates. The c- and N- myc genes showed three general classes of sequence conservation near intrinsic pause, arrest or termination sites: (i) sites where arrest or termination occurred after the synthesis of runs of uridines (Us) preceding the transcript 3" end, (ii) sites downstream of potential RNA hairpins and (iii) sites after nucleotide addition following either a U or a C or following a combination of several pyrimidines near the transcript 3" end. The finding that regions of similarity occur near the sites of pol II pausing, arrest or termination suggests that the mechanism of c- and N- myc regulation at the level of transcript elongation may be similar and not divergent as previously proposed.


Analyzing phase III studies in hospice/palliative care. a solution that sits between intention-to-treat and per protocol analyses: the palliative-modified ITT analysis.
Intention-to-treat (ITT) analyses are the standard way to evaluate randomized controlled trials (RCTs) to minimize Type I errors related to differential rates of noncompletion from one study arm. People in palliative care often die sooner than predicted as a direct result of disease progression, some of whom will be participating in RCTs and who will, therefore, withdraw or die after randomization for reasons unrelated to the intervention. This proportion of withdrawals is statistically negligible in other clinical disciplines, but commonplace in hospice/palliative care, creating a systematic bias away from the true effect. ITT analyses in hospice/palliative care that deem all withdrawals to be treatment failures or that impute data from deteriorating participants systematically underestimate the benefits of interventions, reducing the power of these studies. Equally unacceptable would be a per protocol analysis that excludes all withdrawals after randomization as this will underestimate toxicity. A modified analytic approach is needed on a continuum between ITT and per protocol analyses. To address data after randomization where there is a high rate of withdrawals because of death or deterioration, criteria need to include being: 1) prespecified in the original protocol; 2) clinically absolutely the result of disease progression; 3) identified by the blinded Independent Data Monitoring Committee as being unrelated to the intervention(s); and 4) accounted for in the study's CONSORT diagram. Such data should not be included in the analysis of the primary outcome. This article aims to define a better way of balancing Type I and Type II errors in hospice/palliative care RCT analyses using the palliative-modified ITT analysis. Arguably, the palliative-modified ITT analysis should be the primary evaluation of hospice/palliative care Phase III studies but, as a minimum, should routinely be the key sensitivity analysis.


Primary malignant fibrous histiocytoma of the pleura. A case report.
A rare primary malignant fibrous histiocytoma of the pleura is described. The tumor was found in an elderly male and was followed for more than ten years without treatment. At the terminal stage, the patient developed a malignant pleural effusion, which contained mainly histiocytelike, rounded forms with many bizarre and multinucleated giant tumor cells. The main tumor mass was characterized by dual fibroblastlike and histiocytelike cellular components and a storiform growth pattern. In the solid areas, the tumor cells were mainly fibroblastlike spindle-shaped forms, which produced collagen. The tumor cells in the loose, vascular areas and in the effusion were predominantly histiocytelike, with some exhibiting phagocytic activity. We believe that this is the first reported case of a malignant fibrous histiocytoma of the pleura with a malignant effusion showing a preferential histiocytelike differentiation of tumor cells in the fluid environment.


Tomographic myocardial perfusion imaging with technetium-99m-teboroxime at rest and after dipyridamole.
This study was done to determine whether the rapidly clearing myocardial perfusion agent 99mTc-teboroxime (SQ 30217, Cardiotec) could be combined with tomographic imaging to accurately quantify regional myocardial blood flow distribution in anesthetized dogs. Following stenosis of the anterior descending (LAD, n = 10) or circumflex (LCX, n = 5) coronary arteries, teboroxime was administered simultaneously with radioactive microspheres, at rest and following infusion of dipyridamole (0.15 mg/kg/min x 4 min). Tomographic imaging began 1 min after each teboroxime injection and continued for 12 min. For LAD stenosis, when the dipyridamole study was performed first, teboroxime activity in the center of the ischemic region was closely correlated with tissue microsphere content. However, the severity of the dipyridamole-induced flow deficit was underestimated by teboroxime when the rest study was performed first. Our results show that despite rapid myocardial clearance, tomographic imaging of 99mTc-teboroxime provides reasonably accurate quantitation of dipyridamole-induced anterior wall perfusion defects, but that the flow deficit is underestimated when a rest study is performed first or when the defect is located in the inferior wall.


Reducing exposure to ultraviolet radiation from the sun and indoor tanning: A meta-analysis.
Objective: Skin cancer is the most frequently diagnosed cancer and rates are increasing because of global warming. This article reports a meta-analysis of randomized controlled trials of behavioral interventions to reduce exposure to ultraviolet radiation (UVR). The review aimed to (a) quantify the magnitude of intervention effects on indoor tanning, sun exposure, and sunscreen use, and (b) determine which intervention strategies maximize behavior change. Method: Out of 17,437 records identified via literature searches, 190 independent tests (N = 89,365) met the inclusion criteria. Sample, intervention, and methodological characteristics, and change techniques were coded, and random effects meta-analyses and metaregressions were conducted. Results: The sample-weighted average effect size across all studies was d+ = .193 (95% confidence interval, CI [.161, .226]), and there were significant effects on indoor tanning, sun exposure, and sunscreen use (d+ = .080, .149, and .196, respectively). However, there was evidence of publication bias, and trim and fill analyses indicated that the corrected effects for sun exposure and sunscreen use were of very small magnitude (d+ ~ .06) and were not significantly different from zero for indoor tanning (d+ = -.011, 95% CI [-.096, .074]). Metaregression analyses identified several intervention strategies that predicted effect sizes. For instance, interventions delivered individually that promoted alternatives to tanning were associated with larger effect sizes for indoor tanning. Conclusion: Interventions to date have had only a modest impact on behavioral exposure to UVR. The present findings offer new insights into how the effectiveness of future interventions can be improved. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


A possibility for strengthening family life and health: Family members' lived experience when a sick child receives home care in Sweden.
Families often prefer home care to hospital care, and home-care services for ill children are increasing worldwide with limited knowledge of families' needs during curative and palliative home care. The aim of this study was to elucidate family members' lived experience when a sick child received home care from county-based primary healthcare services. A descriptive qualitative design was chosen and 12 families including sick children receiving home care and their mothers, fathers and siblings in the south of Sweden were interviewed between December 2015 and January 2017. The transcribed interviews were analysed using a hermeneutic phenomenological approach. The family members' lived experience was described in three essential themes: "Strengthening family life" relates to how home care induced freedom and luxury in a strained period of life and supported the families' everyday life. Usual social activities and relations were maintained as time and energy was saved when receiving home care. "Promoting health" relates to how the family members' burden of illness decreased as the child's signs of illness alleviated and the well-being of the whole family increased when the child received care in the home. This provided a peaceful respite for family members' psychosocial recovery. The third theme, "Creating alliances," relates to the importance of creating trustful alliances for communicating participation in care. If trustful alliances were not created, parents felt an overwhelming responsibility and family members became anxious. The findings suggest that care in the family's home is a useful complement to hospital care. Home care should be given with close attention to family members' needs and conditions, as positive effects of home care might be jeopardised when expectations and possibilities are not successfully shared.


Adrenocorticotropic hormone directly stimulates testosterone production by the fetal and neonatal mouse testis.
Adult Leydig cell steroidogenesis is dependent on LH but fetal Leydig cells can function independently of gonadotropin stimulation. To identify factors that may be involved in regulation of fetal Leydig cells expressed sequence tag libraries from fetal and adult testes were compared, and fetal-specific genes identified. The ACTH receptor [melanocortin type 2 receptor (Mc2r)] was identified within this fetal-specific group. Subsequent real-time PCR studies confirmed that Mc2r was expressed in the fetal testis at 100-fold higher levels than in the adult testis. Incubation of fetal or neonatal testes with ACTH in vitro stimulated testosterone production more than 10-fold, although ACTH had no effect on testes from animals aged 20 d or older. The steroidogenic response of fetal and neonatal testes to a maximally stimulating dose of human chorionic gonadotropin was similar to the response shown to ACTH. The ED(50) for ACTH, measured in isolated fetal and neonatal testicular cells, was 5 x 10(-10) M and the lowest dose of ACTH eliciting a response was 2 x 10(-11) M. Circulating ACTH levels in fetal mice were around 8 x 10(-11) M. Neither alpha-MSH nor gamma-MSH had any effect on androgen production in vitro at any age. Fetal testosterone levels were normal in mice that lack circulating ACTH (proopiomelanocortin-null) indicating that ACTH is not essential for fetal Leydig cell function. Results show that both LH and ACTH can regulate testicular steroidogenesis during fetal development in the mouse and suggest that fetal Leydig cells, but not adult Leydig cells, are sensitive to ACTH stimulation.


Recovery of patients with severe depression in inpatient rural psychiatry: a descriptive clinical study.
Objectives: The aim of this study was to investigate the level of and the relationship between symptoms and health-related quality of life (HRQoL) at admittance and recovery at discharge in patients with severe depression, in a rural inpatient psychiatric setting. Furthermore, whether the anxiety level at admission and/or, if the extent of patients' perception of family support from professionals were related to recovery.Method: Patients admitted with depression were consecutively invited to participate during a 12-month period. Depression, anxiety and stress were measured with DASS (The Depression Anxiety Stress Scale) and HRQoL with The Icelandic Quality of Life scale at admission and discharge. Family support was measured with Icelandic Family Perceived Support Questionnaire at discharge.Results: Majority of the participants had severe depression and anxiety scores (93.8% and 76.9%, respectively) at admission and HRQoL was impaired, especially in men. At discharge, almost three quarters of the participants had recovered into the outpatient or functional symptoms level and HRQoL had increased significantly. Morbid anxiety delayed recovery significantly, but perceived cognitive family support was positively related to depression recovery.Conclusion: Hospitalisation is an effective intervention for severe depression in rural Iceland. Positive benefits in both depression and HRQoL occur, where most of the participants reach outpatient or normal level of depression.


The protease activated receptor 2 (PAR2) polymorphic variant F240S constitutively activates PAR2 receptors and potentiates responses to small-molecule PAR2 agonists.
AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]-(4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide] are the first two small-molecule agonists described for the G protein-coupled receptor protease-activated receptor 2 (PAR2), but whether they activate PAR2 through a similar mechanism as its tethered peptide ligand or soluble peptide mimetics of its tethered peptide ligand is unclear. Extracellular loop 2 (ECL2) has been shown to play a critical role in the activation mechanism of PAR2. Therefore, we constructed a series of PAR2 receptors mutated in ECL2, including a previously described polymorphic variant of PAR2 (F240S), and compared AC-55541 and AC-264613 to SLIGRL and a potent analog of SLIGRL called 2-furoyl LIGRLO in a series of functional assays, including cellular proliferation, phosphatidylinositol hydrolysis, and β-arrestin recruitment assays. Surprisingly, receptors with the F240S mutation were constitutively active in all functional assays tested. Furthermore, AC-55541 and AC-264613 were potentiated over 30-fold at the receptors with the F240S mutation, whereas SLIGRL and 2-furoyl LIGRLO were much less affected. In contrast, mutagenesis of charged residues in ECL2 confirmed their important role in the actions of peptide agonists of PAR2, whereas these mutations did not significantly affect activation of PAR2 by AC-55541 or AC-264613. These results suggest that F240S PAR2 receptors may be useful in screens to detect novel small-molecule PAR2 modulators and that further work on the biological importance of the F240S PAR2 variant is warranted.


Predicting which type of push notification content motivates users to engage in a self-monitoring app.
Despite the unprecedented access to self-monitoring health apps, lack of optimal user engagement remains a significant challenge. Push notification prompts with contextually tailored messages offers a promising strategy to improve engagement. To increase the efficacy of push-notifications on engaging individuals with health apps, greater attention to the modifiable components of push notifications that influence responsiveness is needed. This study examines the effect of message content and frequency of push notifications, along with past app usage on responding to notifications within 24 h, and engaging with self-monitoring in JOOL Health smartphone app. Mixed models were applied on a de-identified data set of 18,000 contextually tailored push notifications sent by JOOL Health App to 1414 participants. The content in sent messages on behavioural topics were mapped into either tailored suggestions or tailored insights. Our findings suggest that push notifications with tailored suggestions were more effective overall in encouraging self-monitoring, but amongst frequent app users, push-notifications containing insights was associated with greater self-monitoring. People who were not using the app as frequently were less likely to respond to a prompt. This study suggests that push-notification content does have an impact on subsequent use of key app features, and app developers should consider what content is likely to work best for who, and under what circumstances. Secondary data-analysis of commercial apps presents a unique opportunity to elucidate and optimize health behaviors.


Spinal cord injury-induced gut dysbiosis influences neurological recovery partly through short-chain fatty acids.
Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut-brain interactions and their clinical implications have not been elucidated. We hypothesized that short-chain fatty acids (SCFAs), intestinal microbial bioactive metabolites, may significantly affect the gut-brain axis and enhance functional recovery in a mouse model of SCI. We enrolled 59 SCI patients and 27 healthy control subjects and collected samples. Thereafter, gut microbiota and SCFAs were analyzed using 16 S rDNA sequencing and gas chromatography-mass spectrometry, respectively. We observed an increase in Actinobacteriota abundance and a decrease in Firmicutes abundance. Particularly, the SCFA-producing genera, such as Faecalibacterium, Megamonas, and Agathobacter were significantly downregulated among SCI patients compared to healthy controls. Moreover, SCI induced downregulation of acetic acid (AA), propionic acid (PA), and butyric acid (BA) in the SCI group. Fecal SCFA contents were altered in SCI patients with different injury course and injury segments. Main SCFAs (AA, BA, and PA) were administered in combination to treat SCI mice. SCFA supplementation significantly improved locomotor recovery in SCI mice, enhanced neuronal survival, promoted axonal formation, reduced astrogliosis, and suppressed microglial activation. Furthermore, SCFA supplementation downregulated NF-κB signaling while upregulating neurotrophin-3 expression following SCI. Microbial sequencing and metabolomics analysis showed that SCI patients exhibited a lower level of certain SCFAs and related bacterial strains than healthy controls. SCFA supplementation can reduce inflammation and enhance nourishing elements, facilitating the restoration of neurological tissues and the improvement of functional recuperation. Trial registration: This study was registered in the China Clinical Trial Registry ( www.chictr.org.cn ) on February 13, 2017 (ChiCTR-RPC-17010621).


Placental transfer of cefotiam dihydrochloride.
The concentrations of cefotiam dihydrochloride (CTM) in maternal and fetal blood and in amniotic fluid were determined by bioassay in 38 women at parturition. With an intravenous infusion of 1 g of CTM, the decline in concentration of CTM in maternal blood was biphasic; CTM was not detectable at 6 h after administration. Peak levels of CTM in umbilical cord blood (13.0 to 23.9 micrograms/ml) were attained between 15 and 28 min after intravenous infusion; those in amniotic fluid (19.6 to 23.5 micrograms/ml) were attained at ca. 2.5 h.


Association between obesity and asthma in 4-11 year old children in the UK.
There is evidence of a positive association between asthma and obesity in adults and in children. We investigated, in a large sample of English and Scottish primary school children, whether there is a consistent association between fatness and asthma symptoms in Britain. A cross sectional analysis was made of 18 218 children aged 4-11 years who participated in the 1993 or 1994 surveys of the National Study of Health and Growth (NSHG). Children belonged either to English or Scottish representative samples, or an English inner city sample. Asthma attacks in the previous year, occasional wheeze, or persistent wheeze were the symptoms used in the analysis. Body mass index (BMI) and the sum of triceps and subscapular skinfolds converted to standard deviation scores (SDS) were used to assess levels of fatness. A total of 14 908 children (81.8%) were included in the analysis. In the multiple logistic analysis BMI and asthma (asthma attacks or wheeze) were associated in the representative sample (OR for the comparison of the 10th and 90th centiles of BMI 1.28, 95% CI 1.11 to 1.48), but sum of skinfolds was unrelated to asthma symptoms in most analyses. The association between asthma and BMI was stronger in girls than in boys in the inner city sample, but less convincingly in the representative sample. Levels of obesity are associated with asthma symptoms regardless of ethnicity. The association is more consistent for BMI than for sum of skinfolds, partly because obese children are more advanced in their maturation than other children. There is some evidence that, as in adults, the association is stronger in girls than in boys, but only in the multiethnic inner city sample.


Identity development and exploration among sexual minority adolescents: examination of a multidimensional model.
Based on a multidimensional model of sexual identity development, the current study examined self-labeling, romantic, and sexual experiences among middle and late adolescent sexual minorities. Eighty-two youths between the ages of 14 and 21 were recruited from gay, lesbian, bisexual, and transgender (GLBT) community centers and associated Internet groups. Differences between males and females and between middle and late adolescents were first examined. Males reported markedly different patterns of self-labeling and romantic experiences, relative to females, but few age differences emerged. Additionally, patterns of association between self-labeling and sexual or romantic experiences provided support for the multidimensional model of identity development and exploration. Finally, significant associations emerged between relationship experiences and relational competency, such that adolescents who described themselves as isolated from intimate interpersonal relationships reported less relational esteem and more relational depression than those who reported predominantly engaging in same-sex romantic relationships. In addition, alternative styles of engaging in interpersonal relationships (e.g., same-sex intimate friendships, heterosexual dating) also were also associated with increased relational competency.


Musculoskeletal modelling deconstructs the paradoxical effects of elastic ankle exoskeletons on plantar-flexor mechanics and energetics during hopping.
Experiments have shown that elastic ankle exoskeletons can be used to reduce ankle joint and plantar-flexor muscle loading when hopping in place and, in turn, reduce metabolic energy consumption. However, recent experimental work has shown that such exoskeletons cause less favourable soleus (SO) muscle-tendon mechanics than is observed during normal hopping, which might limit the capacity of the exoskeleton to reduce energy consumption. To directly link plantar-flexor mechanics and energy consumption when hopping in exoskeletons, we used a musculoskeletal model of the human leg and a model of muscle energetics in simulations of muscle-tendon dynamics during hopping with and without elastic ankle exoskeletons. Simulations were driven by experimental electromyograms, joint kinematics and exoskeleton torque taken from previously published data. The data were from seven males who hopped at 2.5 Hz with and without elastic ankle exoskeletons. The energetics model showed that the total rate of metabolic energy consumption by ankle muscles was not significantly reduced by an ankle exoskeleton. This was despite large reductions in plantar-flexor force production (40-50%). The lack of larger metabolic reductions with exoskeletons was attributed to increases in plantar-flexor muscle fibre velocities and a shift to less favourable muscle fibre lengths during active force production. This limited the capacity for plantar-flexors to reduce activation and energy consumption when hopping with exoskeleton assistance.


Digestibility of a new diet for captive short-beaked echidnas (Tachyglossus aculeatus).
Short-beaked echidnas (Tachyglossus aculeatus) are myrmecophages, or ant and termite insectivore specialists, and replicating their exact diet in captivity is problematic. Diets for captive animals often incorporate raw meat, eggs and cat food mixed together with water, and vitamin and mineral supplements. These diets have promoted a number of health problems in captive echidnas, such as gastritis, cystitis, gut impaction, obesity, and diarrhea. A manufactured diet was designed and three echidnas from two zoos were transitioned onto this diet to assess the acceptability and digestibility of this diet for echidnas. The new "test" diet was readily accepted by the echidnas with a 1 week transition period. Daily digestible energy intake was 280 kJ kg-0.75 d-1 , similar to another myrmecophagous species. Digestibility values were above 74% for all macronutrients. It was determined that this diet was an acceptable replacement for the previous diets and it was decided that the remaining echidnas at both institutions would be transitioned to the new diet. The diet will also be used for wild echidnas being rehabilitated in the zoo hospitals prior to release and commercially available within Australia. Further data are being collected to assess the use of this diet for seasonal weight management, transitioning hand-reared puggles and effects on gastrointestinal tract health. Zoo Biol. 36:56-61, 2017. © 2017 Wiley Periodicals, Inc.


Is it possible to estimate the minimal clinically important treatment effect needed to change practice in preterm birth prevention? Results of an obstetrician survey used to support the design of a trial.
Sample sizes for obstetrical trials are often based on the opinion of investigators about clinically important effect size. We surveyed Canadian obstetricians to investigate clinically important effect sizes required before introducing new treatments into practice to prevent preterm birth. Questionnaires were mailed to practicing obstetricians, asking the magnitude of pregnancy prolongation required to introduce treatments into practice. The three prophylactic treatments were of increasing invasiveness: vaginal progesterone, intramuscular progesterone, and cervical cerclage. We also asked about the perceived most relevant outcome measures for obstetrical trials and current obstetrical practice in preterm birth prevention. 544/1293(42.1%) completed questionnaires were received. The majority of respondents required one or two weeks' increase in length of gestation before introducing vaginal (372,77.1%), and intramuscular progesterone(354,67.9%). At least three weeks increase was required before introducing prophylactic cervical cerclage(326,62.8%). Clinicians who already used a treatment required a smaller difference before introducing it into practice. Decreasing neonatal morbidity was cited as the most important outcome for obstetrical trials (349,72.2%). Obstetricians would require a larger increase in treatment effect before introducing more invasive treatments into practice. Although infant morbidity was perceived as a more important outcome, clinicians appeared willing to change practice on the basis of prolongation of pregnancy, a surrogate outcome. We found that there is not a single minimum clinically important treatment effect that will influence all practising clinicians: rather the effect size that will influence physicians is affected by the nature of the treatment, the reported outcome measure and the clinician's own current clinical practice.


Integration of human papillomavirus type 16 DNA sequences: a possible early event in the progression of genital tumors.
The keratinocyte line SK-v harbors only integrated human papillomavirus type 16 (HPV 16) DNA sequences, although it originated from vulvar Bowenoid papules predominantly containing multiple copies of free HPV 16 genomes. We have cloned a fragment of cell DNA that contains the integrated HPV 16 DNA sequences and have shown that integration interrupts the HPV 16 genome in open reading frames E2 and L2 and creates a deletion of 813 base pairs. This allows the expression of open reading frames E6 and E7, as actually substantiated by Northern (RNA) blot analysis of SK-v RNAs with subgenomic HPV 16 RNA probes. Using a unique flanking cellular DNA sequence as the probe, we have shown that the integration of HPV 16 sequences had already occurred in the premalignant lesions from which the SK-v cell line was derived.


Update on models of pulmonary fibrosis therapy for preclinical drug research.
Idiopathic pulmonary fibrosis (IPF) is a disease with high morbidity and mortality for which current medications are not effective. Therefore, identification of potential therapies is of paramount importance. The preclinical evaluation of novel compounds in animal models represents a critical step in drug development. To describe features and limitations of common animal models of pulmonary fibrosis and discuss relevant preclinical and clinical data on novel potential IPF therapies. Review of the existing literature on such models with a special focus on the bleomycin model and its usefulness for the IPF preclinical drug testing. The model of bleomycin-induced pulmonary fibrosis has the advantages of being well established, reproducible and both time- and cost-efficient. However, it has major limitations as it only mimics some features of human IPF. Most importantly, it is initiated by acute lung injury and is at least partially reversible, which is strikingly different from IPF. The failure in establishing effective IPF therapies despite strong efforts in the last decade is partly attributable to our uncritical trust in the models of lung fibrosis and the false belief that they truly reflect what is going on in human disease.


Placental opioid-enhancing factor (POEF): generalizability of effects.
A substance in amniotic fluid and placenta (POEF for Placental Opioid-Enhancing Factor) has been shown to enhance opiate- or opioid-mediated analgesia in rats. Recent studies have only touched on the generalizability of the phenomenon. The present studies further tested the generalizability of the POEF effect: they examined sex specificity of the mechanism; whether POEF activity exists in afterbirth material of species other than the rat; whether POEF activity exists in tissue other than afterbirth material; whether POEF activity could be demonstrated after injection rather than ingestion of afterbirth material; and whether POEF enhances all opioid-mediated phenomena. We found that (a) POEF is effective in male rats as well as in female rats; (b) POEF activity exists in human and dolphin afterbirth material; (c) ingestion of pregnant-rat liver does not produce enhancement of opioid-mediated analgesia; (d) POEF does not seem to be effective when amniotic fluid is injected either IP or SC; and (e) POEF does not modify morphine-induced hyperthermia.


Interaction of influenza A virus NS2/NEP protein with the amino-terminal part of Nup214.
Influenza A viruses have a single-stranded RNA genome consisting of 8 segments. Each RNA segment associates with the nucleoprotein (NP) and viral RNA polymerase to and from a viral ribonucleoprotein (vRNP) particle. The viral mRNA synthesis is dependent on a capped primer derived from nascent host RNA transcripts. For these processes to take place, vRNPs must pass through the cell nuclear pore complex (NPC) to the nucleus. The influenza A virus NS2 protein, also called the nuclear export protein (NES), has an important role in the nucleocytoplasmic transport of vRNPs. This protein interacts with the host cellular nucleoporins during the nuclear export of vRNPs. In this study, the human nucleoporin 214 (Nup214) was identified as an NS2-binding protein by using a yeast two-hybrid assay. The interaction between NS2 and human Nup214 was confirmed in both yeast and mammalian cells. It has been shown that the NS2 protein interacts with the amino terminal FG domain of the Nup214 protein. The influenza viral replication was suppressed in knockdown cells for the Nup214 protein. It was concluded that the FG domains of nucleoporins have an important role in the interaction of the influenza NS2 protein with host NPC for vRNA export.


"I" and "Me": The Self in the Context of Consciousness.
James (1890) distinguished two understandings of the self, the self as "Me" and the self as "I". This distinction has recently regained popularity in cognitive science, especially in the context of experimental studies on the underpinnings of the phenomenal self. The goal of this paper is to take a step back from cognitive science and attempt to precisely distinguish between "Me" and "I" in the context of consciousness. This distinction was originally based on the idea that the former ("Me") corresponds to the self as an object of experience (self as object), while the latter ("I") reflects the self as a subject of experience (self as subject). I will argue that in most of the cases (arguably all) this distinction maps onto the distinction between the phenomenal self (reflecting self-related content of consciousness) and the metaphysical self (representing the problem of subjectivity of all conscious experience), and as such these two issues should be investigated separately using fundamentally different methodologies. Moreover, by referring to Metzinger's (2018) theory of phenomenal self-models, I will argue that what is usually investigated as the phenomenal-"I" [following understanding of self-as-subject introduced by Wittgenstein (1958)] can be interpreted as object, rather than subject of experience, and as such can be understood as an element of the hierarchical structure of the phenomenal self-model. This understanding relates to recent predictive coding and free energy theories of the self and bodily self discussed in cognitive neuroscience and philosophy.


Management of the patient with mental retardation: a case report.
During the course of their careers dental professionals frequently interact with individuals presenting with mental retardation. In order to provide the best possible quality of care they should be aware of the etiology of mental retardation, the medical and dental conditions associated with this disability, and the services which can be incorporated into a treatment plan focused on improving the oral health for these individuals. This article identifies basic information dental professionals need to know when treating people with mental retardation, as well as describing a case report of the dental hygiene services that were provided to a patient presenting with this disability.


Accident investigation reporting deficiencies related to organizational factors in machinery space fires and explosions.
Careful accident investigation provides opportunities to review safety arrangements in socio-technical systems. There is consensus that human intervention is involved in the majority of accidents. Ever cautious of the consequences attributed to such a claim vis-à-vis the apportionment of blame, several authors have highlighted the importance of investigating organizational factors in this respect. Specific regulations to limit what were perceived as unsuitable organizational influences in shipping operations were adopted by the International Maritime Organization (IMO). Guidance is provided for the investigation of human and organizational factors involved in maritime accidents. This paper presents a review of 41 accident investigation reports related to machinery space fires and explosions. The objective was to find out if organizational factors are identified during maritime accident investigations. An adapted version of the Human Factor Analysis and Classification System (HFACS) with minor modifications related to machinery space features was used for this review. The results of the review show that organizational factors were not identified by maritime accident investigators to the extent expected had the IMO guidelines been observed. Instead, contributing factors at the lower end of organizational echelons are over-represented.


Percutaneous transhepatic cholangiography in Sudan.
In 16 patients percutaneous transhepatic cholangiography with a conventional needle was attempted, to establish the diagnosis of obstructive jaundice and show the nature and site of obstruction. The procedure was successful in 15 patients; only one patient subsequently had parenchymal jaundice. The conventional needle allowed bile aspiration (a mean of 22 mls in the 15 patients), which may have been an important factor in avoiding the development of post PTC septicemia. No patient had pain, bile leakage, bleeding or septicemia following the procedure. Surgery was performed as scheduled. Following the use of the conventional sheathed needle, it does not appear necessary to operate immediately.


Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis.
To examine the subgroup of patients with medically intractable epilepsy receiving temporal lobectomies who have pathologically verified mesial temporal sclerosis (MTS) and to determine the relation of demographic and clinical factors, results of diagnostic testing, and details of the surgical procedure with prognosis for achieving control of seizures. All patients receiving surgical treatment for intractable epilepsy between 1991 and 1998 at the University of Washington were reviewed. There were 118 patients who met inclusion criteria of adequate pathological analysis showing MTS without a progressive process and a minimum of 1-year follow-up. Only personal history of status epilepticus demonstrated significant (p = 0.0276) prediction of outcome, increasing the risk of surgical failure. No other factors were significant predictors of outcome, including history of febrile seizures, possible etiologic factors, EEG, magnetic resonance imaging (MRI) or neuropsychological testing results, or extent of resection. Many factors that have been previously described to predict favorable outcome in the overall group of patients receiving temporal lobe resections for intractable epilepsy are, in fact, predictors of MTS and lose their predictive value when the subgroup of patients with confirmed MTS is examined. Neurosurgical treatment of MTS can be very effective even in the presence of significant etiologic factors, or of bilateral or extratemporal abnormalities on EEG or MRI.


An epidemiological survey of eight oil refineries in Britain.
A mortality study of workers employed for at least one year between 1 January 1950 and 31 December 1975 at eight oil refineries in Britain has been carried out. Over 99% of the population were successfully traced to determine their vital status at 31 December 1975. The mortality observed in the study population was compared with that which would be expected from the mortality rates for the all male population of England and Wales, and Scotland, with adjustment for regional variation in mortality for the English and Welsh refineries. The overall mortality observed was considerably lower than that expected on this basis, as was the mortality from heart disease, stroke, bronchitis, and pneumonia. The observed number of deaths from all neoplasms was also very much less than expected, a result almost entirely due to a large deficit of observed deaths from lung cancer. Raised mortality patterns were found in several refineries for cancers of the oesophagus, stomach, intestines, and rectum, although no location was consistently high for all these causes of death. Different year-of-entry cohorts and job groups were also affected. In general, mortality from these causes increased as length of service and interval from starting work increased. There were also significantly more observed deaths than expected from cancer of the nasal cavities and sinus, and melanoma. Further work is required to ascertain whether these are due to an occupational factor and, if so, to identify the physical or chemical nature of the risk.


Sustaining hope and life courage in patients undergoing ovarian cancer surgery - the impact of care.
Ovarian cancer is the leading cause of death from a gynaecological malignancy in the Western World. To explore if experiences of physical comfort influenced hope and life courage during final diagnosis and early treatment, qualitative research interviews were performed with women undergoing surgery for ovarian cancer. By applying a phenomenological-hermeneutic methodology, the findings were systematically identified, put into meaning-structures, interpreted and critically discussed. The empirical material constituted a main theme concerning "Hope and life courage are created in the interplay between body and mind," where findings dealt with personal reflections and experiences in relation to the subthemes: "Experiencing discomfort," "The impact of care" and "Comfort and hope." The women's general health condition became impacted not only by their ovarian cancer disease but also by the treatment, and it was a main finding that sufficient symptom management combined with sensitive attention of the patient sustained her hope, life courage and action competences. Surgery constitutes an essential part of sufficient cancer treatment. However, the diagnostic and pre-operative phase represents an insufficiently investigated area in cancer care. Improvements are therefore vital to reduce the disease burden, and improve patients' general health and quality of life, during and after treatment.


[The potential of reflexotherapy for patients with acquired myopia].
Efficacy of reflexotherapy for patients with acquired myopia is analyzed. Guidelines for different reflexotherapy techniques and their combinations are presented. The best results were obtained when treated with complex technique that included biomaterial "Alloplant" pharmacopuncture.


Wavelength-Dependent Differential Interference Contrast Inversion of Anisotropic Gold Nanoparticles.
Gold nanorods are promising nanoparticle-orientation sensors because they exhibit wavelength and angle-dependent optical patterns in their differential interference contrast (DIC) microscopy images. In this paper, we report a finite-difference time-domain method to simulate DIC images using nanorods as model probes. First, we created a DIC image library of nanorods as a function of imaging wavelength and rotation angle that showed good agreement with experimental results. Second, we used this simulation tool to explain why the patterns inverted from bright to dark when the imaging wavelength increased from below to above the plasmon resonance of the nanorod. We found that this intensity inversion resulted from reversal in electric field direction depending on wavelength relative to the nanorod plasmon resonance. Finally, we showed that this DIC contrast inversion is a general phenomenon by measuring and simulating DIC images from gold nanorods of different sizes and gold nanostars.


Tinea nigra: Report of three pediatrics cases.
Tinea nigra is a superficial mycosis caused by Hortaea werneckii. Its clinical characte ristic is the appearance of a blackish brown macula of rapid growth, caused by the pigment produced by the fungus itself. The presence of a dark, fast growing, acral pigmentary lesion causes concern among patients and their treating physician about the possibility of a malignant pigmentary lesion. To present a series of three clinical cases in pediatric patients with this pathology and to show the tools that help to make a differential diagnosis. Three patients between three and five years of age, which present a macular pigmented lesion on palms or soles, whose parents reported a rapid growth over a short period of time. Two of the patients reported previous trips to the Caribbean. Clinical and dermatoscopy suspicion of tinea nigra lead to a direct mycological exa mination, which confirmed the diagnosis. In all three cases, treatment with topical antifungals led to complete healing of the lesions. Although tinea nigra is rare in a dry climate, increasing travel of patients to tropical countries will increase the number of cases. Dermatoscopy and direct mycological examination are the tools that allow performing a correct diagnosis and avoiding unne cessary biopsies and/or surgeries.


Topical formulations of Aprepitant are safe and effective in relieving pain and inflammation, and drive neural regeneration.
To test long-term ocular toxicity and analgesic/anti-inflammatory efficacy of two novel ocular formulations of neurokinin 1 receptor (NK1R) antagonist Aprepitant. for toxicity studies, two Aprepitant formulations (X and Y) were tested on C57BL/6 N mice. Gold standards were 0.4% Oxybuprocaine, 0.1% Diclofenac, or saline. For efficacy studies, C57BL/6 N mice underwent corneal alkali burn, and then received Aprepitant formulation X, Dexamethasone or saline. Eye-drops were applied 3 times/day for 90 days (toxicity) and 14 days (efficacy). Stromal opacity, corneal epithelial damage, nociception and sensitivity were assessed in vivo. The eye-wiping test and corneal sensitivity were assessed to evaluate analgesic efficacy and nerve function. At the end of the experiments mice were euthanized, and corneas were dissected for immunohistochemistry and RT-PCR analyses. In normal mice, formulation X was not toxic when topically administered for 90 days. Formulation Y was associated with increased leukocyte infiltration in the cornea (p < 0.001). X1 and X2 formulations significantly reduced corneal pain, as Diclofenac and Oxybuprocaine, but did not reduce corneal sensitivity. Formulation Y, instead, was not analgesic at any time point. In the alkali burn model, X1 and X2 formulation enhanced epithelial damage recovery, and reduced inflammation both at day 7 and 14. Moreover, formulation X showed a stronger analgesic effect when compared to the saline and Dexamethasone groups (p < 0.01). Finally, formulation X1 and X2 restored corneal sensitivity by promoting corneal nerve regeneration. Aprepitant X formulation is a promising candidate for the treatment of pain associated with inflammation of the ocular surface.


Opportunities to reduce pollination deficits and address production shortfalls in an important insect-pollinated crop.
Pollinators face multiple pressures and there is evidence of populations in decline. As demand for insect-pollinated crops increases, crop production is threatened by shortfalls in pollination services. Understanding the extent of current yield deficits due to pollination and identifying opportunities to protect or improve crop yield and quality through pollination management is therefore of international importance. To explore the extent of "pollination deficits," where maximum yield is not being achieved due to insufficient pollination, we used an extensive dataset on a globally important crop, apples. We quantified how these deficits vary between orchards and countries and we compared "pollinator dependence" across different apple varieties. We found evidence of pollination deficits and, in some cases, risks of overpollination were even apparent for which fruit quality could be reduced by too much pollination. In almost all regions studied we found some orchards performing significantly better than others in terms of avoiding a pollination deficit and crop yield shortfalls due to suboptimal pollination. This represents an opportunity to improve production through better pollinator and crop management. Our findings also demonstrated that pollinator dependence varies considerably between apple varieties in terms of fruit number and fruit quality. We propose that assessments of pollination service and deficits in crops can be used to quantify supply and demand for pollinators and help to target local management to address deficits although crop variety has a strong influence on the role of pollinators.


Improvement of fertility parameters with Tribulus Terrestris and Anacyclus Pyrethrum treatment in male rats.
Anacyclus Pyrethrum (AP) and Tribulus Terrestris (TT) have been reported as male infertility treatment in several studies; however, in Iranian traditional medicine these two plants are prescribed simultaneously. In this study, we aimed to determine the effects of AP and TT extracts both separately and simultaneously on the male Wistar rat fertility parameters. 32 male Wistar rats were divided into 4 groups: Control, TT, AP, and AT treated groups. Treatment continued for 25 days and rats were weighed daily. Their testes were dissected for histological studies. Sperm analysis including sperm count, viability and motility were performed. Serum was obtained to evaluate testosterone, LH and FSH levels. Histological studies were conducted to study Leydig, and Sertoli cells, spermatogonia and spermatid cell numbers, and to measure seminiferous diameter and epithelium thickness. Sperm count increased in all the treatment groups. Sperm viability and motility in AT and AP groups were elevated. TT and AT groups showed signifi cantly increased testosterone level compared to control group (P=004, P=0.000, respectively) and TT, AP and AT treatment groups showed increased LH level (P=0.002, P=0.03 and P=0.000, respectively) compared to control, while only AT group showed increased FSH (p=0.006) compared to control. Histological studies showed signifi cant increase of spermatogonia, Leydig and Sertoli cell numbers and epithelial thickness in AT group compared to other groups. All the treatment groups had higher number of Leydig, spermatogonia and spermatid cells. TT and AP improved sexual parameters; however, their simultaneous administration had higher improving effects on studied parameters.


Targeting myeloid checkpoint Siglec-10 reactivates antitumor immunity and improves anti-programmed cell death 1 efficacy in gastric cancer.
Immunotherapy has not yielded satisfactory therapeutic responses in gastric cancer (GC). However, targeting myeloid checkpoints holds promise for expanding the potential of immunotherapy. This study aims to evaluate the critical role of Siglec-10+ tumor-associated macrophages (TAMs) in regulating antitumor immunity and to explore the potential of the myeloid checkpoint Siglec-10 as an interventional target. Siglec-10+ TAMs were assessed based on immunohistochemistry on tumor microarrays and RNA-sequencing data. Flow cytometry, RNA sequencing, and single-cell RNA-sequencing analysis were employed to characterize the phenotypic and transcriptional features of Siglec-10+ TAMs and their impact on CD8+ T cell-mediated antitumor immunity. The effectiveness of Siglec-10 blockade, either alone or in combination with anti-programmed cell death 1 (PD-1), was evaluated using an ex vivo GC tumor fragment platform based on fresh tumor tissues. Siglec-10 was predominantly expressed on TAMs in GC, and associated with tumor progression. In Zhongshan Hospital cohort, Siglec-10+ TAMs predicted unfavorable prognosis (n=446, p<0.001) and resistance to adjuvant chemotherapy (n=331, p<0.001), which were further validated in exogenous cohorts. In the Samsung Medical Center cohort, Siglec-10+ TAMs demonstrated inferior response to pembrolizumab in GC (n=45, p=0.008). Furthermore, Siglec-10+ TAMs exhibited an immunosuppressive phenotype and hindered T cell-mediated antitumor immune response. Finally, blocking Siglec-10 reinvigorated the antitumor immune response and synergistically enhances anti-PD-1 immunotherapy in an ex vivo GC tumor fragment platform. In GC, the myeloid checkpoint Siglec-10 contributes to the regulation of immunosuppressive property of TAMs and promotes the depletion of CD8+ T cells, ultimately facilitating immune evasion. Targeting Siglec-10 represents a potential strategy for immunotherapy in GC.


Protein kinase-C in the human fetal adrenal gland.
The fetal zone (FZ) of the human fetal adrenal gland undergoes rapid growth and exhibits a high rate of steroidogenesis throughout fetal life. In addition to cAMP-dependent processes regulating steroidogenesis and possibly growth of the FZ, evidence is accumulating that cAMP-independent mechanisms are also involved. The purpose of this study was to determine if the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent stimulator of protein kinase-C activity, stimulates steroidogenesis in FZ cells and to characterize protein kinase-C activity in FZ, neocortex zone, and anencephalic adrenal tissues. Adrenal glands were obtained from first and second trimester abortions and two anencephalic fetuses. The FZ was dissected from the neocortex. In some experiments, dispersed FZ cells were incubated in the presence and absence of ACTH and TPA for 3 h. TPA and ACTH stimulated steroidogenesis 2- and 5-fold, respectively. In other experiments, the separated zones and anencephalic adrenal tissues were homogenized, and the homogenates were subjected to DEAE-cellulose column chromatography. A single peak with phospholipid- and calcium-dependent activity was found. Subcellular distribution studies demonstrated greatest activity in the cytosolic fraction. The specific activity of protein kinase-C was significantly greater in FZ than neocortex zone, whether expressed per mg protein or per microgram DNA content. The activity in anencephalic tissue was low. In addition, protein kinase-C (80,000-dalton molecular size protein) was detected in adrenal tissues after electrophoresis and immunoblotting using an antibody directed against protein kinase-C. Greater amounts of protein kinase-C were detected in FZ tissue than in NC or anencephalic adrenal tissue. These results indicate that the lower activities of protein kinase-C in neocortex and anencephalic adrenal tissues were due to low amounts of enzyme rather than inactive enzyme. In summary, TPA-stimulated steroidogenesis in fetal zone cells and fetal zone cells contained greater activity and a greater amount of protein kinase-C than neocortex cells. Minimal activity and enzyme protein were found in anencephalic tissues. These results suggest that cAMP-independent mechanisms may play a role in fetal adrenal steroidogenesis.


Safety evaluation of the concomitant use of clozapine and benzodiazepines: a retrospective, cross-sectional chart review.
Previously published case reports have noted severe adverse reactions such as cardiac arrest, respiratory arrest, and sudden death when clozapine (CLZ) and benzodiazepines (BZDs) are used concomitantly. As CLZ and BZD are both used regularly to treat psychiatric illness, it is important to have additional information concerning this potential interaction. The objective of this study was to contribute to the evolving literature by evaluating the occurrence of sudden deaths and cardiac or respiratory events leading to death in patients treated concurrently with CLZ and BZD. A retrospective chart review was conducted at a 240-bed New York State mental health facility. Most patients in this facility have been diagnosed with refractory schizophrenia, resulting in high rates of CLZ use. Electronic and hard copy records of the 490 patients who had been treated with CLZ in this facility at any time from 2001 to 2006 were selected, and the medication records of these patients were assessed for concomitant BZD use. Information on 152 patients who were treated with CLZ and a BZD concomitantly during this time period are included in this study. Data from the facility's mortality review committee were obtained to determine sudden deaths and cardiac or respiratory events leading to death in patients treated with CLZ and BZD concomitantly. Secondary parameters also recorded during the chart review included average duration of CLZ therapy, BZD therapy, and concomitant therapy; average doses of agents used; specific BZD used; number of patients treated with a specific BZD; psychiatric diagnosis; and use of other medications that depress the central nervous system. No deaths occurred as a result of concomitant BZD and CLZ use in the sample examined in this study, suggesting that CLZ and BZD may be safely used concomitantly in many cases. Further study is needed to determine patient characteristics or predisposing factors that might put patients at higher risk of death from this interaction. Our findings are limited by the small sample size and suboptimal frequency of side effect measurements (e.g., measurements of blood pressure and heart rate, reports of hypotensive episodes). Confounding variables that might also play a role in interactions between CLZ and BZDs, but which were not measured in this study, include other types of respiratory compromise, cognitive dysfunction, and organ dysfunction. Precautionary measures that may be used when initiating concomitant CLZ and BZD therapy include slow titration of CLZ, blood pressure monitoring, and/or nightly pulse oximeter measurements.


cis-DA-dependent dispersion by Pseudomonas aeruginosa biofilm and identification of cis-DA-sensory protein DspS.
Dispersion is an essential stage of the biofilm life cycle resulting in the release of bacteria from a biofilm into the surrounding environment. Dispersion contributes to bacterial survival by relieving overcrowding within a biofilm and allowing dissemination of cells into new habitats for colonization. Thus, dispersion can contribute to biofilm survival as well as disease progression and transmission. Cells dispersed from a biofilm rapidly lose their recalcitrant antimicrobial-tolerant biofilm phenotype and transition to a state that is susceptible to antibiotics. However, much of what is known about this biofilm developmental stage has been inferred from exogenously induced dispersion. Our findings provide the first evidence that native dispersion is coincident with reduced cyclic dimeric guanosine monophosphate levels, while also relying on at least some of the same factors that are central to the environmentally induced dispersion response, namely, BdlA, DipA, RbdA, and AmrZ. Additionally, we demonstrate for the first time that cis-DA signaling to induce dispersion is attributed to the two-component sensor/response regulator DspS, a homolog of the DSF sensor RpfC. Our findings also provide a path toward manipulating the native dispersion response as a novel and highly promising therapeutic intervention.


Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model.
Fusion genes induced by chromosomal aberrations are common mutations causally associated with bone and soft tissue sarcomas (BSTS). These fusions are usually disease type-specific, and identification of the fusion genes greatly helps in making precise diagnoses and determining therapeutic directions. However, there are limitations in detecting unknown fusion genes or rare fusion variants when using standard fusion gene detection techniques, such as reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). In the present study, we have identified 19 novel fusion genes using target RNA sequencing (RNA-seq) in 55 cases of round or spindle cell sarcomas in which no fusion genes were detected by RT-PCR. Subsequent analysis using Sanger sequencing confirmed that seven out of 19 novel fusion genes would produce functional fusion proteins. Seven fusion genes detected in this study affect signal transduction and are ideal targets of small molecule inhibitors. YWHAE-NTRK3 expression in mouse embryonic mesenchymal cells (eMCs) induced spindle cell sarcoma, and the tumor was sensitive to the TRK inhibitor LOXO-101 both in vitro and in vivo. The combination of target RNA-seq and generation of an ex vivo mouse model expressing novel fusions provides important information both for sarcoma biology and the appropriate diagnosis of BSTS.


The population, transfer and persistence of fibres on the skin of living subjects.
Fibres were transferred to the bare arms of living subjects and their persistence determined at intervals up to 24 h, during which normal daily activity was undertaken. Decay curves showed an initial rapid loss followed by an apparently exponential decay. No target fibres were found to remain after 24 h. The length distribution showed a shift towards shorter fibre lengths and the differential shedding results for a polyester/cotton mixture showed a small bias towards the retention of cotton. The population of coloured fibres on bare skin was classified according to perceived colour, length, generic class and the presence or absence of delustrant.


Human lung pressure-volume relationships: alveolar collapse and airway closure.
We investigated the effect of airway closure and alveolar collapse on the large-volume deflation and inflation transpulmonary pressure-volume (Ptp-V) curves of five postmortem excised human lungs. For stepwise static cycles, no inflection occurred on the deflation curve, while either one or two inflections occurred on the inflation curve. These relations were stimulated by a multicompartment model, which assumed a bimodal distribution of compartmental collapse-pressure differences. The simulations indicate that alveolar collapse can occur without causing an inflection on the deflation curve and that hysteresis in reopening of collapsed alveoli on inflation can account for a major portion of Ptp-V hysteresis. In contrast, for slow dynamic cycles, an inflection occurred on the experimental deflation Ptp-V curve, and when inflations were begun at sufficiently low volumes, volume did not change until a threshold pressure difference was reached about which PtP began to oscillate as lung volume increased. These differences in the stepwise static and dynamic Ptp-V curves can result from sustained airway closure on deflation and popping-opening on inflation.


Neurological disturbances, premature lethality, and central myelination deficiency in transgenic mice overexpressing the homeo domain transcription factor Oct-6.
Pit, Oct, Unc (POU) homeo domain transcription factors have been implicated in various developmental processes, including cell division, differentiation, specification, and survival of specific cell types. Although expression of the transcription factor Oct-6 in oligodendroglia is confined to the promyelin stage and is downregulated at the myelin stage of development, the effect of Oct-6 overexpression on oligodendrocyte development has not been established. Here we show that transgenic animals overexpressing Oct-6 at late oligodendrocyte development develop a severe neurologic syndrome characterized by action tremors, recurrent seizures, and premature death. Axons in the central nervous system of Oct-6 transgenics were hypomyelinated, hypermyelinated, or dysmyelinated, and ultrastructural analyses suggested that myelin formation was premature. The vulnerability of developing oligodendroglia to Oct-6 deregulation provides evidence that the POU factor may play a direct role in myelin disease pathogenesis in the mammalian CNS.


[Peptidergic mechanisms in the parasympathetic regulation of the heart rate].
Besides the classic cholinergic and adrenergic mechanisms, the regulatory peptides involve in regulating the cardiac rhythm. The localization of the latter in neurons of intracardiac nervous system as well as the possibility of releasing the regulatory peptides, individually or in combination with the classic mediators, during extracardiac nerves is found. The regulatory peptides are capable of affecting the heart autonomy directly or in a mediated way via modulation of the vegetative effects. The paper contains data on the cardiotropic activity of various peptides and direction of their effects relating to parasympathetic control a cardiac rhythm. There is a suggestion concerning an existence of different ways of realization of peptidergic vagotropic effect that presupposes not only variation of severity of parasympathetic chronotropic effect but also a change in its functional organization.


[Postmortem diagnosis of mixed respiratory virus infections in children].
Mixed respiratory virus infection in fatal cases in children was documented in the laboratory in 41% of cases though clinical and morphological signs had been determined only in half of the cases. Most effective tests in diagnosis of the mixed infection include immunofluorescent examinations of impressions of respiratory organs as well as tissue culture infected with blood or specimens of parenchymatous organs. In some cases detection of adenovirus antigen or isolation of adenovirus were regarded as a manifestation of latent infection, particularly when adenovirus antigen was discovered in impressions of the spleen, tonsils or lymph nodes. Only intravital detection of virus antigens in all cases coincided with the presence of clinical and morphological signs of mixed disease.


Expression of periplasmic alpha-amylase of Xanthomonas campestris K-11151 in Escherichia coli and its action on maltose.
A gene encoding the periplasmic alpha-amylase of Xanthomonas campestris K-11151 was cloned into Escherichia coli using pUC19 as a vector. An ORF of 1578 bp was deduced to be the amylase structural gene. The primary structure of the enzyme had little identity with other alpha-amylases, except with the enzyme from Bacillus megaterium. The enzyme was expressed in E. coli from the lac promoter of pUC19 and was found to be transported to the periplasmic space. The expressed enzyme showed the same thermal stability, optimum temperature and substrate specificity as the enzyme from X. campestris. The enzyme formed maltotetraose, but not 6(1)- nor 6(2)-maltosyl-maltose, from maltose by the reverse reaction, and the tetraose was then hydrolysed to maltotriose and glucose. The addition of maltotriose enhanced the production of glucose from maltose. In addition, maltose was formed by the condensation of glucose by the enzyme. Thus, the periplasmic alpha-amylase of X. campestris was shown to produce glucose from maltose by hydrolysing maltotetraose and possibly higher maltooligosaccharides, which were the products of a condensation reaction, as a major pathway, and by direct hydrolysis of maltose as a minor pathway.


Aggressive behaviours track transitions in seasonal phenotypes of female Siberian hamsters.
Seasonally breeding animals exhibit profound physiological and behavioural responses to changes in ambient day length (photoperiod), including changes in reproductive function and territorial aggression.Species where aggression persists when gonads are regressed and circulating levels of gonadal hormones are low, such as Siberian hamsters (Phodopus sungorus) and song sparrows (Melospiza melodia), challenge the well-established framework that gonadal hormones are important mediators of aggression.A solution to this apparent paradox is that a season-specific increase in sensitivity to hormones in brain areas associated with aggression offsets low levels of gonadal hormones during periods of reproductive quiescence.To test this hypothesis, we manipulated photoperiod to induce natural fluctuations in seasonal phenotype across multiple stages of the annual reproductive cycle in female Siberian hamsters that display increased aggression during short-day reproductive quiescence, suggesting that behaviour persists independent of gonadal steroids.Females were housed in long "summer" days or short "winter" days for 10, 24 or 30 weeks to capture gonadal regression, transition back to a reproductively functional state and full gonadal recrudescence, respectively.Long-day animals maintained reproductive functionality and displayed low aggression across all time points. By week 10, short-day reproductively responsive females underwent gonadal regression and displayed increased aggression; non-responsive animals showed no such changes. At week 24, animals were in a transitional period and displayed an intermediate phenotype with respect to reproduction and aggression. By week 30, short-day females were fully recrudesced and returned to long-day-like levels of aggression.Consistent with our hypothesis, gonadally regressed females displayed decreases in 17β-oestradiol (oestradiol) levels, but site-specific increases in the abundance of brain oestrogen receptor-alpha (ERα) in regions associated with aggression, but not reproduction. Increased site-specific ERα may function as a compensatory mechanism to allow increased responsiveness to oestradiol in regulating aggression in lieu of high circulating concentrations of hormones.Collectively, these results broaden our understanding of how breeding phenology maps onto social behaviour and the mechanisms that have evolved to coordinate behaviours that occur in non-breeding contexts.


Date Palm Genetic Diversity Analysis Using Microsatellite Polymorphism.
Date palm (Phoenix dactylifera L.) is considered one of the great socioeconomic resources in the Middle East and the Arab regions. The tree has been and still is at the center of the comprehensive agricultural development. The number of known date palm cultivars, distributed worldwide, is approximately 3000. The success of genetic diversity conservation or any breeding program depends on an understanding of the amount and distribution of the genetic variation already in existence in the genetic pool. Development of suitable DNA molecular markers for this tree may allow researchers to estimate genetic diversity, which will ultimately lead to the genetic conservation of date palm. Simple sequence repeats (SSRs) are DNA strands, consisting of tandemly repeated mono-, di-, tri-, tetra-, or penta-nucleotide units that are arranged throughout the genomes of most eukaryotic species. Microsatellite markers, developed from genomic libraries, belong to either the transcribed region or the non-transcribed region of the genome, and there is rarely available information on their functions. Microsatellite sequences are especially suited to distinguish closely related genotypes due to a high degree of variability making them ideally suitable in population studies and the identification of closely related cultivars. This chapter focuses on the methods employed to characterize date palm genotypes using SSR markers.


Cultivating Engagement and Enjoyment in Exergames Using Feedback, Challenge, and Rewards.
This article reviews theoretical and empirical evidence related to three mechanisms for encouraging enjoyment during exergame play: Feedback, challenge, and rewards. A literature search and narrative review were conducted. Feedback is found in nearly all exergames, and richer, more in-depth feedback is associated with increased activity. Challenge is a vital component of any videogame, and exergames include physical as well as cognitive challenges. Flow states have traditionally been conceptualized as occurring when an optimal match between player skills and game challenge occurs. However, failure and retrial are necessary for feelings of overall satisfaction and fun, despite not necessarily being ideally fun or satisfying themselves. Rewards are a more complicated issue, with significant theoretical and empirical evidence suggesting positive and negative effects of reward systems. How rewards are integrated into the mechanics and storyline of the game likely impacts how they are perceived and, thus, their effectiveness. Finally, integration of these mechanisms into exergames requires specific attention to both cognitive and physical implementations. Movements that are not themselves enjoyable or engaging may lead to cheating and lower energy expenditure. Feedback, challenge, and rewards are promising mechanisms by which exergames could become more enjoyable. How these concepts are operationalized can affect physical and psychological reactions to exergames. Attention to these concepts in future exergame development and implementation would benefit theory, research, and practice.


Potentially Inappropriate Prescribing of Oral Solid Medications in Elderly Dysphagic Patients.
Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first to focus on how hospitalization affected the rate of potentially inappropriate prescriptions (PIPs) and the incidence of dosage form-related PIPs in elderly patients with dysphagia. Data was collected by reviewing patient medical records in the Italian National Research Center on Aging of Ancona. The therapy at admission and discharge was analysed in terms of: inappropriate drug associations, inappropriate drugs for dysphagic patients, inappropriate dosage forms and inappropriate dosage form modifications. Forty-one dysphagic patients with an average age of 88.3 years were included in the study and 451 prescriptions were analysed. PIPs were widespread at admission, and hospitalization did not improve the situation in a statistically significant manner. The most common PIPs identified (>80%) were related to dosage form selection and modification. This study highlights a clear need for continuing medical education about prescription appropriateness and modification of solid dosage forms in patients with dysphagia.


Association of AMY1A/AMY2A copy numbers and AMY1/AMY2 serum enzymatic activity with obesity in Mexican children.
Mexican children are characterized by a high-starch intake diet and high prevalence of obesity. To investigate the association of AMY1A/AMY2A copy numbers (CNs) and AMY1/AMY2 serum enzymatic activity with childhood obesity in up to 427 and 337 Mexican cases and controls. Anthropometric and dietary starch intake data were collected. CN of AMY1A/AMY2A and AMY1/AMY2 serum enzymatic activity were determined using droplet digital PCR (ddPCR) and enzymatic colorimetry, respectively. An individual participant level data meta-analysis of association between AMY1A CNVs and obesity was also performed. A positive association between AMY1A/AMY2A CNs and their corresponding AMY1/AMY2 serum enzyme activity was observed in children with normal weight and obesity. The serum enzyme activity of AMY1 and AMY2 was negatively associated with childhood obesity risk, and the association was restricted to kids eating medium/high amount of starch (Pinteraction = .004). While no association between AMY1A and AMY2A CNs and childhood obesity was observed in our sample, we confirmed a significant association between AMY1A CN and obesity in a meta-analysis of 3100 Mexican children. Our data suggest that genetically determined salivary and pancreatic amylase activity can increase/decrease the risk of obesity in Mexican children, this effect being blunted by a low-starch diet.


Potential fibrinolytic agents: versatile synthetic route to novel 4-(branched alkyl)benzoic acids via beta-monosubstituted or beta,beta-disubstituted styrene-4-carboxylic acids.
A versatile and unambiguous synthetic route to some novel 4-(branched alkyl)benzoic acids via their beta-monosubstituted or beta,beta-disubstituted styrene-4-carboxylic acid precursors is described. The procedure starts with readily available aldehydes or ketones and the common intermediate p-bromobenzyltriphenyl-phosphonium bromide in a Wittig reaction and proceeds in good yield through p-bromostyrene and p-cyanostyrene intermediates. Several benzoic acid derivatives were of potential biological interest as fibrinolytic agents.


The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: VII. Cosmic ray particle dosimetry and trajectory tracing.
Five pocket mice (Perognathus longimembris) were flown on Apollo XVII, each with a solid-state (plastic) nuclear track detector implanted beneath its scalp. The subscalp detectors were sensitive to HZE cosmic ray particles with a LET larger than or equal to 0.15 million electron volts per micrometer (MeV/mjm). A critical aspect of the dosimetry of the experiment involved tracing individual particle trajectories through each mouse head from particle tracks registered in the individual subscalp detectors, thereby establishing a one-to-one correspondence between a trajectory location in the tissue and the presence or absence of a lesion. The other major aspect was the identification of each registered particle. An average of 16 particles with Z larger than or equal to 6 and 2.2 particles with Z larger than or equal to 20 were found per detector. The track density, 29 tracks/cm2, when adjusted for detection volume, was in agreement with the photographic emulsion data from an area dosimeter located next to the flight package.


Clinical characteristics of bipolar vs. unipolar depression in preschool children: an empirical investigation.
Despite retrospective reports of the onset of childhood bipolar disorder during the preschool period, few studies have investigated whether mania symptoms can be identified in preschoolers. A group of children with a cluster of mania symptoms that showed discriminant validity from other disruptive disorders was identified in a large preschool sample. These empirical data add to descriptive studies of mania in clinical preschool populations. An investigation of the characteristics of depression among putative bipolar preschoolers may inform the controversial nosologic questions that surround the diagnosis in this young age group. This study, conducted from 2002 to 2007, investigated major depressive disorder (MDD) symptoms and severity in preschoolers with a bipolar syndrome in comparison to those with unipolar MDD, identified by an age-appropriate structured psychiatric interview, the Preschool Age Psychiatric Assessment (based on DSM-IV). Twenty-one preschoolers were identified who met DSM-IV symptom criteria for bipolar I disorder and MDD and were compared to 54 preschoolers with unipolar MDD. The bipolar depressed preschoolers had significantly higher depression severity (p < .0001) and higher rates of comorbidity than did those with unipolar depression. The study is limited by the exploratory nature of clinical mania characteristics in preschoolers as well as reliance on parent reports of these symptoms. These findings suggest that, similar to adult bipolar patients, preschoolers with a putative bipolar syndrome experience clinically significant and severe depression. Symptom characteristics and comorbidity patterns also distinguished this group from the unipolar depressed preschoolers. Our findings underscore the marked depression that characterizes this putative bipolar syndrome and suggest that further investigation of this domain may clarify the nosology of this early-onset disorder.


Kidney Increase Natriuresis but Not Glomerular Filtration Under Veno-venous ECMO, a Retrospective Study.
Acute kidney injury is a frequent complication of acute respiratory distress syndrome (ARDS). We aim to study the evolution of kidney function in patients presenting severe ARDS and requiring veno-venous extracorporeal membrane oxygenation (VV ECMO). We conducted a multicenter retrospective study, including adult patients requiring VV ECMO for ARDS. The primary outcome was the evolution of the serum creatinine level after VV ECMO initiation. Secondary outcomes were change in urine output, and urine biochemical parameters after VV ECMO initiation. One hundred and two patients were included. VV ECMO was initiated after a median of 6 days of mechanical ventilation, mainly for ARDS caused by COVID-19 (73%). Serum creatinine level did not significantly differ after VV ECMO initiation (P = .20). VV ECMO was associated with a significant increase in daily urine output (+6.6 mL/kg/day, [3.8;9.3] P < .001), even after adjustment for potential confounding factors; with an increase in natriuresis. The increase in urine output under VV ECMO was associated with a reduced risk of receiving kidney replacement therapy (OR 0.4 [0.2;0.8], P = .026). VV ECMO initiation in severe ARDS is associated with an increase in daily urine output and natriuresis, without change in glomerular filtration rate.


Bone grafting options in children.
Retrospective review of the literature. To review the current literature as well as recent trends in bone grafting techniques available for children. The currently accepted gold standard in bone grafting for adolescent idiopathic scoliosis (AIS) is autogenous iliac crest. Due to questions concerning complications such as donor site pain, other options have been explored, including various allograft sources, demineralized bone matrix, and bone morphogenetic protein. A review of the current medical literature was completed and additional case examples are presented. A review of the literature reveals that up to 31% of patients have persistent pain at 2 years post surgery when autogenous iliac crest bone graft is harvested. Allograft supplementation of local autograft has been demonstrated in the literature to be as effective as autogenous iliac crest bone grafting in contributing to a successful posterior spinal fusion in patients with AIS. Modern demineralized bone matrix formulations have been found in both animal models as well as in a recent retrospective clinical review to contribute to a successful posterior spinal fusion in AIS. Bone morphogenetic protein has been shown to contribute to a successful posterior spinal fusion in complex pediatric spinal deformity patients. At 2 years follow-up, patients who underwent a posterior instrumented spinal fusion that was not augmented with any bone graft appear to have successful spinal fusions. Although autogenous iliac bone graft remains the benchmark to which bone grafting materials are compared, other options including the placement of no bone graft at all provides similar fusion rates in patients with AIS.


Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice.
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.


Folic acid in pregnancy and mortality from cancer and cardiovascular disease: further follow-up of the Aberdeen folic acid supplementation trial.
Supplemental periconceptional folic acid is recommended to reduce the risk of fetal neural tube defects. A previous report indicated an elevated risk of breast cancer and all cancer deaths in later life among women randomised by alternate allocation to high-dose (5 mg/day) folic acid in pregnancy compared with placebo; however, findings were based on small numbers of cases. Our aim was to extend the previous analysis by including data from an additional 10 years of follow-up. Records of participants in a large (n=2928) trial of folate supplementation (5 or 0.2 mg folic acid, or placebo) in pregnancy in the 1960s were linked to central registries in Scotland. Unadjusted and adjusted HRs were calculated for all-cause, cardiovascular, all cancer and breast cancer mortality, and all cancer and breast cancer morbidity. Analyses were done using (1) data from the time of the previous linkage (2002) to March 2013; and (2) data from 1980 to March 2013. There was no evidence to suggest an excess risk of morbidity or mortality in either supplementation group compared with placebo for 2002-2013 and no associations were seen for the full time period (1980-2013). Findings from this extended follow-up do not support our previous observation of an elevated risk of mortality from breast cancer or all cancers in later life among women who had taken 5 mg folic acid/day during pregnancy. Furthermore, there were no associations with risk of mortality from all-causes, all cancers or cardiovascular disease.


[Human leptospirosis - infection in inhabitants of the Aricanduva river valley, São Paulo city, Brazil, 1984-5; part. 1 - aspects related to the studied group and the environment].
The article approachs the investigation, from the epidemiological point of view, of one zone that had been flooded in 1983 by the Aricanduva river and its tributaries in the east side of the São Paulo city, Brazil. At that time, zone was affected by human leptospirosis, confirmed by laboratory tests. For the present survey, a population of 61 inhabitants of the region, who dwelled with subjects affected by leptospirosis was studied, in order to establish the level of infection of leptospira remaining in that population. In this paper, the author describes the aspects relatives to the studied group and their environment. It was found that eighteen months after the 1983 outbreak of the disease (1984-5) there still persisted in the environment, risk factors of leptospirotic infection such as floods and the presence of rats. In a next paper, the author will describe the sorological aspects of this investigation.


Cetacean records along a coastal-offshore gradient in the Vitória-Trindade Chain, western South Atlantic Ocean.
Oceanic waters are difficult to assess, and there are many gaps in knowledge regarding cetacean occurrence. To fill some of these gaps, this article provides important cetacean records obtained in the winter of 2010 during a dedicated expedition to collect visual and acoustic information in the Vitória-Trindade seamounts. We observed 19 groups of cetaceans along a 1300-km search trajectory, with six species being identified: the humpback whale (Megaptera novaeangliae, N = 9 groups), the fin whale (Balaenoptera physalus, N = 1), the Antarctic minke whale (Balaenoptera bonaerensis, N = 1), the rough-toothed dolphin (Steno bredanensis, N = 1), the bottlenose dolphin (Tursiops truncatus, N = 2), and the killer whale (Orcinus orca, N = 1). Most humpback whale groups (N = 7; 78%) were observed in the Vitória-Trindade seamounts, especially the mounts close to the Abrolhos Bank. Only one lone humpback whale was observed near Trindade Island after a search effort encompassing more than 520 km. From a total of 28 acoustic stations, humpback whale songs were only detected near the seamounts close to the Abrolhos Bank, where most groups of this species were visually detected (including a competitive group and groups with calves). The presence of humpback whales at the Trindade Island and surroundings is most likely occasional, with few sightings and low density. Finally, we observed a significant number of humpback whales along the seamounts close to the Abrolhos Bank, which may function as a breeding habitat for this species. We also added important records regarding the occurrence of cetaceans in these mounts and in the Western South Atlantic, including the endangered fin whale.