Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017.
A total of 13672 viruses, collected by World Health Organization recognised National Influenza Centres between May 2016 and May 2017, were assessed for neuraminidase inhibitor susceptibility by four WHO Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance Epidemiology and Control of Influenza. The 50% inhibitory concentration (IC50) was determined for oseltamivir and zanamivir for all viruses, and for peramivir and laninamivir in a subset (n = 8457). Of the viruses tested, 94% were obtained from the Western Pacific, Americas and European WHO regions, while limited viruses were available from the Eastern Mediterranean, African and South East Asian regions. Reduced inhibition (RI) by one or more neuraminidase inhibitor was exhibited by 0.2% of viruses tested (n = 32). The frequency of viruses with RI has remained low since this global analysis began (2015/16: 0.8%, 2014/15: 0.5%; 2013/14: 1.9%; 2012/13: 0.6%) but 2016/17 has the lowest frequency observed to date. Analysis of 13581 neuraminidase sequences retrieved from public databases, of which 5243 sequences were from viruses not included in the phenotypic analyses, identified 58 further viruses (29 without phenotypic analyses) with amino acid substitutions associated with RI by at least one neuraminidase inhibitor. Bringing the total proportion to 0.5% (90/18915). This 2016/17 analysis demonstrates that neuraminidase inhibitors remain suitable for treatment and prophylaxis of influenza virus infections, but continued monitoring is important. An expansion of surveillance testing is paramount since several novel influenza antivirals are in late stage clinical trials with some resistance already having been identified.


Embryonic hypoxia programmes postprandial cardiovascular function in adult common snapping turtles (Chelydra serpentina).
Reduced oxygen availability (hypoxia) is a potent stressor during embryonic development, altering the trajectory of trait maturation and organismal phenotype. We previously documented that chronic embryonic hypoxia has a lasting impact on the metabolic response to feeding in juvenile snapping turtles (Chelydra serpentina). Turtles exposed to hypoxia as embryos [10% O2 (H10)] exhibited an earlier and increased peak postprandial oxygen consumption rate, compared with control turtles [21% O2 (N21)]. In the current study, we measured central blood flow patterns to determine whether the elevated postprandial metabolic response in H10 turtles is linked to lasting impacts on convective transport. Five years after hatching, turtles were instrumented to quantify systemic ([Formula: see text]) and pulmonary ([Formula: see text]) blood flows and heart rate (fH) before and after a ∼5% body mass meal. In adult N21 and H10 turtles, fH was increased significantly by feeding. Although total stroke volume (VS,tot) remained at fasted values, this tachycardia contributed to an elevation in total cardiac output ([Formula: see text]). However, there was a postprandial reduction in a net left-right (L-R) shunt in N21 snapping turtles only. Relative to N21 turtles, H10 animals exhibited higher [Formula: see text] due to increased blood flow through the right systemic outflow vessels of the heart. This effect of hypoxic embryonic development, reducing a net L-R cardiac shunt, may support the increased postprandial metabolic rate we previously reported in H10 turtles, and is further demonstration of adult reptile cardiovascular physiology being programmed by embryonic hypoxia.


Consensus statement on transcultural issues in depression and anxiety from the International Consensus Group on Depression and Anxiety.
To provide primary care physicians with a better understanding of transcultural issues in depression and anxiety. The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Five faculty invited by the chair also participated: Laurence J. Kirmayer, Jean-Pierre Lepine, Keh-Ming Lin, Osamu Tajima, and Yutaka Ono. The consensus statement is based on the 5 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. Group meetings were held over a 2-day period. On day 1, the group discussed the review articles, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. The consensus statement underlines the prevalence of depression and anxiety disorders across all cultures and nations while recognizing that cultural differences exist in symptom presentation and prevalence estimates. In all countries, the recognition of depression by clinicians in the primary care setting is low (generally less than 50%), and the consensus group recommends a 2-step process to aid the recognition and diagnosis of depression. In line with the low recognition of depression and anxiety disorders is the finding that only a small proportion of patients with depression or anxiety are receiving appropriate treatments for their condition. Biological diversity across ethnic groups may account for the differential sensitivity of some groups to psychotropic medication, but this area requires further investigation.


Outcome of Surgical or Endovascular Treatment of Giant Intracranial Aneurysms, with Emphasis on Age, Aneurysm Location, and Unruptured Aneuryms--A Systematic Review and Meta-Analysis.
Designing treatment strategies for unruptured giant intracranial aneurysms (GIA) is difficult as evidence of large clinical trials is lacking. We examined the outcome following surgical or endovascular GIA treatment focusing on patient age, GIA location and unruptured GIA. Medline and Embase were searched for studies reporting on GIA treatment outcome published after January 2000. We calculated the proportion of good outcome (PGO) for all included GIA and for unruptured GIA by meta-analysis using a random effects model. We included 54 studies containing 64 study populations with 1,269 GIA at a median follow-up time (FU-T) of 26.4 months (95% CI 10.8-42.0). PGO was 80.9% (77.4-84.4) in the analysis of all GIA compared to 81.2% (75.3-86.1) in the separate analysis of unruptured GIA. For each year added to patient age, PGO decreased by 0.8%, both for all GIA and unruptured GIA. For all GIA, surgical treatment resulted in a PGO of 80.3% (95% CI 76.0-84.6) compared to 84.2% (78.5-89.8, p = 0.27) after endovascular treatment. In unruptured GIA, PGO was 79.7% (95% CI 71.5-87.8) after surgical treatment and 84.9% (79.1-90.7, p = 0.54) after endovascular treatment. PGO was lower in high quality studies and in studies presenting aggregate instead of individual patient data. In unruptured GIA, the OR for good treatment outcome was 5.2 (95% CI 2.0-13.0) at the internal carotid artery compared to 0.1 (0.1-0.3, p < 0.1) in the posterior circulation. Patient sex, FU-T and prevalence of ruptured GIA were not associated with PGO. We found that the chances of good outcome after surgical or endovascular GIA treatment mainly depend on patient age and aneurysm location rather than on the type of treatment conducted. Our analysis may inform future research on GIA.


Ultrasound-Propelled Nanocups for Drug Delivery.
Ultrasound-induced bubble activity (cavitation) has been recently shown to actively transport and improve the distribution of therapeutic agents in tumors. However, existing cavitation-promoting agents are micron-sized and cannot sustain cavitation activity over prolonged time periods because they are rapidly destroyed upon ultrasound exposure. A novel ultrasound-responsive single-cavity polymeric nanoparticle (nanocup) capable of trapping and stabilizing gas against dissolution in the bloodstream is reported. Upon ultrasound exposure at frequencies and intensities achievable with existing diagnostic and therapeutic systems, nanocups initiate and sustain readily detectable cavitation activity for at least four times longer than existing microbubble constructs in an in vivo tumor model. As a proof-of-concept of their ability to enhance the delivery of unmodified therapeutics, intravenously injected nanocups are also found to improve the distribution of a freely circulating IgG mouse antibody when the tumor is exposed to ultrasound. Quantification of the delivery distance and concentration of both the nanocups and coadministered model therapeutic in an in vitro flow phantom shows that the ultrasound-propelled nanocups travel further than the model therapeutic, which is itself delivered to hundreds of microns from the vessel wall. Thus nanocups offer considerable potential for enhanced drug delivery and treatment monitoring in oncological and other biomedical applications.


Multidimensional classification of hippocampal shape features discriminates Alzheimer's disease and mild cognitive impairment from normal aging.
We describe a new method to automatically discriminate between patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) and elderly controls, based on multidimensional classification of hippocampal shape features. This approach uses spherical harmonics (SPHARM) coefficients to model the shape of the hippocampi, which are segmented from magnetic resonance images (MRI) using a fully automatic method that we previously developed. SPHARM coefficients are used as features in a classification procedure based on support vector machines (SVM). The most relevant features for classification are selected using a bagging strategy. We evaluate the accuracy of our method in a group of 23 patients with AD (10 males, 13 females, age+/-standard-deviation (SD)=73+/-6 years, mini-mental score (MMS)=24.4+/-2.8), 23 patients with amnestic MCI (10 males, 13 females, age+/-SD=74+/-8 years, MMS=27.3+/-1.4) and 25 elderly healthy controls (13 males, 12 females, age+/-SD=64+/-8 years), using leave-one-out cross-validation. For AD vs controls, we obtain a correct classification rate of 94%, a sensitivity of 96%, and a specificity of 92%. For MCI vs controls, we obtain a classification rate of 83%, a sensitivity of 83%, and a specificity of 84%. This accuracy is superior to that of hippocampal volumetry and is comparable to recently published SVM-based whole-brain classification methods, which relied on a different strategy. This new method may become a useful tool to assist in the diagnosis of Alzheimer's disease.


Axial binding and host-guest interactions of a phthalocyanine resorcinarene cavitand hybrid.
A Zn phthalocyanine-resorcinarene cavitand hybrid was prepared. The axial binding and host-guest interactions of this hybrid with a pyridinyl-pyrene were investigated by UV-vis and fluorescence spectroscopic means, revealing the encapsulation of the guest maintained by axial coordination to the Zn phthalocyanine. Energy transfer between the pyrene and the phthalocyanine was evidenced.


Giant Cell Tumor of the Larynx Treated by Surgery and Adjuvant Denosumab: Case Report and Review of the Literature.
Giant cell tumor of the larynx (GCTL) is a rare entity; only 34 cases have been reported in the literature. We report a case of GCTL in a 46 year-old male presenting clinical, radiographic, histological and therapeutic features. Previously reported cases are also reviewed.


Do laws impact opioids consumption? A breakpoint analysis based on Italian sales data.
In Italy, where the adoption of opioid analgesics in pain management has been historically poor, an increase in opioids consumption occurred between 2000 and 2015. The aim of this study is to assess, through specific time series analyses for trend changes, the impact of different intervening factors - such as the availability of new drugs, the observance of clinical guidelines, changes in prescription regulations, and in reimbursement policies - on opioids sales to community pharmacies in Italy, focusing on the time period 2000-2010. Five opioids were considered: codeine, tramadol, buprenorphine, morphine, and fentanyl. The analysis is based on sales data collected at wholesale distributors. For each one of the five drugs, time series of the number of Defined Daily Doses per thousand inhabitants per day in the period 2000-2010 were analyzed, and an estimation of breakpoints was performed using segmented linear regression. Drug sales underwent a sharp increase in 2000-2010, although on different scales. Segmented regression analysis highlighted different potential breakpoints, corresponding to either a significant change in value and/or in slope. Sales of the five opioids were affected by at least one relevant event, often due to a synergy of regulatory, marketing, and technological factors. The effect of reimbursement changes has proved important. Between 2000 and 2010, regulatory, technological, and reimbursement changes significantly influenced opioid sales to community pharmacies in Italy. The sales of relatively new drug products seem to be less influenced by changes in reimbursement and regulatory policies than that of more established products, suggesting that physicians are more comfortable with "old" drugs, since their clinical use is supported by established clinical guidelines and protocols.


Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.
Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains. We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke. Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R3-5-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration. Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses. Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood.


ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL.
Eukaryotic genomes are folded into loops. It is thought that these are formed by cohesin complexes via extrusion, either until loop expansion is arrested by CTCF or until cohesin is removed from DNA by WAPL. Although WAPL limits cohesin's chromatin residence time to minutes, it has been reported that some loops exist for hours. How these loops can persist is unknown. We show that during G1-phase, mammalian cells contain acetylated cohesinSTAG1 which binds chromatin for hours, whereas cohesinSTAG2 binds chromatin for minutes. Our results indicate that CTCF and the acetyltransferase ESCO1 protect a subset of cohesinSTAG1 complexes from WAPL, thereby enable formation of long and presumably long-lived loops, and that ESCO1, like CTCF, contributes to boundary formation in chromatin looping. Our data are consistent with a model of nested loop extrusion, in which acetylated cohesinSTAG1 forms stable loops between CTCF sites, demarcating the boundaries of more transient cohesinSTAG2 extrusion activity.


Renal transplantation in children managed with lymphocyte depleting agents and low-dose maintenance tacrolimus monotherapy.
Describe the safety and efficacy of antithymocyte globulin or alemtuzumab preconditioning, steroid avoidance and reduced calcineurin inhibitor (CNI) immunosuppression in 34 children undergoing renal transplantation. ATG (n=8) or alemtuzumab (n=26) were infused at the time of transplantation. This was followed by low-dose twice a day tacrolimus monotherapy with consolidation to once daily dosing by 6 months and once every other day dosing by 12 months. Follow-up ranged from 0.5-2.9 years (mean 1.33 years), with a minimum of 6 months. Both ATG and alemtuzumab were well tolerated. Lymphopenia occurred routinely and resolved after 3-6 months. Acute cellular rejection occurred in 9%; it was related to medical nonadherence in two patients and resulted in one graft loss at 1.5 years. Important adverse events included transient neutropenia in 10 children (none with serious infection), and autoimmune hemolytic anemia in two (resolved with a steroid course in both and conversion to sirolimus in one). Estimated glomerular filtration rate (e-GFR) was stable and averaged 88 mL/min/1.73 m2 at latest follow-up. Fifteen preadolescents had a greater increase in height Z-score at 1 year (1.3 vs. 0.5, P=0.001), and a higher e-GFR (94.8+/-21 vs. 76.6+/-20 ml/min/1.73 m2, P<0.05), when compared to case-matched historical controls who were weaned off steroids by 6 months after transplantation and received twice daily tacrolimus monotherapy. This simple regimen appears safe, has a low risk for acute cellular rejection or other adverse effects, and is associated with excellent growth and renal function. Such a regimen may also improve compliance and limit CNI nephrotoxicity.


Induction of primary, antiviral cytotoxic, and proliferative responses with antigens administered via dendritic cells.
Cytotoxic T lymphocytes (CTL) play an essential role in recovery from viral infections, but induction of CTL responses with nonreplicating antigens is difficult to achieve. Exogenous antigens, such as viral proteins and peptides, normally induce CD4+ T-cell responses unless appropriately delivered to the major histocompatibility complex class I antigen presentation pathway. In vitro studies performed to address this issue revealed a similar scenario, and primary CTL induction with nonreplicating antigens has rarely been reported. This study demonstrated primary antiviral CTL induction in vitro with exogenous antigens delivered in vivo to dendritic cells. This study also evaluated the efficacy of glycoprotein B peptide (free or encapsulated in liposomes), peptide-tripalmitoyl-S-glyceryl cysteinyl conjugate (acylpeptide), and glycoprotein B protein encapsulated in pH-sensitive liposomes as antigen delivery vehicles. Our results show that higher levels of cytotoxicity against herpes simplex virus type 1 resulted from exposure of dendritic cells to peptide-tripalmitoyl-S-glyceryl cysteinyl in liposomes. Macrophages treated in a similar manner were not effective stimulators for primary CTL induction. Our data have relevance to the understanding of mechanisms of antigen processing and presentation and the design of antiviral vaccines.


Coexpression of rat P2X2 and P2X6 subunits in Xenopus oocytes.
Transcripts for P2X(2) and P2X(6) subunits are present in rat CNS and frequently colocalize in the same brainstem nuclei. When rat P2X(2) (rP2X(2)) and rat P2X(6) (rP2X(6)) receptors were expressed individually in Xenopus oocytes and studied under voltage-clamp conditions, only homomeric rP2X(2) receptors were fully functional and gave rise to large inward currents (2-3 microA) to extracellular ATP. Coexpression of rP2X(2) and rP2X(6) subunits in Xenopus oocytes resulted in a heteromeric rP2X(2/6) receptor, which showed a significantly different phenotype from the wild-type rP2X(2) receptor. Differences included reduction in agonist potencies and, in some cases (e.g., Ap(4)A), significant loss of agonist activity. ATP-evoked inward currents were biphasic at the heteromeric rP2X(2/6) receptor, particularly when Zn(2+) ions were present or extracellular pH was lowered. The pH range was narrower for H(+) enhancement of ATP responses at the heteromeric rP2X(2/6) receptor. Also, H(+) ions inhibited ATP responses at low pH levels (<pH 6.3). The pH-dependent blocking activity of suramin was changed at this heteromeric receptor, although the potentiating effect of Zn(2+) on ATP responses was unchanged. Thus, the rP2X(2/6) receptor is a functionally modified P2X(2)-like receptor with a distinct pattern of pH modulation of ATP activation and suramin blockade. Although homomeric P2X(6) receptors function poorly, the P2X(6) subunit can contribute to functional heteromeric P2X channels and may influence the phenotype of native P2X receptors in those cells in which it is expressed.


Factors associated with an evidence-based measure of implementation for the Adolescent Community Reinforcement Approach.
An evidence-based measure of implementation (EBMI) is an implementation outcome measure shown to have predictive validity with one or more future-measured constructs of importance. The current study sought to identify correlates and predictors of an EBMI called procedure exposure. Garner et al. (2016) found procedure exposure to be an EBMI for the Adolescent Community Reinforcement Approach (A-CRA). The dataset included 76 community-based substance use treatment organizations located across the United States. Organizational-level regression analyses, which were framed within the context of Chaudoir et al. (2013) framework for predicting implementation outcomes, were used to examine predictors of A-CRA procedure exposure RESULTS: The Washington Circle's treatment initiation performance measure (B=5.05 [SE=1.60], p=0.002), as well as session exposure (B=0.18 [SE=0.06], p=0.003), were significant predictors of A-CRA procedure exposure in the backward stepwise regression analysis (Adjusted R-square=0.55). The Washington Circle's treatment engagement performance measure (B=7.93 [SE=0.77], p<0.001), as well as time-to-proficiency (B=-0.04 [SE=0.02], p=0.02), each had significant bivariate relationships with A-CRA procedure exposure but were not retained in the final model. Organizations implementing A-CRA are encouraged to make the following high priorities: (a) scheduling and completing a subsequent treatment session within 14days of their index session (treatment initiation) and (b) providing a targeted number of treatment sessions to each client (session exposure). To the extent organizations do this, they may be more likely to achieve higher levels of A-CRA procedure exposure.


Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity.
MTH1 hydrolyzes oxidized nucleoside triphosphates, thereby sanitizing the nucleotide pool from oxidative damage. This prevents incorporation of damaged nucleotides into DNA, which otherwise would lead to mutations and cell death. The high level of reactive oxygen species in cancer cells leads to a higher level of oxidized nucleotides in cancer cells compared to that in nonmalignant cells, making cancer cells more dependent on MTH1 for survival. The possibility of specifically targeting cancer cells by inhibiting MTH1 has highlighted MTH1 as a promising cancer target. The progression of MTH1 inhibitors into the clinic requires animal studies, and knowledge of species differences in the potency of inhibitors is vitally important. We here show that the human MTH1 inhibitor TH588 is approximately 20-fold less potent with respect to inhibition of mouse MTH1 than the human, rat, pig, and dog MTH1 proteins are. We present the crystal structures of mouse MTH1 in complex with TH588 and dog MTH1 and elucidate the structural and sequence basis for the observed difference in affinity for TH588. We identify amino acid residue 116 in MTH1 as an important determinant of TH588 affinity. Furthermore, we present the structure of mouse MTH1 in complex with the substrate 8-oxo-dGTP. The crystal structures provide insight into the high degree of structural conservation between MTH1 proteins from different organisms and provide a detailed view of interactions between MTH1 and the inhibitor, revealing that minute structural differences can have a large impact on affinity and specificity.


Ultrathin rhodium nanosheets.
Despite significant advances in the fabrication and applications of graphene-like materials, it remains a challenge to prepare single-layered metallic materials, which have great potential applications in physics, chemistry and material science. Here we report the fabrication of poly(vinylpyrrolidone)-supported single-layered rhodium nanosheets using a facile solvothermal method. Atomic force microscope shows that the thickness of a rhodium nanosheet is <4 Å. Electron diffraction and X-ray absorption spectroscopy measurements suggest that the rhodium nanosheets are composed of planar single-atom-layered sheets of rhodium. Density functional theory studies reveal that the single-layered Rh nanosheet involves a δ-bonding framework, which stabilizes the single-layered structure together with the poly(vinylpyrrolidone) ligands. The poly(vinylpyrrolidone)-supported single-layered rhodium nanosheet represents a class of metallic two-dimensional structures that might inspire further fundamental advances in physics, chemistry and material science.


The effects of maternal caffeine and chocolate intake on fetal heart rate.
The aim of our study was to analyze the effects of caffeine and chocolate (70% cocoa) on fetal heart rate (FHR). Fifty pregnant women with uncomplicated gestation, matched for age and parity, underwent computerized FHR recording before and after the consumption of caffeine and then, after one week, before and after 70% cocoa chocolate intake. Computerized cardiotocography (cCTG) parameters were expressed as mean and SD. The differences were tested for statistical significance using the paired t-test, with significance at p < 0.05. The number of uterine contraction peaks, the number of small and large accelerations (10 and 15 beats per minute for 15 seconds), the duration of episodes of high variation and the short-term FHR variation were significantly higher (p < 0.001) after maternal coffee intake. The number of large accelerations, the duration of episodes of high variation and the short-term FHR variation were significantly higher (p < 0.001) after maternal consumption of chocolate, whilst no effect of cocoa was found during contractions. Our results suggest that maternal intake of both caffeine and 70% cocoa have a stimulating action on fetal reactivity. This finding is likely due to the pharmacological action of theobromine, a methilxanthine present in coffee and in chocolate. The correlation between maternal caffeine intake and increased uterine contraction peaks is likely due to the effect of caffeine on the uterine muscle.


Effects of Low- vs. High-Load Resistance Training on Muscle Strength and Hypertrophy in Well-Trained Men.
The purpose of this study was to compare the effect of low- versus high-load resistance training (RT) on muscular adaptations in well-trained subjects. Eighteen young men experienced in RT were matched according to baseline strength and then randomly assigned to 1 of 2 experimental groups: a low-load RT routine (LL) where 25-35 repetitions were performed per set per exercise (n = 9) or a high-load RT routine (HL) where 8-12 repetitions were performed per set per exercise (n = 9). During each session, subjects in both groups performed 3 sets of 7 different exercises representing all major muscles. Training was performed 3 times per week on nonconsecutive days, for a total of 8 weeks. Both HL and LL conditions produced significant increases in thickness of the elbow flexors (5.3 vs. 8.6%, respectively), elbow extensors (6.0 vs. 5.2%, respectively), and quadriceps femoris (9.3 vs. 9.5%, respectively), with no significant differences noted between groups. Improvements in back squat strength were significantly greater for HL compared with LL (19.6 vs. 8.8%, respectively), and there was a trend for greater increases in 1 repetition maximum (1RM) bench press (6.5 vs. 2.0%, respectively). Upper body muscle endurance (assessed by the bench press at 50% 1RM to failure) improved to a greater extent in LL compared with HL (16.6 vs. -1.2%, respectively). These findings indicate that both HL and LL training to failure can elicit significant increases in muscle hypertrophy among well-trained young men; however, HL training is superior for maximizing strength adaptations.


Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression.
A sense-antisense gene pair (SAGP) is a gene pair where two oppositely transcribed genes share a common nucleotide sequence region. In eukaryotic genomes, SAGPs can be organized in complex sense-antisense architectures (CSAGAs) in which at least one sense gene shares loci with two or more antisense partners. As shown in several case studies, SAGPs may be involved in cancers, neurological diseases and complex syndromes. However, CSAGAs have not yet been characterized in the context of human disease or cancer. We characterize five genes (TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199) organized in a CSAGA on 17q11.2 (we term this the TNFAIP1/POLDIP2 CSAGA) and demonstrate their strong and reproducible co-regulatory transcription pattern in breast cancer tumours. Genes of the TNFAIP1/POLDIP2 CSAGA are located inside the smallest region of recurrent amplification on 17q11.2 and their expression profile correlates with the DNA copy number of the region. Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA. Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects. Expression of genes-members of the TNFAIP1/POLDIP2 CSAGA also strongly correlated with expression of genes of ERBB2 core region of recurrent amplification on 17q12. We clearly demonstrate that the observed co-regulatory transcription profile of the TNFAIP1/POLDIP2 CSAGA is maintained not only by a DNA amplification mechanism, but also by chromatin remodelling and local transcription activation. We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its co-regulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer. Co-expression pattern of this module correlates with histological grades and a poor prognosis in breast cancer when over-expressed. TNFAIP1/POLDIP2 CSAGA maps the risks of breast cancer relapse onto the complex genomic locus on 17q11.2.


The unhealthy = tasty belief is associated with BMI through reduced consumption of vegetables: A cross-national and mediational analysis.
Obesity is one of the greatest public health challenges of modern times and its prevalence is increasing worldwide. With food so abundant in developed countries, many people face a conflict between desires for short-term taste and the goal of long-term health, multiple times a day. Recent research suggests that consumers often resolve these conflicts based on their lay beliefs about the healthiness and tastiness of food. Consequently, such lay beliefs can play critical roles not just in food choice but also weight gain. In this research, we show, across six countries and through mediation analysis, that adults who believe that tasty food is unhealthy (the Unhealthy = Tasty Intuition, or "UTI"; Raghunathan, Naylor, & Hoyer 2006) are less likely to consume healthy food, and thereby have a higher body mass index (BMI). In Study 1, we conducted a cross-sectional survey in five countries (Australia, Germany, Hong Kong, India, and the UK), and found that greater strength of belief in UTI was associated with higher BMI, and this relationship was mediated by lower consumption of fruits and vegetables. The observed patterns largely converged across the sampled Western and Asian-Pacific countries. In Study 2, we teased apart the mediating role of vegetable versus fruit consumption and also addressed the issue of reversed causality by predicting BMI with a measure of UTI belief taken 30 months previously. We found that vegetable consumption, but not fruit consumption, mediated the association between UTI belief and BMI. Our findings contribute to the literature by showing how lay beliefs about food can have pervasive and long-lasting effects on dietary practices and health worldwide. Implications for public policy and health practitioners are discussed.


SU-E-T-129: Rescaling of IMRT Verification Deviations from Detector Arrays into the Patient.
To discuss a method of "rescaling" failures detected in a Gamma-Index analysis with detector arrays into the patient as a re-evaluation method in IMRT verifications. In a homogeneous phantom, plane signals measured with ionisation chamber arrays during IMRT field-by-field verifications can be understood as resulting from the convolution of the incident photon fluence with two spatially invariant kernels (dose deposition in the measurement plane and spatial detector response). In principle, Gamma-Index deviations between planned and the measured plane signal profiles can therefore be "back-projected" into a deviation of the photon fluence profile from the planned one which can be "forward-projected" as a dose deviation at test points in the patient. Assuming this model for each field under investigation, all Gamma-Index failures in a certain array region can thus be "rescaled" as deviations of the patient dose and evaluated by with patient related tolerances. The method is evaluated in the prostate and H&N region by use of the 2D-ARRAY729 and VeriSoft5.0. The software offers the possibility to project the position of the ionization chambers onto the patient's CT. Thereby, the field specific analysis of deviations between measurements and plan is supported by suitable imaging procedures. Simulated Gamma-Index failures (3mm/3%) have been evaluated according to the method described above and compared with direct dose calculations. The degree of consistency between relative dose deviations predicted from 2D-ARRAY evaluations and corresponding relative dose deviations calculated within the patient is found to be in an acceptable range. The applicability in regions of inhomogeneity boundaries (air-tissue) and out of field regions was not included in this study and will be analyzed in the future. In combination with the described visualization tools, the method offers the possibility to re-evaluate the dose deviations inside the patient when Gamma-Index failures have been detected with 2D-arrays.


Effect of glaucoma on the quality of life of young patients.
To evaluate the quality of life (QOL) of juvenile-onset primary open-angle glaucoma (JOAG) patients by using a utility-based assessment. QOL using time-tradeoff utility values was analyzed in 70 JOAG patients and compared with 108 adult-onset POAG patients. The relationships of utility values to parameters like age at diagnosis, visual acuity, mean deviation, number of medications and surgery, duration of the disease, level of education, and socioeconomic status were assessed. The mean age at diagnosis of JOAG patients was 26 ± 9.8 years, whereas that of the adult onset POAG patients was 62 ± 11.2 years. Overall, there was a decrease in utility values with increasing age (r = -0.3; P < 0.001). The mean utility score among JOAG patients was (0.80 ± 0.18) significantly greater than among adult POAG patients (0.64 ± 0.28; P < 0.001). The differences in utility scores between JOAG and adult POAG patients were significant when adjusted for differences in better eye visual acuity, mean deviation, and the presence of systemic comorbidity among adults (P = 0.02). Among JOAG patients, those needing topical antiglaucoma medications and those with visual acuity worse than 6/12 in the better eye had lower utility values (P = 0.008 and P = 0.002, respectively). Utility values among glaucoma patients in the juvenile age group are better than those of adult POAG patients. Decreasing vision in the better eye and having to use medication decrease the utility scores among young patients with glaucoma.


Negative life events as an account of age-related differences in the genetic aetiology of depression in childhood and adolescence.
Many twin studies have reported that the genetic aetiology of depression differs according to age, with genetic influences being more important for adolescents than younger children. We sought to examine whether this age-related increase in the relative importance of genetic factors is due to an increase in gene-environment correlation specifically involving negative life events. Questionnaires were sent to the families of a population-based sample of twins aged between 8 and 17 years. Parents of all the twins and adolescents aged 11 and over were asked to complete the Mood and Feelings Questionnaire (Costello & Angold, 1988) and a modified version of the Life Events Checklist (Johnson & McCutcheon, 1980). Responses were obtained from 1468 families and data were analysed using genetic model fitting. Bivariate analysis of 1) negative life events and 2) behaviour-dependent life events and depression symptoms was undertaken separately for children (aged 8 to 10 years) and adolescents (aged 11 to 17 years). Differences in genetic and environmental parameters across age groups were tested. Adolescence was associated with a greater number of behaviour-dependent life events. Genetic covariation of negative life events and depression was greater for adolescents than for children. Bivariate model fitting was consistent with the greater heritability of depression seen in adolescence being due to an increase in gene-environment correlation involving negative life events. However, the effects of genes associated specifically with maturation in adolescence, the possibility of 'person' effects and the role of other environmental factors also need to be considered.


Dynamic nucleosomes and gene transcription.
Gene transcription occurs on a nucleosomal template known as chromatin. The recruitment of the transcriptional regulators and the transcription machinery to promoter chromatin is coordinated by a genetic code on the DNA and an epigenetic code on the histone proteins. Chromatin is not a stable environment; rather, the histones, the transcription regulatory proteins and the enzymes that modify and mobilise nucleosomes are in a dynamic state. Thus, at any one time, the factors associated with a region will cooperate or compete to change the rate of inter-conversion between permissive and non-permissive chromatin states, leading to activation or repression of transcription. Here, new concepts such as dynamic nucleosomes and a dynamic histone code in gene transcription are explored.


New hints towards a precision medicine strategy for IDH wild-type glioblastoma.
Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.


Blastoid variant mantle cell lymphoma with complex karyotype including 11q duplication.
We describe a case of blastoid mantle cell lymphoma with a complex karyotype. The blastoid variant is a rare type of non-Hodgkin lymphoma exhibiting an aggressive clinical course. Mantle cell lymphoma is a distinct entity of mature B-cell neoplasms genetically characterized by the presence of t(11;14). In the present case, conventional analysis revealed structural abnormalities of chromosomes 2, 4, 6, 10, 13, and 19, along with 3 additional marker chromosomes. The derivative 1 chromosome determined in the case was a result of t(1p;11q). Our interesting finding was the presence of a different translocation between 11q and chromosome 1 in addition to t(11;14). Thus, the resulting 11q duplication was believed to additionally increase the enhanced expression of cyclin D1 gene, which is responsible in the pathogenesis of the disease. Fluorescence in situ hybridization method by the t(11;14) probe revealed clonal numerical abnormalities of chromosomes 11 and 14 in some cells. The detection of multiple abnormalities explains the bad prognosis in the present case. On the basis of our findings, we can easily conclude that results of cytogenetic analyses of similar mantle cell lymphoma patients would provide clues about new responsible gene regions and disease prognosis. In conclusion, it has been suggested that the presence of multiple chromosomal aberrations in addition to the specific t(11;14) may have a negative impact on clinical course and survival rate.


Social gradients in health for Pakistani and White British women and infants in two UK birth cohorts.
This study aims to examine social gradients in low birth weight (LBW), preterm birth, smoking during pregnancy and maternal health for women and infants of Pakistani origin and White British women and infants in the UK. The sample included women and singleton infants from the Born in Bradford (BiB) study (n = 8181) and the first sweep of the Millennium Cohort Study (MCS) (n = 8980). Social gradients in health for four measures of socioeconomic status (SES): maternal education, means-tested benefits, financial situation, and occupation of the father were analysed in multivariate regression models adjusting for maternal age and parity. For White British mothers and infants in the MCS sample, social gradients in health were observed for at least three out of four measures of SES for each health outcome (p for trend <.01). Similar trends were found for White British mothers and infants in the BiB sample, although these were less likely to be significant. There were few associations between measures of SES and outcomes in the Pakistani samples. The strongest evidence of a social gradient in health for Pakistani women was demonstrated with the self-reported measure of financial situation, in relation to mental health (p for trend <.001 in both cohorts). This study describes a lack of social gradients in health for Pakistani women and infants and discusses potential explanations for this finding.


Skull vibration induced nystagmus in patients with superior semicircular canal dehiscence.
To establish optimum stimulus frequency and location of bone conducted vibration provoking a skull vibration induced nystagmus (SVIN) in superior semi-circular canal dehiscences. SVIN 3D components in 40 patients with semi-circular canal dehiscence (27 unilateral and 13 bilateral) were compared with a group of 18 patients with severe unilateral vestibular loss and a control group of 11 volunteers. In unilateral semi-circular canal dehiscences, SVIN torsional and horizontal components observed on vertex location in 88% beat toward the lesion side in 95%, and can be obtained up to 800Hz (around 500Hz being optimal). SVIN slow-phase-velocity was significantly higher on vertex stimulation at 100 and 300Hz (P=0.04) than on mastoids. SVIN vertical component is more often upbeating than downbeating. A SVIN was significantly more often observed in unilateral than bilateral semi-circular-canal dehiscences (P=0.009) and with a higher slow phase velocity (P=0.008). In severe unilateral vestibular lesions the optimal frequency was 100Hz and SVIN beat toward the intact side. The mastoid stimulation was significantly more efficient than vertex stimulation at 60 and 100Hz (P<0.01). SVIN reveals instantaneously in unilateral semi-circular canal dehiscences a characteristic nystagmus beating, for the torsional and horizontal components, toward the lesion side and with a greater sensitivity toward high frequencies on vertex stimulation. SVIN three components analysis suggests a stimulation of both superior semi-circular canal and utricle. SVIN acts as a vestibular Weber test, assessing a vestibular asymmetrical function and is a useful indicator for unilateral semi-circular canal dehiscence.


Microtubules enable the planar cell polarity of airway cilia.
Airway cilia must be physically oriented along the longitudinal tissue axis for concerted, directional motility that is essential for proper mucociliary clearance. We show that planar cell polarity (PCP) signaling specifies directionality and orients respiratory cilia. Within all airway epithelial cells, a conserved set of PCP proteins shows interdependent, asymmetric junctional localization; nonautonomous signaling coordinates polarization between cells; and a polarized microtubule (MT) network is likely required for asymmetric PCP protein localization. We find that basal bodies dock after polarity of PCP proteins is established and are polarized nearly simultaneously, and that refinement of basal body/cilium orientation continues during airway epithelial development. Unique to mature multiciliated cells, we identify PCP-regulated, planar polarized MTs that originate from basal bodies and interact, via their plus ends, with membrane domains associated with the PCP proteins Frizzled and Dishevelled. Disruption of MTs leads to misoriented cilia. A conserved PCP pathway orients airway cilia by communicating polarity information from asymmetric membrane domains at the apical junctions, through MTs, to orient the MT and actin-based network of ciliary basal bodies below the apical surface.


The opportunistic human pathogen Acinetobacter baumannii senses and responds to light.
Light is a ubiquitous environmental signal that many organisms sense and respond to by modulating their physiological responses accordingly. While this is an expected response among phototrophic microorganisms, the ability of chemotrophic prokaryotes to sense and react to light has become a puzzling and novel issue in bacterial physiology, particularly among bacterial pathogens. In this work, we show that the opportunistic pathogen Acinetobacter baumannii senses and responds to blue light. Motility and formation of biofilms and pellicles were observed only when bacterial cells were incubated in darkness. In contrast, the killing of Candida albicans filaments was enhanced when they were cocultured with bacteria under light. These bacterial responses depend on the expression of the A. baumannii ATCC 17978 A1S_2225 gene, which codes for an 18.6-kDa protein that contains an N-terminal blue-light-sensing-using flavin (BLUF) domain and lacks a detectable output domain(s). Spectral analyses of the purified recombinant protein showed its ability to sense light by a red shift upon illumination. Therefore, the A1S_2225 gene, which is present in several members of the Acinetobacter genus, was named blue-light-sensing A (blsA). Interestingly, temperature plays a role in the ability of A. baumannii to sense and respond to light via the BlsA photoreceptor protein.


US County-Level Trends in Mortality Rates for Major Causes of Death, 1980-2014.
County-level patterns in mortality rates by cause have not been systematically described but are potentially useful for public health officials, clinicians, and researchers seeking to improve health and reduce geographic disparities. To demonstrate the use of a novel method for county-level estimation and to estimate annual mortality rates by US county for 21 mutually exclusive causes of death from 1980 through 2014. Redistribution methods for garbage codes (implausible or insufficiently specific cause of death codes) and small area estimation methods (statistical methods for estimating rates in small subpopulations) were applied to death registration data from the National Vital Statistics System to estimate annual county-level mortality rates for 21 causes of death. These estimates were raked (scaled along multiple dimensions) to ensure consistency between causes and with existing national-level estimates. Geographic patterns in the age-standardized mortality rates in 2014 and in the change in the age-standardized mortality rates between 1980 and 2014 for the 10 highest-burden causes were determined. County of residence. Cause-specific age-standardized mortality rates. A total of 80 412 524 deaths were recorded from January 1, 1980, through December 31, 2014, in the United States. Of these, 19.4 million deaths were assigned garbage codes. Mortality rates were analyzed for 3110 counties or groups of counties. Large between-county disparities were evident for every cause, with the gap in age-standardized mortality rates between counties in the 90th and 10th percentiles varying from 14.0 deaths per 100 000 population (cirrhosis and chronic liver diseases) to 147.0 deaths per 100 000 population (cardiovascular diseases). Geographic regions with elevated mortality rates differed among causes: for example, cardiovascular disease mortality tended to be highest along the southern half of the Mississippi River, while mortality rates from self-harm and interpersonal violence were elevated in southwestern counties, and mortality rates from chronic respiratory disease were highest in counties in eastern Kentucky and western West Virginia. Counties also varied widely in terms of the change in cause-specific mortality rates between 1980 and 2014. For most causes (eg, neoplasms, neurological disorders, and self-harm and interpersonal violence), both increases and decreases in county-level mortality rates were observed. In this analysis of US cause-specific county-level mortality rates from 1980 through 2014, there were large between-county differences for every cause of death, although geographic patterns varied substantially by cause of death. The approach to county-level analyses with small area models used in this study has the potential to provide novel insights into US disease-specific mortality time trends and their differences across geographic regions.


Middle cerebral artery bifurcation aneurysms: an anatomic classification scheme for planning optimal surgical strategies.
Changing landscapes in neurosurgical training and increasing use of endovascular therapy have led to decreasing exposure in open cerebrovascular neurosurgery. To ensure the effective transition of medical students into competent practitioners, new training paradigms must be developed. Using principles of pattern recognition, we created a classification scheme for middle cerebral artery (MCA) bifurcation aneurysms that allows their categorization into a small number of shape pattern groups. Angiographic data from patients with MCA aneurysms between 1995 and 2012 were used to construct 3-dimensional models. Models were then analyzed and compared objectively by assessing the relationship between the aneurysm sac, parent vessel, and branch vessels. Aneurysms were then grouped on the basis of the similarity of their shape patterns in such a way that the in-class similarities were maximized while the total number of categories was minimized. For each category, a proposed clip strategy was developed. From the analysis of 61 MCA bifurcation aneurysms, 4 shape pattern categories were created that allowed the classification of 56 aneurysms (91.8%). The number of aneurysms allotted to each shape cluster was 10 (16.4%) in category 1, 24 (39.3%) in category 2, 7 (11.5%) in category 3, and 15 (24.6%) in category 4. This study demonstrates that through the use of anatomic visual cues, MCA bifurcation aneurysms can be grouped into a small number of shape patterns with an associated clip solution. Implementing these principles within current neurosurgery training paradigms can provide a tool that allows more efficient transition from novice to cerebrovascular expert.


Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer.
Soy isoflavone genistein exhibits growth inhibitory activity against human pancreatic cancer cell lines. We previously reported the potential of genistein to augment chemotherapeutic response of pancreatic cancer cells in vitro. In the present study, we investigated whether genistein pretreatment could be used as a novel strategy for gemcitabine-induced killing in vitro and enhanced antitumor activity in vivo using an orthotopic tumor model. We conducted our studies using paired isogenic human pancreatic cancer cell line with differences in metastatic behavior (COLO 357 and L3.6pl). In vitro studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone. The overall growth inhibition was directly correlated with apoptotic cell death irrespective of the metastatic potential of cells. Several genes that are known to inhibit apoptosis and contribute to chemoresistance such as nuclear factor-kappaB (NF-kappaB) and Akt were assessed to investigate the basis for the observed chemosensitizing effects of genistein. Genistein potentiated the gemcitabine-induced killing by down-regulation of NF-kappaB and Akt. In contrast, Akt and NF-kappaB were found to be up-regulated when pancreatic cancer cells were exposed to gemcitabine alone, suggesting the potential mechanism of acquired chemoresistance. In addition to in vitro results, we show here for the first time, that genistein in combination with gemcitabine is much more effective as an antitumor agent compared with either agent alone in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in genistein-treated animal tumors and that gemcitabine-induced activation of NF-kappaB was completely inhibited in animal tumors treated with genistein and gemcitabine. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of NF-kappaB signaling pathway by genistein could also abrogate gemcitabine-induced activation of NF-kappaB resulting in the chemosensitization of pancreatic tumors to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.


Effect of angiotensin II and of an angiotensin II analogue (Sar1-Ile8-angiotensin II) on blood pressure, plasma aldosterone and plasma renin activity in the dog.
1. The effect of infusions of equimolar doses of angiotensin II (AII) and of the angiotensin analogue Sar1-Ile8-angiotensin II on arterial blood pressure, plasma aldosterone and plasma renin activity were compared in normal anaesthetized dexamethasone suppressed dogs. 2. Angiotensin II induced a significant increase of blood pressure and of plasma aldosterone whereas plasma renin activity decreased. The blood pressure was only slightly affected by large doses of the analogue. Plasma aldosterone, however, increased and plasma renin activity decreased. These changes were significant but less pronounced than after the infusions of angiotensin II. Plasma aldosterone remained high and renin activity low for 40 min after the infusions of the analogue. 3. The results suggest a strong agonistic potency of Sar1-Ile8-angiotensin II at the adrenal and renal angiotensin receptors, and that it is almost ineffective at the vascular receptors. The inhibition of renin secretion by angiotensin seems not be related to its vasoconstrictive activity.


Direct contact with endoderm-like cells efficiently induces cardiac progenitors from mouse and human pluripotent stem cells.
Pluripotent stem cell-derived cardiac progenitor cells (CPCs) have emerged as a powerful tool to study cardiogenesis in vitro and a potential cell source for cardiac regenerative medicine. However, available methods to induce CPCs are not efficient or require high-cost cytokines with extensive optimization due to cell line variations. Based on our in-vivo observation that early endodermal cells maintain contact with nascent pre-cardiac mesoderm, we hypothesized that direct physical contact with endoderm promotes induction of CPCs from pluripotent cells. To test the hypothesis, we cocultured mouse embryonic stem (ES) cells with the endodermal cell line End2 by co-aggregation or End2-conditioned medium. Co-aggregation resulted in strong induction of Flk1(+) PDGFRa(+) CPCs in a dose-dependent manner, but the conditioned medium did not, indicating that direct contact is necessary for this process. To determine if direct contact with End2 cells also promotes the induction of committed cardiac progenitors, we utilized several mouse ES and induced pluripotent (iPS) cell lines expressing fluorescent proteins under regulation of the CPC lineage markers Nkx2.5 or Isl1. In agreement with earlier data, co-aggregation with End2 cells potently induces both Nkx2.5(+) and Isl1(+) CPCs, leading to a sheet of beating cardiomyocytes. Furthermore, co-aggregation with End2 cells greatly promotes the induction of KDR(+) PDGFRa(+) CPCs from human ES cells. Our co-aggregation method provides an efficient, simple and cost-effective way to induce CPCs from mouse and human pluripotent cells.


Arginase 2 deletion reduces neuro-glial injury and improves retinal function in a model of retinopathy of prematurity.
Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP. Studies were performed using wild type (WT) and A2 knockout (A2-/-) mice exposed to Oxygen Induced Retinopathy (OIR). Neuronal injury and apoptosis were assessed using immunohistochemistry, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end) labeling and Western blotting. Electroretinography (ERG) was used to assess retinal function. Neuro-glial injury in WT ROP mice was evident by TUNEL labeling, retinal thinning, decreases in number of rod bipolar cells and glial cell activation as compared with room air controls. Significant reduction in numbers of TUNEL positive cells, inhibition of retinal thinning, preservation of the rod bipolar cells and prevention of glial activation were observed in the A2-/- retinas. Retinal function was markedly impaired in the WT OIR mice as shown by decreases in amplitude of the b-wave of the ERG. This defect was significantly reduced in A2-/- mice. Levels of the pro-apoptotic proteins p53, cleaved caspase 9, cytochrome C and the mitochondrial protein Bim were markedly increased in WT OIR retinas compared to controls, whereas the pro-survival Mitochondrial protein BCL-xl was reduced. These alterations were largely blocked in the A2-/- OIR retina. Our data implicate A2 in neurodegeneration during ROP. Deletion of A2 significantly improves neuronal survival and function, possibly through the regulation of mitochondrial membrane permeability mediated apoptosis during retinal ischemia. These molecular events are associated with decreased activation of glial cells, suggesting a rescue effect on macroglia as well.


The properties of specific binding site of 125I-radioiodinated myotoxin a, a novel Ca++ releasing agent, in skeletal muscle sarcoplasmic reticulum.
It was found that myotoxin a (MYTX), which is isolated from prairie rattlesnakes (Crotalus viridis viridis), is a powerful Ca++ releaser in the heavy fraction of sarcoplasmic reticulum (HSR). 125I-labeled MYTX (125I-MYTX), which has high Ca(++)-releasing ability, was successfully prepared. It specifically bound to a single class of binding sites in HSR with a KD of 0.4 microM and Bmax of 6 nmol/mg of protein. 125I-MYTX binding was markedly inhibited by Na+ and K+, whereas it was little affected by Ca++ and Mg++. The binding activity was markedly decreased by spermine, a blocker of Ca++ releasing channels, and was not affected by the other modulators of Ca++ release such as caffeine, procaine or ruthenium red. Spermine decreased the binding in a concentration-dependent manner with the IC50 value of 20 microM. Scatchard analysis of 125I-MYTX binding indicated that the Bmax value was decreased by spermine, although the KD value was not changed, which indicates a noncompetitive mode of inhibition. 125I-MYTX did not bind to the purified ryanodine receptor. Ca++ electrode experiments indicated that MYTX induced Ca++ release from HSR at doses of 0.1 microM or more; this was abolished by spermine. The maximal response to MYTX (10 microM) was further increased by caffeine (10 mM) in 45Ca++ release, which probably indicates that the effects of MYTX and caffeine are synergistic in Ca(++)-releasing action. These results suggest that MYTX binds to an important regulatory protein of Ca++ release, which is not the ryanodine receptor.


Knowledge of carrier status and barriers to testing among mothers of sons with Duchenne or Becker muscular dystrophy.
Our study objective was to survey female carriers for Duchenne and Becker muscular dystrophy to identify barriers to carrier testing and the impact of carrier risk knowledge on cardiac and reproductive health management. We surveyed women who have or had biological sons with Duchenne or Becker muscular dystrophy and were enrolled in the US DuchenneConnect patient registry, with questions assessing knowledge of carrier status and recurrence risk, knowledge of care standards for carriers, and barriers to testing. Of the 182 eligible respondents, 25% did not know their carrier status and 14% incorrectly classified themselves as not at risk. Cost of testing was the most commonly identified barrier to testing. Women reporting unknown carrier status were 13 times as likely to express uncertainty regarding their recurrence risk compared to women reporting positive carrier status. 37% of women at an increased risk for cardiomyopathy had never had an echocardiogram. Women who were certain of their positive carrier status were twice as likely to have had an echocardiogram in the last five years compared to women with unknown carrier status. Future research on reducing barriers to counseling and carrier testing, such as cost, may improve care standard adherence.


How Do Clinicians Learn About Knowledge Translation? An Investigation of Current Web-Based Learning Opportunities.
Clinicians are important stakeholders in the translation of well-designed research evidence into clinical practice for optimal patient care. However, the application of knowledge translation (KT) theories and processes may present conceptual and practical challenges for clinicians. Online learning platforms are an effective means of delivering KT education, providing an interactive, time-efficient, and affordable alternative to face-to-face education programs. This study investigates the availability and accessibility of online KT learning opportunities for health professionals. It also provides an analysis of the types of resources and associated disciplines retrieved by a range of KT synonyms. We searched a range of bibliographic databases and the Internet (Google advanced option) using 9 KT terms to identify online KT learning resources. To be eligible, resources had to be free, aimed at clinicians, educational in intent, and interactive in design. Each term was searched using two different search engines. The details of the first 100 websites captured per browser (ie, n=200 results per term) were entered into EndNote. Each site was subsequently visited to determine its status as a learning resource. Eligible websites were appraised for quality using the AACODS (Authority, Accuracy, Coverage, Objectivity, Date, Significance) tool. We identified 971 unique websites via our multiple search strategies. Of these, 43 were health-related and educational in intent. Once these sites were evaluated for interactivity, a single website matched our inclusion criteria (Dementia Knowledge Translation Learning Centre). KT is an important but complex system of processes. These processes overlap with knowledge, practice, and improvement processes that go by a range of different names. For clinicians to be informed and competent in KT, they require better access to free learning opportunities. These resources should be designed from the viewpoint of the clinician, presenting KT's multifaceted theories and processes in an engaging, interactive way. This learning should empower clinicians to contextualize and apply KT strategies within their own care settings.


Effect of topical application of raspberry ketone on dermal production of insulin-like growth factor-I in mice and on hair growth and skin elasticity in humans.
Sensory neurons release calcitonin gene-related peptide (CGRP) on activation. We recently reported that topical application of capsaicin increases facial skin elasticity and promotes hair growth by increasing dermal insulin-like growth factor-I (IGF-I) production through activation of sensory neurons in mice and humans. Raspberry ketone (RK), a major aromatic compound contained in red raspberries (Rubus idaeus), has a structure similar to that of capsaicin. Thus, it is possible that RK activates sensory neurons, thereby increasing skin elasticity and promoting hair growth by increasing dermal IGF-I production. In the present study, we examined this possibility in mice and humans. RK, at concentrations higher than 1 microM, significantly increased CGRP release from dorsal root ganglion neurons (DRG) isolated from wild-type (WT) mice and this increase was completely reversed by capsazepine, an inhibitor of vanilloid receptor-1 activation. Topical application of 0.01% RK increased dermal IGF-I levels at 30 min after application in WT mice, but not in CGRP-knockout mice. Topical application of 0.01% RK increased immunohistochemical expression of IGF-I at dermal papillae in hair follicles and promoted hair re-growth in WT mice at 4 weeks after the application. When applied topically to the scalp and facial skin, 0.01% RK promoted hair growth in 50.0% of humans with alopecia (n=10) at 5 months after application and increased cheek skin elasticity at 2 weeks after application in 5 females (p<0.04). These observations strongly suggest that RK might increase dermal IGF-I production through sensory neuron activation, thereby promoting hair growth and increasing skin elasticity.


Evaluating the Performance of Water Models with Host-Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril-Guest Systems.
Computational prediction of thermodynamic components with computational methods has become increasingly routine in computer-aided drug design. Although there has been significant recent effort and improvements in the calculation of free energy, the prediction of enthalpy (and entropy) remains underexplored. Furthermore, there has been relatively little work reported so far that attempts to comparatively assess how well different force fields and water models perform in conjunction with each other. Here, we report a comprehensive assessment of force fields and water models using host-guest systems that mimic many features of protein-ligand systems. These systems are computationally inexpensive, possibly because of their small size compared to protein-ligand systems. We present absolute enthalpy calculations using the multibox approach on a set of 25 cucurbit[7]uril-guest pairs. Eight water models were considered (TIP3P, TIP4P, TIP4P-Ew, SPC, SPC/E, OPC, TIP5P, Bind3P), along with five force fields commonly used in the literature (GAFFv1, GAFFv2, CGenFF, Parsley, and SwissParam). We observe that host-guest binding enthalpies are strongly sensitive to the selection of force field and water model. In terms of water models, we find that TIP3P and its derivative Bind3P are the best performing models for this particular host-guest system. The performance is generally better for aliphatic compounds than for aromatic ones, suggesting that aromaticity remains a difficult property to include accurately in these simple force fields.


Cannabinoid signaling and risk in Huntington's disease.
Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (CB1Rs) are important phenotypes of Huntington's disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio.


Assisted gene flow using cryopreserved sperm in critically endangered coral.
Assisted gene flow (AGF) is a conservation intervention to accelerate species adaptation to climate change by importing genetic diversity into at-risk populations. Corals exemplify both the need for AGF and its technical challenges; corals have declined in abundance, suffered pervasive reproductive failures, and struggled to adapt to climate change, yet mature corals cannot be easily moved for breeding, and coral gametes lose viability within hours. Here, we report the successful demonstration of AGF in corals using cryopreserved sperm that was frozen for 2 to 10 y. We fertilized Acropora palmata eggs from the western Caribbean (Curaçao) with cryopreserved sperm from genetically distinct populations in the eastern and central Caribbean (Florida and Puerto Rico, respectively). We then confirmed interpopulation parentage in the Curaçao-Florida offspring using 19,696 single-nucleotide polymorphism markers. Thus, we provide evidence of reproductive compatibility of a Caribbean coral across a recognized barrier to gene flow. The 6-mo survival of AGF offspring was 42%, the highest ever achieved in this species, yielding the largest wildlife population ever raised from cryopreserved material. By breeding a critically endangered coral across its range without moving adults, we show that AGF using cryopreservation is a viable conservation tool to increase genetic diversity in threatened marine populations.


Zika virus: A new threat to human reproduction.
Zika virus (ZIKV) was first isolated in 1947 in a rhesus monkey from the Zika forest of Uganda. Until 2007, only 14 human cases were reported. The first large human outbreak occurred in 2007 (Yap Island, Federated States of Micronesia, Pacific) followed by French Polynesia in 2013 and Brazil in 2015. The virus is mainly transmitted through Aedes mosquito bites, but sexual and post-transfusion transmissions have been reported. Symptoms include low-grade fever, maculopapular rash, conjunctivitis, myalgia, arthralgia, and asthenia. During the recent outbreaks in French Polynesia and Brazil, ZIKV infection has been associated with two major complications: microcephaly and Guillain-Barré syndrome. Since fetal infection includes other birth defects, congenital Zika syndrome has been used to define in utero infection. The majority of sexual transmission occurred from a symptomatic male to a female, but female-to-male and male-to-male transmission have been reported. Asymptomatic male-to-female transmission has also been described. Importantly, ZIKV RNA can persist at least 6 months in semen. The male urogenital tract may therefore act as a reservoir for the virus. ZIKV RNA was detected in a cervical swab of a patient 3 days after presenting the classic symptoms suggesting a potential tropism for the female genital tract. Long-lasting presence of ZIKV RNA might not indicate that the individual is infectious but makes recommendation for couples potentially exposed to the virus and willing to conceive difficult. It will also be important to determine whether genital ZIKV infection might have a deleterious effect on male and female fertility.


Historical and anthropogenic factors affecting the population genetic structure of Ontario's inland lake populations of Walleye (Sander vitreus).
Populations existing in formerly glaciated areas often display composite historical and contemporary patterns of genetic structure. For Canadian freshwater fishes, population genetic structure is largely reflective of dispersal from glacial refugia and isolation within drainage basins across a range of scales. Enhancement of sport fisheries via hatchery stocking programs and other means has the potential to alter signatures of natural evolutionary processes. Using 11 microsatellite loci genotyped from 2182 individuals, we analyzed the genetic structure of 46 inland lake walleye (Sander vitreus) populations spanning five major drainage basins within the province of Ontario, Canada. Population genetic analyses coupled with genotype assignment allowed us to: 1) characterize broad- and fine-scale genetic structure among Ontario walleye populations; and 2) determine if the observed population divergence is primarily due to natural or historical processes, or recent anthropogenic events. The partitioning of genetic variation revealed higher genetic divergence among lakes than among drainage basins or proposed ancestries-indicative of relatively high isolation among lakes, study-wide. Walleye genotypes were clustered into three major groups, likely reflective of Missourian, Mississippian, and Atlantic glacial refugial ancestry. Despite detectable genetic signatures indicative of anthropogenic influences, province-wide spatial genetic structure remains consistent with the hypothesis of dispersal from distinct glacial refugia and subsequent isolation of lakes within primary drainage basins. Our results provide a novel example of minimal impacts from fishery enhancement to the broad-scale genetic structure of inland fish populations.


Frequent use of medical services. Patient reports of intentions to seek care.
To examine differences between frequent and infrequent users in decisions to seek medical care based on symptom type and duration of experience of the symptom. Retrospective study. University family practice clinic. Fifty-eight of 130 patients returned the completed instruments, a response rate of 45%. The following two instruments were used: the Intentions to Seek Care questionnaire, which measures intention to see a physician, self-treat, or use medications for 11 different symptoms after three time periods--1 day, 3 days, and 1 week of symptom duration--and the SF-36 Health Survey measure. Initial analyses suggested that patients perceive three clusters of symptoms, which we have labeled as serious, mild, and psychological. Scale scores for these groups of symptoms yielded significant reliability and were used in subsequent analyses. Multivariate analysis of variance comparing source of care, symptom duration, and frequent vs infrequent user groups indicated that both user groups are more likely to seek care from physicians for symptoms that are serious. Analysis of mild and psychological symptoms yielded significant three-way interactions, with frequent users more likely than infrequent users to seek care from physicians at a 1-day duration. Such differences disappear by 7 days. Significantly lower scores were obtained on five of the eight SF-36 Health Survey dimensions for the infrequent users. Frequent users are more likely than infrequent users to report that they would seek care for minor symptoms. Infrequent users tend to self-treat for 3 to 7 days, after which time physician advice is sought. Efforts to teach patients optimal timing of use for different symptoms may be an effective intervention.


Individual, behavioural and home environmental factors associated with eating behaviours in young adolescents.
This study aimed to examine individual, behavioural and home environmental factors associated with frequency of consumption of fruit, vegetables and energy-dense snacks among adolescents. Adolescents aged 11-12 years (n = 521, 48% boys) completed a paper-based questionnaire during class-time which included a Food Frequency Questionnaire assessing their consumption of fruit, vegetables, and energy-dense (ED) snacks, and items assessing habits, self-efficacy, eating at the television (TV), eating with parents, parenting practices, and home availability and accessibility of foods. Multiple linear regression analyses showed that eating fruit and vegetables while watching TV and home availability and accessibility of fruit and vegetables were positively associated with frequency of fruit consumption and vegetable consumption, while home accessibility of ED snack foods was negatively associated with frequency of fruit consumption. Habit for eating ED snack foods in front the TV, eating ED snack foods while watching TV, and home availability of ED snacks were positively associated with frequency of ED snack consumption. This study has highlighted the importance of a healthy home environment for promoting fruit and vegetable intake in early adolescents and also suggests that, if snacking while TV viewing occurs, this could be a good opportunity for promoting fruit and vegetable intake. These findings are likely to be useful for supporting the development of multi-faceted interventions and aid us in knowing what advice to give to parents to help them to help their young adolescents to develop and maintain healthy eating habits.


Intrathecal baclofen use in the management of tetanus related spasm: A case report.
Şık G, Aydoseli A, Çıtak A. Intrathecal baclofen use in the management of tetanus related spasm: A case report. Turk J Pediatr 2019; 61: 126-129. Tetanus is an infectious disease of the central nervous system with high mortality rates characterized with respiratory distress and tonic muscle spasms. The most common cause of mortality is cardiovascular complications (40%) and respiratory distress (15%). Despite vaccination programs, tetanus remains to be a significant healthcare issue in developing nations. Prolonged sedation and administration of muscle relaxants prolongs the period on mechanical ventilation and duration of hospitalization in severe tetanus cases. However, intrathecal baclofen (ITB) therapy might shorten the duration of stay at intensive care units, improve patient outcomes, and constitute a treatment option alternative to paralytic agents and sedation. In this manuscript, we present a 12-years-old case diagnosed with tetanus and treated with ITB upon observation of spasms refractory to high dose sedation and muscle relaxants.


Developmental delay during eye morphogenesis underlies optic cup and neurogenesis defects in mab21l2u517 zebrafish mutants.
Shaping the vertebrate eye requires evagination of the optic vesicles. These vesicles subsequently fold into optic cups prior to undergoing neurogenesis and allocating a population of late progenitors at the margin of the eye. mab21l2 encodes a protein of unknown biological function expressed in the developing optic vesicles, and loss of mab21l2 function results in malformed eyes. The bases of these defects are, however, poorly understood. To further study mab21l2 we used CRISPR/Cas9 to generate a new zebrafish mutant allele (mab21l2u517). We characterized eye morphogenesis and neurogenesis upon loss of mab21l2 function using tissue/cell-type-specific transgenes and immunostaining, in situ hybridization and bromodeoxyuridine incorporation. mab21l2u517 eyes fail to grow properly and display an excess of progenitors in the ciliary marginal zone. The expression of a transgene reporter for the vsx2 gene -a conserved marker for retinal progenitors- was delayed in mutant eyes and accompanied by disruptions in the epithelial folding that fuels optic cup morphogenesis. Mutants also displayed nasal-temporal malformations suggesting asynchronous development along that axis. Consistently, nasal retinal neurogenesis initiated but did not propagate in a timely fashion to the temporal retina. Later in development, mutant retinas did laminate and differentiate. Thus, mab21l2u517 mutants present a complex eye morphogenesis phenotype characterized by an organ-specific developmental delay. We propose that mab21l2 facilitates optic cup development with consequences both for timely neurogenesis and allocation of progenitors to the zebrafish ciliary marginal zone. These results confirm and extend previous analyses supporting the role of mab21l2 in coordinating morphogenesis and differentiation in developing eyes.


Wireless solar water splitting using silicon-based semiconductors and earth-abundant catalysts.
We describe the development of solar water-splitting cells comprising earth-abundant elements that operate in near-neutral pH conditions, both with and without connecting wires. The cells consist of a triple junction, amorphous silicon photovoltaic interfaced to hydrogen- and oxygen-evolving catalysts made from an alloy of earth-abundant metals and a cobalt|borate catalyst, respectively. The devices described here carry out the solar-driven water-splitting reaction at efficiencies of 4.7% for a wired configuration and 2.5% for a wireless configuration when illuminated with 1 sun (100 milliwatts per square centimeter) of air mass 1.5 simulated sunlight. Fuel-forming catalysts interfaced with light-harvesting semiconductors afford a pathway to direct solar-to-fuels conversion that captures many of the basic functional elements of a leaf.


Interactions between temperature and intercellular CO2 concentration in controlling leaf isoprene emission rates.
Plant isoprene emissions have been linked to several reaction pathways involved in atmospheric photochemistry. Evidence exists from a limited set of past observations that isoprene emission rate (Is ) decreases as a function of increasing atmospheric CO2 concentration, and that increased temperature suppresses the CO2 effect. We studied interactions between intercellular CO2 concentration (Ci ) and temperature as they affect Is in field-grown hybrid poplar trees in one of the warmest climates on earth - the Sonoran Desert of the southwestern United States. We observed an unexpected midsummer downregulation of Is despite the persistence of relatively high temperatures. High temperature suppression of the Is :Ci relation occurred at all times during the growing season, but sensitivity of Is to increased Ci was greatest during the midsummer period when Is was lowest. We interpret the seasonal downregulation of Is and increased sensitivity of Is to Ci as being caused by weather changes associated with the onset of a regional monsoon system. Our observations on the temperature suppression of the Is :Ci relation are best explained by the existence of a small pool of chloroplastic inorganic phosphate, balanced by several large, connected metabolic fluxes, which together, determine the Ci and temperature dependencies of phosphoenolpyruvate import into the chloroplast.


Scrotal allografts of fetal ovaries.
Fifty allografts of 17 day rat fetal ovaries were placed in the bottom of the scrotal wall of 25 normal and 25 castrated adult male rats. Of these, 5 did not take and 11 were destroyed by the allograft reaction. The remaining 34, which were reasonably tolerated, showed, whether the hosts were castrated or not, suppression of the cortical part of the ovary and stimulation of the medullary part, as evidenced by development of well-organized seminiferous tubules. This is presumably a reaction to the relatively cool environment of the scrotal wall.


Non-random decay of chordate characters causes bias in fossil interpretation.
Exceptional preservation of soft-bodied Cambrian chordates provides our only direct information on the origin of vertebrates. Fossil chordates from this interval offer crucial insights into how the distinctive body plan of vertebrates evolved, but reading this pre-biomineralization fossil record is fraught with difficulties, leading to controversial and contradictory interpretations. The cause of these difficulties is taphonomic: we lack data on when and how important characters change as they decompose, resulting in a lack of constraint on anatomical interpretation and a failure to distinguish phylogenetic absence of characters from loss through decay. Here we show, from experimental decay of amphioxus and ammocoetes, that loss of chordate characters during decay is non-random: the more phylogenetically informative are the most labile, whereas plesiomorphic characters are decay resistant. The taphonomic loss of synapomorphies and relatively higher preservation potential of chordate plesiomorphies will thus result in bias towards wrongly placing fossils on the chordate stem. Application of these data to Cathaymyrus (Cambrian period of China) and Metaspriggina (Cambrian period of Canada) highlights the difficulties: these fossils cannot be placed reliably in the chordate or vertebrate stem because they could represent the decayed remains of any non-biomineralized, total-group chordate. Preliminary data suggest that this decay filter also affects other groups of organisms and that 'stem-ward slippage' may be a widespread but currently unrecognized bias in our understanding of the early evolution of a number of phyla.


BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen.
An attenuated dosing (AD) sunitinib regimen of 37.5 mg daily has been suggested to reduce the toxicity reported with the standard dosing regimen to metastatic renal cell carcinoma (mRCC) patients. The aim of this study was to characterize the population pharmacokinetic (PK) properties of sunitinib and SU12662, the active metabolite, in patients receiving the AD regimen and to ascertain significant covariates influencing PK parameters. Thirty-one mRCC patients receiving AD sunitinib regimen were included. Plasma samples were collected on day 29 of each treatment cycle after the start of the therapy. Nonlinear mixed-effects modeling was applied to estimate the population PK properties of sunitinib and SU12662 as well as the effect of covariates on PK parameters. Monte Carlo simulation was also performed to predict the total trough level (TTL) of sunitinib and SU12662. Sunitinib population means for CL/F and V d /F central were 13.8 L/h and 1720 L, respectively. SU12662 population means for CL/F and V d /F were 42.1 L/h and 1410 L, respectively. Body surface area (BSA) and ABCB1 polymorphism significantly influenced the CL/F variability of sunitinib: CL/F parent = 13.8 × exp((BSA - 1.75) × 2.08 + (ABCB1 genotype - 0.67) × 0.61), ABCB1-0: wild genotype, 1: mutant genotype. The effect size of ABCB1 mutant genotype and BSA greater than 1.75 m(2) in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group. Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite.


Prevalence of tetracyclines in children's teeth. II. A resurvey after five years.
The capacity of the tetracyclines to discolour teeth has been widely recognized for over 10 years. This survey examined recent trends in tetracycline usage as shown by deposits of the antibiotic in primary molars extracted from 505 children aged from 3 to 5 years.It was found that 70% of the children had been given the antibiotic during their first three years of life, each having received on average 2.4 courses. This represented an increase of 12% in tetracycline usage in children of this age as compared with a similar series five years ago. There was no evidence of increasing preference by prescribers for oxytetracycline (the analogue least likely to cause dental discoloration). Staining of the permanent incisor teeth frequently occurs if tetracyclines are given to children under 6 years of age and it is predicted that some degree of staining will occur in about 23% of the children in this series.All things considered, there appears to be a strong case for stopping the manufacture of paediatric preparations of tetracycline except for those comprised of oxytetracycline for use in exceptional cases.


The role of life context and self-defined well-being in the outcomes that matter to people with a diagnosis of schizophrenia.
Conduct a deep exploration of the outcomes that matter to people with a diagnosis of schizophrenia and understand from their perspective how these outcomes can be achieved. In-depth qualitative interviews were conducted with 22 people with a diagnosis of schizophrenia. Interviews were analysed using thematic frameworks, and a realist informed theories of change approach. Our study revealed the potential causal relationships between the context of a person's life, short-term goals and long-term outcomes. We provide a nuanced and detailed exploration of outcomes that matter for people with schizophrenia in relation to self-defined well-being. Achieving life milestones, feeling safe and outcomes related to improved physical health along with employment, a positive sense of self and psychosocial outcomes, were highly valued. For short- and long-term outcomes to be achieved, individuals required medication with minimal side-effects, cognitive behavioural therapy, family/social support and meaningful activities in their lives. Well-being was influenced by life context and short- and long-term outcomes, but in a circular nature also framed what short-term goals could be achieved. Working with people with a diagnosis of schizophrenia to identify and achieve better outcomes will necessitate a person-centred approach. This will require an appreciation of the relationship between the statutory and non-statutory resources that are available and a consideration of an individual's current well-being status. This approach acknowledges personal strengths and encourages ownership of goals and supports self-management.


The Intensive Diet and Exercise for Arthritis (IDEA) trial: design and rationale.
Obesity is the most modifiable risk factor, and dietary induced weight loss potentially the best nonpharmacologic intervention to prevent or to slow osteoarthritis (OA) disease progression. We are currently conducting a study to test the hypothesis that intensive weight loss will reduce inflammation and joint loads sufficiently to alter disease progression, either with or without exercise. This article describes the intervention, the empirical evidence to support it, and test-retest reliability data. This is a prospective, single-blind, randomized controlled trial. The study population consists of 450 overweight and obese (BMI = 27-40.5 kg/m2) older (age > or = 55 yrs) adults with tibiofemoral osteoarthritis. Participants are randomized to one of three 18-month interventions: intensive dietary restriction-plus-exercise; exercise-only; or intensive dietary restriction-only. The primary aims are to compare the effects of these interventions on inflammatory biomarkers and knee joint loads. Secondary aims will examine the effects of these interventions on function, pain, and mobility; the dose response to weight loss on disease progression; if inflammatory biomarkers and knee joint loads are mediators of the interventions; and the association between quadriceps strength and disease progression. Test-retest reliability results indicated that the ICCs for knee joint load variables were excellent, ranging from 0.86 - 0.98. Knee flexion/extension moments were most affected by BMI, with lower reliability with the highest tertile of BMI. The reliability of the semi-quantitative scoring of the knee joint using MRI exceeded previously reported results, ranging from a low of 0.66 for synovitis to a high of 0.99 for bone marrow lesion size. The IDEA trial has the potential to enhance our understanding of the OA disease process, refine weight loss and exercise recommendations in this prevalent disease, and reduce the burden of disability. NCT00381290.


The seroepidemiology of malaria in Middle America. II. Studies on the Pacific coast of Costa Rica.
Serologic studies for malaria using the indirect fluorescent antibody technique suggest that active transmission is either absent or very low in 6 villages on the Pacific side of Costa Rica. Positive titers (1:20 or higher) were seen in the under-15-year age group in three of the study localities, but only 5 such responses were encountered among 249 people examined in this age range. In the adults (15 years and over) from the same 3 villages there were 68 positive titers among 161 examined. There were 43 positive responses in 189 adults from the remaining 3 villages where none of 307 persons under 15 years of age showed a titer of 1:20 or higher to any of the 3 malaria antigens tested (Plasmodium falciparum, P. vivax and P. malariae). These data suggest that the positive responses in the latter villages are more likely to be associated with old or imported cases than with current local transmission. Serologic responses of 1:80 or higher to the P. falciparum antigen suggested the continued presence of this parasite in the population in spite of the paucity of positive blood smears with this species in recent years. Positive titers with the P. malariae antigen suggest that this parasite is probably still present in the area. Such serologic studies help to indicate areas where malaria transmission is active and provide information on parasite reservoirs in particular populations.


Blood pressure parameters as determinants of small artery structure in human essential hypertension.
1. Adaptive changes in small arteries may be more closely correlated with pulse pressure than with systolic, diastolic or mean blood pressures in human essential hypertension. 2. An analysis was performed on the structure of small arteries, age and blood pressure measurements obtained from 56 patients with untreated essential hypertension and 56 matched normotensive volunteers to examine the association between age, blood pressure and small artery structural parameters. 3. Essential hypertension was associated with an increase in media thickness and a decrease in lumen diameter, resulting in an increase in media/lumen ratio. 4. There was a significant correlation between age and media/lumen ratio in normotensive volunteers but not in patients with essential hypertension. 5. There was no correlation between any blood pressure and structural parameter in normotensive volunteers. 6. Both diastolic and mean blood pressures in essential hypertension correlated with media/lumen ratio (P < 0.01); systolic blood pressure correlated less well (P < 0.02). However, pulse pressure did not correlate with media/lumen ratio, suggesting that it is not a significant determinant of small artery structure in untreated essential hypertension.


Anonymised and aggregated crowd level mobility data from mobile phones suggests that initial compliance with COVID-19 social distancing interventions was high and geographically consistent across the UK.
Background: Since early March 2020, the COVID-19 epidemic across the United Kingdom has led to a range of social distancing policies, which have resulted in reduced mobility across different regions. Crowd level data on mobile phone usage can be used as a proxy for actual population mobility patterns and provide a way of quantifying the impact of social distancing measures on changes in mobility. Methods: Here, we use two mobile phone-based datasets (anonymised and aggregated crowd level data from O2 and from the Facebook app on mobile phones) to assess changes in average mobility, both overall and broken down into high and low population density areas, and changes in the distribution of journey lengths. Results: We show that there was a substantial overall reduction in mobility, with the most rapid decline on the 24th March 2020, the day after the Prime Minister's announcement of an enforced lockdown. The reduction in mobility was highly synchronized across the UK. Although mobility has remained low since 26th March 2020, we detect a gradual increase since that time. We also show that the two different datasets produce similar trends, albeit with some location-specific differences. We see slightly larger reductions in average mobility in high-density areas than in low-density areas, with greater variation in mobility in the high-density areas: some high-density areas eliminated almost all mobility. Conclusions: These analyses form a baseline from which to observe changes in behaviour in the UK as social distancing is eased and inform policy towards the future control of SARS-CoV-2 in the UK.