Genomic architecture of haddock (Melanogrammus aeglefinus) shows expansions of innate immune genes and short tandem repeats.
Increased availability of genome assemblies for non-model organisms has resulted in invaluable biological and genomic insight into numerous vertebrates, including teleosts. Sequencing of the Atlantic cod (Gadus morhua) genome and the genomes of many of its relatives (Gadiformes) demonstrated a shared loss of the major histocompatibility complex (MHC) II genes 100 million years ago. An improved version of the Atlantic cod genome assembly shows an extreme density of tandem repeats compared to other vertebrate genome assemblies. Highly contiguous assemblies are therefore needed to further investigate the unusual immune system of the Gadiformes, and whether the high density of tandem repeats found in Atlantic cod is a shared trait in this group. Here, we have sequenced and assembled the genome of haddock (Melanogrammus aeglefinus) - a relative of Atlantic cod - using a combination of PacBio and Illumina reads. Comparative analyses reveal that the haddock genome contains an even higher density of tandem repeats outside and within protein coding sequences than Atlantic cod. Further, both species show an elevated number of tandem repeats in genes mainly involved in signal transduction compared to other teleosts. A characterization of the immune gene repertoire demonstrates a substantial expansion of MCHI in Atlantic cod compared to haddock. In contrast, the Toll-like receptors show a similar pattern of gene losses and expansions. For the NOD-like receptors (NLRs), another gene family associated with the innate immune system, we find a large expansion common to all teleosts, with possible lineage-specific expansions in zebrafish, stickleback and the codfishes. The generation of a highly contiguous genome assembly of haddock revealed that the high density of short tandem repeats as well as expanded immune gene families is not unique to Atlantic cod - but possibly a feature common to all, or most, codfishes. A shared expansion of NLR genes in teleosts suggests that the NLRs have a more substantial role in the innate immunity of teleosts than other vertebrates. Moreover, we find that high copy number genes combined with variable genome assembly qualities may impede complete characterization of these genes, i.e. the number of NLRs in different teleost species might be underestimates.


Population genetics inference for longitudinally-sampled mutants under strong selection.
Longitudinal allele frequency data are becoming increasingly prevalent. Such samples permit statistical inference of the population genetics parameters that influence the fate of mutant variants. To infer these parameters by maximum likelihood, the mutant frequency is often assumed to evolve according to the Wright-Fisher model. For computational reasons, this discrete model is commonly approximated by a diffusion process that requires the assumption that the forces of natural selection and mutation are weak. This assumption is not always appropriate. For example, mutations that impart drug resistance in pathogens may evolve under strong selective pressure. Here, we present an alternative approximation to the mutant-frequency distribution that does not make any assumptions about the magnitude of selection or mutation and is much more computationally efficient than the standard diffusion approximation. Simulation studies are used to compare the performance of our method to that of the Wright-Fisher and Gaussian diffusion approximations. For large populations, our method is found to provide a much better approximation to the mutant-frequency distribution when selection is strong, while all three methods perform comparably when selection is weak. Importantly, maximum-likelihood estimates of the selection coefficient are severely attenuated when selection is strong under the two diffusion models, but not when our method is used. This is further demonstrated with an application to mutant-frequency data from an experimental study of bacteriophage evolution. We therefore recommend our method for estimating the selection coefficient when the effective population size is too large to utilize the discrete Wright-Fisher model.


Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor.
Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive malignancy that affects mainly adolescents and young adults. A defining characteristic of DSRCT is a specific chromosomal translocation, t(11;22)(p13;q12), that fuses EWS with WT1, leading to a production of two isoforms of chimeric transcription factor, EWS/WT1(-KTS) and EWS/WT1(+KTS). The chimeric proteins are thought to play critical roles in various stages of oncogenesis through aberrant transcription of different genes, but only a few of these genes have been identified. We report the identification of a new target of EWS/WT1, ENT4 (equilibrative nucleoside transporter 4) which encodes a pH-dependent adenosine transporter. ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. Furthermore, ENT4 is highly and specifically expressed in primary tumors of DSRCT as well as in a DSRCT cell line, JN-DSRCT-1. Treatment of JN-DSRCT-1 cells with adenosine analogs, such as 2-chloro-2'-deoxyadenosine (2-CdA), resulted in an increased cytotoxic response in dose- and pH-dependent manner. Our detailed analyses of a novel target of EWS/WT1 in DSRCT reveal an insight into the oncogenic mechanism of EWS-fusion chromosomal translocation gene products and provide a new marker for DSRCT. Furthermore, identification of ENT4 as a highly expressed transcript in DSRCT may represent an attractive pathway for targeting chemotherapeutic drugs into DSRCT.


Dissociation: the clinical realities.
An attempt was made by the authors of DSM-III to restrict its focus to the experimental, the observable, and the measurable. The intention was to free the nosology from the influence of unproven theories, and the philosophy was driven largely by the importance of research being able to identify diagnostic categories to facilitate the study of homogeneous groups. So it is of interest that the authors accepted dissociation-an ambiguous event linked to an explicit theoretical concept that had been introduced by Janet-as the basis for classification of clinical presentations that were formerly included under the rubric of hysteria, a similarly unclear category. Since DSM-III, there have been an increasing number of reports of dissociative experiences and dissociative identity disorder (formerly known as multiple personality disorder), but neither of these clinical presentations seems able to withstand the concern that it is dramatically influenced by environmental cues, e.g., the expectations of the therapist. Thus, a restricted phenomenological perspective does not fully appreciate the distorting potential of suggestibility and imagination on the nature of the emerging clinical picture. These factors might well have contributed to and laid the conceptual groundwork for the growth in the number of reports of dissociation.


Assessment of antisperm antibodies in a sample of Egyptian patients with hepatitis C virus infection.
Association of hepatitis C virus (HCV) with autoimmune phenomena and impaired semen parameters has been previously reported. The aim of this study was to investigate the influence of HCV infection on the development of antisperm antibodies (ASAs) in HCV-positive males. The study was conducted on 30 HCV-infected individuals and 30 healthy control subjects. In both patients and control groups, liver enzymes and reproductive hormones were measured; computer-assisted semen analysis (CASA) was performed; HCV-RNA in serum was measured and IgG and IgA ASAs in semen were determined. Free testosterone, sperm concentration, progressive and total motility were significantly lower in HCV patients than in the control group, whereas ASAs of the IgG and IgA classes were significantly higher in HCV patients. However, correlations between viral load and the examined semen parameters and ASAs were nonsignificant. In conclusion, HCV may be responsible for the increased ASAs detected in HCV patients in the present study, possibly providing another plausible explanation for the decreased sperm motility reported in HCV patients. These findings could be of value in fertility management of HCV patients.


Effects of menstrual cycle on blood lactate, O2 delivery, and performance during exercise.
The effects of the menstrual cycle on cardiorespiratory variables, blood lactate, and performance were studied in exercising females. Nine healthy subjects, 20--24 yr of age, were investigated in midfollicular and midluteal phases of the menstrual cycle at 33, 66, and 90% of maximum power output (light, heavy, and exhaustive exercise). Occurrence of ovulation was confirmed in all subjects by measurement of progesterone, which increased from 0.6 +/- 0.1 (mean +/- SE) in the follicular to 8.9 +/- 2.2 ng/ml in the luteal phase. There was no difference in heart rate (HR), ventilation, O2 uptake, or CO2 output between the two phases during light and heavy exercise, and there was no difference in HR at exhaustion. Cardiac output measured midway through light and heavy exercise periods was not affected by the phase of testing. Time for which exhaustive exercise could be maintained increased from 1.57 +/- 0.32 in the follicular to 2.97 +/- 0.63 min in the luteal phase (P less than 0.02). Blood lactate was higher in the follicular phase after heavy exercise (6.62 +/- 0.8 vs. 4.92 +/- 0.5 mmol/l) (P less than 0.05) and at exhaustion (8.12 +/- 0.9 vs. 6.76 +/- 0.6 mmol/L) (P less than 0.01). A further study showed no effect of cycle phase on lactate disappearance during exercise. We conclude that while aerobic performance and the cardiorespiratory adaptations to exercise are not influenced by the phase of the menstrual cycle, performance of high-intensity exercise is improved, and lactate production appears to be decreased in the luteal phase when estradiol and progesterone levels are elevated.


Transcriptome Profiling Reveals Differential Effect of Interleukin-17A Upon Influenza Virus Infection in Human Cells.
Influenza A virus (IAV) has developed elegant strategies to utilize cellular proteins and pathways to promote replication and evade the host antiviral response. Identification of these sabotaged host factors could increase the number of potential antiviral drug targets. Here, IAV A/PR/8/34 (PR8)- and A/California/04/2009-infected A549 and 293T cells displayed differential virus replication. To determine the host cellular responses of A549 and 293T cells to IAV infection, RNA-seq was used to identify differentially expressed genes. Our data revealed that IAV-infected A549 cells activated stronger virus-sensing signals and highly expressed cytokines, which play significant roles in initiating the innate immune and inflammatory responses. In addition, IAV-infected 293T cells displayed weak immune signaling and cytokine production. Remarkably, IL-17A and associated genes were highly enriched in IAV-infected 293T cells. Furthermore, IL-17A can partially facilitate A549 cell infection by the PR8 strain and PR8-infected IL-17A knock-out mice consistently exhibited decreased weight loss and reduced lung immunopathology, as compared to controls. This work uncovered the differential responses of cells infected with two H1N1 IAV strains and the potential roles of IL-17A in modulating virus infection.


Improving memory after interruption: exploiting soft constraints and manipulating information access cost.
Forgetting what one was doing prior to interruption is an everyday problem. The recent soft constraints hypothesis (Gray, Sims, Fu, & Schoelles, 2006) emphasizes the strategic adaptation of information processing strategy to the task environment. It predicts that increasing information access cost (IAC: the time, and physical and mental effort involved in accessing information) encourages a more memory-intensive strategy. Like interruptions, access costs are also intrinsic to most work environments, such as when opening documents and e-mails. Three experiments investigated whether increasing IAC during a simple copying task can be an effective method for reducing forgetting following interruption. IAC was designated Low (all information permanently visible), Medium (a mouse movement to uncover target information), or High (an additional few seconds to uncover such information). Experiment 1 found that recall improved across all three levels of IAC. Subsequent experiments found that High IAC facilitated resumption after interruption, particularly when interruption occurred on half of all trials (Experiment 2), and improved prospective memory following two different interrupting tasks, even when one involved the disruptive effect of using the same type of resource as the primary task (Experiment 3). The improvement of memory after interruption with increased IAC supports the prediction of the soft constraints hypothesis. The main disadvantage of a high access cost was a reduction in speed of task completion. The practicality of manipulating IAC as a design method for inducing a memory-intensive strategy to protect against forgetting is discussed.


Development of spatial density maps based on geoprocessing web services: application to tuberculosis incidence in Barcelona, Spain.
Health professionals and authorities strive to cope with heterogeneous data, services, and statistical models to support decision making on public health. Sophisticated analysis and distributed processing capabilities over geocoded epidemiological data are seen as driving factors to speed up control and decision making in these health risk situations. In this context, recent Web technologies and standards-based web services deployed on geospatial information infrastructures have rapidly become an efficient way to access, share, process, and visualize geocoded health-related information. Data used on this study is based on Tuberculosis (TB) cases registered in Barcelona city during 2009. Residential addresses are geocoded and loaded into a spatial database that acts as a backend database. The web-based application architecture and geoprocessing web services are designed according to the Representational State Transfer (REST) principles. These web processing services produce spatial density maps against the backend database. The results are focused on the use of the proposed web-based application to the analysis of TB cases in Barcelona. The application produces spatial density maps to ease the monitoring and decision making process by health professionals. We also include a discussion of how spatial density maps may be useful for health practitioners in such contexts. In this paper, we developed web-based client application and a set of geoprocessing web services to support specific health-spatial requirements. Spatial density maps of TB incidence were generated to help health professionals in analysis and decision-making tasks. The combined use of geographic information tools, map viewers, and geoprocessing services leads to interesting possibilities in handling health data in a spatial manner. In particular, the use of spatial density maps has been effective to identify the most affected areas and its spatial impact. This study is an attempt to demonstrate how web processing services together with web-based mapping capabilities suit the needs of health practitioners in epidemiological analysis scenarios.


Incorporating biologic measurements (SF(2), CFE) into a tumor control probability model increases their prognostic significance: a study in cervical carcinoma treated with radiation therapy.
To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF(2)) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance. Measurements of SF(2) and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp(alpha,rho)). Regression analysis was performed to assess the prognostic power of tcp(alpha,rho) vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF(2) and CFE measurements alone. In a univariate regression analysis of 44 patients, tcp(alpha,rho) was a better prognostic factor for both local control and survival (p < 0.001 and p = 0.049, respectively) than SF(2) alone (p = 0.009 for local control, p = 0.29 for survival) or CFE alone (p = 0.015 for local control, p = 0.38 for survival). In multivariate analysis, tcp(alpha,rho) emerged as the most important prognostic factor for local control (p < 0.001, relative risk of 2.81). After allowing for tcp(alpha,rho), CFE was still a significant independent prognostic factor for local control, whereas SF(2) was not. The sensitivities of tcp(alpha,rho) and SF(2) as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively. A Poisson tcp model incorporating individual SF(2), CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients.


Dau c 1.01 and Dau c 1.02-silenced transgenic carrot plants show reduced allergenicity to patients with carrot allergy.
Pathogenesis-related protein-10 (PR10) is a ubiquitous small plant protein induced by microbial pathogens and abiotic stress that adversely contributes to the allergenic potency of many fruits and vegetables, including carrot. In this plant, two highly similar genes encoding PR10 isoforms have been isolated and designated as allergen Dau c 1.01 and Dau c 1.02. The aim of the study was to generate PR10-reduced hypoallergenic carrots by silencing either one of these genes in transgenic carrots by means of RNA interference (RNAi). The efficiency of gene silencing by stably expressed hairpin RNA (hnRNA) was documented by means of quantitative RT-PCR (qPCR) and immunoblotting. Quantification of the residual protein revealed that PR10 accumulation was strongly decreased compared with untransformed controls. Treatment of carrot plants with the PR protein-inducing chemical salicylic acid resulted in an increase of PR10 isoforms only in wild-type but not in Dau c 1-silenced mutants. The decrease of the allergenic potential in Dau c 1-silenced plants was sufficient to cause a reduced allergenic reactivity in patients with carrot allergy, as determined with skin prick tests (SPT). However, simultaneous silencing of multiple allergens will be required to design hypoallergenic carrots for the market. Our findings demonstrate the feasibility of creating low-allergenic food by using RNAi. This constitutes a reasonable approach to allergen avoidance.


The use of harmonic scalpels in thyroidectomies: clinical experiences.
Many studies have been conducted to investigate the efficacy of harmonic scalpels in thyroidectomies. Here, we present our clinical experiences with the instrument. The study was conducted at the General Surgery Department of the Ataturk University School of Medicine between January 2005 and July 2008. It was a prospective, randomized, controlled study. Patients with benign nodular goiter (BNG) were included in the study and randomly divided into three groups. The first group consisted of 47 patients, the second group consisted of 57 patients, and the third group consisted of 41 patients. Patients in the first group underwent the classical thyroidectomy. Those in the second group had only the superior thyroid arteries and veins ligated (with silk or polyglactin), while the other vascular structures were divided using a harmonic scalpel. In the third group, all arteries and veins of the thyroid gland were divided using a harmonic scalpel. In each group, mean operation time, amount of bleeding, amount of postoperative drainage, and other postoperative complications were recorded. Operation time was significantly lower for patients in the third group. The degree of bleeding and postoperative drainage was lower in the second and third groups with respect to the first group. There was no significant difference among the groups in terms of the development of transient hypocalcemia or voice impairment. We conclude that the use of harmonic scalpels for a thyroidectomy is safe, shortens operative time, and decreases intraoperative bleeding.


Anthocyanin-rich fractions from red raspberries attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis.
Edible berries have a broad spectrum of biomedical functions, including improving immune responses and reducing risk for chronic diseases. In this study, the anti-inflammatory activities of crude extracts (CEs), anthocyanin-rich fractions (ARFs), and des-anthocyanin fractions (DAFs) from seven berries were evaluated based on their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)/IFN-γ-activated RAW264.7 macrophages. ARFs from red raspberries (RR-ARFs) exhibited the highest efficiency in suppressing NO synthesis. The anti-inflammatory properties were also demonstrated by reducing the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1β) and IL-6 in RAW264.7 cells. The luciferase reporter assay demonstrated that the activities of NF-κB and AP-1 signaling pathways were significantly suppressed by RR-ARFs. Further studies showed that RR-ARFs decreased the phosphorylation of IKK, IκBα, p65 and JNK and the nuclear translocation of p65 in LPS/IFN-γ-stimulated RAW264.7 cells. In a mouse colitis model, dextran sulfate sodium (DSS)-induced weight loss and histological damage were significantly ameliorated by RR-ARFs treatment. Taken together, our results indicate that RR-ARFs attenuate inflammation both in vitro and in vivo primarily by inhibiting the activation of NF-κB and MAPKs. The anti-inflammatory of RR-ARFs could be harnessed and applied in animal agriculture, drug and food industries.


Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche.
The long prevailing model of metastasis recognizes the importance of both "seed" and "soil" for metastatic progression [1]. Much attention has focused on understanding the molecular and genetic factors that confer an intrinsic metastatic advantage to certain tumor cells. Meanwhile, changes occurring within distant tissues, creating a "soil" conducive for tumor invasion, have been largely neglected. Bone marrow-derived hematopoietic progenitor cells (HPCs) recently emerged as key players in initiating these early changes, creating a receptive microenvironment at designated sites for distant tumor growth and establishing the "Pre-Metastatic Niche" [2]. This insight into the earliest stages in the metastatic cascade revises our concept of the metastatic "microenvironment" to include physiological cells recruited from the bone marrow. Moreover, the concept of pre-metastatic tissues as 'niches' similar to physiological stem cell niches establishes a paradigm in which disseminated tumor cells may reside within a highly defined microcosm, both supportive and regulatory, and which may confer specific functions on indwelling cells. Understanding the cellular and molecular cross-talk between "seed" and "soil" may further our understanding of the factors that govern both site-specific patterning in metastasis and the phenomenon of tumor dormancy. This may lead to therapeutic strategies to detect and prevent metastasis at its earliest inception.


Regulation of aromatic alcohol production in Candida albicans.
Colonization by the fungal pathogen Candida albicans varies significantly, depending upon the pH and availability of oxygen. Because of our interest in extracellular molecules as potential quorum-sensing molecules, we examined the physiological conditions which regulate the production of the aromatic alcohols, i.e., phenethyl alcohol, tyrosol, and tryptophol. The production of these fusel oils has been well studied for Saccharomyces cerevisiae. Our data show that aromatic alcohol yields for C. albicans are determined by growth conditions. These conditions include the availability of aromatic amino acids, the pH, oxygen levels, and the presence of ammonium salts. For example, for wild-type C. albicans, tyrosol production varied 16-fold merely with the inclusion of tyrosine or ammonium salts in the growth medium. Aromatic alcohol production also depends on the transcription regulator Aro80p. Our results are consistent with aromatic alcohol production-aromatic transaminases (gene products for ARO8 and ARO9), aromatic decarboxylase (ARO10), and alcohol dehydrogenase (ADH)-via the fusel oil pathway. The expression of ARO8, ARO9, and ARO10 is also pH dependent. ARO8 and ARO9 were alkaline upregulated, while ARO10 was alkaline downregulated. The alkaline-dependent change in expression of ARO8 was Rim101 independent, while the expression of ARO9 was Rim101 dependent.


TNF alpha blockade in rheumatoid arthritis: rationale, clinical outcomes and mechanisms of action.
Tumor necrosis factor alpha (TNF alpha) is a cytokine with many biological functions of relevance to inflammatory disease. Although only one of several inflammatory mediators produced in abundance in rheumatoid arthritis (RA), experimental data suggest that it is in a dominant position within a cytokine hierarchy and is therefore a prime target for directed immunotherapy in this disease. We have targeted TNF alpha in vivo using a chimerised monoclonal anti-TNF alpha antibody and have now demonstrated beneficial responses to treatment in three different clinical trials. The results confirm that TNF alpha is of central importance in the inflammatory process in RA and define a new treatment strategy in this disease.


Lung transplantation: perioperative pharmacology and anesthetic considerations.
In the past two decades, lung transplantation has become an increasingly important surgical option for the patient with end stage lung disease. Compared with the other solid organ transplants (heart, liver and kidney), lung transplantation carries immense clinical and logistic challenges; long-term organ viability is particularly problematic, with an expected five-year mortality of 40-50%. The number of lung transplants performed in the U.S. has been increasing steadily since 1988, when UNOS (United Network for Organ Sharing) started recording statistical data. In that year, 33 cases of lung transplantation were performed. As of today, a total of 23,815 lung transplants have been performed, and the largest number of yearly lung transplants (n=1,822) was performed in 2009. From appropriate patient selection, to optimal organ selection, surgical procedure, and immediate and long-term postoperative care, the medical process involves multiple healthcare providers and requires a very well-organized and committed healthcare system to achieve optimal surgical results. Understanding the pharmacology involved in the care of the lung transplant patient is of utmost importance to achieve appropriate organ preservation, immunosuppression, hemodynamic stability, and adequate anesthetic depth, while avoiding drug toxicity and side effects. The purpose of this review is to summarize the pharmacokinetics and pharmacodynamics of the medications most commonly administered to this patient population, throughout the perioperative period.


A Generalized Stress State and Temperature Dependent Damage Indicator Framework for Ductile Failure Prediction in Heat-Assisted Forming Operations.
Heat-assisted forming processes are becoming increasingly important in the manufacturing of sheet metal parts for body-in-white applications. However, the non-isothermal nature of these processes leads to challenges in evaluating the forming limits, since established methods such as Forming Limit Curves (FLCs) only allow the assessment of critical forming strains for steady temperatures. For this reason, a temperature-dependent extension of the well-established GISSMO (Generalized Incremental Stress State Dependent Damage Model) fracture indicator framework is developed by the authors to predict forming failures under non-isothermal conditions. In this paper, a general approach to combine several isothermal FLCs within the temperature-extended GISSMO model into a temperature-dependent forming limit surface is investigated. The general capabilities of the model are tested in a coupled thermo-mechanical FEA using the example of warm forming of an AA5182-O sheet metal cross-die cup. The obtained results are then compared with state of the art of evaluation methods. By taking the strain and temperature path into account, GISSMO predicts greater drawing depths by up to 20% than established methods. In this way the forming and so the lightweight potential of sheet metal parts can by fully exploited. Moreover, the risk and locus of failure can be evaluated directly on the part geometry by a contour plot. An additional advantage of the GISSMO model is the applicability for low triaxialities as well as the possibility to predict the materials behavior beyond necking up to ductile fracture.


Intermittent levosimendan infusions in advanced heart failure: a real world experience.
Objective To analyse the effects of levosimendan infusions in advanced heart failure. Methods Patients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality. Results Twenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group. Conclusion Intermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.


BioNetLink - an architecture for working with network data.
The visualization of biological data gained increasing importance in the last years. There is a large number of methods and software tools available that visualize biological data including the combination of measured experimental data and biological networks. With growing size of networks their handling and exploration becomes a challenging task for the user. In addition, scientists also have an interest in not just investigating a single kind of network, but on the combination of different types of networks, such as metabolic, gene regulatory and protein interaction networks. Therefore, fast access, abstract and dynamic views, and intuitive exploratory methods should be provided to search and extract information from the networks. This paper will introduce a conceptual framework for handling and combining multiple network sources that enables abstract viewing and exploration of large data sets including additional experimental data. It will introduce a three-tier structure that links network data to multiple network views, discuss a proof of concept implementation, and shows a specific visualization method for combining metabolic and gene regulatory networks in an example.


River discharge reduces reef coral diversity in Palau.
Coral community structure is often governed by a suite of processes that are becoming increasingly influenced by land-use changes and related terrestrial discharges. We studied sites along a watershed gradient to examine both the physical environment and the associated biological communities. Transplanted corals showed no differences in growth rates and mortality along the watershed gradient. However, coral cover, coral richness, and coral colony density increased with increasing distance from the mouth of the bay. There was a negative relationship between coral cover and mean suspended solids concentration. Negative relationships were also found between terrigenous sedimentation rates and the richness of adult and juvenile corals. These results have major implications not only for Pacific islands but for all countries with reef systems downstream of rivers. Land development very often leads to increases in river runoff and suspended solids concentrations that reduce coral cover and coral diversity on adjacent reefs.


Updating the emotional content of working memory in social anxiety.
Cognitive accounts suggest that information processing biases have an important role in the etiology and maintenance of social anxiety (SA). Empirical evidence support this notion has been established in variety of cognitive domains. Yet, it is still not known how social anxious individuals process emotional content in working memory (WM). Maladaptive WM updating may influence emotion regulation and anxiety during social situations in SA. Thus, the aim of the present study was to explore biases when updating emotional content in SA. 31 participants with high SA and 34 control participants performed an emotional 2-back task. Biases were assessed by intrusion cost in reaction times, which reflects the conflict between the inhibition of irrelevant content and the activation of relevant content. Results revealed a diminished intrusion cost in reaction times for irrelevant positive content in the high, but not in the low SA group. No differences were found for negative or neutral content. In the present study we used an analogue sample of students with high SA rather than a true clinical sample. Further research is needed to examine WM updating in clinical population. These findings suggest that individuals with SA are better at inhibiting irrelevant positive information, a maladaptive cognitive bias that may prevent positive feedback from entering the cognitive system. This cognitive bias in WM may play a role in the etiology and maintenance of SA.


Pattern differentiation in co-culture biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa.
Biofilm infections may not simply be the result of colonization by one bacterium, but rather the consequence of pathogenic contributions from several bacteria. Interspecies interactions of different organisms in mixed-species biofilms remain largely unexplained, but knowledge of these is very important for understanding of biofilm physiology and the treatment of biofilm-related infectious diseases. Here, we have investigated interactions of two of the major bacterial species of cystic fibrosis lung microbial communities -Pseudomonas aeruginosa and Staphylococcus aureus- when grown in co-culture biofilms. By growing co-culture biofilms of S. aureus with P. aeruginosa mutants in a flow-chamber system and observing them using confocal laser scanning microscopy, we show that wild-type P. aeruginosa PAO1 facilitates S. aureus microcolony formation. In contrast, P. aeruginosa mucA and rpoN mutants do not facilitate S. aureus microcolony formation and tend to outcompete S. aureus in co-culture biofilms. Further investigations reveal that extracellular DNA (eDNA) plays an important role in S. aureus microcolony formation and that P. aeruginosa type IV pili are required for this process, probably through their ability to bind to eDNA. Furthermore, P. aeruginosa is able to protect S. aureus against Dictyostelium discoideum phagocytosis in co-culture biofilms.


Hermansky Pudlak Syndrome and Pulmonary Alveolar Proteinosis at the same patient: first case report in the world literature.
Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder presenting with oculocutaneous albinism, bleeding diathesis and lysosomal accumulation of ceroid lipofuscin which leads to interstitial fibrosis in lung. Pulmonary fibrosis which is usually associated with HPS-1 and HPS-4 subtypes usually manifests in the third/fourth decades of life representing with giant lamellar bodies of alveolar type-II-cells and their apparent degeneration causes restrictive lung disease. Pulmonary manifestation of this syndrome may lead to premature death. Pulmonary Alveolar Proteinosis(PAP) is another rare disease characterized by alveolar deposition of surfactant phospholipids and proteins secondary to defective clearance by alveolar macrophages. PAP may occur as autoimmune diseases and/or secondary to toxic inhalation, systemic infections or hematological disorders. None of the cases were reported secondary to HPS according to the best our knowledge. As well, pulmonary involvement of HPS was never reported as PAP. We report the first case of PAP in a patient with HPS.


Meropenem Utilization Evaluation in a Referral Teaching Hospital in Iran.
Inappropriate use of antibiotics is associated with detrimental effects including emergence of antibiotic resistance. This study aimed to evaluate the use of meropenem, an extended-spectrum antibiotic, in a referral teaching hospital to detect different types of errors in its prescription. In a cross-sectional study performed over a 6-month period (2014-2015), hospitalized adult patients who received meropenem for any indication were randomly selected. The collected data included the indication for prescription and its correctness, the basis of prescription (empirical or culture based), administered dose, duration of treatment, the status of demanding sample culture in the case of empirical prescription, the status of dose adjustment in the case of renal impairment, and the treatment outcome. Over the study period, 123 patients were evaluated. The most frequent indication for prescription of meropenem was pneumonia (31.7%) and soft-tissue infections (18.7%). Out of these prescriptions, 62.6% (77 prescriptions) were incorrect. All meropenem prescriptions were initially empirical. Furthermore, sample culture and antibiotic susceptibility test were requested for only 52% of patients (n = 66). Treatment duration was correct for 53.7% of patients. Seventeen patients (13.8%) received an inappropriate dose of the antibiotic. Furthermore, of 51 patients who needed meropenem dose adjustment because of renal impairment, 17 patients (33.33%) received unadjusted dose. High rate of errors exists in the utilization of meropenem in our hospital, especially in the rank order of selection for treatment (indication), dose adjustment, and treatment duration. Therefore, modification strategies are necessary to promote the rational use of meropenem in this center.


Antithrombotic Treatment Following Intracerebral Hemorrhage in Patients With and Without Atrial Fibrillation.
Patients who survive intracerebral hemorrhage (ICH) often have compelling indications for anticoagulant and antiplatelet medication. This nationwide observational study aimed to determine the extent and predictors of antithrombotic treatment after ICH in Sweden. Patients with a first-ever ICH in the Swedish Stroke Register (Riksstroke) 2005 to 2012 who survived hospital discharge were included. Riksstroke data were individually linked with other national registers to determine comorbid conditions and dispensed prescriptions of antithrombotic agents. Among the 2777 patients with atrial fibrillation (AF), the proportion with a dispensed prescription of antithrombotic agents was 8.5% (anticoagulants) and 36.6% (antiplatelet agents) within 6 months and 11.1% (anticoagulants) and 43.6% (antiplatelet agents) within 1 year. Among the 11 268 patients without AF, the corresponding figures were 1.6% (anticoagulants) and 13.8% (antiplatelet agents) within 6 months and 2.0% (anticoagulants) and 17.5% (antiplatelet agents) within 1 year. In patients with AF, predictors of anticoagulant treatment were less severe ICH, younger age, previous anticoagulation, valvular disease, and previous ischemic stroke. High CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke [doubled], vascular disease, age, and sex category [female]) scores did not correlate with anticoagulant treatment. There was a positive correlation between high CHA2DS2-VASc and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol) scores (rs=0.590, P<0.001). In majority of patients who receive antithrombotic agents, treatment is initiated within 6 months of ICH. Still, many patients with compelling indications for antithrombotic treatment are not prescribed antithrombotic agents. Factors other than high risk of embolic stroke by CHA2DS2-VASc in ICH survivors with concurrent AF are used to guide the anticoagulant treatment decision in Swedish clinical practice.


Autologous Blood Injection Works for Recalcitrant Lateral Epicondylitis.
Recalcitrant lateral epicondylitis may be a disabling condition. Treatment of this condition is still controversial. In the present prospective study, we evaluated the long-term results of autologous blood injection for the treatment of recalcitrant lateral epicondylitis. Prospective clinical study. A total of 42 elbows of 40 consecutive patients (28 female, 12 male) were enrolled in this prospective study. Seven patients left the study (3 patients moved to another city, 1 patient died in the second week due to a heart condition, 1 patient quit the study because of the resolution of pain in the fourth week and 2 patients did not agree to the second injection). Thirteen patients were lost to third year follow-up. Therefore, a total of 21 elbows of 20 patients with 3 years of follow-up were included in this study. The mean age of the patients was 47.25 years (range, 20-68 years). Visual analogue scale (VAS), Nirschl score and grip strength were significantly improved after injections when compared to before treatment. The best improvement in terms of grip strength, Nirschl score and VAS score was detected at the one year follow-up. The improvement in Nirschl and VAS score sustained until the third year. We suggest that autologous blood injection for the treatment of recalcitrant lateral epicondylitis is an effective, safe and successful procedure in the long-term.


Evaluation of natural killer activity in human schistosomiasis.
Natural killer (NK) activity was assayed in peripheral blood mononuclear cells of patients with schistosomiasis, of patients following treatment, and of uninfected control subjects. The patient populations were from villages in the Qalyub Province, Egypt and around Belo Horizonte , Brazil. NK activity was assayed by the cytotoxicity of 51Cr-labelled K562 target tumor cells. In neither infected population were significant alterations from normal levels found in the percent cytotoxicity per 10(6) cells, or in the lytic units that expressed 25% cytotoxicity. Likewise, prior treatment (2 and 6 months previously) did not alter the group NK activity detected. Similarly, in the Egyptian study there was no difference in the percentage of large granular lymphocytes between the infected and uninfected groups. In parallel studies in Egyptian and Brazilian schistosomiasis patients we did not find any evidence that this chronic infection consistently altered circulating NK activity.


Electro-optical effects in porous PET films filled with liquid crystal: new possibilities for fiber optics and THZ applications.
The results of investigation of electro-optical properties of porous polyethylene terephthalate films filled with a nematic liquid crystal (5 CB) are presented. It is established that the optical response of the samples on the applied voltage drastically depends on the frequency range. At low frequencies of applied electrical field (f<fc) after the sharp change of the polarity the optical response arises as an impulse of light intensity, which decays for the time essentially shorter than the electric pulse duration. At high frequencies (f>fc) electric field induces an overall change in the light intensity, which is typical for an electro-optical response of a liquid crystal (LC) layer in a conventional "sandwich"-like cell. The dependences of critical frequency fc, threshold voltages, and characteristic times on a pore diameter d were established. The peculiarities of electro-optical effects can be explained in the framework of the approach which connects the variations of light intensity with the corresponding changes of the effective refractive index n(eff) of a composite LC media. The unusual behavior of the electro-optical response at low frequencies is assigned to the orienting action of the specific shear flow typical for electrokinetic phenomena in polar liquids.


Role of soluble CD14 in cerebrospinal fluid as a regulator of glial functions.
Proteomic analysis of cerebrospinal fluid (CSF) samples derived from patients with Alzheimer's disease (AD) or Parkinson's disease (PD) was performed. On the basis of liquid chromatography-tandem mass spectrometry, two-dimensional gel electrophoresis analysis, and Western blot validation, it was found that the level of soluble form of monocyte differentiation antigen CD14 precursor was elevated in CSF from AD or PD patients compared with normal subjects. The soluble CD14 protein and mRNA expression was detected in microglia cells, indicating that microglia may be a cellular source of soluble CD14 in CSF. Next, the role of soluble CD14 in the regulation of glial functions was investigated. Soluble CD14 inhibited lipopolysaccharide (LPS)- or LPS/interferon-gamma-induced nitric oxide production and cell death of microglia and astrocytes. Soluble CD14 suppressed glial neurotoxicity in a coculture of glia/neuroblastoma. In addition, soluble CD14 moderately enhanced phagocytic activity of microglia. These results suggest that microglia-derived soluble CD14 is a candidate CSF biomarker for AD and PD, and the soluble CD14 may inhibit glial activation by interfering with LPS effects.


In vitro characterization of bicuspid aortic valve hemodynamics using particle image velocimetry.
The congenital bicuspid aortic valve (BAV) is associated with increased leaflet calcification, ascending aortic dilatation, aortic stenosis (AS) and regurgitation (AR). Although underlying genetic factors have been primarily implicated for these complications, the altered mechanical environment of BAVs could potentially accelerate these pathologies. The objective of the current study is to characterize BAV hemodynamics in an in vitro system. Two BAV models of varying stenosis and jet eccentricity and a trileaflet AV (TAV) were constructed from excised porcine AVs. Particle Image Velocimetry (PIV) experiments were conducted at physiological flow and pressure conditions to characterize fluid velocity fields in the aorta and sinus regions, and ensemble averaged Reynolds shear stress and 2D turbulent kinetic energy were calculated for all models. The dynamics of the BAV and TAV models matched the characteristics of these valves which are observed clinically. The eccentric and stenotic BAV showed the strongest systolic jet (V = 4.2 m/s), which impinged on the aortic wall on the non-fused leaflet side, causing a strong vortex in the non-fused leaflet sinus. The magnitudes of TKE and Reynolds stresses in both BAV models were almost twice as large as comparable values for TAV, and these maximum values were primarily concentrated around the central jet through the valve orifice. The in vitro model described here enables detailed characterization of BAV flow characteristics, which is currently challenging in clinical practice. This model can prove to be useful in studying the effects of altered BAV geometry on fluid dynamics in the valve and ascending aorta. These altered flows can be potentially linked to increased calcific responses from the valve endothelium in stenotic and eccentric BAVs, independent of concomitant genetic factors.


Community v. non-community assault among adults in Khayelitsha, Western Cape, South Africa: a case count and comparison of injury severity.
Community assault (CA) or vigilantism is widespread in the township of Khayelitsha, Cape Town, South Africa (SA). Anecdotal evidence suggests that victims of CA are worse off than other assault cases. However, scientific data on the rate and severity of CA cases are lacking for SA. To contribute to CA prevention and management strategies by estimating the rate of CA among adults in Khayelitsha and comparing the injury severity and survival probability between cases of CA and other assault (non-CA) cases. We studied four healthcare centres in Khayelitsha during July - December 2012. A consecutive case series was conducted to capture all CA cases during this period. A retrospective folder review was performed on all cases of CA and on a control group of non-CA cases to compare injury severity and estimate survival probability. A total of 148 adult cases of CA occurred (case rate 1.1/1 000 person-years) over the study period. The Injury Severity Scores (ISSs) in the CA group were significantly higher than in the non-CA group (p < 0.001), with a median (interquartile range) ISS of 3 (2 - 6) in CA cases v. 1 (1 - 2) in non-CA cases. Comparison between the CA v. non-CA groups showed that a Glasgow Coma Scale < 15 (20.1% v. 5.4%, respectively), referral to the tertiary hospital (33.8% v. 22.6%, respectively), and crush syndrome (25.7% v. 0.0%, respectively) were all more common in CA cases. Survival probabilities were similar in both groups (CA v. non-CA 99.2% v. 99.3%, respectively). The rate of CA among adults in Khayelitsha is high, and the severity of injuries sustained by CA victims is substantially higher than in other assault cases.


Nutritional supplements as adjunctive therapy for children with chronic/recurrent sinusitis: pilot research.
Inflammation and edema of the sinonasal mucosa are important in the pathophysiology of sinusitis. Based on the similarities between otitis media (OM) and sinusitis, and our previous research on OM, we hypothesized that nutritional supplements would be effective adjunctive therapy for the treatment of children with chronic/recurrent sinusitis. We performed a 4 month, open-label, dose-titration study; subjects were enrolled from late January to early March 2003. Each subject served as his own control. Study supplements were a lemon-flavored cod liver oil and a children's multivitamin-mineral with selenium, prescribed in escalating doses; at higher doses, fish oil was substituted for cod liver oil. Subjects were private pediatric otolaryngology outpatients with a clinical diagnosis of chronic/recurrent sinusitis, whose symptoms were refractory to treatment with antibiotics. Our four subjects were Caucasian males, ranging in age from 4.2 to 9.8 years, with chronic/recurrent sinusitis for at least 3 years prior to entry in the study. Three subjects had a positive response; one subject dropped out for administrative reasons. Four, six, and eight weeks after beginning study supplements, the responders had decreased sinus symptoms, fewer episodes of acute sinusitis, and fewer doctor visits for acute illnesses. Their parents reported that they had begun to recover from upper respiratory illnesses without complications, which was unusual for these children, as was improvement in springtime; their improvement had previously been limited to the summer months or periods of home-schooling. Use of flavored cod liver oil and a multivitamin-mineral with selenium as adjunctive therapy for children with chronic/recurrent sinusitis is an inexpensive, non-invasive intervention that clinicians can use for selected patients, pending the performance of definitive, large, well-controlled studies.


Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models.
While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models. PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins. Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcinomas with neuroendocrine differentiation. The annotated clinical characteristics of these PDXs were correlated with their marker expression profile. Our results demonstrate the clinical relevance of this series of PDXs as a platform for both basic science studies and therapeutic discovery/drug development. The present report provides the prostate cancer community with a summary of the basic characteristics and a contact information for collaborations using these models.


Proteasome activation by hepatitis C core protein is reversed by ethanol-induced oxidative stress.
The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected by ethanol exposure. These interactions were examined in Huh-7 cell lines that expressed inducible HCV core protein and/or constitutive cytochrome P450 2E1 (CYP2E1) and as purified components in a cell-free system. Chymotrypsin-like proteasome activity was measured fluorometrically. Proteasome activity in core-positive 191-20 cells was 20% higher than that in core-negative cells and was enhanced 3-fold in CYP2E1-expressing L14 cells. Exposure of core-positive cells to glutathione ethyl ester, catalase, or the CYP2E1 inhibitor diallyl sulfide partially reversed the elevation of proteasome activity in core-positive cells, whereas ethanol exposure suppressed proteasome activity. The results indicate that proteasome activity was up-regulated by low levels of core-induced oxidative stress but down-regulated by high levels of ethanol-elicited stress. These findings were partially mimicked in a cell-free system. Addition of core protein enhanced the peptidase activity of purified 20S proteasome containing the proteasome activator PA28 and was further potentiated by addition of liver mitochondrial and/or microsome fractions. However, proteasome activation was significantly attenuated when fractions were obtained from ethanol-fed animals. HCV core protein interacts with PA28, mitochondrial, and endoplasmic reticulum proteins to cause low levels of oxidant stress and proteasome activation, which is dampened during ethanol metabolism when oxidant generation is higher.


The moderating role of experiential avoidance in the relationships between internal distress and smoking behavior during a quit attempt.
Recent smoking cessation studies have shown that decreasing experiential avoidance (EA; i.e., tendency to reduce or avoid internal distress) improves success, but to date none have examined the moderating effect of EA on the role of specific internal distress in smoking cessation. This study examined whether prequit general EA (Acceptance and Action Questionnaire) and smoking-specific EA (Avoidance and Inflexibility Scale) moderated the relations between 4 measures of postquit internal distress (depressive symptoms, negative affect, physical withdrawal symptoms, craving) and smoking. Forty adult smokers participated in a randomized controlled trial of distress tolerance treatment for smokers with a history of early lapse. Multilevel models showed that prequit smoking-specific EA, but not general EA, significantly moderated the relationship between all measures of internal distress, except craving, and smoking over 13 weeks postquit. When examined over 26 weeks, these relations remained unchanged for all, but the moderating effect became trend-level for depressive symptoms. Significant associations between postquit internal distress and smoking were found only in those with high prequit smoking-specific EA. Moreover, prequit smoking-specific EA did not predict postquit levels or changes in internal distress, suggesting that decreasing smoking-specific EA prequit may not reduce internal distress, but may instead reduce smoking risk in response to such distress during a quit attempt. Results mainly supported hypothesized relations, but only for smoking-specific EA. Smoking cessation interventions focusing on EA reduction may especially benefit those vulnerable to greater postquit depressive and withdrawal symptoms, and those who smoke to regulate aversive internal states. (PsycINFO Database Record


Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1.
SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers. This program of myeloid cell activation required reverse transcription, cGAS and STING, and signaling through the IFN receptor. Furthermore, SAMHD1 reduced the induction of virus-specific cytotoxic T cells in vivo. Therefore, virus restriction by SAMHD1 limits the magnitude of IFN and T cell responses. This demonstrates a competition between cell-autonomous virus control and subsequent innate and adaptive immune responses, a concept with important implications for the treatment of infection.


Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study.
Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients. GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.


Behavioral Measures of Listening Effort in School-Age Children: Examining the Effects of Signal-to-Noise Ratio, Hearing Loss, and Amplification.
Increased listening effort in school-age children with hearing loss (CHL) could compromise learning and academic achievement. Identifying a sensitive behavioral measure of listening effort for this group could have both clinical and research value. This study examined the effects of signal-to-noise ratio (SNR), hearing loss, and personal amplification on 2 commonly used behavioral measures of listening effort: dual-task visual response times (visual RTs) and verbal response times (verbal RTs). A total of 82 children (aged 6-13 years) took part in this study; 37 children with normal hearing (CNH) and 45 CHL. All children performed a dual-task paradigm from which both measures of listening effort (dual-task visual RT and verbal RT) were derived. The primary task was word recognition in multi-talker babble in three individually selected SNR conditions: Easy, Moderate, and Hard. The secondary task was a visual monitoring task. Listening effort during the dual-task was quantified as the change in secondary task RT from baseline (single-task visual RT) to the dual-task condition. Listening effort based on verbal RT was quantified as the time elapsed from the onset of the auditory stimulus to the onset of the verbal response when performing the primary (word recognition) task in isolation. CHL completed the task aided and/or unaided to examine the effect of amplification on listening effort. Verbal RTs were generally slower in the more challenging SNR conditions. However, there was no effect of SNR on dual-task visual RT. Overall, verbal RTs were significantly slower in CHL versus CNH. No group difference in dual-task visual RTs was found between CNH and CHL. No effect of amplification was found on either dual-task visual RTs or verbal RTs. This study compared dual-task visual RT and verbal RT measures of listening effort in the child population. Overall, verbal RTs appear more sensitive than dual-task visual RTs to the negative effects of SNR and hearing loss. The current findings extend the literature on listening effort in the pediatric population by demonstrating that, even for speech that is accurately recognized, school-age CHL show a greater processing speed decrement than their normal-hearing counterparts, a decrement that could have a negative impact on learning and academic achievement in the classroom.


Clinical Evidence for Association of Acupuncture and Acupressure With Improved Cancer Pain: A Systematic Review and Meta-Analysis.
Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent. To evaluate the existing randomized clinical trials (RCTs) for evidence of the association of acupuncture and acupressure with reduction in cancer pain. Three English-language databases (PubMed, Embase, and CINAHL) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through March 31, 2019. Randomized clinical trials that compared acupuncture and acupressure with a sham control, analgesic therapy, or usual care for managing cancer pain were included. Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. Random-effects modeling was used to calculate the effect sizes of included RCTs. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. The primary outcome was pain intensity measured by the Brief Pain Inventory, Numerical Rating Scale, Visual Analog Scale, or Verbal Rating Scale. A total of 17 RCTs (with 1111 patients) were included in the systematic review, and data from 14 RCTs (with 920 patients) were used in the meta-analysis. Seven sham-controlled RCTs (35%) were notable for their high quality, being judged to have a low risk of bias for all of their domains, and showed that real (compared with sham) acupuncture was associated with reduced pain intensity (mean difference [MD], -1.38 points; 95% CI, -2.13 to -0.64 points; I2 = 81%). A favorable association was also seen when acupuncture and acupressure were combined with analgesic therapy in 6 RCTs for reducing pain intensity (MD, -1.44 points; 95% CI, -1.98 to -0.89; I2 = 92%) and in 2 RCTs for reducing opioid dose (MD, -30.00 mg morphine equivalent daily dose; 95% CI, -37.5 mg to -22.5 mg). The evidence grade was moderate because of the substantial heterogeneity among studies. This systematic review and meta-analysis found that acupuncture and/or acupressure was significantly associated with reduced cancer pain and decreased use of analgesics, although the evidence level was moderate. This finding suggests that more rigorous trials are needed to identify the association of acupuncture and acupressure with specific types of cancer pain and to integrate such evidence into clinical care to reduce opioid use.


Beyond Components of Wellbeing: The Effects of Relational and Situated Assemblage.
Despite multiple axes of variation in defining wellbeing, the paper argues for the dominance of a 'components approach' in current research and practice. This approach builds on a well-established tradition within the social sciences of attending to categories whether for their identification, their value or their meanings and political resonance. The paper critiques the components approach and explores how to move beyond it towards conceptually integrating the various categories and dimensions through a relational and situated account of wellbeing. Drawing on more fluid social sciences, wellbeing is framed as an effect, dependent on the mobilisation of resources from everyday encounters with complex assemblages of people, things and places. Through such a framing, wellbeing can be conceived of as stable and amenable to change, as individual and collective and as subjective and objective. Policy interventions then need to attend to the relationalities of particular social and spatial contexts.


Optimal point process filtering and estimation of the coalescent process.
The coalescent process is a widely used approach for inferring the demographic history of a population, from samples of its genetic diversity. Several parametric and non-parametric coalescent inference methods, involving Markov chain Monte Carlo, Gaussian processes, and other algorithms, already exist. However, these techniques are not always easy to adapt and apply, thus creating a need for alternative methodologies. We introduce the Bayesian Snyder filter as an easily implementable and flexible minimum mean square error estimator for parametric demographic functions on fixed genealogies. By reinterpreting the coalescent as a self-exciting Markov process, we show that the Snyder filter can be applied to both isochronously and heterochronously sampled datasets. We analytically solve the filter equations for the constant population size Kingman coalescent, derive expressions for its mean squared estimation error, and estimate its robustness to prior distribution specification. For populations with deterministically time-varying size we numerically solve the Snyder equations, and test this solution on common demographic models. We find that the Snyder filter accurately recovers the true demographic history for these models. We also apply the filter to a well-studied, dataset of hepatitis C virus sequences and show that the filter compares well to a popular phylodynamic inference method. The Snyder filter is an exact (given discretised priors, it does not approximate the posterior) and direct Bayesian estimation method that has the potential to become a useful alternative tool for coalescent inference.


EGFR mutation specific immunohistochemistry is a useful adjunct which helps to identify false negative mutation testing in lung cancer.
Mutations in EGFR guide treatment in non-small cell lung cancer (NSCLC). The most common mutations, exon 19 (delE746-A750) and exon 21 (L858R), can be identified by mutation specific immunohistochemistry (IHC). We present our prospective experience of universal reflex IHC and molecular testing in non-squamous NSCLC in the routine clinical setting.A total of 411 specimens from 332 patients were encountered over two years. Of these, 326 (98%) patients underwent EGFR IHC, 15 (5%) were positive for exon 19 deletions and 27 (8%) for exon 21 (L858R); 244 (73%) patients underwent molecular testing. Seventy-six mutations in 64 patients (19% of all patients encountered; 26% with sufficient material for testing) were identified. These comprised nine exon 18 (G719X) mutations, three also with exon 20 mutations; 24 exon 19 deletions, six also with exon 20 mutations; 23 exon 21 (L858R), three also with exon 20 mutations; and 8 exon 20 alone.All 15 exon 19 IHC positive patients were proven mutated (100% specificity, 63% sensitivity). Twenty-two of 27 exon 21 IHC positive cases were proven mutated while three patients had insufficient material for molecular testing (92% specificity, 96% sensitivity). The overall specificity and sensitivity of IHC for any EGFR mutation was 95% and 58%. Five patients initially thought to be wild type for EGFR but IHC positive underwent repeat molecular testing because of the discrepancy which confirmed the IHC result in three cases (60%).We conclude IHC is very specific but not sensitive. Whilst IHC cannot replace molecular testing, it is a useful adjunct which requires minimal tissue and identifies false negative molecular results which occurred in 5% of our patients with eventually confirmed EGFR mutations.


Step by step towards citizen science - deconstructing youth participation in BioBlitzes.
BioBlitzes, typically one-day citizen science (CS) events, provide opportunities for the public to participate in data collection for research and conservation, potentially promoting deeper engagement with science. We observed 81 youth at 15 BioBlitzes in the U.S. and U.K., identifying five steps participants use to create a biological record (Exploring, Observing, Identifying, Documenting and Recording). We found 67 youth engaged in at least one of the steps, but seldom in all, with rare participation in Recording which is crucial for contributing data to CS. These findings suggest BioBlitzes should reduce barriers to Recording for youth to increase engagement with science.


Genome-wide identification of Xenopus matrix metalloproteinases: conservation and unique duplications in amphibians.
Matrix metalloproteinases (MMPs) are members of the superfamily of Zn2+ dependent extracellular or membrane-bound endopeptidases which have been implicated to play critical roles in vertebrate development and human pathogenesis. A number of MMP genes have been found to be upregulated in some or all organs during frog metamorphosis, suggesting that different MMPs may have different functions in various organs/tissues. The recent advances in EST (expressed sequence tag) sequencing and the completion of the genome of Xenopus (X.) tropicalis prompted us to systematically analyze the existence of MMPs in the Xenopus genome. We examined X. laevis and X. tropicalis ESTs and genomic sequences for MMPs and obtained likely homologs for 20 out of the 25 MMPs known in higher vertebrates. Four of the five missing MMPs, i.e. MMPs 8, 10, 12 and 27, were all encoded on human Chromosome 11 and the other missing MMP, MMP22 (a chicken MMP), was also absent in human genome. In addition, we identified several novel MMPs which appears to be derived from unique duplications over evolution, are present in the genomes of both Xenopus species. We identified the homologs of most of the mammalian MMPs in Xenopus and discovered a number of novel MMPs. Our results suggest that MMP genes undergo dynamic changes over evolution. It will be of interest in the future to investigate whether MMP expression and functions during vertebrate development are conserved. The sequence information reported here should facilitate such an endeavor in the near future.


A randomised, double-blind placebo-controlled trial of ascorbic acid supplementation for the prevention of preterm labour.
In a previous study from this institution, patients at high risk for preterm labour were screened for the presence of bacterial vaginosis (BV). When BV was present, they were randomised to receive either treatment (metronidazole) or placebo (vitamin C). There were significantly more patients with preterm labour in the metronidazole group. The aim of this double-blind randomised placebo-controlled trial study was to determine whether vitamin C could indeed reduce the recurrence risk of preterm labour. Patients with a history of preterm labour in a preceding pregnancy were randomised to receive 250 mg vitamin C or a matching placebo twice daily until 34 weeks' gestation. They attended a dedicated premature labour clinic. Significantly more women delivered before term in the group that received vitamin C, but there was no difference in the outcome of the babies between the two groups. Supplementation with vitamin C did not prevent premature labour.


[From bench to bedside: new insights into the treatment of heart failure].
Despite significant advances in pharmacological and clinical treatment, heart failure remains a leading cause of morbidity and mortality worldwide. G-protein coupled receptors are a wide superfamily of plasma membrane receptors which represent an important target of heart failure drug therapy. Since heart failure is characterized by the overactivity of different neurohormones, such as catecholamines and angiotensin II, responsible for several detrimental effects on the cardiovascular system, over the last decade therapeutic strategies targeting beta-adrenergic and angiotensin receptors have been developed. Despite the introduction of successful drug classes, such as beta-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors and sartans, heart failure still poses an enormous challenge, thus indicating the urgent need to develop innovative treatments that might counteract mechanisms involved in heart failure onset and progression. It is now established that a single receptor, activated by the same agonist, can elicit several different signaling pathways often resulting in opposite cellular responses, some beneficial and some detrimental. However, drugs currently used in heart failure target receptors on their extracellular domain by competing with the endogenous agonists. Thus, they can inhibit non-specifically all the receptor-related signaling pathways including those with beneficial activity whose blockade would not be desirable in heart failure. These observations stress the need for the generation of new therapeutic molecules able to target specific signaling pathways which might result in innovative therapies for cardiovascular disease.


Physcomitrella patens: a model to investigate the role of RAC/ROP GTPase signalling in tip growth.
Polarized cell expansion plays an important role in plant morphogenesis. Tip growth is a dramatic form of this process, which is widely used as a model to study its regulation by RAC/ROP GTPase signalling. During the dominant haploid phase of its life cycle, the moss Physcomitrella patens contains different types of cells that expand by tip growth. Physcomitrella is a highly attractive experimental system because its genome has been sequenced, and transgene integration by homologous recombination occurs in this plant at frequencies allowing effective gene targeting. Furthermore, together with the vascular spikemoss Selaginella moellendorffii, whose genome has also been sequenced, the non-vascular moss Physcomitrella provides an evolutionary link between green algae and angiosperms. BLAST searches established that the Physcomitrella and Selaginella genomes encode not only putative RAC/ROP GTPases, but also homologues of all known regulators of polarized RAC/ROP signalling, as well as of key effectors acting in signalling cascades downstream of RAC/ROP activity. Nucleotide sequence relationships within seven different families of Physcomitrella, Selaginella, Arabidopsis thaliana and Nicotiana tabacum (tobacco) genes with distinct functions in RAC/ROP signalling were characterized based on extensive maximum likelihood and Neighbor-Joining analyses. The results of these analyses are interpreted in the light of current knowledge concerning expression patterns and molecular functions of RAC/ROP signalling proteins in angiosperms. A key aim of this study is to facilitate the use of Physcomitrella as a model to investigate the molecular control of tip growth in plants.


Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD.
We explored the cardiac safety of the osteoporosis treatment strontium ranelate in the UK Clinical Practice Research Datalink. While known cardiovascular risk factors like obesity and smoking were associated with increased cardiac risk, use of strontium ranelate was not associated with any increase in myocardial infarction or cardiovascular death. It has been suggested that strontium ranelate may increase risk for cardiac events in postmenopausal osteoporosis. We set out to explore the cardiac safety of strontium ranelate in the Clinical Practice Research Datalink (CPRD) and linked datasets. We performed a nested case-control study. Primary outcomes were first definite myocardial infarction, hospitalisation with myocardial infarction, and cardiovascular death. Cases and matched controls were nested in a cohort of women treated for osteoporosis. The association with exposure to strontium ranelate was analysed by multivariate conditional logistic regression. Of the 112,445 women with treated postmenopausal osteoporosis, 6,487 received strontium ranelate. Annual incidence rates for first definite myocardial infarction (1,352 cases), myocardial infarction with hospitalisation (1,465 cases), and cardiovascular death (3,619 cases) were 3.24, 6.13, and 14.66 per 1,000 patient-years, respectively. Obesity, smoking, and cardiovascular treatments were associated with significant increases in risk for cardiac events. Current or past use of strontium ranelate was not associated with increased risk for first definite myocardial infarction (odds ratio [OR] 1.05, 95 % confidence interval [CI] 0.68-1.61 and OR 1.12, 95 % CI 0.79-1.58, respectively), hospitalisation with myocardial infarction (OR 0.84, 95 % CI 0.54-1.30 and OR 1.17, 95 % CI 0.83-1.66), or cardiovascular death (OR 0.96, 95 % CI 0.76-1.21 and OR 1.16, 95 % CI 0.94-1.43) versus patients who had never used strontium ranelate. Analysis in the CPRD did not find evidence for a higher risk for cardiac events associated with the use of strontium ranelate in postmenopausal osteoporosis.


Asthma deaths in England and Wales 1931-85: evidence for a true increase in asthma mortality.
A recent increase in asthma mortality has been reported in several countries. Such increases can be brought about by changes in factors acting close to the time of death, but they may also be caused by risk factors determined by the generation into which a person is born, as indicated by the year of birth. Asthma mortality rates since 1931 are independently associated with birthdate as well as date of death. In particular there has been an increase in asthma mortality in birth cohorts born since the 1940s. Such changes are unlikely to be due to a change in reporting of asthma deaths, and other evidence including the reported increase in the prevalence of eczema in succeeding National Birth cohorts supports the view that these changes may be due to an increased prevalence of atopy. In the absence of any further improvements in the management of asthma, such an increased prevalence of atopy implies that the mortality rate is unlikely to decline substantially for some years to come.


Treating eating disorders using the internet.
This article evaluates the empirical standing of online treatment (eTherapy) for people with an established eating disorder. There have been four randomized controlled trials of eTherapy for people with an eating disorder. All four focused on eating disorders characterized by binge eating and recruited adult participants direct from the community. The interventions were cognitive behavioural in nature, lasted between 3 and 7 months, and were accompanied by external support. In common with eTherapy for other mental health problems, there were problems engaging and retaining the users, and maximizing their implementation of the intervention. A minority (10-37%, intent-to-treat figures) improved substantially. This is a new field. The findings of the four randomized controlled trials are consistent with the earlier reports indicating that guided eTherapy interventions of a cognitive behavioural nature are acceptable to (female) adults with a binge eating problem and that a subgroup improves substantially. More effective interventions are required and their use in different healthcare settings needs to be investigated. Direct-to-sufferer eTherapy interventions have the potential to increase access to effective forms of treatment and, in younger cases, they might serve as a form of secondary prevention.


The role of monitoring and evaluation to ensure functional access to community-based early diagnosis and treatment in a malaria elimination programme in Eastern Myanmar.
Improving access to early diagnosis and treatment (EDT) has increasingly proven to be a major contributor to decreasing malaria incidence in low-transmission settings. The Malaria Elimination Task Force (METF) has deployed malaria posts set up in Eastern Myanmar, providing free uninterrupted community-based access to EDT in more than 1200 villages. Ensuring high quality services are provided by these malaria posts is essential to reaching elimination targets. The present study aimed to determine the functionality of the malaria posts in the METF programme. This report analysed routinely collected data (weekly reports, individual consultation, diagnostic test quality control) and data collected specifically during monitoring and evaluation visits using descriptive statistics and univariate logistic regression. The presence of major dysfunctions (stock-outs and reported closing; likely to impair the ability of the population to access EDT) or minor dysfunctions (no formal METF training, lack of regular salary, forms and manual not on-site, and low frequency of supervisor visits) and the ability to anticipate dysfunctions through analysis of weekly reports were assessed. A total of 65% of malaria posts had no major dysfunction identified during monitoring and evaluation visits, while 86% of malaria posts were fully stocked with tests and medicines used for treatment. Diagnosis was correctly conducted with few false positives and rare mis-speciation of results. Malaria post worker knowledge of malaria treatments showed few gaps, mostly in the treatment of more complex presentations. Malaria posts were well utilized in the population, with 94% of consultations occurring within the first 3 days of fever. In the regression analysis, reported stock-outs and delayed weekly reports were associated with observed major and minor dysfunctions in monitoring and evaluation visits, emphasizing the need to reinforce support to malaria post supervisors, who were responsible for the local logistics of supply and data transmission and day-to-day supervision. The malaria posts operating under the METF programme perform to a high standard, with the majority offering uninterrupted access to diagnosis and treatment, and high service uptake in the villages serviced by the programme. However, programme operations can be strengthened by increasing malaria post supervisor visits and re-training malaria post workers.


Growth advantage and vascularization induced by basic fibroblast growth factor overexpression in endometrial HEC-1-B cells: an export-dependent mechanism of action.
The human endometrial adenocarcinoma HEC-1-B cell line was transfected with an expression vector harboring the human basic fibroblast growth factor (bFGF) cDNA under the control of the human beta-actin gene promoter. Stable transfectants were obtained in which a constitutive, limited overexpression of M(r) 24,000, 22,000, and 18,000 bFGF isoforms was observed. When transfectants were screened for the capacity to release the growth factor, significant amounts of bFGF were present in the conditioned medium and extracellular matrix of the bFGF-B9 clone but not of the bFGF-A8 clone, even though both cell lines produced similar levels of intracellular bFGF. When compared to parental cells, bFGF-B9 cells showed down-regulation of tyrosine kinase fibroblast growth factor receptors along with up-regulation of urokinase-type plasminogen activator expression which was abolished by incubation of the cell cultures with neutralizing anti-bFGF antibody. In vivo, bFGF-B9 cells formed highly vascularized tumors growing faster than parental cells when injected s.c. in nude mice. Also, they were more potent than nontransfected cells in inducing an angiogenic response in the rabbit cornea assay. In contrast, the bFGF-A8 cell phenotype was indistinguishable from parental cells both in vitro and in vivo. In conclusion, clonal differences exist within the HEC-1-B cell line in the capacity to release bFGF. bFGF export by human endometrial adenocarcinoma cells results in autocrine and paracrine effects that confer a growth advantage in vivo associated with increased neovascularization.


Phytoremediation of aspirin and tetracycline by Brassica juncea.
With the increasing release of pharmaceutical drugs in the environment, research is in progress for investigating alternative methods for their remediation. Various studies have shown the phytoremediation potential of Brassica juncea for metals. The current study was aimed at evaluating the phytoremediation potential of B. juncea for two different pharmaceutical drugs i.e. aspirin and tetracycline in in-vitro conditions. The seeds of B. juncea were germinated and grown for a period of 28 and 24 days for aspirin and tetracycline, respectively. The study analyzed the remediation rate of B. juncea for the selected drugs in three different sets of varying concentration along with any phytotoxic effects exerted by the drugs on the seeds. Preliminary results showed that the average remediation rate of aspirin and tetracycline at the end of experiment was approximately 90% and 71%, respectively. As initial drug concentrations were increased in the media, the remediation rate also improved. However, at higher concentrations, the plants showed phytotoxicity as depicted by the decrease in shoot length of the germinated seeds. These preliminary results indicated that B. juncea could tolerate and remediate pharmaceutical drugs such as analgesics and antibiotics.


Mitosin and pHH3 predict poorer survival in astrocytomas WHO grades II and III.
The limitations of the current WHO classification of astrocytomas call for a sustained effort to improve diagnostic and prognostic accuracy. The relationship between tumour growth and clinical outcome suggests that proliferative activity should be examined. The objective of this study was to evaluate the diagnostic and prognostic value of the proliferation markers mitosin and phosphohistone H3 (pHH3) in infiltrative astrocytomas WHO grades II and III and compare the findings with mitotic count and Ki-67/MiB-1 immunostaining. Fifty-nine and thirty-three infiltrative astrocytomas WHO grades II and III, respectively, were immunostained with the proliferation markers mitosin and pHH3 using standard immunohistochemical procedures. The expression was quantified as a proliferative index (PI) and statistically evaluated with Spearman's rank correlation test, Wilcoxon-Mann-Whitney U test, and univariable and multivariable COX regression survival analyses. Significant positive correlations were found between these proliferation markers. The number of mitoses, pHH3 mitotic figures (MFs), the Ki-67/MiB-1 PI and the mitosin PI were greater in WHOgrade III anaplastic astrocytomas compared to WHO grade II diffuse astrocytomas, while pHH3 PI only showed a trend. All proliferation markers were associated with poorer prognosis, but mitotic count was not. Ki-67/MiB-1, mitosin and pHH3 MF achieved statistical significance in the univariable analyses of both time to relapse (TTR) and overall survival (OS). Only mitosin remained significant in both multivariable analyses. pHH3 was significant in the multivariable analysis of OS but not of TTR. Clinical factors including age, extent of surgical resection and WHO performance status were also significantly correlated with survival. In conclusion, mitosin and pHH3 immunostaining have prognostic and diagnostic value in the clinical assessment of patients with infiltrative astrocytomas. The inclusion of proliferation markers in a layered diagnosis should be considered in the upcoming revision of the WHO classification system.


The challenges and opportunities of global neurosurgery in East Africa: the Neurosurgery Education and Development model.
The objective of this study was to describe the experience of a volunteering neurosurgeon during an 18-week stay at the Neurosurgery Education and Development (NED) Institute and to report the general situation regarding the development of neurosurgery in Zanzibar, identifying the challenges and opportunities and explaining the NED Foundation's model for safe practice and sustainability. The NED Foundation deployed the volunteer neurosurgeon coordinator (NC) for an 18-week stay at the NED Institute at the Mnazi Mmoja Hospital, Stonetown, Zanzibar. The main roles of the NC were as follows: management of patients, reinforcement of weekly academic activities, coordination of international surgical camps, and identification of opportunities for improvement. The improvement opportunities were categorized as clinical, administrative, and sociocultural and were based on observations made by the NC as well as on interviews with local doctors, administrators, and government officials. During the 18-week period, the NC visited 460 patients and performed 85 surgical procedures. Four surgical camps were coordinated on-site. Academic activities were conducted weekly. The most significant challenges encountered were an intense workload, deficient infrastructure, lack of self-confidence among local physicians, deficiencies in technical support and repairs of broken equipment, and lack of guidelines. Through a series of interviews, the sociocultural factors influencing the NED Foundation's intervention were determined. Factors identified for success were the activity of neurosurgical societies in East Africa; structured pan-African neurosurgical training; the support of the Foundation for International Education in Neurological Surgery (FIENS) and the College of Surgeons of East, Central and Southern Africa (COSECSA); motivated personnel; and the Revolutionary Government of Zanzibar's willingness to collaborate with the NED Foundation. International collaboration programs should balance local challenges and opportunities in order to effectively promote the development of neurosurgery in East Africa. Support and endorsement should be sought to harness shared resources and experience. Determining the caregiving and educational objectives within the logistic, administrative, social, and cultural framework of the target hospital is paramount to success.


Design of thin-film Luneburg lenses for maximum focal length control.
The application of thin-film Luneburg lenses to integrated optical circuits will require accurate control of their focal length to permit the necessary alignment between the various circuit elements. Of particular interest is the design of lenses for application to a silicon-based integrated optical rf spectrum analyzer. This study analyzes the sensitivity of the focal length of Luneburg lenses to thickness variation at the lens center resulting from fabrication process tolerances. It is shown that this sensitivity can be minimized by properly selecting the refractive index of the waveguide material, using a larger focal length and employing a longer optical wavelength.


Quantum corral resonance widths: lossy scattering as acoustics.
We present an approach to predicting extrinsic electron resonance widths within quantum corral nanostructures based on analogies with acoustics. Established quantum mechanical methods for calculating resonance widths, such as multiple scattering theory, build up the scattering atom by atom, ignoring the structure formed by the atoms, such as walls or enclosures. Conversely, particle-in-a-box models, assuming continuous walls, have long been successful in predicting quantum corral energy levels, but not resonance widths. In acoustics, partial reflection from walls and various enclosures has long been incorporated for determining reverberation times. Pursuing an exact analogy between the local density of states of a quantum corral and the acoustic impedance of a concert hall, we show electron lifetimes in nanoscopic structures of arbitrary convex shape are well accounted for by the Sabine formula for acoustic reverberation times. This provides a particularly compact and intuitive prescription for extrinsic finite lifetimes in a particle-in-a-box with leaky walls, including quantum corral atomic walls, given single particle scattering properties.


Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases.
Metabolic function and energy production in eukaryotic cells are regulated by mitochondria, which have been recognized as the intracellular 'powerhouses' of eukaryotic cells for their regulation of cellular homeostasis. Mitochondrial function is important not only in normal developmental and physiological processes, but also in a variety of human pathologies, including cardiac diseases. An emerging topic in the field of cardiovascular medicine is the implication of mitochondrial nucleoid for metabolic reprogramming. This review describes the linear/3D architecture of the mitochondrial nucleoid (e.g., highly organized protein-DNA structure of nucleoid) and how it is regulated by a variety of factors, such as noncoding RNA and its associated R-loop, for metabolic reprogramming in cardiac diseases. In addition, we highlight many of the presently unsolved questions regarding cardiac metabolism in terms of bidirectional signaling of mitochondrial nucleoid and 3D chromatin structure in the nucleus. In particular, we explore novel techniques to dissect the 3D structure of mitochondrial nucleoid and propose new insights into the mitochondrial retrograde signaling, and how it regulates the nuclear (3D) chromatin structures in mitochondrial diseases.


Knee osteoarthritis: when arthroscopy can help
Arthroscopic surgery of the knee is one of the most common orthopedic procedures performed globally. Recently, a lot of attention has been directed towards the role of arthroscopic surgery in the setting of osteoarthritis (OA) and its role in degenerative knee pathology. A number of recent randomized control trials and systematic reviews have suggested limited benefit for arthroscopic surgery and partial meniscectomy for this indication. With this recent focus on the use of arthroscopy in OA, it is often forgotten that arthroscopy plays an important role in the management of other pathologies involving the knee in patients who may have a concomitant diagnosis of OA. This evidence‑based review highlights indications for when arthroscopic intervention is warranted in such patients.