The activities and participation of adolescents with autism spectrum disorders in Singapore: findings from an ICF-based instrument.
This study sought to describe the activities and participation of adolescents with autism spectrum disorders (ASD) in Singapore and to examine the suitability of the Activity and Participation component of the International Classification of Functioning, Disability and Health for achieving this purpose. This information may guide the development of intervention programmes for adolescents and adults as well as the provision of a means to document meaningful outcomes. Parents of 20 adolescents with ASD attending special schools in Singapore were interviewed using the Vineland Adaptive Behavioural Scales - Second Edition and the Activities and Participation Rating Scale (APRS), which was developed for this study. The adolescents with ASD were rated to have more difficulties with participation than with the engagement of activities. Individual domain analyses indicate no difficulties with mobility and mild difficulties with self-care. The performance of general tasks and demands were rated as less problematic than domestic, major life areas, communication and interpersonal interactions. The adolescents with ASD were rated to have more difficulties in communication and community environments than in at home. In addition, analysis of associations between the APRS and Vineland Adaptive Behavioural Scales - Second Edition reveal a pattern of strong relationships between sub-tests. This study highlights the imperative for researchers and practitioners alike to develop a focus on strengths, generalisation and the quality of life of adolescents with ASD. The APRS also shows promise in helping document outcomes for adolescents with ASD in Asia and further development of this instrument is needed.


Effect of a synbiotic on infantile acute gastroenteritis.
Acute gastroenteritis is still a common disease worldwide. Synbiotics are being used to alleviate the effects of acute gastroenteritis-related diarrhoea. The objective of this study was to determine the efficacy of a synbiotic in reducing the duration of diarrhoea in children with acute gastroenteritis. The study has been carried out on data gathered from children with acute gastroenteritis between the age of three months and 14 years seen in paediatric polyclinics between August 2009 and April 2010. While synbiotic group patients got a sachet containing Bifidobacterium lactis 2211 with a minimum of 5×10⁶ cfu active bacteria and 900 mg chicory inulin twice daily for five days together with an oral rehydration solution, the control group only received an oral rehydration solution. Therapy with synbiotic plus an oral rehydration solution shortened the duration of acute diarrhoea in children by approximately one day compared to oral rehydration solution only.


Macroporous organosilicon nanocomposites co-deliver Bcl2-converting peptide and chemotherapeutic agent for synergistic treatment against multidrug resistant cancer.
Therapeutic biomacromolecules are confronted with in vivo challenges of low bio-stability and poor tumor tissue-penetration. Herein, we report for the first time, our development and characterization of a hybrid nanocomposite for delivering a Bcl-2-converting peptide (NuBCP9, N9 hereafter) and testing its efficacy alone or together with doxorubicin (DOX). The hybrid nanocomposite is composed of the internal large pore sized-mesoporous silica nanoparticles (MSNs) and the external highly-branched polyamidoamine (PAMAM) dendrimers, into which N9 peptide and DOX were encapsulated for the different sub-cellular delivery to treat drug-resistant cancer. The nanocomposite possessed the particle and pore sizes of ~37 nm and ~8 nm, which displayed the superior tumor penetration capacity over naked MSNs both in cultured-3D tumor sphere and in live animal models. Moreover, the dual drug nanocomposite exhibited a great synergistic anticancer effect on Bcl-2-positive cancer cells in vitro and animals with the negligible toxic side effects. The tumor inhibition rate of the nanocomposite (89%) was five times as much as the two drugs combination. This design provides a new effective, safe and versatile strategy to fabricate large pore-sized MSNs with the organic-inorganic hybrid framework to concurrently transport therapeutic peptides and chemotherapeutics to the specific sub-cellular locations for the synergistic cancer therapy and drug resistance reversal, which has significant impact on the development of improved cancer therapeutics.


Understanding the consequences of epigenetic mechanisms and its effects on transcription in health and disease.
Over the course of thirty-five years of research into the chromosome we are confronted with a number of general conclusions central to chromatin biology, perhaps most pertinent of these is that organization of higher order nucleosome structures play a fundamental role in DNA behavior. Folding and packaging of DNA is linked with a number of processes ranging from transcriptional regulation, genome stability, chromosome segregation, including replication and repair. Intrinsic to nuclear function is chromatin structure and the relationship with epigenetic modification. While we are aware that genetic and epigenetic changes can influence tumorigenesis, it is still unclear what protein components are specified on chromatin or the molecular events that underlie the link between chromosomes and cancer. In recent years, our understanding of DNA methylation with cancer development has revealed some surprising findings with particular emphasis on the antithetical character of hypo- and hyper- methylation of DNA. The molecular mechanism by which methylation is responsible for increased cancer risk has received widespread attention and is relavent to our understanding of genetic stability. The biological significance of other epigenetic modifications such as histone tail changes and active chromatin remodeling are also a major driving force in chromosome research in cancer. In light of recent advances in the understanding of epigenetic changes in disease we have organized a focused review series and discuss the significance of Epigenetics in Normal Control and Deregulation in Cancer. Authors from divergent fields of study have contributed articles that examine chromatin dynamics in cancer, bringing together research interests from a wide variety of fields. In this vein, we discuss the consequences of deregulating epigenetic mechanisms with a viewpoint on transcriptional control, chromatin function and human disease.


Polysomal RNA in Semliki Forest virus infected Aedes albopictus cells.
Polysomes from Aedes albopictus cells were identified by their rapid labelling with radioactive amino acids and their sensitivity to EDTA, RNase and puromycin. The major ribosome component in cytoplasmic extracts had a sedimentation coefficient of approx. 95S and may be a ribosome dimer. In Semiki Forest virus infected Aedes albopictus cells, 42S and 26S RNA were the major virus RNA species detected up to 10 h post infection. Virus RNA was detected in association with pre-labelled ribosomes and banded at a buoyant density of 1-55 g/ml. 42S, 38S and 26S virus RNA species were associated with polysomes.


Retrieval properties of a Hopfield model with random asymmetric interactions.
The process of pattern retrieval in a Hopfield model in which a random antisymmetric component is added to the otherwise symmetric synaptic matrix is studied by computer simulations. The introduction of the anti-symmetric component is found to increase the fraction of random inputs that converge to the memory states. However, the size of the basin of attraction of a memory state does not show any significant change when asymmetry is introduced in the synaptic matrix. We show that this is due to the fact that the spurious fixed points, which are destabilized by the introduction of asymmetry, have very small basins of attraction. The convergence time to spurious fixed-point attractors increases faster than that for the memory states as the asymmetry parameter is increased. The possibility of convergence to spurious fixed points is greatly reduced if a suitable upper limit is set for the convergence time. This prescription works better if the synaptic matrix has an antisymmetric component.


BM-MSC-derived small extracellular vesicles (sEV) from trained animals presented nephroprotective potential in unilateralureteral obstruction model.
The efficacy of bone marrow mesenchymal stromal cells (BM-MSC) and its extracellular vesicles has been demonstrated for a broad spectrum of indications, including kidney diseases. However, BM-MSC donor characteristics and their potential are not usually considered. Therefore, the present work aims to evaluate the nephroprotective capacity of sEV secreted by BM-MSC from trained rats inunilateral ureteral obstruction (UUO) model. BM-MSC was characterized by their differentiation potential and immunophenotypic markers. The sEV were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis and western blot. Its miRNA cargo was examined by quantitative PCR analysis for miR-26a, 126a, and 296. Wistar rats were submitted to UUO procedure and concomitantly treated with sEV secreted by BM-MSC from the untrained andtrained rats. The kidney tissue from all groups was evaluated for fibrosis mediators (transforming growth factor beta1 and collagen), CD34-angiogenesis marker, and hypoxia-inducible factor 1 alpha (HIF-1α). Treadmill training stimulated in BM-MSC the production of sEV loaded with pro-angiogenic miR-296. The treatment with this sEVin UUO-rats was able to attenuate collagen accumulation and increase CD34 and HIF-1α in the kidney tissue when compared to untrained ones. Tubular proximal cells under hypoxia and exposed to BM-MSC sEV demonstrate accumulation in HIF-1α and NFR-2 (nuclear factor erythroid 2-related factor 2), possibly to mediate the response to hypoxia and oxidative stress, under these conditions. The BM-MSC sEV from trained animals presented an increased nephroprotective potential compared to untrained vesicles by carrying 296-angiomiR and contributing to angiogenesis in UUO model.


Conserving vedalia beetle, Rodolia cardinalis (Mulsant) (Coleoptera: Coccinellidae), in citrus: a continuing challenge as new insecticides gain registration.
The effects of insecticides used for California citrus pest management were evaluated using larval and adult stages of vedalia beetle, Rodolia cardinalis (Mulsant). This predatory beetle is essential for control of cottony cushion scale Icerya purchasi (Williston) (Homoptera: Margarodidae) in San Joaquin Valley citrus. When adult beetles were exposed to treated citrus leaves, adult survival was significantly reduced by the foliar neonicotinoid imidacloprid and the pyrethroid cyfluthrin. Progeny production was significantly reduced by imidacloprid, cyfluthrin, fenpropathrin, and buprofezin. Buprofezin, pyriproxifen, and foliar imidacloprid also significantly reduced successful development of larvae into the adult stage. When vedalia stages were fed insecticide-treated cottony cushion scale reared on Pittosporum tobira (Thunb.) Ait, toxic effects were more severe than contact toxicity alone. Adult beetle survival was most profoundly reduced by the pyrethroids and to a lesser extent the foliar neonicotinoids acetamiprid and imidacloprid. Progeny production and larval development to adulthood were reduced by all insecticides but were most severely affected by pyriproxifen and the pyrethroids. Systemically applied neonicotinoids were toxic to vedalia larvae feeding on cottony cushion scale that had ingested these insecticides. These data demonstrate that IGRs, neonicotinoid insecticides, and pyrethroid insecticides have a significant, negative impact on vedalia beetles. Depending on the rate of insecticide used, the number and timing of applications, and the level of coverage of the tree, disruption of vedalia can be minimized. However, the situation is made difficult when pests such as citrus thrips Scirtothrips citri (Moulton) (Thysanoptera: Thripidae), forktailed bush katydid Scuddaria furcata Brunner von Wattenwyl (Orthoptera: Tettigoiniidae), or glassy-winged sharpshooter Homalodisca coagulata Say (Homoptera: Cicadellidae) require these pesticide treatments during periods of vedalia beetle activity.


Clustering Through Hybrid Network Architecture With Support Vectors.
In this paper, we propose a clustering algorithm based on a two-phased neural network architecture. We combine the strength of an autoencoderlike network for unsupervised representation learning with the discriminative power of a support vector machine (SVM) network for fine-tuning the initial clusters. The first network is referred as prototype encoding network, where the data reconstruction error is minimized in an unsupervised manner. The second phase, i.e., SVM network, endeavors to maximize the margin between cluster boundaries in a supervised way making use of the first output. Both the networks update the cluster centroids successively by establishing a topology preserving scheme like self-organizing map on the latent space of each network. Cluster fine-tuning is accomplished in a network structure by the alternate usage of the encoding part of both the networks. In the experiments, challenging data sets from two popular repositories with different patterns, dimensionality, and the number of clusters are used. The proposed hybrid architecture achieves comparatively better results both visually and analytically than the previous neural network-based approaches available in the literature.


Use of the child health questionnaire in a sample of moderate and low-income inner-city children with asthma.
The Child Health Questionnaire (CHQ-PF50) is one of several recent efforts to gauge pediatric, health-related quality of life from the patient's (or parent's) perspective. Although tested extensively with healthy children, more information is needed about CHQ performance among children with chronic conditions such as asthma. The current study extends previous work by examining the CHQ's psychometric performance in a sample of children with asthma, overrepresenting those at high risk for poor outcomes. Seventy-four adult caregivers of children with asthma completed the CHQ. Internal consistency reliability was consistently high for all but one scale. Intraclass correlation coefficients ranged from a low of 0.37 to a high of 0.84. Tests of validity found CHQ scales better at distinguishing levels of disease severity as defined by symptom activity than medication use or pulmonary function tests. Performance of the CHQ-PF50 in a sample of low-income to moderate income inner-city parents of children with asthma presented mixed results. The instrument addresses a broad range of concepts but some scales may be more salient than others in assessing health status of children at highest risk for asthma morbidity. Future efforts must compare condition-specific and generic instruments to evaluate their relative strengths and weakness, as well as potential links between them.


A glimpse into the fungal metabolomic abyss: Novel network analysis reveals relationships between exogenous compounds and their outputs.
Fungal specialized metabolites are a major source of beneficial compounds that are routinely isolated, characterized, and manufactured as pharmaceuticals, agrochemical agents, and industrial chemicals. The production of these metabolites is encoded by biosynthetic gene clusters that are often silent under standard growth conditions. There are limited resources for characterizing the direct link between abiotic stimuli and metabolite production. Herein, we introduce a network analysis-based, data-driven algorithm comprising two routes to characterize the production of specialized fungal metabolites triggered by different exogenous compounds: the direct route and the auxiliary route. Both routes elucidate the influence of treatments on the production of specialized metabolites from experimental data. The direct route determines known and putative metabolites induced by treatments and provides additional insight over traditional comparison methods. The auxiliary route is specific for discovering unknown analytes, and further identification can be curated through online bioinformatic resources. We validated our algorithm by applying chitooligosaccharides and lipids at two different temperatures to the fungal pathogen Aspergillus fumigatus. After liquid chromatography-mass spectrometry quantification of significantly produced analytes, we used network centrality measures to rank the treatments' ability to elucidate these analytes and confirmed their identity through fragmentation patterns or in silico spiking with commercially available standards. Later, we examined the transcriptional regulation of these metabolites through real-time quantitative polymerase chain reaction. Our data-driven techniques can complement existing metabolomic network analysis by providing an approach to track the influence of any exogenous stimuli on metabolite production. Our experimental-based algorithm can overcome the bottlenecks in elucidating novel fungal compounds used in drug discovery.


MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10.
Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-β1 (TGF-β1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.


Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system.
Hypothalamic neurons containing orexin (hypocretin) are activated during motivated behaviors and active waking. We show that injection of orexin-A into the ventromedial hypothalamus (VMH) of mice or rats increased glucose uptake and promoted insulin-induced glucose uptake and glycogen synthesis in skeletal muscle, but not in white adipose tissue, by activating the sympathetic nervous system. These effects of orexin were blunted in mice lacking beta-adrenergic receptors but were restored by forced expression of the beta(2)-adrenergic receptor in both myocytes and nonmyocyte cells of skeletal muscle. Orexin neurons are activated by conditioned sweet tasting and directly excite VMH neurons, thereby increasing muscle glucose metabolism and its insulin sensitivity. Orexin and its receptor in VMH thus play a key role in the regulation of muscle glucose metabolism associated with highly motivated behavior by activating muscle sympathetic nerves and beta(2)-adrenergic signaling.


Species-specific Differences among KCNMB3 BK beta3 auxiliary subunits: some beta3 N-terminal variants may be primate-specific subunits.
The KCNMB3 gene encodes one of a family of four auxiliary beta subunits found in the mammalian genome that associate with Slo1 alpha subunits and regulate BK channel function. In humans, the KCNMB3 gene contains four N-terminal alternative exons that produce four functionally distinct beta3 subunits, beta3a-d. Three variants, beta3a-c, exhibit kinetically distinct inactivation behaviors. Since investigation of the physiological roles of BK auxiliary subunits will depend on studies in rodents, here we have determined the identity and functional properties of mouse beta3 variants. Whereas beta1, beta2, and beta4 subunits exhibit 83.2%, 95.3%, and 93.8% identity between mouse and human, the mouse beta3 subunit, excluding N-terminal splice variants, shares only 62.8% amino acid identity with its human counterpart. Based on an examination of the mouse genome and screening of mouse cDNA libraries, here we have identified only two N-terminal candidates, beta3a and beta3b, of the four found in humans. Both human and mouse beta3a subunits produce a characteristic use-dependent inactivation. Surprisingly, whereas the hbeta3b exhibits rapid inactivation, the putative mbeta3b does not inactivate. Furthermore, unlike hbeta3, the mbeta3 subunit, irrespective of the N terminus, mediates a shift in gating to more negative potentials at a given Ca(2+) concentration. The shift in gating gradually is lost following patch excision, suggesting that the gating shift involves some regulatory process dependent on the cytosolic milieu. Examination of additional genomes to assess conservation among splice variants suggests that the putative mbeta3b N terminus may not be a true orthologue of the hbeta3b N terminus and that both beta3c and beta3d appear likely to be primate-specific N-terminal variants. These results have three key implications: first, functional properties of homologous beta3 subunits may differ among mammalian species; second, the specific physiological roles of homologous beta3 subunits may differ among mammalian species; and, third, some beta3 variants may be primate-specific ion channel subunits.


Rapid and label-free isolation of small extracellular vesicles from biofluids utilizing a novel insulator based dielectrophoretic device.
Exosomes are nano-scale membrane-encapsulated vesicles produced by the majority of cells and have emerged as a rich source of biomarkers for a wide variety of diseases. Although many approaches have been developed for exosome isolation from biofluids, most of them have substantial shortcomings including long processing time, inefficiency, high cost, lack of specificity and/or surface marker-dependency. To address these issues, here we report a novel insulator-based dielectrophoretic (iDEP) device predicated on an array of borosilicate micropipettes to rapidly isolate exosomes from conditioned cell culture media and biofluids, such as plasma, serum, and saliva. The device is capable of exosome isolation from small sample volumes of 200 μL within 20 minutes under a relatively low (10 V cm-1) direct current (DC). This device is easy to fabricate thus, no cleanroom facility and expensive equipment are needed. Therefore, the iDEP device offers a rapid and cost-effective strategy for exosome isolation from biofluids in timely manner while maintaining the yield and purity.


Internet-delivered treatment for young adults with anxiety and depression: Evaluation in routine clinical care and comparison with research trial outcomes.
Mood and anxiety disorders typically emerge in adolescence and early adult life, but young adults are often reluctant to seek treatment. The Mood Mechanic course is a transdiagnostic internet-delivered psychological intervention for symptoms of depression and anxiety, targeted at people aged 18-24 years. The current study compared the efficacy of the course when delivered under strict research trial conditions (research trial; n = 192) with its effectiveness in a routine health-care setting (routine care; n = 222). Symptoms of depression, anxiety and general distress at baseline, during, and after treatment were measured by the Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7), and Kessler 10-Item Scale (K-10), respectively. Both groups showed significant symptom reductions on all measures at post-treatment and 3-month follow-up. Deterioration rates were low, within-group effect sizes were large (>1.0) and both groups reported high levels of treatment satisfaction. Patients in routine care were less likely to complete post-treatment or follow-up symptom questionnaires. The study is based on self-reported data from treatment-seeking individuals that were motivated enough to start the course, and the absence of a control group and a formal diagnosis in the routine care sample means that some caution is needed in generalising the results. The results show that the Mood Mechanic course is effective and acceptable in routine clinical care, and that online psychological interventions designed for young adults are an effective treatment option for this hard-to-reach group.


Can a Left Ventricular Assist Device in Individuals with Advanced Systolic Heart Failure Improve or Reverse Frailty?
Frailty, characterized by low physiological reserves, is strongly associated with vulnerability to adverse outcomes. Features of frailty overlap with those of advanced heart failure, making a distinction between them difficult. We sought to determine whether implantation of a left ventricular assist device (LVAD) would decrease frailty. Prospective, cohort study. Five academic medical centers. Frail individuals (N = 29; mean age 70.6 ± 5.5, 72.4% male). Frailty, defined as having 3 or more of the Fried frailty criteria, was assessed before LVAD implantation and 1, 3, and 6 months after implantation. Other domains assessed included quality of life, using the Kansas City Cardiomyopathy Questionnaire; mood, using the Patient Health Questionnaire; and cognitive function, using the Trail-Making Test Part B. After 6 months, three subjects had died, and one had undergone a heart transplant; of 19 subjects with serial frailty measures, the average number of frailty criteria decreased from 3.9 ± 0.9 at baseline to 2.8 ± 1.4 at 6 months (P = .003). Improvements were observed after 3 to 6 months of LVAD support, although 10 (52.6%) participants still had 3 or more Fried criteria, and all subjects had at least one at 6 months. Changes in frailty were associated with improvement in QOL but not with changes in mood or cognition. Higher estimated glomerular filtration rate at baseline was independently associated with a decrease in frailty. Frailty decreased in approximately half of older adults with advanced heart failure after 6 months of LVAD support. Strategies to enhance frailty reversal in this population are worthy of additional study.


Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for κ and λ expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.


Multifaceted approach to a rare clinical case of calciphylaxis in a renal transplant recipient.
Calcific uremic arteriolopathy (CUA) is a highly morbid condition usually found in ESRD patients that has rarely been reported after renal transplantation and renal function restoration. Furthermore, little is known about the optimal management of CUA in this setting. Herein, we report on the clinical case of AB, a 70-year-old woman who developed CUA after renal transplantation and renal function restoration. However, other risk factors for CUA such as diabetes and warfarin treatment, due to mechanical aortic valve implantation, were present. Thirty-eight months after renal transplantation she developed erythema and livedo reticularis in both legs and a gradually enlarging skin ulcer in the right leg. A skin biopsy of the ulcer showed features compatible with the CUA, such as sub-intimal calcification and luminal obstruction of the small dermal arterioles, tissue ischemia and signs of adipocytes degeneration. A multidisciplinary approach was adopted, including medical and non-medical treatments such as surgical debridement and vacuum-assisted closure therapy. Medical treatments included a five weeks course of once a week intravenous infusion of pamidronate and intravenous sodium thiosulfate (STS) at increasing doses. Four months after beginning the therapy with STS, a complete healing of the ulcer on the right leg and the disappearance of the livedo reticularis on the left leg was noted. In conclusion, although rare CUA may develop also in renal transplanted patients, a timely and combined therapeutic approach is essential for its resolutive treatment. Sodium thiosulfate therapy has proven to be effective and tolerated.


Computers in ophthalmology practice.
Computers are already in widespread use in medical practice throughout the world and their utility and popularity is increasing day by day. While future generations of medical professionals will be computer literate with a corresponding increase in use of computers in medical practice, the current generation finds itself in a dilemma of how best to adapt to the fast-evolving world of information technology. In addition to practice management, information technology has already had a substantial impact on diagnostic medicine, especially in imaging techniques and maintenance of medical records. This information technology is now poised to make a big impact on the way we deliver medical care in India. Ophthalmology is no exception to this, but at present very few practices are either fully or partially computerized. This article provides a practical account of the uses and advantages of computers in ophthalmic practice, as well as a step-by-step approach to the optimal utilization of available computer technology.


Machine learning in cardiovascular magnetic resonance: basic concepts and applications.
Machine learning (ML) is making a dramatic impact on cardiovascular magnetic resonance (CMR) in many ways. This review seeks to highlight the major areas in CMR where ML, and deep learning in particular, can assist clinicians and engineers in improving imaging efficiency, quality, image analysis and interpretation, as well as patient evaluation. We discuss recent developments in the field of ML relevant to CMR in the areas of image acquisition & reconstruction, image analysis, diagnostic evaluation and derivation of prognostic information. To date, the main impact of ML in CMR has been to significantly reduce the time required for image segmentation and analysis. Accurate and reproducible fully automated quantification of left and right ventricular mass and volume is now available in commercial products. Active research areas include reduction of image acquisition and reconstruction time, improving spatial and temporal resolution, and analysis of perfusion and myocardial mapping. Although large cohort studies are providing valuable data sets for ML training, care must be taken in extending applications to specific patient groups. Since ML algorithms can fail in unpredictable ways, it is important to mitigate this by open source publication of computational processes and datasets. Furthermore, controlled trials are needed to evaluate methods across multiple centers and patient groups.


Fabrication of Implantable Microelectrode Array using Cyclic Olefin Copolymer and SU-8 via Photocrosslinking Lamination.
In this work, a fabrication process for implantable electrodes using a Cyclic Olefin Copolymer (COC) substrate and a SU-8 passivation layer was presented. COC and SU-8 were shown to be suitable for implantable neural electrodes due to their biocompatibility, chemical resistance, and thermal stability. The electrodes were successfully patterned on the COC film, and the SU-8 passivation layer was coated while maintaining site-opened via photolithography. The photocrosslinking lamination of the substrate and passivation layer was used to produce electrodes with fine line widths of 20um without applying heat.


The validation of new phase-dependent gait stability measures: a modelling approach.
Identification of individuals at risk of falling is important when designing fall prevention methods. Current measures that estimate gait stability and robustness appear limited in predicting falls in older adults. Inspired by recent findings on changes in phase-dependent local stability within a gait cycle, we devised several phase-dependent stability measures and tested for their usefulness to predict gait robustness in compass walker models. These measures are closely related to the often-employed maximum finite-time Lyapunov exponent and maximum Floquet multiplier that both assess a system's response to infinitesimal perturbations. As such, they entail linearizing the system, but this is realized in a rotating hypersurface orthogonal to the period-one solution followed by estimating the trajectory-normal divergence rate of the swing phases and the foot strikes. We correlated the measures with gait robustness, i.e. the largest perturbation a walker can handle, in two compass walker models with either point or circular feet to estimate their prediction accuracy. To also test for the dependence of the measures under state space transform, we represented the point feet walker in both Euler-Lagrange and Hamiltonian canonical form. Our simulations revealed that for most of the measures their correlation with gait robustness differs between models and between different state space forms. In particular, the latter may jeopardize many stability measures' predictive capacity for gait robustness. The only exception that consistently displayed strong correlations is the divergence of foot strike. Our results admit challenges of using phase-dependent stability measures as objective means to estimate the risk of falling.


Perceived social support and depression among Veterans with multiple sclerosis.
To examine the association between perceived social support and self-reported depression among Veterans of the US Armed Forces ('Veterans') with multiple sclerosis (MS), and differences in this relationship between specific support subtypes (tangible, positive social interaction, emotional/informational and affective). Participants were Veterans with MS (N = 451) receiving medical services through the Veterans Health Administration who completed mailed surveys. Hierarchical regression examined the extent to which global perceived social support concurrently predicted depression among a predominantly male sample of individuals with MS. Exploratory correlational analyses examined the relationship between specific subtypes of perceived social support and depression. Greater global perceived social support was associated with less depression after controlling for sociodemographic and disease-related variables. In follow-up analyses examining specific subtypes of support, greater positive social interaction, greater emotional/informational support, and greater affective support were related to less depression. There was no relationship between perceived tangible support and depression. Interventions aimed at increasing positive social interactions, expressed affection and emotional/information support may be particularly helpful for individuals with MS and their caregivers.


Rheumatological Assessment Is Important for Interstitial Lung Disease Diagnosis.
Interstitial lung diseases (ILD) form a diverse group of parenchymal lung disorders. Currently, a multidisciplinary team (MDT) including pulmonologists, radiologists, and pathologists is the gold standard for ILD diagnosis. Recently, additional subtypes of connective tissue disease (CTD)-ILD with autoimmune features were defined, making the rheumatological assessment increasingly important. We aimed to assess the effect of adding a rheumatologist to the MDT for routine rheumatology assessment. A prospective study that assessed newly diagnosed ILD patients by 2 parallel blinded arms; all patients were evaluated by both MDT (e.g., history, physical examination, blood tests, pulmonary function tests, and biopsies, if needed) and a rheumatologist (e.g., history, physical examination, blood and serological tests). Sixty patients were assessed with the mean age of 67.3 ± 12 years, 55% male, and 28% smokers. The rheumatological assessment reclassified 21% of the idiopathic pulmonary fibrosis as CTD. Moreover, the number of CTD-ILD with autoimmune features was increased by 77%. These included antineutrophil cytoplasmic antibody-associated vasculitis, antisynthetase syndrome, and IgG4-related ILD. Retrospectively, rheumatological evaluation could have saved 7 bronchoscopies and 1 surgical biopsy. Adding routine rheumatology assessments could significantly increase diagnostic accuracy and reduce invasive procedures.


Assessing agreement of repeated binary measurements with an application to the CDC's anthrax vaccine clinical trial.
Cohen's kappa coefficient, which was introduced in 1960, serves as the most widely employed coefficient to assess inter-observer agreement for categorical outcomes. However, the original kappa can only be applied to cross-sectional binary measurements and, therefore, cannot be applied in the practical situation when the observers evaluate the same subjects at repeated time intervals. This study summarizes six methods of assessing agreement of repeated binary outcomes under different assumptions and discusses under which condition we should use the most appropriate method in practice. These approaches are illustrated using data from the CDC anthrax vaccine adsorbed (AVA) human clinical trial comparing the agreement for two solicited adverse events after AVA between the 1-3 day in-clinic medical record and the patient's diary on the same day. We hope this article can inspire researchers to choose the most appropriate method to assess agreement for their own study with longitudinal binary data.


Antibacterial Characterization of Novel Synthetic Thiazole Compounds against Methicillin-Resistant Staphylococcus pseudintermedius.
Staphylococcus pseudintermedius is a commensal organism of companion animals that is a significant source of opportunistic infections in dogs. With the emergence of clinical isolates of S. pseudintermedius (chiefly methicillin-resistant S. pseudintermedius (MRSP)) exhibiting increased resistance to nearly all antibiotic classes, new antimicrobials and therapeutic strategies are urgently needed. Thiazole compounds have been previously shown to possess potent antibacterial activity against multidrug-resistant strains of Staphylococcus aureus of human and animal concern. Given the genetic similarity between S. aureus and S. pseudintermedius, this study explores the potential use of thiazole compounds as novel antibacterial agents against methicillin-sensitive S. pseudintermedius (MSSP) and MRSP. A broth microdilution assay confirmed these compounds exhibit potent bactericidal activity (at sub-microgram/mL concentrations) against both MSSA and MRSP clinical isolates while the MTS assay confirmed three compounds (at 10 μg/mL) were not toxic to mammalian cells. A time-kill assay revealed two derivatives rapidly kill MRSP within two hours. However, this rapid bactericidal activity was not due to disruption of the bacterial cell membrane indicating an alternative mechanism of action for these compounds against MRSP. A multi-step resistance selection analysis revealed compounds 4 and 5 exhibited a modest (two-fold) shift in activity over ten passages. Furthermore, all six compounds (at a subinihibitory concentration) demonstrated the ability to re-sensitize MRSP to oxacillin, indicating these compounds have potential use for extending the therapeutic utility of β-lactam antibiotics against MRSP. Metabolic stability analysis with dog liver microsomes revealed compound 3 exhibited an improved physicochemical profile compared to the lead compound. In addition to this, all six thiazole compounds possessed a long post-antibiotic effect (at least 8 hours) against MRSP. Collectively the present study demonstrates these synthetic thiazole compounds possess potent antibacterial activity against both MSSP and MRSP and warrant further investigation into their use as novel antimicrobial agents.


Efficient Estimation of Children's Language Exposure in Two Bilingual Communities.
Purpose The language that children hear early in life is associated with their speech-language outcomes. This line of research relies on naturalistic observations of children's language input, often captured with daylong audio recordings. However, the large quantity of data that daylong recordings generate requires novel analytical tools to feasibly parse thousands of hours of naturalistic speech. This study outlines a new approach to efficiently process and sample from daylong audio recordings made in two bilingual communities, Spanish-English in the United States and Quechua-Spanish in Bolivia, to derive estimates of children's language exposure. Method We employed a general sampling with replacement technique to efficiently estimate two key elements of children's early language environments: (a) proportion of child-directed speech (CDS) and (b) dual language exposure. Proportions estimated from random sampling of 30-s segments were compared to those from annotations over the entire daylong recording (every other segment), as well as parental report of dual language exposure. Results Results showed that approximately 49 min from each recording or just 7% of the overall recording was required to reach a stable proportion of CDS and bilingual exposure. In both speech communities, strong correlations were found between bilingual language estimates made using random sampling and all-day annotation techniques. A strong association was additionally found for CDS estimates in the United States, but this was weaker at the Bolivian site, where CDS was less frequent. Dual language estimates from the audio recordings did not correspond well to estimates derived from parental report collected months apart. Conclusions Daylong recordings offer tremendous insight into children's daily language experiences, but they will not become widely used in developmental research until data processing and annotation time substantially decrease. We show that annotation based on random sampling is a promising approach to efficiently estimate ambient characteristics from daylong recordings that cannot currently be estimated via automated methods.


Catalytic formal cycloadditions between anhydrides and ketones: excellent enantio and diastereocontrol, controllable decarboxylation and the formation of adjacent quaternary stereocentres.
It has been shown for the first time that enolisable anhydrides can participate in highly efficient and diastereo/enantioselective additions to activated ketones. In these reactions the anhydride component formally acts (initially) as the nucleophilic component. These processes are promoted by novel, readily prepared urea-substituted cinchona alkaloid-derived catalysts at low loadings under mild conditions. Three classes of enolisable anhydride and three different types of activated ketone were shown to be compatible with the process - generating a diverse range of structurally distinct and densely functionalised lactone products with the formation of two new stereocentres, one of which is quaternary. In one example, a product incorporating two contiguous quaternary stereocentres (one all carbon) was formed with outstanding enantiocontrol. It has been shown in the case of glutaconic anhydride derivatives that the cycloaddtion process is reversible, and can be accompanied by decarboxylation and olefin isomerisation. Reaction conditions can be modified to give access to three types of product with good-excellent ee.


Metagrating absorber: design and implementation.
The extent to which the introduction of subwavelength spatial modulation of electromagnetic properties improves absorption performances is studied. The proposed absorber represents an evolution from the Salisbury screen, whereby the uniform resistive layer is replaced by a metagrating. A periodic supercell that supports only the specular reflection is first designed, and load impedances are then engineered to suppress this diffraction mode. To experimentally demonstrate the concept, four prototypes are fabricated and tested in the microwave domain around 10 GHz. Furthermore, the performances assessed by a merit factor derived from Rozanov's bound show that the use of metagratings opens up good perspectives for improving the state of the art. Our findings can pave the way toward the development of high performance absorbers for applications across a broad frequency spectrum.


In yeast, the 3' untranslated region or the presequence of ATM1 is required for the exclusive localization of its mRNA to the vicinity of mitochondria.
We isolated mitochondria from Saccharomyces cerevisiae to selectively study polysomes bound to the mitochondrial surface. The distribution of several mRNAs coding for mitochondrial proteins was examined in free and mitochondrion-bound polysomes. Some mRNAs exclusively localize to mitochondrion-bound polysomes, such as the ones coding for Atm1p, Cox10p, Tim44p, Atp2p, and Cot1p. In contrast, mRNAs encoding Cox6p, Cox5a, Aac1p, and Mir1p are found enriched in free cytoplasmic polysome fractions. Aac1p and Mir1p are transporters that lack cleavable presequences. Sequences required for mRNA asymmetric subcellular distribution were determined by analyzing the localization of reporter mRNAs containing the presequence coding region and/or the 3'-untranslated region (3'UTR) of ATM1, a gene encoding an ABC transporter of the mitochondrial inner membrane. Biochemical analyses of mitochondrion-bound polysomes and direct visualization of RNA localization in living yeast cells allowed us to demonstrate that either the presequence coding region or the 3'UTR of ATM1 is sufficient to allow the reporter mRNA to localize to the vicinity of the mitochondrion, independently of its translation. These data demonstrate that mRNA localization is one of the mechanisms used, in yeast, for segregating mitochondrial proteins.


EEG Changes in Time and Time-Frequency Domain During Movement Preparation and Execution in Stroke Patients.
This study investigated electroencephalogram (EEG) changes during movement preparation and execution in stroke patients. EEG-based event-related potential (ERP) technology was used to measure brain activity changes. Seventeen stroke patients participated in this study and completed ERP tests that were designed to measure EEG changes during unilateral upper limb movements in preparation and execution stages, with Instruction Response Movement (IRM) and Cued Instruction Response Movement (CIRM) paradigms. EEG data were analyzed using motor potential (MP) in the time domain and the mu-rhythm and beta frequency band response mean value (R-means) in the time-frequency domain. In IRM, the MP amplitude at Cz was higher during hemiplegic arm movement than during unaffected arm movement. MP latency was shorter at Cz and the contralesional motor cortex during hemiplegic arm movement in CIRM compared to IRM. No significant differences were found in R-means among locations, between movement sides in both ERP tests. This study presents the brain activity changes in the time and time-frequency domains in stroke patients during movement preparation and execution and supports the contralesional compensation and adjacent-region compensation mechanism of post-stroke brain reconstruction. These findings may contribute to future rehabilitation research about neuroplasticity and technology development such as the brain-computer interface.


Defect in signal transduction at the level of the plasma membrane accounts for inability of insulin to activate pyruvate dehydrogenase in white adipocytes of lactating rats.
1. The mechanism responsible for the failure of insulin to activate pyruvate dehydrogenase (PDH) in white adipose tissue in vivo during lactation was investigated. 2. Insulin failed to increase PDH in isolated adipocytes from lactating rats. 3. Insulin binding to plasma membranes from adipocytes was unchanged by lactation. 4. Incubation of plasma membranes plus permeabilized mitochondria from adipocytes in the presence of insulin resulted in activation of PDH when the plasma membranes were obtained from virgin rats, whereas no activation was observed when plasma membranes from lactating rats were used. 5. The results show that the failure of insulin to activate PDH in adipose tissue from lactating rats is due to a failure of the signal-transduction system in the plasma membrane at steps subsequent to insulin binding to the insulin receptor.


Proposed definitions for the audit of postoperative infection: a discussion paper. Surgical Infection Study Group.
Infection is an important arbiter of success or failure of surgical practice and the incidence of infection is incorporated into all surgical audit systems. If audit is to be of value the outcome end points of clinical practice must be defined. We have attempted to derive clinical definitions suitable for bedside diagnosis of infection and believe that these should bs supported by, but not be dependent upon, the results of laboratory or imaging techniques. The proposed definitions are intended to form the basis for clinical audit and to allow meaningful comparisons to be made on clear clinical criteria.


Investigators' successful strategies for working with Institutional Review Boards.
This study was designed to identify successful strategies used by investigators for working with their Institutional Review Boards (IRBs) in conducting human subjects research. Telephone interviews were conducted with 46 investigators representing nursing, medicine, and social work. Interview transcripts were analyzed using qualitative descriptive methods. Investigators emphasized the importance of intentionally cultivating positive relationships with IRB staff and members, and managing bureaucracy. A few used evasive measures to avoid conflict with IRBs. Few successful strategies were identified for working with multiple IRBs. Although most investigators developed successful methods for working with IRBs, further research is needed on how differences in IRB culture affect human subjects protection, and on best approaches for obtaining IRB approval of multi-site studies.


A Study on the Correlations between Musculoskeletal Disorders and Work-Related Psychosocial Factors among Nursing Aides in Long-Term Care Facilities.
Among the nursing aides employed at long-term care facilities (LTCFs), those with musculoskeletal disorders (MSDs) are most likely to experience disability or develop an intention to leave. The purpose of this study was to investigate the association of work-related psychological factors among nursing aides in LTCFs with MSDs in Taiwan. Purposive sampling was used in this cross-sectional study to enrol 308 nursing aides from residential LTCFs in Taiwan as research subjects. A demographic and job background survey, a job content questionnaire (JCQ), and the Nordic musculoskeletal questionnaire (NMQ) were used to collect data. Lower job control associated with higher psychological job demands, and lower social support was associated with more severe MSDs for the nursing aides (p < 0.001). Among the MSDs reported by nursing aides in LTCFs, lower back pain was the most serious. In addition, nationality, age, exercise habits, chronic diseases, worksite, lack of rest time, lack of assistive devices, low coworker support, and high psychological job demands were significant factors affecting MSDs. In total, 42.1% of the variance in MSDs among nursing aides in LTCFs was explained. Work-related psychological factors among nursing aides in LTCFs have an important association with MSDs. For nursing aides, coworker support should be improved, and their psychological demands at work should be reduced.


Supplementation with hydrocortisone on the 3rd-5th day following dexamethasone premedicated chemotherapy eliminated severe dizziness and postural hypotension.
We present the case of a 60 year-old woman with a stage III fallopian tube cancer submitted to hysterectomy and bilateral salpingo-oophorectomy with partial omenectomy, followed by six courses of chemotherapy and revision surgery. After each course of chemotherapy (paclitaxel + carboplatin) preceded by premedication with dexamethasone, she suffered from side- -effects, of which the most unpleasant was severe dizziness appearing on the third, fourth and fifth day following the listed combination of drugs. It was revealed that dizziness with concomitant sweating and rapid pulse, noted in the standing position, was combined with marked postural hypotension. Considering the possibility of a temporary pituitary-adrenal axis suppression caused by premedication with a very large dose of dexamethasone, during those three days she was supplemented with small doses of hydrocortisone, which caused almost complete disappearance of the mentioned symptoms. Our conclusion is that postural hypotension causing severe dizziness initially linked with chemotherapeutic drugs can be eliminated or markedly reduced by three days supplementation with hydrocortisone applied after the expected wash out of the dexamethasone.


Adverse outcomes of frailty in the elderly: the Rotterdam Study.
To investigate the prevalence of frailty in a Dutch elderly population and to identify adverse health outcomes associated with the frailty phenotype independent of the comorbidities. Cross-sectional and longitudinal analyses within the Rotterdam Study (the Netherlands), a prospective population-based cohort study in persons aged ≥55 years. Frailty was defined as meeting three or more of five established criteria for frailty, evaluating nutritional status, physical activity, mobility, grip strength and exhaustion. Intermediate frailty was defined as meeting one or two frailty criteria. Comorbidities were objectively measured. Health outcomes were assessed by means of questionnaires, physical examinations and continuous follow-up through general practitioners and municipal health authorities for mortality. Of 2,833 participants (median age 74.0 years, inter quartile range 9) with sufficiently evaluated frailty criteria, 163 (5.8 %) participants were frail and 1,454 (51.3 %) intermediate frail. Frail elderly were more likely to be older and female, to have an impaired quality of life and to have fallen or to have been hospitalized. 108 (72.0 %) frail participants had ≥2 comorbidities, compared to 777 (54.4 %) intermediate frail and 522 (44.8 %) non-frail participants. Adjusted for age, sex and comorbidities, frail elderly had a significantly increased risk of dying within 3 years (HR 3.4; 95 % CI 1.9-6.4), compared to the non-frail elderly. This study in a general Dutch population of community-dwelling elderly able to perform the frailty tests, demonstrates that frailty is common and that frail elderly are at increased risk of death independent of comorbidities.


From fetus to adult--an allometric analysis of the giraffe vertebral column.
As mammalian cervical vertebral count is almost always limited to seven, the vertebral column of the giraffe (Giraffa camelopardalis) provides an interesting study on scaling and adaptation to shape in light of these constraints. We have defined and described the growth rates of the lengths, widths, and heights of the vertebrae from fetal through neonatal life to maturity. We found that the disproportionate elongation of the cervical vertebrae is not a fetal process but occurs after birth, and that each cervical (C2-C7) vertebrae elongates at the same rate. C7 is able to specialize toward elongation as its function has been shifted to T1. We concluded that T1 is a transitional vertebra whose scaling exponent and length is between that of the cervical and thoracic series. Despite its transitional nature, T1 is still regarded as thoracic, as it possesses an articulating rib that attaches to the sternum. The other dimensions taken (width, height, and spinous process length) show that giraffe vertebral morphology exhibit adaptations to biomechanical strain, and we have underlined the importance of the thoracic spinous processes in supporting the head and neck.


Factors Associated with Leukoaraiosis Severity in Acute Stroke Patients.
Age-related cerebral white matter abnormalities, commonly termed leukoaraiosis (LA), are frequent manifestation of cerebral microvascular disease. Aging and hypertension are well linked to LA. We compared additional vascular risk factors and socioeconomic factors with LA severity in acute stroke patients. We analyzed 271 patients with acute ischemic or hemorrhagic stroke from a hospital registry. We collected clinical and socioeconomic data prospectively with a standardized questionnaire during acute stroke hospitalization. We scored LA severity on all available head computed tomography and magnetic resonance imaging (MRI) scans with the Wahlund LA scale. Mean response modeling analyzed for associations between LA severity and multiple potential predictors. Among 238 patients with CT LA scores, ageing and history of hypertension emerged as independent predictors of LA severity in multivariable analysis. Among 186 patients with MRI LA scores, ageing and severe left ventricular hypertrophy emerged as independent predictors of LA severity in multivariable analysis. We did not find an independent significant association between LA severity and the other factors we tested. Our study confirms the association of LA severity with ageing, and with hypertension. However, other vascular and socioeconomic factors we tested were not independently associated with LA severity.


Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma.
Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of adults and adolescents with asthma. We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted authors of identified RCTs for other relevant published and unpublished studies and pharmaceutical manufacturers. Most recent search: November 2006. All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. In original review, two reviewers independently assessed trial quality and extracted data, similarly in this update two reviewers undertook this. Study authors were contacted for additional information. Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV(1) predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.


An integrated methodology for assessing the impact of food matrix and gastrointestinal effects on the biokinetics and cellular toxicity of ingested engineered nanomaterials.
Engineered nanomaterials (ENMs) are increasingly added to foods to improve their quality, sensory appeal, safety and shelf-life. Human exposure to these ingested ENMs (iENMS) is inevitable, yet little is known of their hazards. To assess potential hazards, efficient in vitro methodologies are needed to evaluate particle biokinetics and toxicity. These methodologies must account for interactions and transformations of iENMs in foods (food matrix effect) and in the gastrointestinal tract (GIT) that are likely to determine nano-biointeractions. Here we report the development and application of an integrated methodology consisting of three interconnected stages: 1) assessment of iENM-food interactions (food matrix effect) using model foods; 2) assessment of gastrointestinal transformations of the nano-enabled model foods using a three-stage GIT simulator; 3) assessment of iENMs biokinetics and cellular toxicity after exposure to simulated GIT conditions using a triculture cell model. As a case study, a model food (corn oil-in-water emulsion) was infused with Fe2O3 (Iron(III) oxide or ferric oxide) ENMs and processed using this three-stage integrated platform to study the impact of food matrix and GIT effects on nanoparticle biokinetics and cytotoxicity . A corn oil in phosphate buffer emulsion was prepared using a high speed blender and high pressure homogenizer. Iron oxide ENM was dispersed in water by sonication and combined with the food model. The resulting nano-enabled food was passed through a three stage (mouth, stomach and small intestine) GIT simulator. Size distributions of nano-enabled food model and digestae at each stage were analyzed by DLS and laser diffraction. TEM and confocal imaging were used to assess morphology of digestae at each phase. Dissolution of Fe2O3 ENM along the GIT was assessed by ICP-MS analysis of supernatants and pellets following centrifugation of digestae. An in vitro transwell triculture epithelial model was used to assess biokinetics and toxicity of ingested Fe2O3 ENM. Translocation of Fe2O3 ENM was determined by ICP-MS analysis of cell lysates and basolateral compartment fluid over time. It was demonstrated that the interactions of iENMs with food and GIT components influenced nanoparticle fate and transport, biokinetics and toxicological profile. Large differences in particle size, charge, and morphology were observed in the model food with and without Fe2O3 and among digestae from different stages of the simulated GIT (mouth, stomach, and small intestine). Immunoflorescence and TEM imaging of the cell culture model revealed markers and morphology of small intestinal epithelium including enterocytes, goblet cells and M cells. Fe2O3 was not toxic at concentrations tested in the digesta. In biokinetics studies, translocation of Fe2O3 after 4 h was <1% and ~2% for digesta with and without serum, respectively, suggesting that use of serum proteins alters iENMs biokinetics and raises concerns about commonly-used approaches that neglect iENM - food-GIT interactions or dilute digestae in serum-containing media. We present a simple integrated methodology for studying the biokinetics and toxicology of iENMs, which takes into consideration nanoparticle-food-GIT interactions. The importance of food matrix and GIT effects on biointeractions was demonstrated, as well as the incorporation of these critical factors into a cellular toxicity screening model. Standardized food models still need to be developed and used to assess the effect of the food matrix effects on the fate and bioactivity of iENMs since commercial foods vary considerably in their compositions and structures.


JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia.
An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph(+)CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.


Accuracy of MR findings in characterizing peroneal tendons disorders in comparison with surgery.
Previous studies have shown that magnetic resonance imaging (MRI) has a high sensitivity for peroneal tendon pathology but more studies with surgery as a reference standard are needed. To evaluate the accuracy of MRI compared to surgery for characterizing chronic peroneal tendon pathology. Ninety-seven patients (57 men, 40 women; mean age, 39 years; range, 15-64 years) with chronic lateral ankle instability underwent MRI followed by surgery, with a mean MR to surgery interval of 30 days. Sagittal, coronal, and axial T1-weighted spin-echo and fat-suppressed T2-weighted fast spin-echo images were obtained for all patients. Two blinded observers evaluated the MR images without clinical information, and the results were compared to surgical findings. The following peroneal injuries were observed: tendon split, interstitial tear, swelling of the tendon, fluid collection, superior peroneal retinaculum injury, and tendon dislocation. Swelling of the peroneus longus tendon was the most common finding on MR imaging, followed by fluid collection and a split of the peroneus brevis tendon. Surgical findings showed that nine cases (9%) of interstitial tears were in the peroneus brevis and two cases (2%) were in the peroneus longus, with eight cases (8%) of splits in the peroneus brevis tendon. The sensitivity and specificity for detecting interstitial tears in the peroneus brevis were 44% and 99%, respectively. The sensitivity and specificity for detecting swelling in the peroneus brevis were 50% and 99%, respectively. The sensitivity and specificity for detecting interstitial tears for peroneus longus injuries were 50% and 96%, respectively. The sensitivity and specificity for detecting swelling in these injuries were and 100% and 96%, respectively. MRI findings of chronic peroneal tendon pathology are diagnostically specific but not sensitive. MRI showed high sensitivity for diagnosing tendon swelling in the peroneus longus, but not in the peroneus brevis. MRI is sensitive but not specific for detecting negative findings.


Prosocial behavior and psychopathology: An 11-year longitudinal study of inter- and intraindividual reciprocal relations across childhood and adolescence.
The current study investigated whether prosocial behavior and emotional problems, peer problems, conduct problems, and hyperactivity and inattention problems were long-term longitudinally and bidirectionally related at inter- and or intra-individual levels from early childhood through mid-adolescence. Parents in the United Kingdom reported their child's prosocial behavior and multidimensional psychopathology at ages 3, 5, 7, 11, and 14 years (N = 16,984, 51% male, 83% White). Four random intercepts cross-lagged panel models were fitted. Higher levels of earlier prosocial behavior were associated with greater than expected decrements in psychopathology. At an intraindividual, within-person level, prosocial behavior was negatively bidirectionally associated with peer, conduct, and hyperactivity and inattention problems. Also at an intraindividual, within-person level, prosocial behavior was unidirectionally protective against emotional problems. At an interindividual level, prosocial behavior and each dimension of psychopathology were negatively associated. Therefore, engaging in prosocial behavior can reduce psychopathological symptoms over time (and vice versa), and youth who are more prosocial also tend to experience fewer psychopathological symptoms. Intraindividual associations were small while interindividual associations were moderate to large. Implications for theory, future research, and evidence-based interventions are discussed.


[Adaptation to sports by insulin-treated diabetics].
Performing muscular exercise regularly is generally recommended to diabetics; indeed, exercise increases muscle insulin sensitivity, helps fighting overweight and, at least partly, tends to correct plasma lipids abnormalities, thus contributing to limit the development of atherosclerosis. Moreover, the practice of sport is beneficial from a psychological point of view, because, thanks to it, diabetic patients can match, even surpass, "the others" and overcome what they often consider as a disability. However, diabetes--especially type 1, insulin dependent, diabetes--deeply modifies the metabolic adaptations to muscular exercise; consequently, exercise must be performed only in good metabolic control conditions, for avoiding a worsening of ketonaemia. In adequately controlled diabetics, muscular exercise can be beneficial by reducing blood glucose levels; it can also lead to hypoglycaemia occurring during or after the exercise bout. In order to reduce the risk of exercise-induced hypoglycaemia, diabetics have to know how to modify three essential parameters of their treatment: (1) increase carbohydrate intake before, during or after exercise; (2) reduce the dose of the insulin acting during exercise, and this in relation to the usual doses and to exercise intensity; (3) under some circumstances, modify the site of insulin injection according to the type of exercise performed. Taking into account these parameters, some general rules can be assessed, which are to be adapted to every particular situation; the use of home blood glucose monitoring before and after exercise is not only useful but sometimes mandatory.(ABSTRACT TRUNCATED AT 250 WORDS)


A systematic review of instruments related to family caregivers of palliative care patients.
Support for family caregivers is a core function of palliative care. However, there is a lack of consistency in the way needs are assessed, few longitudinal studies to examine the impact of caregiving, and a dearth of evidence-based interventions. In order to help redress this situation, identification of suitable instruments to examine the caregiving experience and the effectiveness of interventions is required. A systematic literature review was undertaken incorporating representatives of the European Association for Palliative Care's International Palliative Care Family Caregiver Research Collaboration and Family Carer Taskforce. The aim of the review was to identify articles that described the use of instruments administered to family caregivers of palliative care patients (pre and post-bereavement). Fourteen of the 62 instruments targeted satisfaction with service delivery and less than half were developed specifically for the palliative care context. In approximately 25% of articles psychometric data were not reported. Where psychometric results were reported, validity data were reported in less than half (42%) of these cases. While a considerable variety of instruments have been administered to family caregivers, the validity of some of these requires further consideration. We recommend that others be judicious before developing new instruments for this population.


Quantitative near-field characterization of surface plasmon polaritons on monocrystalline gold platelets.
Near-field microscopy allows for visualization of both the amplitude and phase of surface plasmon polaritons (SPPs). However, their quantitative characterization in a reflection configuration is challenging due to complex wave patterns arising from the interference between several excitation channels. Here, we present near-field measurements of SPPs on large monocrystalline gold platelets in the visible. We study systematically the influence of the incident angle of the exciting light on the SPPs launched by an atomic force microscope tip. We find that the amplitude and phase signals of these SPPs are best disentangled from other signals at grazing incident angle relative to the edge of the gold platelet. Furthermore, we introduce a simple model to extract the wavelength and in particular the propagation length of the tip-launched plasmons. Our experimental results are in excellent agreement with our theoretical model. The presented method allows the quantitative analysis of polaritons occurring in different materials at visible wavelengths.


"We are Forgotten": Forced Migration, Sexual and Gender-Based Violence, and Coronavirus Disease-2019.
Adopting a structural violence approach, this article explores, with survivors and practitioners, how early coronavirus disease-2019 pandemic conditions affected forced migrant sexual and gender-based violence survivors' lives. Introducing a new analytical framework combining violent abandonment, slow violence, and violent uncertainty, we show how interacting forms of structural violence exacerbated by pandemic conditions intensified existing inequalities. Abandonment of survivors by the state increased precarity, making everyday survival more difficult, and intensified prepandemic slow violence, while increased uncertainty heightened survivors' psychological distress. Structural violence experienced during the pandemic can be conceptualized as part of the continuum of violence against forced migrants, which generates gendered harm.


Great expectations: An analysis of researchers' and policy makers' perceptions of the potential value of the Australian indigenous burden of disease study for policy.
The "Burden of disease and injury in Aboriginal and Torres Strait Islander Peoples" was commissioned by the Australian government as part of the Australian Burden of Disease study. This paper explores the extent to which key actors in the research and policy communities expected the Indigenous Burden of Disease study's findings to inform, influence, or drive federal decisions concerning Indigenous health in Australia. This qualitative research undertook interviews with 13 key informants with significant involvement in the Indigenous Burden of Disease study: six researchers, five policy makers, and two knowledge brokers. Interviews were recorded, transcribed, and analyzed, and the findings were triangulated with a review of the literature. Policy makers and researchers anticipated that the Indigenous Burden of Disease study would improve the available information for policy deliberations about Indigenous health. Beyond that, their expectations about its policy influence differed substantially, with researchers more confident of the study's capacity to guide health priorities, and policy makers situating findings in the context of other critical inputs. Expectations of policy influence are shaped by the disciplinary perspectives of actors, and their relationship to policy outcomes and cannot be examined without also considering the policy, political, and financing context of the study being analyzed.


Emerging on-chip surface acoustic wave technology for small biomaterials manipulation and characterization.
A surface acoustic wave (SAW) is a sound wave travelling on the surface of an elastic material. SAW offers a robust control of the acoustic energy leading to an unparalleled versatility. As an actuator, SAW can exert acoustic forces on particles and fluids thus enabling dexterous micro/nanoscale manipulations. As a sensor, SAW has a unique sensing capability upon changes in the environment. On-chip SAW technology, in which SAW is integrated with modern lab-on-a-chip (LOC), has drawn a lot of attention in recent years and found various exciting applications in micro/nanosystems. In particular, its well-known biocompatibility provides on-chip SAW technology as an exceptional platform for biomaterials research at the small-scale. In this minireview, we highlighted recent advances of on-chip SAW technology for biomaterials manipulation and characterization with a focus on cell-based (e.g. single-cell and multicellular) biomaterials. We also discussed and shared our perspective on future directions for this emerging research field.


Properties of Venezuelan equine encephalomyelitis virus accompanying attenuation in vitro.
Virus obtained during serial plaque passage of the virulent parent egg seed (PES) of the Trinidad strain of Venezuelan equine encephalomyelitis (VEE) virus produced only large plaques during either 3 serial plaque passages in chick fibroblasts or 10 plaque passages in L cells, and was lethal for mice by the intraperitoneal route. Virus showing these characteristics was designated the stable large-plaque (Ls) type. In contrast, virus obtained during serial plaque passage of the attenuated 9t strain in chick fibroblasts formed only very small plaques and was not lethal for mice by the intraperitoneal route. Virus showing these properties was designated the stable small-plaque (Ss) type. Under other passage conditions, however, large-plaque virus that yielded about 90% large and 10% small plaques was obtained; this virus was designated the unstable large or Lu type because it differed from the Ls type, which yielded only large plaques. The Lu type continued to yield the same ratio of large to small plaques for several plaque-to-plaque passages. In addition, small-plaque virus that yielded both large and small plaques and that showed a reduced capability to infect mice was also recovered. This virus was designated the unstable small or Su type because it differed from the Ss type in its higher level of virulence and in its plaque-forming properties. Thus, based upon the properties of virulence for mice and plaque size, four viral types could be discerned. The evidence suggests that serial passage in cell culture imposed environmental pressures that sequentially selected the following viral types: Ls, Lu, Su, and Ss.


Impact of Processing Method on AQF Functionality in Bakery Items.
Aquafaba (AQF) has the unique ability to foam like egg whites and is a waste product of cooked chickpea that is not currently utilized by the food industry. Thus, the goal of this research was to concentrate the solids by reverse osmosis (cAQF) followed by drying. Dried AQF was prepared by cooking chickpea in excess water. After removal of the chickpea, the liquid AQF was subjected to reverse osmosis followed by freeze, tray, or spray drying. The resulting AQF products were incorporated into standard cake mix and sugar cookie formulas. Hardness, gumminess, and chewiness of cakes made with eggs were significantly higher compared to the cakes made with AQF. Spread factor was significantly greater for cookies made with AQF compared to eggs while hardness was significantly lower in cookies with AQF. Higher flavor and overall acceptability scores were observed in cookies made with AQF compared to cookies made with egg. However, sensory characteristics were generally not different among cakes. In general, cAQF and spray-dried AQF tended to produce cakes and cookies with the best quality and sensory characteristic. This research supports the use of RO and drying methods in producing AQF ingredients for baking applications.


A Patient-centered Approach to Evaluate the Information Needs of Women With Ductal Carcinoma In Situ.
To evaluate the information needs of ductal carcinoma in situ (DCIS) patients. Four focus groups involving 24 previously treated DCIS patients were conducted to develop a comprehensive list of questions they felt were important to have answered at the time of diagnosis. Using a survey, a separate group of patients treated for DCIS then rated the importance of having each of these questions addressed before treatment decision making. Response options were "essential," "desired," "not important," "no opinion," and "avoid." For each essential/desired question, respondents specified how addressing it would help them: "understand," "decide," "plan," "not sure," or "other." Focus group participants generated 117 questions used in the survey. Fifty-seven patients completed the survey (55% response rate). Respondents rated a median of 66 questions as essential. The most commonly cited reason for rating a question essential was to "understand," followed by to "decide." The top questions women deemed essential to help them understand were disease specific, whereas the top questions deemed essential to help women decide were predominantly treatment specific, pertaining to available options, recurrence and survival outcomes, and timelines to decide and start treatment. DCIS patients want a large number of questions answered, mostly for understanding, and also for deciding and planning. A core set of questions that most patients consider essential for decision making has been formulated and may be used in the clinical setting and in research to develop educational resources and decision-making tools specific to DCIS.


Substituting lifestyle management for pharmacological control of blood pressure: a pilot study in Australian general practice.
The HEART project was conducted in general practice to determine whether lifestyle strategies, aimed at increasing physical activity and dietary modification, can be substituted for drug therapy in patients who have been well controlled on antihypertensive medication. In addition to blood pressure (BP) and risk factor outcomes, lifestyle behaviours, quality of life of patients, and the acceptability of the approach to both general practitioners (GPs) and patients involved in the trial were assessed. Patients (n = 45) with a history of hypertension and who had been well controlled for at least the past 6 months (BP < 160/ 95 mmHg) were randomised to a continued medication (C) group (n = 24) or a withdrawal (W) group (n = 21). Subjects had received antihypertensive therapy for an average of 7.8 years (range 1-28 years). Drug therapy in the W group was recommenced if BP exceeded 160/95 mmHg on two consecutive visits. Both groups were counselled regarding lifestyle behaviour change by their GP throughout the study and were provided with specifically developed self-help materials. Subjects were reviewed at least monthly over a 9-month period. Following randomisation, there were no significant differences between the two groups for BP, heart rate, age, duration of therapy, total cholesterol or body mass index. All but three subjects (one from the W and two from the C group) completed 9 months of monitoring following randomisation and there were no cardiovascular events; 71% of subjects remained off drug therapy and were well controlled at the 9-month follow-up (15/21) with mean BP of 141/85 mmHg (W) and 139/ 86 mmHg (C). Systolic BP tended to increase during the study period in both W and C groups, however, no significant differences were observed in mean systolic or diastolic BP either between the two groups or within each group in comparison to baseline values. Resting heart rate, body mass index and cholesterol levels remained unchanged in both W and C groups after 9 months follow-up. There were no changes attributable to the lifestyle intervention in the subjects continuing drug therapy in BP or lifestyle variables over the study period. However, the group stopping therapy had a 6% reduction in body mass index after 9 months. These data suggest that a proportion of motivated patients willing to trial a lifestyle approach can cease drug therapy and be adequately maintained by the prescription of lifestyle advice via their GP for at least a 9-month period. Cessation of drug therapy may be an important motivating factor to achieve weight loss in this group.


The influence of compliance with the use of refractive correction in hyperopic children on accommodation.
To indicate the relationship between constant, correct use of hyperopic spectacles and relaxation of accommodation in children. After thorough ophthalmic examination (cycloplegia included), 52 children 2.5 to 9 years old were detected with hyperopia >3 D, out of all examined within a year. These children were fully or partially corrected, with hyperopic glasses, depending on whether accommodative esotropia was or was not present. Constant and correct use of spectacles was strongly suggested to all children. During follow-up 3 and 6 months later, the amount of manifest hyperopia was measured in each case by an autorefractometer (without the use of cycloplegic factor). Out of the 52 children, 37 who participated in our study fully complied with hyperopic spectacle treatment, wearing their glasses constantly and correctly. The 15 others wore their glasses partially or not at all or made incorrect use of them. During follow-up 3 and 6 months later, refractive measurements of manifest hyperopia in the first group of children were identical or similar to the refractive power of their glasses. On the contrary, in the second group of children, strong accommodation did not allow the expression of hyperopia, and in a few cases myopic refractive measurements appeared (similar to those on the first examination, before spectacle treatment was prescribed). Constant and correct use of hyperopic spectacles leads to relaxation of accommodation in children and is thus an accurate indicator of compliance.


Use of an enhanced surveillance system for encephalitis and aseptic meningitis for the detection of neurologic manifestations of dengue in Puerto Rico, 2003.
Dengue infection has been implicated as a cause of neurologic manifestations since the beginning of the 20th century. An enhanced surveillance system for encephalitis and aseptic meningitis developed by the Puerto Rico Department of Health in collaboration with the Dengue Branch, Centers for Disease Control and Prevention, identified eleven laboratory positive dengue patients presenting with neurologic manifestations in 2003. Anti-dengue IgM antibody was detected in serum of eight patients and in cerebrospinal fluid of one patient. DENV-2 and DENV-3 were isolated from the serum of one patient each. All patients were negative for serologic markers of West Nile Virus and St. Louis encephalitis. Nine (82%) of the 11 patients had symptoms compatible with encephalitis. Their median age was 46 years (range: 9 months - 82 years) and five were males. Symptoms included severe headache, seizures, altered mental status, confusion, and coma. A motor disorder (upper extremities weakness and Guillain Barré Syndrome, respectively) occurred in two additional patients. Most patients recovered but there were two fatalities. Neurologic manifestations of dengue were rarely reported in Puerto Rico until the institution of enhanced surveillance, which resulted in the recognition of severe and fatal cases.


Using the acetabulum to estimate age at death of adult males.
The acetabular region is often present and adequately preserved in adult human skeletal remains. Close morphological examination of the 242 left male os coxae from the identified collection of Coimbra (Portugal) has enabled the recognition of seven variables that can be used to estimate age at death. This paper describes these variables and argues their appropriateness by analyzing the correlation between these criteria and the age, the intra- and interobserver consistence, and the accuracy in age prediction using Bayesian inference to estimate age of identified specimens. Results show significant close correlation between the acetabular criteria and age, nonsignificant differences in intra- and interobserver test, and 89% accuracy in Bayes prediction. Obtained estimated age of the specimens had similar accuracy in all ages. These results indicate that these seven variables, based on the acetabular area, are potentially useful to estimate age at death for adult specimens.


Carryover effects from natal habitat type upon competitive ability lead to trait divergence or source-sink dynamics.
Local adaptation to rare habitats is difficult due to gene flow, but can occur if the habitat has higher productivity. Differences in offspring phenotypes have attracted little attention in this context. We model a scenario where the rarer habitat improves offspring's later competitive ability - a carryover effect that operates on top of local adaptation to one or the other habitat type. Assuming localised dispersal, so the offspring tend to settle in similar habitat to the natal type, the superior competitive ability of offspring remaining in the rarer habitat hampers immigration from the majority habitat. This initiates a positive feedback between local adaptation and trait divergence, which can thereafter be reinforced by coevolution with dispersal traits that match ecotype to habitat type. Rarity strengthens selection on dispersal traits and promotes linkage disequilibrium between locally adapted traits and ecotype-habitat matching dispersal. We propose that carryover effects may initiate isolation by ecology.


Cancer Core Europe: a consortium to address the cancer care-cancer research continuum challenge.
European cancer research for a transformative initiative by creating a consortium of six leading excellent comprehensive cancer centres that will work together to address the cancer care-cancer research continuum. Prerequisites for joint translational and clinical research programs are very demanding. These require the creation of a virtual single 'e-hospital' and a powerful translational platform, inter-compatible clinical molecular profiling laboratories with a robust underlying computational biology pipeline, standardised functional and molecular imaging, commonly agreed Standard Operating Procedures (SOPs) for liquid and tissue biopsy procurement, storage and processing, for molecular diagnostics, 'omics', functional genetics, immune-monitoring and other assessments. Importantly also it requires a culture of data collection and data storage that provides complete longitudinal data sets to allow for: effective data sharing and common database building, and to achieve a level of completeness of data that is required for conducting outcome research, taking into account our current understanding of cancers as communities of evolving clones. Cutting edge basic research and technology development serve as an important driving force for innovative translational and clinical studies. Given the excellent track records of the six participants in these areas, Cancer Core Europe will be able to support the full spectrum of research required to address the cancer research- cancer care continuum. Cancer Core Europe also constitutes a unique environment to train the next generation of talents in innovative translational and clinical oncology.


Unequal retinal illuminance and the binoculus.
An investigation was carried out in the relationship between the position of the binoculus and the depth (transmittance) of a monocular filter. The method used relied on changes in motor function and the linearity of the relationship found by previous workers, who used purely visual techniques, was confirmed. Some anomalous results were found which remain unexplained.


The N-terminal fragment of human islet amyloid polypeptide is non-fibrillogenic in the presence of membranes and does not cause leakage of bilayers of physiologically relevant lipid composition.
Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus (DM2). The formation of hIAPP fibrils has been shown to cause membrane damage which most likely is responsible for the death of pancreatic islet beta-cells during the pathogenesis of DM2. Previous studies have shown that the N-terminal part of hIAPP, hIAPP(1-19), plays a major role in the initial interaction of hIAPP with lipid membranes. However, the exact role of this N-terminal part of hIAPP in causing membrane damage is unknown. Here we investigate the structure and aggregation properties of hIAPP(1-19) in relation to membrane damage in vitro by using membranes of the zwitterionic lipid phosphatidylcholine (PC), the anionic lipid phosphatidylserine (PS) and mixtures of these lipids to mimic membranes of islet cells. Our data reveal that hIAPP(1-19) is weakly fibrillogenic in solution and not fibrillogenic in the presence of membranes, where it adopts a secondary structure that is dependent on lipid composition and stable in time. Furthermore, hIAPP(1-19) is not able to induce leakage in membranes of PC/PS or PC bilayers, indicating that the membrane interaction of the N-terminal fragment by itself is not responsible for membrane leakage under physiologically relevant conditions. In bilayers of the anionic lipid PS, the peptide does induce membrane damage, but this leakage is not correlated to fibril formation, as it is for mature hIAPP. Hence, membrane permeabilization by the N-terminal fragment of hIAPP in anionic lipids is most likely an aspecific process, occurring via a mechanism that is not relevant for hIAPP-induced membrane damage in vivo.


Significance of the Microfluidic Flow Inside the Organ of Corti.
We study the vibration modes of a short section in the middle turn of the gerbil cochlea including both longitudinal and radial interstitial fluid spaces between the pillar cells (PC) and the sensory hair cells to determine the role of the interstitial fluid flow within the organ of corti (OoC). Three detailed finite element (FE) models of the cochlear short section (CSS) are studied. In model 1, the CSS is without fluids; model 2 includes the OoC fluid, but not the exterior scalae fluids; and model 3 is the CSS with both scalae and OoC fluids. We find that: (1) the fundamental mode shape of models 1 or 3 is similar to the classical basilar membrane (BM) bending mode that includes pivoting of the arch of corti, and hence determines the low frequency vibrational mode shape of the cochlea in the presence of the cochlear wave. (2) The fundamental mode shape of model 2 is characterized by a cross-sectional shape change similar to the passive response of the cochlea. This mode shape includes a tilting motion of the inner hair cell (IHC) region, a fluid motion within the tunnel of corti (ToC) in the radial direction and along the OoC, and a bulging motion of the reticular lamina (RL) above the outer hair cell (OHC). Each of these motions provides a plausible mode of excitation of the sensory hair cells. (3) The higher vibrational modes of model 1 are similar to the electrically evoked response within the OoC and suggests that the higher vibrational modes are responsible for the active response of the cochlea. We also observed that the fluid flow through the OoC interstitial space is significant, and the model comparison suggests that the OoC fluid contributes to the biphasic BM motion seen in electrical stimulation experiments. The effect of fluid viscosity on cilium deflection was assessed by performing a transient analysis to calculate the cilium shearing gain. The gain values are found to be within the range of experimentally measured values reported by Dallos et al. (1996, The Cochlea, Springer-Verlag, New York).


[Thyroid hormones and mitochondrial cytochrome c oxidoreductase activity].
In the experiments on albino male rats it was shown that thyroid hormones, exerting organospecific effect, control both the activity and the amount of cytochrome-c-oxidoreductase in hepatic, renal, cardiac and cerebral mitochondria. In the mechanism of cytochrome-c-oxidoreductase regulation thyroxin effect is likely to be mediated by cytochrome c amount. Supraphysiological thyroxin concentrations exert a direct action on the enzyme, whereas its physiological levels regulate cytochrome-c-oxidase, acting as an inductor.