Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention.
Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1-9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA.


An evaluation of multi-probe locality sensitive hashing for computing similarities over web-scale query logs.
Many modern applications of AI such as web search, mobile browsing, image processing, and natural language processing rely on finding similar items from a large database of complex objects. Due to the very large scale of data involved (e.g., users' queries from commercial search engines), computing such near or nearest neighbors is a non-trivial task, as the computational cost grows significantly with the number of items. To address this challenge, we adopt Locality Sensitive Hashing (a.k.a, LSH) methods and evaluate four variants in a distributed computing environment (specifically, Hadoop). We identify several optimizations which improve performance, suitable for deployment in very large scale settings. The experimental results demonstrate our variants of LSH achieve the robust performance with better recall compared with "vanilla" LSH, even when using the same amount of space.


Hypoxic gene expression and metastasis.
Solid tumors possess malformed vasculature that results in the exposure of tumor cells to a low oxygen environment. Tumor hypoxia has been demonstrated in human and mouse tumors through the use of oxygen microelectrodes, hypoxic specific biomarkers, specific transcriptional changes induced by hypoxia, and secreted proteins. While many elegant experiments have demonstrated that hypoxia enhances metastatic potential, it is still unknown what mechanisms are involved in this enhancement. In this review, we discuss the clinical and basic science studies that support an important role for hypoxia in increasing the metastatic potential of tumor cells by promoting tissue remodeling, inducing angiogenesis and reducing apoptosis. Particular emphasis is given to recent findings that provide insight to the role of hypoxia in the metastatic process.


Developing a self-healing supramolecular nucleoside hydrogel.
Low molecular weight gelator hydrogels provide a viable alternative to traditional polymer based drug delivery platforms, owing to their tunable stability and in most cases inherent biocompatibility. Here we report the first self-healing nucleoside hydrogel using N4-octanoyl-2'-deoxycytidine (0.5% w/v) for drug delivery. The hydrogel's cross-linked nanofibrillar structure, was characterised using oscillatory rheology and confirmed using SEM and TEM imaging. The potential of this gel for drug delivery was explored in vitro using fluorescently labelled tracers. Cell viability assays were conducted using pancreatic cell lines which tolerated the gels well; whilst no adverse effects on the viability or proliferation of cells were observed for fibroblast cell lines.


Analysis of autoantibody profiles in osteoarthritis using comprehensive protein array concepts.
Osteoarthritis (OA) is the most common rheumatic disease and one of the most disabling pathologies worldwide. To date, the diagnostic methods of OA are very limited, and there are no available medications capable of halting its characteristic cartilage degeneration. Therefore, there is a significant interest in new biomarkers useful for the early diagnosis, prognosis, and therapeutic monitoring. In the recent years, protein microarrays have emerged as a powerful proteomic tool to search for new biomarkers. In this study, we have used two concepts for generating protein arrays, antigen microarrays, and NAPPA (nucleic acid programmable protein arrays), to characterize differential autoantibody profiles in a set of 62 samples from OA, rheumatoid arthritis (RA), and healthy controls. An untargeted screen was performed on 3840 protein fragments spotted on planar antigen arrays, and 373 antigens were selected for validation on bead-based arrays. In the NAPPA approach, a targeted screening was performed on 80 preselected proteins. The autoantibody targeting CHST14 was validated by ELISA in the same set of patients. Altogether, nine and seven disease related autoantibody target candidates were identified, and this work demonstrates a combination of these two array concepts for biomarker discovery and their usefulness for characterizing disease-specific autoantibody profiles.


Measurement of the Lambda b0 lifetime in Lambda b0-->J/psi Lambda 0 in pp collisions at square root s=1.96 TeV.
We report a measurement of the Lambda b0 lifetime in the exclusive decay Lambda b0-->J/psi Lambda 0 in pp collisions at square root s=1.96 TeV using an integrated luminosity of 1.0 fb-1 of data collected by the CDF II detector at the Fermilab Tevatron. Using fully reconstructed decays, we measure tau(Lambda b0)=1.593(-0.078)(+0.083)(stat)+/-0.033(syst) ps. This is the single most precise measurement of tau(Lambda b0) and is 3.2sigma higher than the current world average.


vCLAP, a caspase-recruitment domain-containing protein of equine Herpesvirus-2, persistently activates the Ikappa B kinases through oligomerization of IKKgamma.
vCLAP, the E10 gene product of equine herpesvirus-2, is a caspase-recruitment domain (CARD)-containing protein that has been shown to induce both apoptosis and NF-kappaB activation in mammalian cells. vCLAP has a cellular counterpart, Bcl10/cCLAP, which is also an activator of apoptosis and NF-kappaB. Recent studies demonstrated that vCLAP activates NF-kappaB through an IkappaB kinase (IKK)-dependent pathway, but the underlying mechanism remains unknown. In this report, we demonstrate that vCLAP associates stably with the IKK complex through direct binding to the C-terminal region of IKKgamma. Consistent with this finding, IKKgamma was found to be essential for vCLAP-induced NF-kappaB activation, and the association between vCLAP and the IKK complex induced persistent activation of the IKKs. Moreover, enforced oligomerization of the isolated C-terminal region of vCLAP, which interacts with IKKgamma, can trigger NF-kappaB activation. Finally, substitution of the C-terminal region of IKKgamma, which interacts with vCLAP, with the CARD of vCLAP or Bcl10 produced a molecule that was able to activate NF-kappaB when ectopically expressed in IKKgamma-deficient cells. These data suggest that vCLAP-induced oligomerization of IKKgamma, which is mediated by the CARD of vCLAP, could be the mechanism by which vCLAP induces activation of NF-kappaB.


Lack of Adiponectin Drives Hyperosteoclastogenesis in Lipoatrophic Mice.
Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlighted the dual bone phenotype of PPARγ null mice: one the one hand, the increased bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explored the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibited mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.


Optimized atom position and coefficient coding for matching pursuit-based image compression.
In this paper, we propose a new encoding algorithm for matching pursuit image coding. We show that coding performance is improved when correlations between atom positions and atom coefficients are both used in encoding. We find the optimum tradeoff between efficient atom position coding and efficient atom coefficient coding and optimize the encoder parameters. Our proposed algorithm outperforms the existing coding algorithms designed for matching pursuit image coding. Additionally, we show that our algorithm results in better rate distortion performance than JPEG 2000 at low bit rates.


Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant.
The development of targeted therapies for antiestrogen-resistant breast cancer requires a detailed understanding of its molecular characteristics. To further elucidate the molecular events underlying acquired resistance to the antiestrogens tamoxifen and fulvestrant, we established drug-resistant sublines from a single colony of hormone-dependent breast cancer MCF7 cells. These model systems allowed us to examine the cellular and molecular changes induced by antiestrogens in the context of a uniform clonal background. Global changes in both basal and estrogen-induced gene expression profiles were determined in hormone-sensitive and hormonal-resistant sublines using Affymetrix Human Genome U133 Plus 2.0 Arrays. Changes in DNA methylation were assessed by differential methylation hybridization, a high-throughput promoter CpG island microarray analysis. By comparative studies, we found distinct gene expression and promoter DNA methylation profiles associated with acquired resistance to fulvestrant versus tamoxifen. Fulvestrant resistance was characterized by pronounced up-regulation of multiple growth-stimulatory pathways, resulting in estrogen receptor alpha (ERalpha)-independent, autocrine-regulated proliferation. Conversely, acquired resistance to tamoxifen correlated with maintenance of the ERalpha-positive phenotype, although receptor-mediated gene regulation was altered. Activation of growth-promoting genes, due to promoter hypomethylation, was more frequently observed in antiestrogen-resistant cells compared with gene inactivation by promoter hypermethylation, revealing an unexpected insight into the molecular changes associated with endocrine resistance. In summary, this study provides an in-depth understanding of the molecular changes specific to acquired resistance to clinically important antiestrogens. Such knowledge of resistance-associated mechanisms could allow for identification of therapy targets and strategies for resensitization to these well-established antihormonal agents.


Relationship between dendritic cells and activated eosinophils in induced sputum of asthmatics.
It has been suggested that dendritic cells (DCs) are critical antigen presenting cells for eosinophilic airway inflammation in a mouse model of asthma, and cysteinyl leukotrienes may play a role in DC trafficking in asthmatics. We investigated whether the number of DCs is increased in the induced sputum of both atopic and nonatopic asthmatics and is related to activated eosinophil count in the sputum. Sputum was induced by inhalation of hypertonic saline in 9 atopic and 12 nonatopic asthmatics and 10 nonatopic normal controls, and differential cell counts were performed. DCs and activated eosinophils were identified by immunocytochemistry with monoclonal antibodies (anti-CD1a and EG2, respectively). There were significantly higher percentages of eosinophils, EG2+ cells, and CD1a+ DC in the sputum of atopic and nonatopic asthmatics compared with normal controls, respectively. In asthmatics, the percentage of CD1a+ DC was significantly correlated with that of EG2+ cells (Rs=0.62, p=0.004). We demonstrated that the increased number of DCs was evident in the induced sputum of both atopic and nonatopic asthmatics, and the DC number was related to the activated eosinophil count, which suggests that DCs may contribute to the ongoing eosinophilic inflammation in asthmatic airways, and vice versa.


Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice.
Induced pluripotent stem cell-derived (iPS-derived) neural precursor cells may represent the ideal autologous cell source for cell-based therapy to promote remyelination and neuroprotection in myelin diseases. So far, the therapeutic potential of reprogrammed cells has been evaluated in neonatal demyelinating models. However, the repair efficacy and safety of these cells has not been well addressed in the demyelinated adult CNS, which has decreased cell plasticity and scarring. Moreover, it is not clear if these induced pluripotent-derived cells have the same reparative capacity as physiologically committed CNS-derived precursors. Here, we performed a side-by-side comparison of CNS-derived and skin-derived neural precursors in culture and following engraftment in murine models of adult spinal cord demyelination. Grafted induced neural precursors exhibited a high capacity for survival, safe integration, migration, and timely differentiation into mature bona fide oligodendrocytes. Moreover, grafted skin-derived neural precursors generated compact myelin around host axons and restored nodes of Ranvier and conduction velocity as efficiently as CNS-derived precursors while outcompeting endogenous cells. Together, these results provide important insights into the biology of reprogrammed cells in adult demyelinating conditions and support use of these cells for regenerative biomedicine of myelin diseases that affect the adult CNS.


Talking the Walk: Perceptions of Neighborhood Characteristics from Users of Open Streets Programs in Latin America and the USA.
Physical inactivity is estimated to be the fourth leading cause of global mortality. Strategies to increase physical activity (PA) increasingly emphasize environmental and policy changes including the modification of neighborhood environments to promote walking and other forms of healthy activity. Open Streets (OS) initiatives, an important and growing strategy to modify neighborhood environments for PA, create temporary parks for recreational activity by closing streets to motor vehicle traffic, thereby offering health and community building benefits. We used the Stanford Neighborhood Discovery Tool (DT)-photo/voice software on a tablet-to train neighborhood residents to act as "citizen scientist" observers of the local built environment on a non-event day and during an OS initiative. The purposes of this project were as follows: (1) to assess adult residents' perceptions of neighborhood characteristics of the OS initiative in three socioeconomically diverse sites and (2) to test the DT for use in three international urban settings with OS initiatives; Bogota, Colombia; San Francisco, USA; and Temuco, Chile, among a multigenerational, multiethnic sample of adults including, for the first time, a vulnerable population of homeless adults (Bogota). Using the DT, participants walked an OS route taking photos and recording reasons for the photos, then completed a 25-item demographic/environmental observation survey and a 16-item Reflection Survey on perceived environmental changes. A total of 18 themes were reported by participants with areas of overlapping themes (e.g., Community and Social Connectedness) and areas where a single site reported a theme (e.g., Social Isolation in Older Adults). Ten of the 18 themes were identified by at least two sites including "Bike Resources" and "Services", indicating the value of programming at OS initiatives. The themes of "Festive Environment" and "Family Friendly Environment" reflect the quality of the overall environment for participants. Four themes (Community and Social Connectedness, Family Friendly Environment, PA, and Safety) were reported by all sites. Three of the four unifying themes were also ranked among the highest reported categories of "seemed better" on the Reflection Survey (Ease of Walking, Overall Safety of Neighborhood, and Friendliness of Environment), providing additional confirmation of the shared experience of social, health, and psychological benefits from OS initiatives. OS initiatives offer a global strategy for increasing neighborhood opportunities for PA and a potential site for training citizen scientists to document environmental influences on PA.


Histone H2AX phosphorylation in normal human cells irradiated with focused ultrasoft X rays: evidence for chromatin movement during repair.
DNA repair within the cell nucleus is a dynamic process involving a close interaction between repair proteins and chromatin structure. Recent studies have indicated a quantitative relationship between DNA double-strand break induction and histone H2AX phosphorylation. The dynamics of this process within individual cell nuclei is unknown. To address this, we have used a novel focused ultrasoft X-ray microprobe that is capable of inducing localized DNA damage within a subnuclear area of intact cells with a 2.5-microm-diameter beam spot. The present investigation was undertaken to explore the influence of focused irradiation of individual nuclei with 1.49 keV characteristic aluminum K-shell (AlK) X rays on H2AX phosphorylation in normal human cells. Immunofluorescence analyses revealed that significant diffusion of the initial spots of clustered foci of phosphorylated H2AX occurred in a time-dependent fashion after exposure to AlK X rays. Irradiation under cooled conditions resulted in a reduction in the size of spots of clustered foci of phosphorylated H2AX as well as of individual phosphorylated H2AX foci. These findings strongly suggest that diffusion of the chromatin microenvironment occurs during the repair of DNA damage. We also found that AlK ultrasoft X rays (71 foci per gray) were 2.2-fold more effective at the initial formation of phosphorylated H2AX foci than with conventional X rays (32 foci per gray), and that the time required to eliminate 50% of the initial number of foci was 3.4-fold longer in AlK-irradiated cells than that in cells exposed to conventional X rays. For conventional X rays, we also report significant accumulation of larger-sized foci at longer times after irradiation.


Pulmonary vascular overreactivity in systemic hypertension. A pathophysiological link between the greater and the lesser circulation.
This study was undertaken to test whether the emphasized systemic vasomotion during sympathetic activation in hypertension is shared by the pulmonary circulation. To this end, 10 normotensive and 29 primary hypertensive subjects were investigated during adrenergic stimulation by mental arithmetic and cold pressor test. Both stimuli induced a systemic pressor reaction in both groups, which was mediated through an increase in cardiac output and a mild reduction in vascular resistance during arithmetic and through a predominant rise in systemic vascular resistance during cold. Each of these changes was emphasized in the hypertensive population as compared with the normotensive one. Pressure in the pulmonary artery remained unchanged during cold and was slightly raised (systolic) during arithmetic in normotensive subjects. On the contrary, in hypertensive subjects systolic and diastolic pulmonary pressures were consistently augmented by both stimuli, and pulmonary arteriolar resistance (dyn sec cm-5) rose from 92 in the baseline to 125 (p less than 0.01) during arithmetic and to 124 (p less than 0.01) during the cold test. This reaction is interpreted as reflecting a neurally mediated vasoconstriction and not as the consequence of mechanical or chemical changes, since no difference was observed in pulmonary wedge pressure, pleural pressure, arterial blood gas levels, and pH between controls and hypertensive subjects in the steady state and during either stressful stimulation. Baseline pulmonary arteriolar resistance was also found to correlate positively with systemic vascular resistance in the hypertensive group. When pressure changes occurred, the time course was similar in the two circuits; resistance increased to a proportionally similar degree in the two districts during the cold stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)


Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration.
We report here the identification of an angiopoietin-related growth factor (AGF). To examine the biological function of AGF in vivo, we created transgenic mice expressing AGF in epidermal keratinocytes (K14-AGF). K14-AGF mice exhibited swollen and reddish ears, nose and eyelids. Histological analyses of K14-AGF mice revealed significantly thickened epidermis and a marked increase in proliferating epidermal cells as well as vascular cells in the skin compared with nontransgenic controls. In addition, we found rapid wound closure in the healing process and an unusual closure of holes punched in the ears of K14-AGF mice. Furthermore, we observed that AGF is expressed in platelets and mast cells, and detected at wounded skin, whereas there was no expression of AGF detected in normal skin tissues, suggesting that AGF derived from these infiltrated cells affects epidermal proliferation and thereby plays a role in the wound healing process. These findings demonstrate that biological functions of AGF in epidermal keratinocytes could lead to novel therapeutic strategies for wound care and epidermal regenerative medicine.


STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADalpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADalpha expression. STRADalpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADalpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.


An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry.
Mortality data have been updated for a further 12 years for a cohort of workers in the reinforced plastics and composites industry with exposures to styrene monomer and other chemicals. The cohort consisted of 15,826 male and female employees who were exposed to styrene for at least six months between 1948 and 1977 at 30 participating manufacturing plants in the United States. A total of 1628 deaths were reported during the extended observation period, 1948-89. Mortality from several causes showed significant increases--namely, all causes, all cancers, oesophageal cancer, lung cancer, cancer of the cervix uteri, cancer of other female genital organs, hypertensive heart disease, certain non-malignant respiratory diseases, motor vehicle accidents, and homicides. When, however, mortality data were examined in terms of duration of employment, durations of styrene exposure, and cumulative styrene exposure no upward trend was detected in any of these causes of death. Most of the increases in mortality were among workers who were employed for only six months to a year or who had very low cumulative exposure (< 10 ppm-years). Therefore, the increased mortality was not likely to be related to exposure to styrene. Several explanations for the increased mortality are offered, including low socioeconomic class, smoking, and lifestyle factors characteristic of short term workers. There was no increased mortality from lymphatic and haematopoietic cancers overall or from any specific haematological malignancies. In particular, no increase in mortality from non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or leukaemia was found. Furthermore, detailed exposure-response analyses did not show any relation between exposure to styrene and any of these haematological malignancies. The lack of an exposure-response relation further supports the conclusion that workers in the reinforced plastics industry in this study did not experience any increased risk of lymphatic and haematopoietic cancers as a result of their exposure to styrene.


Inhibitory Control Predicts Grammatical Ability.
We present evidence that individual variation in grammatical ability can be predicted by individual variation in inhibitory control. We tested 81 5-year-olds using two classic tests from linguistics and psychology (Past Tense and the Stroop). Inhibitory control was a better predicator of grammatical ability than either vocabulary or age. Our explanation is that giving the correct response in both tests requires using a common cognitive capacity to inhibit unwanted competition. The implications are that understanding the developmental trajectory of language acquisition can benefit from integrating the developmental trajectory of non-linguistic faculties, such as executive control.


Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial.
Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood. We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232. Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C. Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study. This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.


Patient-controlled Analgesia With Propacetamol-Fentanyl Mixture for Prevention of Postoperative Nausea and Vomiting in High-risk Patients Undergoing Spine Surgery: A Randomized Controlled Trial.
This randomized trial evaluated the effect of intravenous patient-controlled analgesia (IV-PCA) based on fentanyl mixed with either propacetamol or an equivalent volume of normal saline on postoperative nausea and vomiting (PONV) in highly susceptible patients undergoing spinal surgery. One hundred eight nonsmoking female patients were randomly and evenly allocated to receive IV-PCA with either propacetamol (4 g) or normal saline mixed to fentanyl (20 μg/kg). Primary study outcome was PONV incidence at 24 hours postsurgery. Secondary outcomes were nausea severity, pain intensity (100-mm visual analog scale), use of rescue antiemetics and analgesics, patient satisfaction, and adverse events at 6, 12, and 24 hours postsurgery. Postsurgery, the propacetamol versus normal saline group had lower PONV incidence at 24 hours (41% vs. 66%, P=0.011); pain intensity at rest and rescue analgesic requirements at 6 to 12 hours (30±15 vs. 41±19, P=0.008; and 25% vs. 49%, P=0.036, respectively) and at 12 to 24 hours (25±15 vs. 35±17, P=0.008; and 19% vs. 42%, P=0.044, respectively); and higher patient satisfaction score (6.4±1.4 vs. 5.7±1.8, P=0.028). In patients undergoing spinal surgery and at risk of developing PONV, continuous IV-PCA based on propacetamol mixed to fentanyl, relative to fentanyl alone, effectively reduced the incidence of PONV, pain intensity at rest, and additional use of rescue analgesics with higher patient satisfaction.


A single-amino-acid change in murine norovirus NS1/2 is sufficient for colonic tropism and persistence.
Human norovirus (HuNoV) is the major cause of acute nonbacterial gastroenteritis worldwide but has no clear animal reservoir. HuNoV can persist after the resolution of symptoms, and this persistence may be essential for viral maintenance within the population. Many strains of the related murine norovirus (MNV) also persist, providing a tractable animal model for studying norovirus (NoV) persistence. We have used recombinant cDNA clones of representative persistent (CR6) and nonpersistent (CW3) strains to identify a domain within the nonstructural gene NS1/2 that is necessary and sufficient for persistence. Furthermore, we found that a single change of aspartic acid to glutamic acid in CW3 NS1/2 was sufficient for persistence. This same conservative change also caused increased growth of CW3 in the proximal colon, which we found to be a major tissue reservoir of MNV persistence, suggesting that NS1/2 determines viral tropism that is necessary for persistence. These findings represent the first identified function for NoV NS1/2 during infection and establish a novel model system for the study of enteric viral persistence.


Vision and academic performance in primary school children.
Vision is considered important for academic performance in children; however, the evidence in this area tends to be inconsistent and inconclusive. This study explored the association between vision function and visual information processing measures and standardised academic achievement scores in Grade 3 Australian children. Participants included 108 Grade 3 primary school children (M = 8.82 ± 0.32 years) from three state primary schools in South-East Queensland. All participants underwent a standard vision screening, including distance visual acuity (VA), binocular vision testing and stereoacuity (SA). A computer-based battery of visual information processing tests including the Development Eye Movement (DEM) test, Visual Sequential Memory (VSM) and Symbol Search (SS) was also administered. Australian National Assessment Program for Literacy and Numeracy (NAPLAN) scores across five subtests of academic performance were obtained for each child: Reading, Writing, Spelling, Grammar/Punctuation and Numeracy. The DEM adjusted horizontal and vertical times were most strongly associated with all of the NAPLAN subtest scores (p < 0.01), adjusted for age and the socio-economic status of the school; the DEM ratio was not significantly associated with any of the NAPLAN subtests. VSM and SS scores were significantly associated with one or more NAPLAN subtests, as were worse and better eye VA; SA showed no significant association with any of the NAPLAN subtests. Performance on the horizontal and vertical DEM subtests was most strongly associated with academic performance. These data, in conjunction with other clinical data, can provide useful information to clinicians regarding their prescribing and management philosophy for children with lower levels of uncorrected refractive error and binocular vision anomalies.


Usefulness of genetic polymorphisms and conventional risk factors to predict coronary heart disease in patients with familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder with an associated high risk of coronary heart disease (CHD). The considerable variation in age of onset of CHD in patients with FH is believed to arise from conventional risk factors, as well as genetic variation other than in the low-density lipoprotein receptor gene. The degree to which currently known genetic variants can improve the prediction of CHD risk beyond conventional risk factors in this disorder was investigated. Fourteen genetic variants recently identified for association with CHD in a Dutch FH population were considered. Prediction models were constructed using Cox proportional hazards models, and predictive value was assessed using a concordance statistic (c statistic). A total of 1,337 patients with FH were completely genotyped for all genetic variants. Hazard ratios of the genetic variants ranged from 0.61 to 0.74 and 1.24 to 2.33. The c statistic of the CHD prediction model based on genetic variants was 0.59, denoting little discrimination. The model based on conventional risk factors had a c statistic of 0.75, denoting moderate discrimination. Adding genetic test results to this model increased the c statistic to 0.76. In conclusion, the contribution of 14 genetic variants to the prediction of CHD risk in patients with FH was limited. To improve genome-based prediction of CHD, larger numbers of genetic variants need to be identified that either on their own or in gene-gene interaction have substantial effects on CHD risk.


Addition of a biomarker panel to a clinical score to identify patients at low risk for appendicitis.
The diagnosis of pediatric acute appendicitis can be difficult. Although scoring systems such as the Pediatric Appendicitis Score (PAS) are helpful, they lack adequate sensitivity and specificity as standalone diagnostics. When used for risk stratification, they often result in large percentages of moderate-risk patients requiring further diagnostic evaluation. We applied a biomarker panel (the APPY1 Test) that has high sensitivity and negative predictive value (NPV) to patients with PAS in the moderate-risk range (3-7) and reclassified those patients with a negative result to the low-risk group. We compared the specificity, sensitivity, and NPV of the original and reclassified low-risk groups at several different PAS low-risk cutoffs. The application of a negative biomarker panel to a group of patients with a moderate risk for appendicitis (PAS, 3-7) resulted in 4 times more patients (586 vs 145) being safely classified as low risk. Reclassification increased the overall specificity or the proportion of patients without appendicitis who were correctly identified as low risk, from 10.3% to 42.0%. The high NPV (97.2%) in the original group was preserved (97.6%) in the reclassified low-risk group, as was the sensitivity (original 99.1% vs reclassified 96.9%). The addition of negative biomarker test results to patients with a moderate risk of appendicitis based on the PAS can safely reclassify many to a low-risk group. This may allow clinicians to provide more conservative management in children with suspected appendicitis and decrease unnecessary resource utilization.


The relationship between cow's milk exposure and type 1 diabetes.
Environmental factors are important for the development of Type 1 diabetes mellitus. They likely account for changes in the incidence of this disease over time, as well as the well-documented differences in incidence in ethnically and genetically similar people living in different parts of the world. There is a relationship between early cow's milk exposure and the development of Type 1 diabetes in humans, and between early cow's milk exposure and the development of autoimmune diabetes in rodent models of Type 1 diabetes. Moreover, some immunological studies have suggested a possible mechanism whereby exposure to cow's milk protein could result in beta-cell directed autoimmunity and subsequent Type 1 diabetes. Although provocative, the existence of alternative explanations for these epidemiological and biological observations, suggest that the data are insufficient to conclude that the observed associations represent causal relationships or to mandate changes in recommendations for infant feeding. The question of whether or not avoidance of cow's milk protein in infancy will prevent Type 1 diabetes can, however, be tested in an international randomized clinical trial of infant diets, which is currently under review.


Enhanced detection of broadband incoherent light with nanoridge plasmonics.
Emerging photonic integrated circuit technologies require integrative functionality at ultrahigh speed and dimensional compatibility with ultrasmall electronics. Plasmonics offers a promise of addressing these challenges with novel nanophotonic approaches for on-chip information processing or sensing applications. Short communication range and strong light-matter interaction enabled by on-chip plasmonics allow us to extend beyond a conventional approach of integrating coherent and narrowband light source. Such hybrid electronic and photonic interconnection desires a on-chip photodetector that is highly responsive to broadband incoherent light, yet provides elegant design for nanoscale integration. Here we demonstrate an ultracompact broadband photodetection with greatly enhanced photoresponsivity using plasmonic nanoridge geometry. The nanoridge photodetector confines a wide spectrum of electromagnetic energy in a nanostructure through the excitation of multiple plasmons, which thus enables the detection of weak and broadband light. With nanoscale design, material, and dimensional compatibility for the integration, the nanoridge photodetector opens up a new possibility of highly sensitive on-chip photodetection for future integrated circuits and sensing applications.


An In Vitro Comparative Evaluation of Antimicrobial Efficacy of Propolis, Morinda Citrifolia Juice, Sodium Hypochlorite and Chlorhexidine on Enterococcus faecalis and Candida albicans.
To evaluate the antimicrobial effectiveness of Propolis, Morinda citrifolia juice, Sodium hypochlorite and Chlorhexidine onEnterococcus feacalis (E. feacalis) and Candida albicans (C. albicans), as endodontic irrigants. Four clinical isolates and one standard ATCC sample (29212) of E. feacalis and ATCC sample (90028) of C. albicans were inoculated into 5ml of peptone water each and incubated at 37° C for 3 to 4 hours to attain the turbidity corresponding to 0.5 McFarland standard CFU. We followed Disc and well diffusion Kirby-Bauer method to attain the zones of inhibition. Overall comparison of reagents revealed a significant difference among zones of inhibition. The standard concentration of 5% sodium hypochlorite, 2% chlorhexidine, 10% Propolis and 100% Morinda citrifolia juice illustrated the maximum inhibition zone for both test organisms. All four reagents had an antimicrobial effect on the microorganisms tested. Sodium hypochlorite and Chlorhexidine were more effectual than Propolis and Morinda citrifolia juice and there was increased antimicrobial efficacy with increasing concentrations. A study for finding safe herbal agents that can be used as endodontic irrigants revealed that Propolis, Morinda citrifolia juice has antibiotic properties and can replace routinely used agents thereby limiting the side effects.


The doctor-patient relationship in living donor kidney transplantation.
A therapeutic and effective doctor-patient relationship and patient-doctor relationship is at the core of all successful medical care. The medical and psychological evaluation of a potential kidney donor serves to protect the long-term health of both the donor and the potential recipient. Careful assessment of risk and donor education is at the core of donor evaluation and the decision to progress with donation requires refined clinical judgment by the medical team and critical thinking by the donor. Increasing pressure to increase the numbers of living donor transplants and suggestions by some that the process should be commercialized make it timely to consider the nature of the relationship between the doctor and the patient in the unusual circumstance of living donation. A high rate of complications in recipients of purchased kidneys and a lack of knowledge of the fate of paid donors have been reported. Commercialization of transplantation undermines the therapeutic doctor-patient relationship and threatens the healthy development of the international transplant endeavor.


Human Basal Tear Peptidome Characterization by CID, HCD, and ETD Followed by in Silico and in Vitro Analyses for Antimicrobial Peptide Identification.
Endogenous peptides are valuable targets in the analysis of biological processes. The tear film contains proteins and peptides released by the tear duct mucosal cells, including antimicrobial peptides involved in the protection against exogenous pathogens; however, the peptide content of the tear liquid remains poorly characterized. We analyzed naturally occurring peptides isolated from human basal tears. Mass spectrometry analysis of endogenous peptides presents a number of drawbacks, including size heterogeneity and nonpredictable fragmentation patterns, among others. Therefore, CID, ETD, and HCD methods were used for the characterization of the tear peptide content. The contribution of DMSO as an additive of the chromatographic solvents was also evaluated. We identified 157, 131, and 122 peptides using CID-, ETD-, and HCD-based methods, respectively. Altogether, 234 different peptides were identified, leading to the generation of the biggest data set of endogenous tear peptides to date. The antimicrobial activity prediction analysis performed in silico revealed different putative antimicrobial peptides. Two of the extracellular glycoprotein lacritin peptides were de novo synthesized, and their antimicrobial activity was confirmed in vitro. Our findings demonstrate the benefits of using different fragmentation methods for the analysis of endogenous peptides and provide a useful approach for the discovery of peptides with antimicrobial activity.


Self-motion perception in the elderly.
Self-motion through space generates a visual pattern called optic flow. It can be used to determine one's direction of self-motion (heading). Previous studies have already shown that this perceptual ability, which is of critical importance during everyday life, changes with age. In most of these studies subjects were asked to judge whether they appeared to be heading to the left or right of a target. Thresholds were found to increase continuously with age. In our current study, we were interested in absolute rather than relative heading judgments and in the question about a potential neural correlate of an age-related deterioration of heading perception. Two groups, older test subjects and younger controls, were shown optic flow stimuli in a virtual-reality setup. Visual stimuli simulated self-motion through a 3-D cloud of dots and subjects had to indicate their perceived heading direction after each trial. In different subsets of experiments we varied individually relevant stimulus parameters: presentation time, number of dots in the display, stereoscopic vs. non-stereoscopic stimulation, and motion coherence. We found decrements in heading performance with age for each stimulus parameter. In a final step we aimed to determine a putative neural basis of this behavioral decline. To this end we modified a neural network model which previously has proven to be capable of reproduce and predict certain aspects of heading perception. We show that the observed data can be modeled by implementing an age related neuronal cell loss in this neural network. We conclude that a continuous decline of certain aspects of motion perception, among them heading, might be based on an age-related progressive loss of groups of neurons being activated by visual motion.


Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients.
The 9q Subtelomeric Deletion Syndrome (9qSTDS) is clinically characterized by mental retardation, childhood hypotonia, and facial dysmorphisms. Haploinsufficiency of the EHMT1 gene has been demonstrated to be responsible for its core phenotype. In a significant number of patients behavioral abnormalities like aggression, impulsivity, and chaotic behaviors are present as well as epileptic phenomena. Reports about the developmental, behavioral, and neuropsychiatric aspects of 9qSTDS are scarce and mostly limited to young patients only. In this report, the behavioral and neuropsychiatric characteristics of one male and one female middle-aged patient are described in whom the genetic diagnosis, interstitial and telomeric 9q deletion, respectively, was established recently. In both patients a remarkable sleep disturbance, characterized by frequent awakenings and daytime sleepiness, was present as well as a prominent apathy syndrome. The observed motor signs such as rigid flexure of the arms and finger stereotypies persisted over a period of many years and could therefore not be viewed as symptoms of catatonia. It is concluded that the proposed behavioral phenotype of 9qSTDS comprises at least an erratic sleep pattern and an enduring severe apathy.


Adaptation in single units in visual cortex: the tuning of aftereffects in the spatial domain.
Cat striate cortical neurons were investigated using a new method of studying adaptation aftereffects. Stimuli were sinusoidal gratings of variable contrast, spatial frequency, and drift direction and rate. A series of alternating adapting and test trials was presented while recording from single units. Control trials were completely integrated with the adapted trials in these experiments. Every cortical cell tested showed selective adaptation aftereffects. Adapting at suprathreshold contrasts invariably reduced contrast sensitivity. Significant aftereffects could be observed even when adapting at low contrasts. The spatial-frequency tuning of aftereffects varied from cell to cell. Adapting at a given spatial frequency generally resulted in a broad response reduction at test frequencies above and below the adapting frequency. Many cells lost responses predominantly at frequencies lower than the adapting frequency. The tuning of aftereffects varied with the adapting frequency. In particular, the strongest aftereffects occurred near the adapting frequency. Adapting at frequencies just above the optimum for a cell often altered the spatial-frequency tuning by shifting the peak toward lower frequencies. The fact that the tuning of aftereffects did not simply match the tuning of the cell, but depended on the adapting stimulus, implies that extrinsic mechanisms are involved in adaptation effects.


Development of a simple in vitro assay for estimating net rumen acid load from diet ingredients.
The objective of these experiments was to develop a simple in vitro technique for evaluating the production and neutralization of acid as feeds ferment in the rumen. An in vitro approach was adopted to eliminate animal factors. The procedure was based on the method of Tilley and Terry, with some modifications developed in this project. Residual acidity (acidogenicity value) was determined by the dissolution of Ca from CaCO3 powder added to the media at the end of 24-h incubations. Acidogenicity values (AV) were higher when 20% strength buffer was used, while lowering buffer pH increased values, equally across all feeds. There was no effect of donor animal diet, but considerable day-to-day variation in the fermentation activity of rumen fluid. This variation likely reflected the substrate preferences of differing microbial populations, so that several standard feeds may be required to account for this effect. A series of 28 diverse feed ingredients was evaluated for AV using a mixture design, with 85 combinations of ingredients: 100% of each ingredient (n = 28); 50% of each ingredient and an equal mixture of all others (n = 28); equal mixture of all ingredients, excluding one (n = 28); and an equal mixture of all ingredients (n = 1). The effects of most ingredients on AV were essentially linear, though some extreme ingredients showed nonlinear effects. Protein sources had low AV, forages intermediate AV and starchy feeds high AV. Calcium contained within feeds contributed to AV, particularly for legumes, sugar beet pulp, and citrus pulp, and must be accounted for.


Where am I? The neurological correlates of self and other.
Although still controversial, there is growing evidence that information about the self is processed in the right hemisphere, specifically the right frontal lobe. It has also been hypothesized that self-awareness and mental state attribution (inferences about the mental experience of others) are part of a similar neurocognitive process [Am. J. Primatol. 2 (1982) 237]. Here we measured blood oxygen level-dependent (BOLD) activity when viewing self-faces and when thinking about the mental states of others. We found significant activation in right superior, middle, and inferior frontal gyri when activation associated with self-face processing was compared with activation associated with familiar famous face processing. Mental state attribution, as measured by a computerized version of the Mind in the Eyes--Revised Test, was associated with activation in the right superior and middle frontal gyri, medial superior frontal gyrus, and left middle frontal gyrus and superior temporal gyrus/temporal pole. Self-face recognition and mental state attribution were colocalized to the middle and superior frontal gyri in the right hemisphere. These data support a model developed over two decades ago by Gallup [Am. J. Primatol. 2 (1982) 237] that posits that self-awareness and mental state attribution are part of a shared neurocognitive suite of processing and that neural architecture implicated in processing knowledge about the self is called upon when inferring knowledge in others.


Using Information and Communication Technologies to Prevent Suicide Among Secondary School Students in Two Regions of Chile: A Randomized Controlled Trial.
Background: There is an increasing concern for addressing suicide among adolescents in Latin America. Recent mental health policies encourage the development and implementation of preventive interventions for suicide. Such initiatives, however, have been scarcely developed, even in countries with solid mental health services such as Chile. The use of information and communications technology (ICT) might contribute to create accessible, engaging, and innovative platforms to promote well-being and support for adolescents with mental health needs and suicide risk. Objective: To evaluate a program based on ICT to prevent suicide and enhance mental health among adolescents in Chile. A cluster randomized controlled trial (RCT) will be conducted including 428 high-school students aged 18-14 years in two regions of Chile. Study procedures will take place as follows: (1) design of the intervention model and creation of prototype; (2) selection and randomization of the participating public schools; (3) implementation of the 3-month intervention and evaluation at baseline, post-intervention period, and a 2-month follow-up. Suicidal ideation at the 2-month follow up is the primary outcome in this study. Secondary outcomes include negative psychological outcomes (e.g., stigma, depression, anxiety) as well as a number of protective psychological and social factors. Indicators regarding the study implementation will be also gathered. Here we describe a novel program based on technological devices and aimed to target youth suicide in Chile. This is the first clinical trial of such a program in Latin America, and to our knowledge, the first of its kind in any middle income country. Trial Registration: gov Identifier: NCT03514004.


Longitudinal Follow-Up of Two Patients with Dysspondyloenchondromatosis due to Novel Heterozygous Mutations in COL2A1.
Dysspondyloenchondromatosis (DSC) is a rare form of generalized enchondromatosis and characterized by short stature with unequal limb length, multiple enchondromas in metaphyseal and diaphyseal parts of the long tubular bones, and progressive kyphoscoliosis. Although the COL2A1 gene mutation was found to be responsible for DSC, a case of DSC with no pathogenic mutation in the COL2A1 gene has also been reported, suggesting that the condition is genetically heterogeneous. Here, we report 2 novel heterozygous mutations in COL2A1 in 2 patients with DSC. They had prenatal onset short stature with unequal limb length and generalized enchondroma-like lesions in metaphyseal and diaphyseal parts of the long tubular bones, and osteopenia. The first patient was diagnosed at 3 months of age and followed for 10.5 years. Severe lumbosacral scoliosis and recurrent fractures were observed. The second patient was diagnosed at the age of 4 years. Mild deterioration in scoliosis was observed during the 3-year-long follow-up period. However, skeletal radiography of both patients showed the improvement of enchondromatous lesions. In conclusion, we verified that the COL2A1 gene mutations are responsible for the DSC phenotype. We observed severe osteopenia and fractures which were not reported previously.


Diode laser--pumped solid-state lasers.
Diode laser-pumped solid-state lasers are efficient, compact, all solid-state sources of coherent optical radiation. Major advances in solid-state laser technology have historically been preceded by advances in pumping technology. The helical flash lamps used to pump early ruby lasers were superseded by the linear flash lamp and arc lamp now used to pump neodymium-doped yttrium-aluminum-garnet lasers. The latest advance in pumping technology is the diode laser. Diode laser-pumped neodymium lasers have operated at greater than 10 percent electrical to optical efficiency in a single spatial mode and with linewidths of less than 10 kilohertz. The high spectral power brightness of these lasers has allowed frequency extension by harmonic generation in nonlinear crystals, which has led to green and blue sources of coherent radiation. Diode laser pumping has also been used with ions other than neodymium to produce wavelengths from 946 to 2010 nanometers. In addition, Q-switched operation with kilowatt peak powers and mode-locked operation with 10-picosecond pulse widths have been demonstrated. Progress in diode lasers and diode laser arrays promises all solid-state lasers in which the flash lamp is replaced by diode lasers for average power levels in excess of tens of watts and at a price that is competitive with flash lamp-pumped laser systems. Power levels exceeding 1 kilowatt appear possible within the next 5 years. Potential applications of diode laser-pumped solid-state lasers include coherent radar, global sensing from satellites, medical uses, micromachining, and miniature visible sources for digital optical storage.


The mammalian exercise pressor reflex in health and disease.
The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise. In heart failure, the cardiovascular response to exercise is augmented. Owing to the peripheral skeletal myopathy that develops in heart failure (e.g. muscle atrophy, decreased peripheral blood flow, fibre-type transformation and reduced oxidative capacity), the exercise pressor reflex has been implicated as a possible mechanism by which the cardiovascular response to physical activity is exaggerated in this disease. Accumulating evidence supports this conclusion. This review therefore focuses on the role of the exercise pressor reflex in regulating the cardiovascular system during exercise in both health and disease. Updates on our current understanding of the exercise pressor reflex neural pathway as well as experimental models used to study this reflex are presented. In addition, special emphasis is placed on the changes in exercise pressor reflex activity that develop in heart failure, including the contributions of the muscle mechanoreflex and metaboreflex to this pressor reflex dysfunction.


Electrostatic interactions between particles through heterogeneous fluid phases.
We investigated the electrostatic interactions between particles acting through heterogeneous fluid phases. An oil lens system floating on the surface of water was used to trap particles at different fluid-fluid interfaces. The inner particles are located at the centrosymmetrically curved oil-water interface inside the oil lens while satellite particles are located at the curved air-water interface, separated by a particular distance from the triple phase boundary. The satellite particles are likely to be captured in an energy minimum state due to electrostatic repulsions by the inner particles balanced with the gravity-induced potential energy. As the size of the oil lens decreases upon evaporation, the satellite particles escape from the gravitational confinement at a critical moment. The self-potential values of the inner particles and the satellite particles were calculated by employing an energy balance and the experimentally obtained geometric parameter values. It was found that the self-potential values of the inner particles decrease as oil evaporates over time and that the magnitude of the self-potential of the satellite particles is a hundred times larger than that of the inner particles. These results demonstrate significant effects of the thickness and shape of the nonpolar superphase on the electrostatic interactions between the particles trapped at different fluid-fluid interfaces.


Physician-Assisted Suicide and Euthanasia: Emerging Issues From a Global Perspective.
Medical professional societies have traditionally opposed physician-assisted suicide and euthanasia (PAS-E), but this opposition may be shifting. We present 5 reasons why physicians shouldn't be involved in PAS-E. 1. Slippery slopes: There is evidence that safeguards in the Netherlands and Belgium are ineffective and violated, including administering lethal drugs without patient consent, absence of terminal illness, untreated psychiatric diagnoses, and nonreporting; 2. Lack of self-determination: Psychological and social motives characterize requests for PAS-E more than physical symptoms or rational choices; many requests disappear with improved symptom control and psychological support; 3. Inadequate palliative care: Better palliative care makes most patients physically comfortable. Many individuals requesting PAS-E don't want to die but to escape their suffering. Adequate treatment for depression and pain decreases the desire for death; 4. Medical professionalism: PAS-E transgresses the inviolable rule that physicians heal and palliate suffering but never intentionally inflict death; 5. Differences between means and ends: Proeuthanasia advocates look to the ends (the patient's death) and say the ends justify the means; opponents disagree and believe that killing patients to relieve suffering is different from allowing natural death and is not acceptable. Physicians have a duty to eliminate pain and suffering, not the person with the pain and suffering. Solutions for suffering lie in improving palliative care and social conditions and addressing the reasons for PAS-E requests. They should not include changing medical practice to allow PAS-E.


Automated counting of platelets on the Bayer ADVIA 120 analyser.
Precise counting of platelets is difficult particularly in the low thrombocytopenic range or when large platelets exist. The recently available Bayer ADVIA 120 analyser uses a method of counting platelets based on two dimensional laser light scatter. We have evaluated this technique on an analysis of 217 peripheral blood samples and found significant differences in platelet counts compared with values obtained by impedance technology, when the causes of thrombocytopenia were due to peripheral platelet consumption. Moreover, such differences were more marked in those samples from severely thrombocytopenic individuals with large platelets on the blood film. These differences, which warrant further study, may have significant implications for the management of patients with very low platelet counts.


Core Genome Multi-locus Sequence Typing Analyses of Leptospira spp. Using the Bacterial Isolate Genome Sequence Database.
With the advent of whole-genome sequencing (WGS), comparative analysis has led to the use of core genome MLST (cgMLST) schemes for the high-resolution reproducible typing of bacterial isolates. In cgMLST, hundreds of loci are used for gene-by-gene comparisons of assembled genomes for studying the genetic diversity of clinically important pathogens. Combination of the cgMLST data and metadata of the isolates is useful for epidemiological investigations.Here we present a cgMLST scheme for the high-resolution typing of isolates from the whole Leptospira genus, enabling identification at the level of species, clades, clonal groups, and sequence types. We show several examples how the cgMLST Leptospira database, which is a publicly available web-based database, can be used for the analyses of WGS data of Leptospira isolates. This effort was undertaken in order to facilitate international collaborations and support the global surveillance of leptospirosis.


Breathers and thermal relaxation as a temporal process: a possible way to detect breathers in experimental situations.
Breather stability and longevity in thermally relaxing nonlinear arrays is investigated under the scrutiny of the analysis and tools employed for time series and state reconstruction of a dynamical system. We briefly review the methods used in the analysis and characterize a breather in terms of the results obtained with such methods. Our present work focuses on spontaneously appearing breathers in thermal Fermi-Pasta-Ulam arrays but we believe that the conclusions are general enough to describe many other related situations; the particular case described in detail is presented as another example of systems where three incommensurable frequencies dominate their chaotic dynamics (reminiscent of the Ruelle-Takens scenario for the appearance of chaotic behavior in nonlinear systems). This characterization may also be of great help for the discovery of breathers in experimental situations where the temporal evolution of a local variable (like the site energy) is the only available/measured data.


Modification of the existing maximum residue levels for cyflufenamid in blackberries and raspberries.
In accordance with Article 6 of Regulation (EC) No 396/2005, the Federal Public Service (FPS) Health, Food chain Safety and Environment submitted a request on behalf of Belgium (evaluating Member State, EMS) to modify the existing maximum residue levels (MRLs) for the active substance cyflufenamid in blackberries and raspberries (red and yellow). The data submitted in support of the request were found to be sufficient to derive MRL proposals for blackberries and raspberries (red and yellow). Adequate analytical methods are available to control the residues of cyflufenamid according to the enforcement residue definition on the commodities under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of cyflufenamid according to the reported agricultural practices is unlikely to present a risk to consumer health.


Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility.
We have validated the association of two genes on chromosome 20q13.31-33 with tuberculosis susceptibility. A previous genome-wide linkage study performed by Cooke et al identified the genes melanocortin-3-receptor (MC3R) and cathepsin Z (CTSZ) as possible candidates in tuberculosis susceptibility. MC3R has been implicated in obesity studies and is known to play a role in many biological systems including the regulation of energy homeostasis and fat metabolism. CTSZ has been detected in immune cells, such as macrophages and monocytes, and it is hypothesized that the protein may play a role in the immune response. In our South African population a case-control study confirmed the previously reported association with a single-nucleotide polymorphism (SNP) in CTSZ and found an association in MC3R with a SNP not previously implicated in tuberculosis susceptibility. Six SNPs in MC3R and eight in CTSZ were genotyped and haplotypes were inferred. SNP rs6127698 in the promoter region of MC3R (cases = 498; controls = 506) and rs34069356 in the 3'UTR of CTSZ (cases = 396; controls = 298) both showed significant association with tuberculosis susceptibility (P = 0.0004 and < 0.0001, respectively), indicating that pathways involving these proteins, not previously researched in this disease, could yield novel therapies for tuberculosis.


Systemic dissemination of viral vectors during intratumoral injection.
Intratumoral injection is a routine method for local viral gene delivery that may improve interstitial transport of viral vectors in tumor tissues and reduce systemic toxicity. However, the concentration of transgene products in normal organs, such as in the liver, may still exceed normal tissue tolerance if the products are highly toxic. The elevated concentration in normal tissues is likely to be caused by the dissemination of viral vectors from the tumor. Therefore, we investigated transgene expression in the liver, the serum, and a mouse mammary carcinoma (4T1) in mice after intratumoral injection of adenoviral vectors for mouse interleukin-12, luciferase, enhanced green fluorescence protein, or beta-galactosidase. We also performed numerical simulations of virus transport in tumors after intratumoral injection, based on the Krogh cylinder model. Our experimental data and numerical simulations demonstrated that virus dissemination was significant in mice and it occurred mainly during the intratumoral injection. To reduce virus dissemination, we mixed these vectors with a viscous alginate solution and injected the mixture into the tumors. Our data showed that the alginate solution could significantly reduce virus dissemination while having minimal effects on transgene expression in tumors and on interleukin-12-induced tumor growth delay. These data suggest that virus dissemination is a potential problem in local viral gene therapy of cancer and that the dissemination could be significantly reduced by the alginate solution without compromising the efficacy of gene therapy.


Error analysis of robust optical flow estimation by least median of squares methods for the varying illumination model.
The apparent pixel motion in an image sequence, called optical flow, is a useful primitive for automatic scene analysis and various other applications of computer vision. In general, however, the optical flow estimation suffers from two significant problems: the problem of illumination that varies with time and the problem of motion discontinuities induced by objects moving with respect to either other objects or with respect to the background. Various integrated approaches for solving these two problems simultaneously have been proposed. Of these, those that are based on the LMedS (Least Median of Squares) appear to be the most robust. The goal of this paper is to carry out an error analysis of two different LMedS-based approaches, one based on the standard LMedS regression and the other using a modification thereof as proposed by us recently. While it is to be expected that the estimation accuracy of any approach would decrease with increasing levels of noise, for LMedS-like methods, it is not always clear as to how much of that decrease in performance can be attributed to the fact that only a small number of randomly selected samples is used for forming temporary solutions. To answer this question, our study here includes a baseline implementation in which all of the image data is used for forming motion estimates. We then compare the estimation errors of the two LMedS-based methods with the baseline implementation. Our error analysis demonstrates that, for the case of Gaussian noise, our modified LMedS approach yields better estimates at moderate levels of noise, but is outperformed by the standard LMedS method as the level of noise increases. For the case of salt-and-pepper noise, the modified LMedS method consistently performs better than the standard LMedS method.


Sodium and calcium gating currents in an Aplysia neurone.
1. Currents generated by depolarizing the hyperpolarizing voltage pulses were recorded at temperatures of 4--12 degrees C in the voltage-clamped soma of R15 in aplysia abdominal ganglia exposed to solutions which suppressed ionic currents. 2. Subtraction of linear capacitive and leakage currents from current generated by voltage pulses to levels more positive than -20mV revealed non-linear transient outward displacement currents at the onset of the clamp step (on-current) and transient inward displacement currents after the membrane potential returned to the holding potential (off-current). Only on-currents were studied. 3. Pulses to membrane potentials of -20 to 0 mV generated a displacement current with rapid onset and exponential decay. At membrane potentials more positive than o mV a second displacement current with a much slower onset and slower exponential decay was seen. Because the different threshold potentials for the two displacement currents were close to the different threshold potentials for Na and Ca ion currents, the two displacement currents were called Na and Ca 'gating' currents. 4. The amount of charge transfer during Ca gating currents increased sigmoidally with increasing depolarization, reaching a maximum at +30 to +40 mV. Half-maximum charge transfer occurred at +15 mV. 5. Total charge movement during Ca gating currents was maximal with holding potentials of -30 to -40 mV. More positive or more negative holding potentials produced a decrease in charge movement. 6. The time course of the gating currents, but not the total charge displaced, was very sensitive to temperature. The time constant of decay of Ca gating currents had a Q10 of about 3, whereas the total amount of charge displaced had a Q10 of 1.2. 7. The charge transfer during both Na and Ca gating currents and the amplitude of Na and Ca (but not K) ionic currents were reduced in solutions containing 1 mm-n-octanol.


DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality.
The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. ClinicalTrials.gov NCT01959529.


Automatic, three-segment, MR-based attenuation correction for whole-body PET/MR data.
The combination of positron emission tomography (PET) and magnetic resonance (MR) tomography in a single device is anticipated to be the next step following PET/CT for future molecular imaging application. Compared to CT, the main advantages of MR are versatile soft tissue contrast and its capability to acquire functional information without ionizing radiation. However, MR is not capable of measuring a physical quantity that would allow a direct derivation of the attenuation values for high-energy photons. To overcome this problem, we propose a fully automated approach that uses a dedicated T1-weighted MR sequence in combination with a customized image processing technique to derive attenuation maps for whole-body PET. The algorithm automatically identifies the outer contour of the body and the lungs using region-growing techniques in combination with an intensity analysis for automatic threshold estimation. No user interaction is required to generate the attenuation map. The accuracy of the proposed MR-based attenuation correction (AC) approach was evaluated in a clinical study using whole-body PET/CT and MR images of the same patients (n = 15). The segmentation of the body and lung contour (L-R directions) was evaluated via a four-point scale in comparison to the original MR image (mean values >3.8). PET images were reconstructed using elastically registered MR-based and CT-based (segmented and non-segmented) attenuation maps. The MR-based AC showed similar behaviour as CT-based AC and similar accuracy as offered by segmented CT-based AC. Standardized uptake value (SUV) comparisons with reference to CT-based AC using predefined attenuation coefficients showed the largest difference for bone lesions (mean value ± standard variation of SUV(max): -3.0% ± 3.9% for MR; -6.5% ± 4.1% for segmented CT). A blind comparison of PET images corrected with segmented MR-based, CT-based and segmented CT-based AC afforded identical lesion detectability, but slight differences in image quality were found. Our MR-based attenuation correction method offers similar correction accuracy as offered by segmented CT. According to the specialists involved in the blind study, these differences do not affect the diagnostic value of the PET images.


Assessing the impact of continuous quality improvement/total quality management: concept versus implementation.
This study examines the relationships among organizational culture, quality improvement processes and selected outcomes for a sample of up to 61 U. S. hospitals. Primary data were collected from 61 U. S. hospitals (located primarily in the midwest and the west) on measures related to continuous quality improvement/total quality management (CQI/TQM), organizational culture, implementation approaches, and degree of quality improvement implementation based on the Baldrige Award criteria. These data were combined with independently collected data on perceived impact and objective measures of clinical efficiency (i.e., charges and length of stay) for six clinical conditions. The study involved cross-sectional examination of the named relationships. Reliable and valid scales for the organizational culture and quality improvement implementation measures were developed based on responses from over 7,000 individuals across the 61 hospitals with an overall completion rate of 72 percent. Independent data on perceived impact were collected from a national survey and independent data on clinical efficiency from a companion study of managed care. A participative, flexible, risk-taking organizational culture was significantly related to quality improvement implementation. Quality improvement implementation, in turn, was positively associated with greater perceived patient outcomes and human resource development. Larger-size hospitals experienced lower clinical efficiency with regard to higher charges and higher length of stay, due in part to having more bureaucratic and hierarchical cultures that serve as a barrier to quality improvement implementation. What really matters is whether or not a hospital has a culture that supports quality improvement work and an approach that encourages flexible implementation. Larger-size hospitals face more difficult challenges in this regard.


Factors affecting symptomatic vs asymptomatic vein graft stenoses in lower extremity bypass grafts.
To determine differences in patients undergoing lower extremity vein graft revisions presenting with and without recurrence of preoperative symptoms. Retrospective case-control study of a prospectively maintained database. University and veterans' administration hospitals Two hundred nineteen lower extremity vein graft revisions were performed in 161 patients from January 1995 to January 2007. Patients were categorized as asymptomatic or symptomatic (recurrence of initial symptoms) at the time of revision. Univariate analysis was performed to assess differences in patient demographics, details of initial operation, site of recurrent lesion, and follow-up surveillance data between symptomatic and asymptomatic patients. Independent predictors of symptomatic recurrence were identified with multivariate logistic regression. Primary assisted patency was compared between revisions performed for symptomatic and asymptomatic lesions. Vein graft stenoses were asymptomatic in 125 cases (57%) and symptomatic in 94 cases (43%). Symptomatic recurrences were associated with a significantly greater drop in ankle brachial index than asymptomatic lesions (mean [SD], 0.21 [0.03] vs 0.11 [0.02]; P = .003). Distal graft or outflow lesions were significantly associated with symptom recurrence (P = .048). Multivariate analysis identified ankle brachial index decrease (odds ratio, 6.803; 95% confidence interval, 1.418-32.258; P = .02) and the use of alternate graft conduit (odds ratio, 2.633, 95% confidence interval, 1.243-5.578; P = .01) as independent predictors of recurrent symptoms. Overall 5-year patency was the same regardless of preoperative symptoms (82% symptomatic and 88% asymptomatic; P = .30). Symptomatic recurrences are associated with larger decreases in ankle brachial index, distal lesions, and alternate conduit grafts. Duplex surveillance is necessary to identify asymptomatic vein graft stenoses. Because graft patency is independent of preoperative symptoms, surveillance consisting of clinical follow-up with ankle brachial index evaluation warrants further consideration.


Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
Chronic hepatitis is accompanied by progressive deposit of hepatic fibrosis, which may lead to cirrhosis. Evaluation of liver fibrosis is, thus, of great clinical interest and, up to now, has been assessed with liver biopsy. This work aims to evaluate a new noninvasive device to quantify liver fibrosis: the shear elasticity probe or fibroscan. This device is based on one-dimensional (1-D) transient elastography, a technique that uses both ultrasound (US) (5 MHz) and low-frequency (50 Hz) elastic waves, whose propagation velocity is directly related to elasticity. The intra- and interoperator reproducibility of the technique, as well as its ability to quantify liver fibrosis, were evaluated in 106 patients with chronic hepatitis C. Liver elasticity measurements were reproducible (standardized coefficient of variation: 3%), operator-independent and well correlated (partial correlation coefficient = 0.71, p < < 0.0001) to fibrosis grade (METAVIR). The areas under the receiver operating characteristic (ROC) curves were 0.88 and 0.99 for the diagnosis of patients with significant fibrosis (>/= F2) and with cirrhosis ( = F4), respectively. The Fibroscan is a noninvasive, painless, rapid and objective method to quantify liver fibrosis.


Biased escorts: offspring sex, not relatedness explains alloparental care patterns in a cooperative breeder.
Kin selection theory predicts that animals should direct costly care where inclusive fitness gains are highest. Individuals may achieve this by directing care at closer relatives, yet evidence for such discrimination in vertebrates is equivocal. We investigated patterns of cooperative care in banded mongooses, where communal litters are raised by adult 'escorts' who form exclusive caring relationships with individual pups. We found no evidence that escorts and pups assort by parentage or relatedness. However, the time males spent escorting increased with increasing relatedness to the other group members, and to the pup they had paired with. Thus, we found no effect of relatedness in partner choice, but (in males) increasing helping effort with relatedness once partner choices had been made. Unexpectedly, the results showed clear assortment by sex, with female carers being more likely to tend to female pups, and male carers to male pups. This sex-specific assortment in helping behaviour has potential lifelong impacts on individual development and may impact the future size and composition of natal groups and dispersing cohorts. Where relatedness between helpers and recipients is already high, individuals may be better off choosing partners using other predictors of the costs and benefits of cooperation, without the need for possibly costly within-group kin discrimination.


Characterization of Physiologic (18)F FSPG Uptake in Healthy Volunteers.
Purpose To evaluate the normal biodistribution and kinetics of (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid ((18)F FSPG) in healthy volunteers and to compare (18)F FSPG mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) with those of (18)F fluorodeoxyglucose (FDG) across a variety of organs. Materials and Methods This protocol was reviewed and approved by all appropriate regulatory authorities. An 8-mCi (±10%) dose of (18)F FSPG was given to five subjects (three women, two men), and seven whole-body positron emission tomography (PET) scans were performed 5, 10, 20, 30, 45, 150, and 240 minutes after injection. Regions of interest were analyzed on the resultant (18)F FSPG images to evaluate the kinetics of this radiotracer. The images obtained 45 minutes after injection were used to measure SUVmean and SUVmax in additional regions of the body. These values were compared with similar values obtained with (18)F FDG PET published previously. Descriptive statistics, including average and standard deviation across the five subjects, were used. (18)F FSPG SUVmean and SUVmax were compared. Results On the (18)F FSPG images obtained 45 minutes after injection, there was only low-grade background activity in the majority of analyzed regions. Prominent activity was seen throughout the pancreas. Clearance of the radiotracer through the kidneys and collection in the bladder also were seen. SUV quantification shows notable differences between (18)F FSPG and (18)F FDG in the pancreas ((18)F FSPG SUVmean, 8.2; (18)F FDG SUVmean, 1.3), stomach ((18)F FSPG SUVmax, 3.6; (18)F FDG SUVmax, 1.6), and brain ((18)F FSPG SUVmean, 0.08; (18)F FDG SUVmean, 7.8). The kinetic data showed rapid clearance of the radiotracer from the blood pool and most organs, except the pancreas. Conclusion (18)F FSPG is a PET radiopharmaceutical characterized by rapid clearance from most healthy tissues, except the pancreas and kidneys. A consistent biodistribution pattern was observed with low background uptake. The physiologic uptake of this new radiotracer throughout the body is described in more detail, which is important for improved interpretative accuracy and understanding potential clinical applications. (©) RSNA, 2016.


Identifying blood biomarkers and physiological processes that distinguish humans with superior performance under psychological stress.
Attrition of students from aviation training is a serious financial and operational concern for the U.S. Navy. Each late stage navy aviator training failure costs the taxpayer over $1,000,000 and ultimately results in decreased operational readiness of the fleet. Currently, potential aviators are selected based on the Aviation Selection Test Battery (ASTB), which is a series of multiple-choice tests that evaluate basic and aviation-related knowledge and ability. However, the ASTB does not evaluate a person's response to stress. This is important because operating sophisticated aircraft demands exceptional performance and causes high psychological stress. Some people are more resistant to this type of stress, and consequently better able to cope with the demands of naval aviation, than others. Although many psychological studies have examined psychological stress resistance none have taken advantage of the human genome sequence. Here we use high-throughput -omic biology methods and a novel statistical data normalization method to identify plasma proteins associated with human performance under psychological stress. We identified proteins involved in four basic physiological processes: innate immunity, cardiac function, coagulation and plasma lipid physiology. The proteins identified here further elucidate the physiological response to psychological stress and suggest a hypothesis that stress-susceptible pilots may be more prone to shock. This work also provides potential biomarkers for screening humans for capability of superior performance under stress.


Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease.
To describe the differences between patients with systemic sclerosis (SSc) having childhood versus adult onset evaluated at a single medical center. Patients were divided into those with childhood onset (first SSc symptom or finding before age 16 yrs) and those with early adult and late adult onset. The 3 groups were compared with respect to disease classification, clinical, laboratory and serologic data, and survival. One hundred eleven childhood onset SSc cases seen between 1960 and 2003 were compared with 2559 adult onset SSc cases (1087 with onset age 16-40 and 1472 with onset after age 40 yrs) first evaluated between 1972 and 2001. Age distribution at onset was unimodal, suggesting that childhood disease is part of the spectrum of adult onset SSc. A significantly greater proportion of childhood onset patients had overlap syndromes, most frequently with polymyositis-dermatomyositis (PM-DM), and skeletal muscle involvement. Children with diffuse cutaneous (dc) SSc had significantly lower maximum mean total skin thickness scores than adult patients with dcSSc. Renal involvement was uncommon in childhood onset cases, and the frequency increased with age of onset. Serum anti-PM-Scl and anti-U1RNP antibodies were detected significantly more frequently in childhood than in adult onset cases. In contrast, anti-RNA polymerase III and anticentromere antibodies were found significantly more frequently in adults. Survival was significantly better among childhood than all adult onset cases combined, but similar to survival in young adult onset SSc cases. Scleroderma heart disease was a frequent cause of death among children with SSc. Patients with juvenile onset SSc more frequently have an overlap syndrome with PM-DM, higher frequency of skeletal muscle involvement, serum anti-PM-Scl and anti-U1RNP antibody, fatal cardiac disease, and improved survival compared with adult onset SSc cases.


Multichannel Electrotactile Feedback With Spatial and Mixed Coding for Closed-Loop Control of Grasping Force in Hand Prostheses.
Providing somatosensory feedback to the user of a myoelectric prosthesis is an important goal since it can improve the utility as well as facilitate the embodiment of the assistive system. Most often, the grasping force was selected as the feedback variable and communicated through one or more individual single channel stimulation units (e.g., electrodes, vibration motors). In the present study, an integrated, compact, multichannel solution comprising an array electrode and a programmable stimulator was presented. Two coding schemes (15 levels), spatial and mixed (spatial and frequency) modulation, were tested in able-bodied subjects, psychometrically and in force control with routine grasping and force tracking using real and simulated prosthesis. The results demonstrated that mixed and spatial coding, although substantially different in psychometric tests, resulted in a similar performance during both force control tasks. Furthermore, the ideal, visual feedback was not better than the tactile feedback in routine grasping. To explain the observed results, a conceptual model was proposed emphasizing that the performance depends on multiple factors, including feedback uncertainty, nature of the task and the reliability of the feedforward control. The study outcomes, specific conclusions and the general model, are relevant for the design of closed-loop myoelectric prostheses utilizing tactile feedback.


Metabolomics profiling reveals novel markers for leukocyte telomere length.
Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers to investigate potential underlying pathways. Five metabolites were associated with LTL: Two lysolipids, 1-stearoylglycerophosphoinositol (P=1.6×10(-5)) and 1-palmitoylglycerophosphoinositol (P=1.6×10(-5)), were found to be negatively associated with LTL and positively associated with phospholipase A2 expression levels suggesting an involvement of fatty acid metabolism and particularly membrane composition in biological aging. Moreover, two gamma-glutamyl amino acids, gamma-glutamyltyrosine (P=2.5×10(-6)) and gamma-glutamylphenylalanine (P=1.7×10(-5)), were negatively correlated with LTL. Both are products of the glutathione cycle and markers for increased oxidative stress. Metabolites were also correlated with functional measures of aging, i.e. higher blood pressure and HDL cholesterol levels and poorer lung, liver and kidney function. Our results suggest an involvement of altered fatty acid metabolism and increased oxidative stress in human biological aging, reflected by LTL and age-related phenotypes of vital organ systems.