Activation of superior colliculi in humans during visual exploration

<p>Abstract</p> <p>Background</p> <p>Visual, oculomotor, and – recently – cognitive functions of the superior colliculi (SC) have been documented in detail in non-human primates in the past. Evidence for corresponding functions of the SC in humans is still rare. We examined activity changes in the human tectum and the lateral geniculate nuclei (LGN) in a visual search task using functional magnetic resonance imaging (fMRI) and anatomically defined regions of interest (ROI). Healthy subjects conducted a free visual search task and two voluntary eye movement tasks with and without irrelevant visual distracters. Blood oxygen level dependent (BOLD) signals in the SC were compared to activity in the inferior colliculi (IC) and LGN.</p> <p>Results</p> <p>Neural activity increased during free exploration only in the SC in comparison to both control tasks. Saccade frequency did not exert a significant effect on BOLD signal changes. No corresponding differences between experimental tasks were found in the IC or the LGN. However, while the IC revealed no signal increase from the baseline, BOLD signal changes at the LGN were consistently positive in all experimental conditions.</p> <p>Conclusion</p> <p>Our data demonstrate the involvement of the SC in a visual search task. In contrast to the results of previous studies, signal changes could not be seen to be driven by either visual stimulation or oculomotor control on their own. Further, we can exclude the influence of any nearby neural structures (e.g. pulvinar, tegmentum) or of typical artefacts at the brainstem on the observed signal changes at the SC. Corresponding to findings in non-human primates, our data support a dependency of SC activity on functions beyond oculomotor control and visual processing.</p

Sampling-Based Approaches to Improve Estimation of Mortality among Patient Dropouts: Experience from a Large PEPFAR-Funded Program in Western Kenya

Monitoring and evaluation (M&E) of HIV care and treatment programs is impacted by losses to follow-up (LTFU) in the patient population. The severity of this effect is undeniable but its extent unknown. Tracing all lost patients addresses this but census methods are not feasible in programs involving rapid scale-up of HIV treatment in the developing world. Sampling-based approaches and statistical adjustment are the only scaleable methods permitting accurate estimation of M&E indices.In a large antiretroviral therapy (ART) program in western Kenya, we assessed the impact of LTFU on estimating patient mortality among 8,977 adult clients of whom, 3,624 were LTFU. Overall, dropouts were more likely male (36.8% versus 33.7%; p = 0.003), and younger than non-dropouts (35.3 versus 35.7 years old; p = 0.020), with lower median CD4 count at enrollment (160 versus 189 cells/ml; p<0.001) and WHO stage 3-4 disease (47.5% versus 41.1%; p<0.001). Urban clinic clients were 75.0% of non-dropouts but 70.3% of dropouts (p<0.001). Of the 3,624 dropouts, 1,143 were sought and 621 had their vital status ascertained. Statistical techniques were used to adjust mortality estimates based on information obtained from located LTFU patients. Observed mortality estimates one year after enrollment were 1.7% (95% CI 1.3%-2.0%), revised to 2.8% (2.3%-3.1%) when deaths discovered through outreach were added and adjusted to 9.2% (7.8%-10.6%) and 9.9% (8.4%-11.5%) through statistical modeling depending on the method used. The estimates 12 months after ART initiation were 1.7% (1.3%-2.2%), 3.4% (2.9%-4.0%), 10.5% (8.7%-12.3%) and 10.7% (8.9%-12.6%) respectively. CONCLUSIONS/SIGNIFICANCE ABSTRACT: Assessment of the impact of LTFU is critical in program M&E as estimated mortality based on passive monitoring may underestimate true mortality by up to 80%. This bias can be ameliorated by tracing a sample of dropouts and statistically adjust the mortality estimates to properly evaluate and guide large HIV care and treatment programs

Fast- or Slow-inactivated State Preference of Na+ Channel Inhibitors: A Simulation and Experimental Study

Sodium channels are one of the most intensively studied drug targets. Sodium channel inhibitors (e.g., local anesthetics, anticonvulsants, antiarrhythmics and analgesics) exert their effect by stabilizing an inactivated conformation of the channels. Besides the fast-inactivated conformation, sodium channels have several distinct slow-inactivated conformational states. Stabilization of a slow-inactivated state has been proposed to be advantageous for certain therapeutic applications. Special voltage protocols are used to evoke slow inactivation of sodium channels. It is assumed that efficacy of a drug in these protocols indicates slow-inactivated state preference. We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e.g., a shift of the “steady-state slow inactivation curve”), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast- and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery, respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated

Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial

<p>Abstract</p> <p>Background</p> <p>Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.</p> <p>Methods/Design</p> <p>This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 (¹²⁵I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with ¹²⁵I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during ¹²⁵I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.</p> <p>The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.</p> <p>Discussion</p> <p>To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.</p> <p>Trial registration</p> <p>UMIN000003992</p

A flowgraph model for bladder carcinoma

Background: Superficial bladder cancer has been the subject of numerous studies for many years, but the evolution of the disease still remains not well understood. After the tumor has been surgically removed, it may reappear at a similar level of malignancy or progress to a higher level. The process may be reasonably modeled by means of a Markov process. However, in order to more completely model the evolution of the disease, this approach is insufficient. The semi-Markov framework allows a more realistic approach, but calculations become frequently intractable. In this context, flowgraph models provide an efficient approach to successfully manage the evolution of superficial bladder carcinoma. Our aim is to test this methodology in this particular case. Results: We have built a successful model for a simple but representative case. Conclusion: The flowgraph approach is suitable for modeling of superficial bladder cancer.Rubio Navarro, G.; García Mora, MB.; Santamaria Navarro, C.; Pontones Moreno, JL. (2014). A flowgraph model for bladder carcinoma. Theoretical Biology and Medical Modelling. 11(1):1-11. doi:10.1186/1742-4682-11-S1-S3S111111van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009, 56: 430-42. 10.1016/j.eururo.2009.06.028.Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006, 49: 475-7.Fernández-Gómez J, Madero R, Solsona E, Unda M, neiro LMP, González M, Portillo J, Ojea A, Pertusa C, Rodríguez-Molina J, Camacho J, Rabadan M, Astobieta A, Montesinos M, Isorna S, nola PM, Gimeno A, Blas M, neiro JAMP: The EORTC Tables Overestimate the Risk of Recurrence and Progression in Patients with Non-Muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guerin: External Validation of the EORTC Risk Tables. Eur Urol. 2011, 60: 423-30. 10.1016/j.eururo.2011.05.033.Butler RW, Huzurbazar AV: Stochastic network models for survival analysis. J Am Statist Assoc. 1997, 92: 246-57. 10.1080/01621459.1997.10473622.Klein JP, Moeschberger ML: Suvival Analysis Techniques for Censored and Truncated Data. 2003, Springer, segundaNeuts MF: Matrix Geometric Solutions in Stocastic Models An Algoritmic Approach. 1981, Baltimore: The Johns Hopkins University PressLatouche G, Ramaswami V: Introduction to Matrix Analytic Methods in Stochastic Modeling. 1999, Philadelphia: SIAMPérez-Ocón R, Segovia MC: Modeling lifetimes using phase-type distributions. Risk, Reliability and Societal Safety, Proceedings of the European Safety and Reliability Conference 2007 (ESREL 2007). Edited by: Taylor & Francis re. 2007Huzurbazar A, Williams B: Incorporating Covariates in Flowgraph Models: Applications to Recurrent Event Data. Thecnometrics. 2010, 52: 198-208. 10.1198/TECH.2010.08044.Collins DH, Huzurbazar AV: System reliability and safety assessment using non-parametric flowgraph models. Proceedings of the Institution of Mechanical Engineers, Part O: Journal of Risk and Reliability December 1, 2008 vol 222 no 4. 2008, 667-664.Huzurbazar A: Multistate Models, Flowgraph Models, and Semi-Markov Processes. Communications in Statistics - Theory and Methods. 2004, 33: 457-474. 10.1081/STA-120028678.Huzurbazar A: Flowgraph Models for Multistate Time-To-Event Data. 2005, New York: WileyMullen KM, van Stokkum IHM: nnls: The Lawson-Hanson algorithm for non-negative least squares (NNLS). 2012, [R package version 1.4], http://CRAN.R-project.org/package=nnlsAbate J, Whitt W: The Fourier-Series Method For Inverting Transforms Of Probability Distributions. Queueing Syst. 1992, 5-88.Collins DH, Huzurbazar AV: Prognostic models based on statistical flowgraphs. 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PhD thesis. 2012, Universitat de ValènciaTeam RDC: R: A Language and Environment for Statistical Computing. 2010, R Foundation for Statistical Computing, Vienna, Austria,Goulet V, Dutang C, Maechler M, Firth D, Shapira M, Stadelmann M, expm-developers@listsR-forgeR-projectorg: expm: Matrix exponential. 2011, [R package version 0.98-5], http://CRAN.R-project.org/package=expmBates D, Maechler M: Matrix: Sparse and Dense Matrix Classes and Methods. 2011, R package version 1.0-1.Therneau T: survival: Survival analysis, including penalised likelihood. 2011, original Splus: R port by Thomas Lumley, [R package version 2.36-10], http://CRAN.R-project.org/package=survivalJackson CH: Multi-State Models for Panel Data: The msm Package for R. Journal of Statistical Software. 2011, 38 (8): 1-29. http://www.jstatsoft.org/v38/i08

Plant DNA barcodes and assessment of phylogenetic community structure of a tropical mixed dipterocarp forest in Brunei Darussalam (Borneo)

DNA barcoding is a fast and reliable tool to assess and monitor biodiversity and, via community phylogenetics, to investigate ecological and evolutionary processes that may be responsible for the community structure of forests. In this study, DNA barcodes for the two widely used plastid coding regions rbcL and matK are used to contribute to identification of morphologically undetermined individuals, as well as to investigate phylogenetic structure of tree communities in 70 subplots (10 × 10m) of a 25-ha forest-dynamics plot in Brunei (Borneo, Southeast Asia). The combined matrix (rbcL + matK) comprised 555 haplotypes (from ≥154 genera, 68 families and 25 orders sensu APG, Angiosperm Phylogeny Group, 2016), making a substantial contribution to tree barcode sequences from Southeast Asia. Barcode sequences were used to reconstruct phylogenetic relationships using maximum likelihood, both with and without constraining the topology of taxonomic orders to match that proposed by the Angiosperm Phylogeny Group. A third phylogenetic tree was reconstructed using the program Phylomatic to investigate the influence of phylogenetic resolution on results. Detection of non-random patterns of community assembly was determined by net relatedness index (NRI) and nearest taxon index (NTI). In most cases, community assembly was either random or phylogenetically clustered, which likely indicates the importance to community structure of habitat filtering based on phylogenetically correlated traits in determining community structure. Different phylogenetic trees gave similar overall results, but the Phylomatic tree produced greater variation across plots for NRI and NTI values, presumably due to noise introduced by using an unresolved phylogenetic tree. Our results suggest that using a DNA barcode tree has benefits over the traditionally used Phylomatic approach by increasing precision and accuracy and allowing the incorporation of taxonomically unidentified individuals into analyses

Exercise and manual physiotherapy arthritis research trial (EMPART): a multicentre randomised controlled trial

BACKGROUND: Osteoarthritis (OA) of the hip is a major cause of functional disability and reduced quality of life. Management options aim to reduce pain and improve or maintain physical functioning. Current evidence indicates that therapeutic exercise has a beneficial but short-term effect on pain and disability, with poor long-term benefit. The optimal content, duration and type of exercise are yet to be ascertained. There has been little scientific investigation into the effectiveness of manual therapy in hip OA. Only one randomized controlled trial (RCT) found greater improvements in patient-perceived improvement and physical function with manual therapy, compared to exercise therapy. METHODS AND DESIGN: An assessor-blind multicentre RCT will be undertaken to compare the effect of a combination of manual therapy and exercise therapy, exercise therapy only, and a waiting-list control on physical function in hip OA. One hundred and fifty people with a diagnosis of hip OA will be recruited and randomly allocated to one of 3 groups: exercise therapy, exercise therapy with manual therapy and a waiting-list control. Subjects in the intervention groups will attend physiotherapy for 6-8 sessions over 8 weeks. Those in the control group will remain on the waiting list until after this time and will then be re-randomised to one of the two intervention groups. Outcome measures will include physical function (WOMAC), pain severity (numerical rating scale), patient perceived change (7-point Likert scale), quality of life (SF-36), mood (hospital anxiety and depression scale), patient satisfaction, physical activity (IPAQ) and physical measures of range of motion, 50-foot walk and repeated sit-to stand tests. DISCUSSION: This RCT will compare the effectiveness of the addition of manual therapy to exercise therapy to exercise therapy only and a waiting-list control in hip OA. A high quality methodology will be used in keeping with CONSORT guidelines. The results will contribute to the evidence base regarding the clinical efficacy for physiotherapy interventions in hip OA

The impact of inflammation on bone mass in children

Bone is a dynamic tissue. Skeletal bone integrity is maintained through bone modeling and remodeling. The mechanisms underlying this bone mass regulation are complex and interrelated. An imbalance in the regulation of bone remodeling through bone resorption and bone formation results in bone loss. Chronic inflammation influences bone mass regulation. Inflammation-related bone disorders share many common mechanisms of bone loss. These mechanisms are ultimately mediated through the uncoupling of bone remodeling. Cachexia, physical inactivity, pro-inflammatory cytokines, as well as iatrogenic factors related to effects of immunosuppression are some of the common mechanisms. Recently, cytokine signaling through the central nervous system has been investigated for its potential role in bone mass dysregulation in inflammatory conditions. Growing research on the molecular mechanisms involved in inflammation-induced bone loss may lead to more selective therapeutic targeting of these pathological signaling pathways