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What nervous systems do:Early evolution, input-output, and the skin brain thesis
No full textNervous systems are standardly interpreted as information processing input-output devices. They receive environmental information from their sensors as input, subsequently process or adjust this information, and use the result to control effectors, providing output. Through-conducting activity is here the key organizational feature of nervous systems. In this paper, we argue that this input-output interpretation is not the most fundamental feature of nervous system organization. Building on biological work on the early evolution of nervous systems, we provide an alternative proposal: the skin brain thesis (SBT). The SBT postulates that early nervous systems evolved to organize a new multicellular effector: muscle tissue, the primary source of animal motility. Early nervous systems provided a new way of inducing and coordinating self-organized contractile activity across an extensive muscle surface underneath the skin. The main connectivity in such nervous systems runs across a spread out effector and is transverse to sensor-effector signaling. The SBT therefore constitutes a fundamental conceptual shift in understanding both nervous system operation and what nervous systems are. Nervous systems are foremost spatial organizers that turn large multi-cellular animal bodies into dynamic self-moving units. At the end, we briefly discuss some theoretical connections to central issues within the behavioral, cognitive and neurosciences.</p
Protein refolding in peroxisomes is dependent upon an HSF1-regulated function
No full textPost-heat shock refolding of luciferase requires chaperones. Expression of a dominant negative HSF1 mutant (dnHSF1), which among other effects depletes cells of HSF1-regulated chaperones, blocked post-heat shock refolding of luciferase targeted to the cytoplasm, nucleus, or peroxisomes, while refolding of endoplasmic reticulum (ER)-targeted luciferase was inhibited by about 50 %. Luciferase refolding in the cytoplasm could be partially restored by expression of HSPA1A and fully by both HSPA1A and DNAJB1. For full refolding of ER luciferase, HSPA1A expression sufficed. Neither nuclear nor peroxisomal refolding was rescued by HSPA1A. A stimulatory effect of DNAJB1 on post-heat shock peroxisomal luciferase refolding was seen in control cells, while refolding in the cytoplasm or nucleus in control cells was inhibited by DNAJB1 expression in the absence of added HSPA1A. HSPB1 also improved refolding of peroxisomal luciferase in control cells, but not in dnHSF1 expressing cells. HSP90, HSPA5, HSPA6, and phosphomevalonate kinase (of which the synthesis is also downregulated by dnHSF1) had no effect on peroxisomal refolding in either control or chaperone-depleted cells. The chaperone requirement for post-heat shock refolding of peroxisomal luciferase in control cells is thus unusual in that it can be augmented by DNAJB1 or HSPB1 but not by HSPA1A; in dnHSF1 expressing cells, expression of none of the (co)-chaperones tested was effective, and an as yet to be identified, HSF1-regulated function is required.</p
Narrow band imaging is a new technique in visualization of recurrent respiratory papillomatosis
No full textObjectives/Hypothesis: Recurrent respiratory papillomatosis (RRP) is a rare, benign, wart-like disease for which no curative treatment exists. The goal of treatment is total surgical removal of the epithelial lesions to keep the airway open and the voice sufficient. Therefore, it is essential to visualize all papillomatous lesions. The present study aims to evaluate the sensitivity of additional use of narrow band imaging (NBI) in detecting RRP during microlaryngoscopy. Study Design: Prospective study. Methods: Between January 2011 and July 2011, patients with RRP underwent systematic inspection during microlaryngoscopy using conventional white light (WL) immediately followed by inspection with NBI. Consensus was achieved about the number of lesions and number of RRP suspect lesions. All lesions were subsequently excised and sent for histopathological examination. Results: Eighty-six excisional biopsies were taken in 24 microlaryngoscopies performed in 14 RRP patients. Eleven out of the 13 additional biopsies taken, induced by the second inspection with NBI, proved to be papillomata after histopathological examination. The sensitivity increased from 80% with WL up to 97% with WL + NBI (P <.01), whereas the specificity remained poor (32% and 28%, respectively). Conclusions: NBI is an additional diagnostic tool in increasing the sensitivity of visualizing papillomata during microlaryngoscopy. Laryngoscope, 2012</p
Cost-Effectiveness of Lanthanum Carbonate in the Treatment of Hyperphosphatemia in Dialysis Patients:A Canadian Payer Perspective
No full textBackground: Hyperphosphatemia is a common and potentially harmful condition in patients with end-stage kidney disease. In Canada, first-line treatment of hyperphosphatemia consists primarily of calcium carbonate (CC). Lanthanum carbonate (LC) and sevelamer hydrochloride (SH) are non-calcium phosphate binders that have been used as second-line therapy in patients intolerant of or not responsive to CC.Objectives: The primary objective of the present study was to assess the costs and clinical benefits of second-line use of LC after therapy failure with CC in patients receiving dialysis, from a Canadian payer perspective. The secondary objective was to perform an economic comparison between second-line LC therapy and second-line SH therapy, from a Canadian payer perspective. Short-term outcomes were treatment response and cost per additional responder, and long-term outcomes were survival, number of all-cause hospitalizations, and quality of life.Methods: A cost-effectiveness Markov model was populated with simulated cohorts of 1000 patients receiving incident dialysis, followed life-long. Patients not responsive to CC with a serum phosphate concentration >1.78 rarnol/L (>5.5 mg/dL) received a trial regimen with LC. Patients not responsive to LC returned to CC therapy. Patient data from a randomized controlled trial of 800 patients receiving dialysis were used. Extensive (probabilistic) sensitivity analyses were performed. When available, model parameters were based on Canadian data or from a Canadian perspective. All costs are in 2010 Canadian dollars (C2600 (C2800). Over patients' lifetimes, the second-line LC strategy resulted in a gain of 48.8 (37.1-61.3) life-years and 29.3 (21.4-38.1) quality-adjusted life-years (QALYs). The cost-effectiveness of the second-line LC strategy was C1800-C13,200 (C25,100) per QALY gained. Most sensitivity analyses did not change the cost-effectiveness outcomes; however, including unrelated future costs raised the incremental cost-effectiveness ratio to C133,300-C$191,600) per QALY gained. Compared with second-line SH therapy, second-line LC therapy had similar effectiveness and was 23% less expensive.Conclusions: Second-line treatment with LC is cost-effective in the treatment of end-stage kidney disease in patients with hyperphosphatemia, from a Canadian payer perspective. Second-line treatment with LC is less expensive, with similar effectiveness as second-line treatment with SH. The primary limitation of health economic evaluations of phosphate binders is the relative scarcity of clinical data on the association between phosphate concentration and long-term outcome. (Clin Ther. 2012;34:1531-1543) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.</p
