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991.
992.
Essert C Haegelen C Lalys F Abadie A Jannin P 《International journal of computer assisted radiology and surgery》2012,7(4):517-532
Purpose
The optimal electrode trajectory is needed to assist surgeons in planning Deep Brain Stimulation (DBS). A method for image-based trajectory planning was developed and tested. 相似文献993.
Mickaël Hiligsmann MPH MSc Olivier Ethgen PhD Olivier Bruyère PhD Florent Richy PhD Henry-Jean Gathon PhD Jean-Yves Reginster MD PhD 《Value in health》2009,12(5):687-696
Objective: Markov models are increasingly used in economic evaluations of treatments for osteoporosis. Most of the existing evaluations are cohort-based Markov models missing comprehensive memory management and versatility. In this article, we describe and validate an original Markov microsimulation model to accurately assess the cost-effectiveness of prevention and treatment of osteoporosis.
Methods: We developed a Markov microsimulation model with a lifetime horizon and a direct health-care cost perspective. The patient history was recorded and was used in calculations of transition probabilities, utilities, and costs. To test the internal consistency of the model, we carried out an example calculation for alendronate therapy. Then, external consistency was investigated by comparing absolute lifetime risk of fracture estimates with epidemiologic data.
Results: For women at age 70 years, with a twofold increase in the fracture risk of the average population, the costs per quality-adjusted life-year gained for alendronate therapy versus no treatment were estimated at €9105 and €15,325, respectively, under full and realistic adherence assumptions. All the sensitivity analyses in terms of model parameters and modeling assumptions were coherent with expected conclusions and absolute lifetime risk of fracture estimates were within the range of previous estimates, which confirmed both internal and external consistency of the model.
Conclusion: Microsimulation models present some major advantages over cohort-based models, increasing the reliability of the results and being largely compatible with the existing state of the art, evidence-based literature. The developed model appears to be a valid model for use in economic evaluations in osteoporosis. 相似文献
Methods: We developed a Markov microsimulation model with a lifetime horizon and a direct health-care cost perspective. The patient history was recorded and was used in calculations of transition probabilities, utilities, and costs. To test the internal consistency of the model, we carried out an example calculation for alendronate therapy. Then, external consistency was investigated by comparing absolute lifetime risk of fracture estimates with epidemiologic data.
Results: For women at age 70 years, with a twofold increase in the fracture risk of the average population, the costs per quality-adjusted life-year gained for alendronate therapy versus no treatment were estimated at €9105 and €15,325, respectively, under full and realistic adherence assumptions. All the sensitivity analyses in terms of model parameters and modeling assumptions were coherent with expected conclusions and absolute lifetime risk of fracture estimates were within the range of previous estimates, which confirmed both internal and external consistency of the model.
Conclusion: Microsimulation models present some major advantages over cohort-based models, increasing the reliability of the results and being largely compatible with the existing state of the art, evidence-based literature. The developed model appears to be a valid model for use in economic evaluations in osteoporosis. 相似文献
994.
The circadian clock stops ticking during deep hibernation in the European hamster 总被引:4,自引:0,他引:4
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Revel FG Herwig A Garidou ML Dardente H Menet JS Masson-Pévet M Simonneaux V Saboureau M Pévet P 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(34):13816-13820
Hibernation is a fascinating, yet enigmatic, physiological phenomenon during which body temperature and metabolism are reduced to save energy. During the harsh season, this strategy allows substantial energy saving by reducing body temperature and metabolism. Accordingly, biological processes are considerably slowed down and reduced to a minimum. However, the persistence of a temperature-compensated, functional biological clock in hibernating mammals has long been debated. Here, we show that the master circadian clock no longer displays 24-h molecular oscillations in hibernating European hamsters. The clock genes Per1, Per2, and Bmal1 and the clock-controlled gene arginine vasopressin were constantly expressed in the suprachiasmatic nucleus during deep torpor, as assessed by radioactive in situ hybridization. Finally, the melatonin rhythm-generating enzyme, arylalkylamine N-acetyltransferase, whose rhythmic expression in the pineal gland is controlled by the master circadian clock, no longer exhibits day/night changes of expression but constantly elevated mRNA levels over 24 h. Overall, these data provide strong evidence that in the European hamster the molecular circadian clock is arrested during hibernation and stops delivering rhythmic output signals. 相似文献
995.
Carpentier C Lejeune J Gros F Everhard S Marie Y Kaloshi G Laigle-Donadey F Hoang-Xuan K Delattre JY Sanson M 《Journal of neuro-oncology》2007,84(3):249-253
Background The MNS16A polymorphism is located in the downstream region of the hTERT gene and affects telomerase activity.
Methods MNS16A has been investigated as a potential risk factor and/or prognostic marker for malignant glioma in a cohort of 352 patients
(205 glioblastoma, 147 anaplastic gliomas) and 305 controls.
Results The S (“short”) allele (which results in a higher telomerase activity) was significantly more frequent in glioma patients
compared to the control population (278/704 = 39.5% vs. 200/610 = 32.8%; P = 0.012). The odd ratios were 1 for LL (taken as reference), 1.33 [0.96; 1.84] for SL and 2.05 [1.22; 3.44] for SS. However,
in contrast to a previous report, no significant difference of survival was found between SS, LL and SL allelotypes.
Conclusion We found here the short allele of MNS16A more frequent in glioma patients, but it did not seem to be predictive of survival. 相似文献
996.
Kassai B Gueyffier F Boissel JP Boutitie F Cucherat M 《Journal of clinical epidemiology》2003,56(10):977-982
The absolute benefit (AB) is extensively used to summarize the results of clinical trials. As the AB depends directly on the patient's baseline risk, therapeutic decisions based on AB tend to favor patients at high risk. To evaluate the consequences of this decision's procedure for life-long therapy, we compare the AB with the gain in event-free life expectancy in a simulated hypertensive population. Our results show that the AB goes through a maximum and then declines as the duration of treatment increases. The amplitude of the variation of AB is independent of the baseline risks but the maximum is reached more quickly in the high-risk patients. Considering the gain in event-free life expectancy, low-risk patients benefit more than high-risk patients do, at the expense of a longer treatment exposure. The interpretation of the AB changes depending on follow-up. 相似文献
997.
Satoshi Nakamizo Charles-Antoine Dutertre Ahad Khalilnezhad Xiao Meng Zhang Shawn Lim Josephine Lum Geraldine Koh Charlene Foong Pearly Jean Ai Yong Kahbing Jasmine Tan Reiko Sato Kaori Tomari Laurent Yvan-Charvet Helen He Emma Guttman-Yassky Benoit Malleret Rintaro Shibuya Masashi Iwata Baptiste Janela Tsuyoshi Goto Tan Siyun Lucinda Mark B.Y. Tang Colin Theng Valerie Julia Feriel Hacini-Rachinel Kenji Kabashima Florent Ginhoux 《The Journal of experimental medicine》2021,218(9)
Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO. 相似文献
998.
Sophie G. Dove David I. Kline Olga Pantos Florent E. Angly Gene W. Tyson Ove Hoegh-Guldberg 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(38):15342-15347
Increasing atmospheric partial pressure of CO2 (pCO2) is a major threat to coral reefs, but some argue that the threat is mitigated by factors such as the variability in the response of coral calcification to acidification, differences in bleaching susceptibility, and the potential for rapid adaptation to anthropogenic warming. However the evidence for these mitigating factors tends to involve experimental studies on corals, as opposed to coral reefs, and rarely includes the influence of multiple variables (e.g., temperature and acidification) within regimes that include diurnal and seasonal variability. Here, we demonstrate that the inclusion of all these factors results in the decalcification of patch-reefs under business-as-usual scenarios and reduced, although positive, calcification under reduced-emission scenarios. Primary productivity was found to remain constant across all scenarios, despite significant bleaching and coral mortality under both future scenarios. Daylight calcification decreased and nocturnal decalcification increased sharply from the preindustrial and control conditions to the future scenarios of low (reduced emissions) and high (business-as-usual) increases in pCO2. These changes coincided with deeply negative carbonate budgets, a shift toward smaller carbonate sediments, and an increase in the abundance of sediment microbes under the business-as-usual emission scenario. Experimental coral reefs demonstrated highest net calcification rates and lowest rates of coral mortality under preindustrial conditions, suggesting that reef processes may not have been able to keep pace with the relatively minor environmental changes that have occurred during the last century. Taken together, our results have serious implications for the future of coral reefs under business-as-usual environmental changes projected for the coming decades and century.Tropical coral reef ecosystems face significant challenges from anthropogenic changes in ocean temperature and chemistry (1). Short periods of anomalously high sea temperatures have triggered mass coral bleaching and mortality events since the early 1980s (2, 3), and projected pH and carbonate ion concentrations reduce the calcification rate of many organisms such as reef-building corals and crustose coralline algae (reviewed in ref. 4). Generally, the projected impacts associated with future increases in sea temperature have been examined independently of those associated with ocean acidification (2, 5–8). When multiple drivers have been considered, extrapolation of the results to the future outlook of coral reefs has been complicated by a lack of replication, the use of artificial light, and/or experimental designs that exclude the potentially important influence of natural variation in ocean temperature and chemistry over diel and seasonal cycles (9–11). Furthermore, most studies have focused on corals or calcareous algae in isolation rather than on broader communities that may better represent the responses of coral reefs (9–11). Excluding the interaction of changing temperature and ocean chemistry, natural variability, and the wider set of organisms and processes places important limitations on our ability to understand the future and ascertain whether, for coral reefs, there is any real difference between action and no action regarding CO2 emissions. This issue is fundamentally important given the time lag between reducing CO2 emissions and establishing atmospheric stability, but has not been addressed adequately via studies that seek mechanistic understandings for the individual effects of temperature and acidification on specific organisms, because the sum of the parts may not equal the whole.Some argue that the potential and imminent threat to coral reefs posed by anthropogenic CO2 emissions is mitigated by potential rapid evolutionary adaptation by key reef organisms such as corals (12). Within this argument, greater inherent environmental variability is seen as a facilitator of adaptation (13), and the transition within some corals to thermally tolerant symbionts is presented as a current coral plasticity that is likely to enhance adaptation toward warmer water (12). The latter suggestion is debatable because the enhancement in host performance is not typically recorded in terms of a property that belongs uniquely to the host (e.g., coral survival, growth, or reproduction) but rather as properties (bleaching tolerance, sustained maximum quantum yields of photosystem II) that may be more attributable to the symbiont than to the host (14). That is, it is not always clear that the statement “having thermally tolerant symbionts leads to thermally tolerant hosts” is anything more than a tautology. Especially given observations in the current literature that corals harboring thermally tolerant symbionts experience reduced growth (15, 16), that heterotrophic feeding can sustain some coral species postbleaching (17), and finally that while food may be relatively unavailable in the oceans that surround reefs, this is not typically the case on a reef (reviewed in ref. 18). Evolution will occur over multiple generations. Presently, however, we lack the experimental evidence to support scientifically the contention that organism evolution over the next decades will protect features such as the maintenance of a positive carbonate balance that are essential to reef viability and the functional utility of reefs to mankind (1). However, the ocean environment has changed significantly over the last 100 y in terms of both ocean temperature and acidification (19, 20), suggesting that reefs in the Southern Great Barrier Reef (GBR), where seasonal environmental variability is great, should provide ample opportunity to evaluate experimentally the degree to which key ecosystem features are retained over decadal time frames.In the present study, we simulated past and future ocean temperature and chemistry on replicated patches of coral reef reconstructed from a broad range of organisms collected from the growth zone of a coral reef (Harry’s Bommie, Heron Island, GBR, 151.9357°E, 23.4675°S) (Fig. S1). The experiment was designed to answer two major questions. The first was whether processes such as the maintenance of maximum net reef calcification rates, measured independently of episodic events such as cyclones, are optimal under the preindustrial (PRE) or present-day (control) scenarios. The second was whether the response of coral reefs differs between action scenarios that result in business-as-usual unabated rates of CO2 emission (A1FI) as compared to reduced rates of CO2 emission (B1) through 2050. Here, the Special Report on Emission Scenarios (SRES) A1FI is equivalent to a Representation Concentration Pathway (RCP) 8.5; and, SRES B1 is equivalent to RCP4.5 (21).
Open in a separate windowAll organisms were collected from a depth of ca. 5 m at Harry’s Bommie, Heron Island Reef, GBR, Australia.*Corals excluded from buoyant weight assessment.To incorporate natural variability at day and seasonal scales, a computer-control system tracked water temperature and ocean partial pressure of CO2 (pCO2) look-up tables established from two or three hourly measurements made at our reference site (Harry’s Bommie, www.pmel.noaa.gov/co2/story/Heron+Island) during 2010 and 2011 (Fig. S1). Then treatment conditions (with similar natural levels of diurnal and seasonal variability) were established by applying past and projected future anomalies as offsets to these look-up table values (Fig. 1). The precision and accuracy of the control system is evident from the comparison of the data from 2010 and 2011 (black trace in Fig. 1) with the condition replicated in the control (today) mesocosms (blue symbols). PRE conditions were established by reducing the seawater (SW) pCO2 by 104 ± 11 µatm and temperature by 1 °C. Future conditions were established using anomalies appropriate to the lower (B1: +174 ± 9 µatm, +2 °C) and upper (A1FI: +572 ± 11 µatm, +4 °C) ends of respective scenarios. Temperature profiles for representative mesocosms are shown in Fig. 1, along with the average pH conditions (± SE) measured at 30-min intervals. Experimental treatments were preceded by 2.5 mo in which the coral reef communities were acclimatized to treatment conditions by slowly increasing the relative proportion of treatment water to inner reef flat water [control (field) rates of changes over acclimatization period were 0.04 °C d−1 and 6 μatm·pCO2·d−1; A1FI rates were 0.09 °C·d−1 and 14 μatm·pCO2·d−1]. Full treatments were applied over the austral summer from early November 2011 to early February 2012 under light conditions appropriate to the reference site.Open in a separate windowFig. 1.Treatment conditions established over the experimental period: daily temperature profiles and average treatment pH obtained through the course of the experiment. PRE, pre-industrial treatment; C, control treatment set to mimic conditions at the reference site (Harry’s Bommie, GBR, Australia, indicated by the solid black line) measured by the Commonwealth Scientific and Industrial Research Organization between November 2010 and February 2011; B1, SRES B1/RCP4.5, reduced CO2 emission scenario; A1FI, SRES A1FI/RCP 8.5 business-as-usual emissions scenario. The upper dashed line represents the maximum monthly mean (MMM) + 1 °C, established for Heron Island using 50-km pixel satellite data (http://coralreefwatch.noaa.gov). The lower dashed line represents MMM+1 specific to the reference site established by relating satellite nighttime temperatures to same-day average night temperatures logged at Harry’s Bommie. Triangles represent sampling days for community O2 flux and calcification measurements. Average pCO2s across sampling days were PRE = 301 ± 11 µatm, C = 405 ± 25 µatm, B1 = 611 ± 17 µatm, and A1FI = 1,009 ± 8 µatm (Table S1). 相似文献
Table 1.
November composition of the reassembled patch-reefsType | Principal components | % cover |
Hard coral | Acropora formosa; Seriatopora hystrix*; Stylophora pistillata; Porites cylindrical; Plating Montipora sp.; Goniastrea aspera; Lobophyllia sp.*; Fungia sp. | 35 ± 1 |
Macroalgae | Crustose calcareous algae; red, green, brown filamentous algae; Halimeda sp.; Lobophora sp.; Chlorodesmis fastigiata; Hypnea sp. | 15 ± 3 |
Other invertebrates | Zoanthids; Xenia sp.; sponges (Cliona orientalis); sea cucumbers (Holothuria atra); snails (herbivorous); xanthid crabs | 2 ± 0 |
Vertebrates | Three lawnmower blennies (Salarias fasciatus) | |
Sediments | Skeletons of corals, crustose calcareous algae, foraminifers, mollusks, and Halimeda (39) | 48 ± 3 |
999.
Hannah E. Boycott Camille S. M. Barbier Catherine A. Eichel Kevin D. Costa Raphael P. Martins Florent Louault Gilles Dilanian Alain Coulombe Stéphane N. Hatem Elise Balse 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(41):E3955-E3964
Atrial myocytes are continuously exposed to mechanical forces including shear stress. However, in atrial myocytes, the effects of shear stress are poorly understood, particularly with respect to its effect on ion channel function. Here, we report that shear stress activated a large outward current from rat atrial myocytes, with a parallel decrease in action potential duration. The main ion channel underlying the increase in current was found to be Kv1.5, the recruitment of which could be directly observed by total internal reflection fluorescence microscopy, in response to shear stress. The effect was primarily attributable to recruitment of intracellular pools of Kv1.5 to the sarcolemma, as the response was prevented by the SNARE protein inhibitor N-ethylmaleimide and the calcium chelator BAPTA. The process required integrin signaling through focal adhesion kinase and relied on an intact microtubule system. Furthermore, in a rat model of chronic hemodynamic overload, myocytes showed an increase in basal current despite a decrease in Kv1.5 protein expression, with a reduced response to shear stress. Additionally, integrin beta1d expression and focal adhesion kinase activation were increased in this model. This data suggests that, under conditions of chronically increased mechanical stress, the integrin signaling pathway is overactivated, leading to increased functional Kv1.5 at the membrane and reducing the capacity of cells to further respond to mechanical challenge. Thus, pools of Kv1.5 may comprise an inducible reservoir that can facilitate the repolarization of the atrium under conditions of excessive mechanical stress.The electrical properties of the myocardium are governed by the interplay of ion channels, whose expression and regulation determines the precise electrical responses of the tissue. The activity of ion channels can be regulated in a variety of ways: for example, interaction with accessory subunits (1), phosphorylation (2), oxidation state (3), and gene expression (4). Recently, increased attention has been focused on trafficking as a means to regulate ion channel function, notably by modulating the number of active channels present at the plasma membrane (5, 6). This regulation is a complex process derived from a balance between trafficking of newly synthesized channel, endocytosis, and recycling/degradation. Trafficking of ion channels is known to be a dynamically regulated process that depends on Rab-GTPases as well as dynamin motors (7, 8). Indeed, certain antiarrhythmogenic drugs have been shown to exert their activity by modifying the number of channels at the plasma membrane (9). In this context, we previously showed that ion channels are recruited from a submembranous pool in response to cholesterol depletion (10). In addition, several ion channels are regulated by mechanical forces, which directly affect the gating of the channel (11) or indirectly activate intracellular signaling pathways to alter channel properties (12).The myocardium is subjected to a variety of forces with each contraction and therefore must adapt to the various associated mechanical stresses. The response to stretch has been well-studied and includes gene regulation (13), activation of stretch-activated ion channels (14–17), and the release of atrial natriuretic peptide (ANP) (18–21). In addition, it has been shown that direct stretch of β1 integrins activates ICl,swell as well as a cation current (22). Less well-studied are the responses of cardiomyocytes to shear stress. Shear forces in the myocardium arise from blood flow and the relative movement of sheets of myocytes, causing cell deformation as the myocardial layers slide against each other with each heart beat (23, 24). Although the effect of shear stress upon cardiomyocytes has not been extensively explored, it has been shown that increased shear stress stimulates intracellular calcium transients (25, 26), induces an increase in the beating rate of neonatal ventricular myocytes (27), and triggers propagating action potentials (APs) in monolayers of ventricular myocytes (28). Thus far, the response to shear stress remains relatively unknown, particularly with regard to ion channel regulation. Ion channel activity determines both the shape of the AP and the firing frequency of excitable cells. Therefore, the response of cardiomyocytes to shear stress is important for normal cardiac excitability and could be central in pathological conditions in which the working conditions of the myocardium are altered.In this study, we investigate the response of native adult rat cardiomyocytes to shear stress, reproduced in vitro by laminar flow. Using a combination of whole-cell patch-clamp and single-channel recordings, high spatial resolution 3-dimensional and total internal reflection fluorescence (TIRF) microscopy, we show that shear stress induces an increase in outward current and shortens AP duration within the range of a few minutes. This phenomenon is saturable and reversible, and is caused by Kv1.5 exocytosis from the recycling endosome. We identify the mechanotransduction pathway of this recruitment, which involves integrin/focal adhesion kinase (FAK) signaling. Finally, the response to shear stress is altered in chronically hemodynamically overloaded and dilated atria. 相似文献