What does an anecdote about John Snow have to do with modern-day epidemiology? And why use it to introduce an issue of the Journal highlighting the challenges of studying disease risks associated with low dose environmental exposures? In this issue, Lilienfeld describes John Snow giving expert-witness testimony on behalf of industry (1). Besides being interesting on a historical basis, this incident raises several issues that are pertinent today. Lilienfeld's paper and the accompanying commentary by Vandenbroucke (2) deal directly or indirectly with the role and responsibilities of expert witnesses, the extrapolation of data on health effects from high dose exposures to low dose exposures, the importance of epidemiology to the development of public health policy, the current debates on environmental justice (3), and the use of the precautionary principle (4) in standard-setting. Furthermore, if faced with an issue similar to that faced by Snow—namely, local residents' being worried about health consequences associated with emanations from factories—would modern-day environmental epidemiologists be any better positioned to carry out appropriate studies and reach sound conclusions? Snow can be seen at once as victim and perpetrator of sins that are common in epidemiology in general and in environmental epidemiology in particular. Was Snow victimized by the medical establishment, including The Lancet, for expressing views that were not commonly held by the scientists of the day? Were his peers outraged because of the reactionary social position he was taking (as suggested by Vandenbroucke)? On the other hand, was he as guilty as proponents of the miasma theory for trying to apply his theory of disease transmission to all situations without allowing for the possibility of multiple disease pathways? Did he fall into the trap of equating the absence of data with an absence of effect? When Snow contended that emanations from the bone-boiling factories were not causing ill health in the community at large, he invoked arguments that are often raised when unexpected health effects are encountered following supposed low dose exposures. One argument is that such health effects are implausible given what we know about high dose exposures. In this instance, Snow noted that the factory workers were not dying and therefore health effects in the community at large were not plausible. A related argument is that, even if workers are dying or suffering other health effects, because of the distance from the exposure source, the exposure levels in the community are probably too low to plausibly affect health. Health effects of low dose exposures are often seen as implausible, even in the face of accumulated consistent evidence. Such arguments have frequently been invoked in environmental epidemiology. Examples of low dose exposures that have been deemed implausible contributors to disease risk based on what is known about high dose exposures include passive smoking, residential radon exposure, childhood lead exposure, electromagnetic fields, and residence near nuclear facilities. If one begins with a fixed idea of what is plausible, arguments regarding susceptible subgroups, inverse dose rate, hormesis, multiple pathways, multifactor etiologies, and complex exposures (e.g., the different constituents of sidestream and mainstream smoke) are untenable. But how do we know that the factory workers were not dying or suffering other ill effects? Snow cited no studies. All too often the absence of data is argued as proof of no effect. This issue becomes especially difficult when regulatory decisions are being made. In the absence of evidence, can something be considered safe? While science is important, it is ultimately social forces, as much as science, that guide regulators in decision-making. Snow's statements and the questions that were put to him call to mind some of the fundamental difficulties inherent in environmental epidemiology. Today, there are numerous examples of residents who live near potential environmental hazards claiming health effects that can never be proven beyond a reasonable doubt. Although the “gold standard” is an unbiased risk estimate with precise confidence limits, studies focused on overt health effects are invariably underpowered because of the small numbers of residents in the neighborhoods of interest. Other creative approaches to assessment of subclinical health effects are more costly and difficult to implement, but even these studies are often too small for conclusive results. Yet, what is the right thing to do? If we wait for strong scientific evidence before we act—if we require proof that workers are dying or evidence of overt illness in the community—have we waited too long? Few clusters are ever resolved with the identification of a causal link between some localized exposure and disease. While many apparent clusters may be artifacts, what is the real cost of the true hazards that cannot be proven? These were the issues facing Parliament when Snow testified on behalf of industry. What is the role of the epidemiologist in this quagmire? In Snow's London, the living conditions of people near the factories were likely to have been dismal. There were no doubt residents who perceived their symptoms as being related to the smells—smells that, if nothing else, impacted the quality of life. Policy-makers must balance “doing the right thing” with regard to human suffering and quality of life with the financial costs of doing so. Epidemiology can only go so far in providing the answers. It is this political and social tug-of-war that makes environmental epidemiology especially difficult. On the one hand, there are well—funded industries with a financial stake in the outcome of such research. As Vandenbroucke notes (2), these industries often are in a position to exploit the many weaknesses that epidemiologists are trained to identify in their own studies and in the work of others to cast potentially damaging results in a more favorable light. On the other hand, there are environmental groups committed to proving that a particular environmental exposure can be linked to a variety of personal complaints; these groups may be motivated by the possibility of effecting social change through science or by the prospect of receiving needed medical attention or financial compensation. Those who attempt to work in this arena often find themselves and their research attacked from all directions. Environmental epidemiology is difficult to conduct today for other reasons as well. Adequate tools with which to measure and quantify exposures are lacking. Studies are often unable to detect meaningful effects because exposures are low, infrequent, or difficult to measure with certainty. How many investigators are willing to tackle this problem? In the case of the bone-boiling factories, would research linking questionnaire data on symptoms to factory releases be believed? Would a study relating distance from the factory to disease be sufficient evidence of effect? What health effects would be plausible based on known biologic mechanisms? How well could those effects be measured, and could they be measured objectively? Is there a biomarker of exposure? If a biomarker exists, does it measure relevant past exposures? Is the measure unaffected by current health status—particularly the disease under study? In addition to Lilienfeld's historical report and Vandenbroucke's commentary, this issue of the Journal features papers that illustrate various aspects of the difficulties faced in studying health effects of environmental exposures. Several of these include innovative attempts to improve the quality of such research. The paper by Viel et al. (5) may come closest to what many may think of as environmental epidemiology. The authors have examined the spatial distribution of soft tissue sarcomas and non-Hodgkin's lymphomas around an incinerator with high dioxin emissions. Their results are suggestive but need to be followed by studies incorporating more rigorous exposure assessment—perhaps a biologic measure of exposure such as that used in the study of polychlorinated biphenyls and breast cancer reported by Zheng et al. (6). Other studies described in this issue used a variety of approaches to exposure assessment. Rondeau et al. (7) linked estimates of levels of aluminum and silica in drinking water to risks of dementia and Alzheimer's disease. Laden et al. (8) used questionnaire data on use of electric blankets to estimate exposure to electromagnetic fields, and Gustavsson et al. (9) used questionnaire data and expert assessment by industrial hygienists to classify environmental and occupational exposures. Radiation workers are one of the few groups for which historical records of personal exposure typically are available. Dupree-Ellis et al. (10) took advantage of such records to estimate cumulative external radiation exposure. Several of the papers evaluate methods for assessing exposure. For example, Oglesby et al. (11) average individual-level annoyance scores to estimate community-level exposure to air pollution. The authors propose that this measure better accounts for exposure variability than data from fixed-site monitoring stations. This is an interesting twist in a field where much work is based on linking data from monitoring stations with population-level mortality statistics. The measure seems to be easy to operationalize, and it correlates well with monitoring station data, although its ultimate utility may be limited. The real gold standard—a more precise direct measure of individual exposure, rather than another indirect measure—is what is needed. Hwang et al. (12) propose an alternative modeling approach whereby air pollution monitoring station data are used to ascribe exposures to individuals with and without school absences due to respiratory disease. Auvinen et al. (13) compare several possible methods for measuring and classifying exposure to electromagnetic fields. This is a topic that has been hurt by the lack of consensus on the best and most appropriate exposure measure, and results tend to vary for studies employing different exposure metrics. The paper by Karagas et al. (14) attempts to link a biologic measure, arsenic in toenails, with an environmental measure of arsenic in water. The toenail measure is likely to reflect total body burden, but it appears to correlate with water only when water levels are high. This presents an interesting regulatory dilemma. The best epidemiologic research may be based on a direct measure of body burden such as levels in toenails, whereas it is water levels that need to be regulated. Studies of toenail arsenic levels may not shed direct light on the link between water levels and disease. As these papers demonstrate, technological advances are making possible a wide range of new study designs and strategies to better assess both exposures and outcomes. Although progress has been made, research in environmental epidemiology is far from perfect. As epidemiologists face pressures and criticisms from industry, regulatory bodies, and other scientific disciplines, it is important to not lose sight of the lessons from John Snow.
We propose a zero-knowledge interactive proof based identification and signature scheme. The protocol is based on Euler's totient function and discrete logarithms over the ring Z/nZ , and can be applied to smart cards. A prover keeps a signed subgroup generator provided by a trusted center as its secret information. Our scheme has symmetricity in the sense that the same computational complexity and the same hardware both for Prover and for Verifier are required. Also, it requires minimal amount of computation and communications for secret information. The protocol is versatile enough to be applicable to digital signature scheme, multiple digital signature scheme and key exchange protocol. We outline those protocols to show the versatility of our protocol.
This paper takes a fresh look at the trade-off between centralized and decentralized provision of local public goods. The point of departure is to model a centralized system as one in which public spending is financed by general taxation, but districts can receive different levels of local public goods. In a world of benevolent governments, the disadvantages of centralization stressed in the existing literature disappear, suggesting that the case for decentralization must be driven by political economy considerations. Our political economy analysis assumes that under decentralization public goods are selected by locally elected representatives, while under a centralized system policy choices are determined by a legislature consisting of elected representatives from each district. We then study the role of taste heterogeneity, spillovers and legislative behaviour in determining the case for centralization.
With an introduction to the overall underdevelopment of higher education in China compared with the American counterpart, this article briefly examines the main trends of over two decades of development of the governance and financing systems of China's higher education sector. This article analyzes the resource allocation from governments and revenue generation in institutions under the reform policies of administrative decentralization and financing diversification. The new "Great Leap Forward" in higher education in 1999 and beyond, i.e., the radical and, to a certain extent, desperate mass higher education policy and practice of expanding enrollments in order to spur domestic consumption, is critically analyzed. By examining the ongoing institutional merging and "co-building" and the most recent enrollment expansion, the writer points out the economic significance for higher education of overcoming diseconomies of scale and inefficiencies. However, the long-range outcomes of the seemingly exciting investment in and consumption of mass higher education are difficult to predict.
Charles F. Minto, Thomas W. Schnider, Timothy G. Short, Keith M. Gregg · 6 authors
Click on the links below to access all the ArticlePlus for this article.Please note that ArticlePlus files may launch a viewer application outside of your web browser.DRUG interactions are the basis of anesthetic practice. For example, induction of anesthesia may consist of intravenous administration of a benzodiazepine before induction, a hypnotic to achieve loss of consciousness, and an opioid to blunt the response to noxious stimulation. Similarly, anesthesia often is maintained with a combination of a hypnotic (e.g. , propofol, isoflurane) and an analgesic (e.g. , fentanyl, nitrous oxide). Anesthetic drugs are often combined because they interact synergistically to create the anesthetized state.Pharmacodynamic drug interactions are typically described using mathematical models. The basic model is that of an isobole. Isoboles are iso-effect curves, curves that show dose combinations that result in equal effect. 1The combination of two doses (d1and d2) can be represented by a point on a graph, the axes of which are the dose axes of the individual drugs (fig. 1). The isobole connects isoeffective doses of the two drugs when administered alone, D1and D2. If the isobole is straight (fig. 1A), then the relation is additive. If the isobole bows toward the origin (fig. 1B), then smaller amounts of both drugs are needed to produce the drug effect when administered together, so the relation is supraadditive or synergistic. If the isobole bows away from the origin (fig. 1C), then greater amounts of both drugs are needed to produce the drug effect when administered together, so the relation is infraadditive. In table 1we propose a set of criteria that pharmacodynamic models of drug interactions should meet. In this article we propose an interaction model that meets these criteria, based on response-surface methodology. Response surfaces are a powerful statistical methodology for estimating and interpreting the response of a dependent variable to multiple inputs. 2Response-surface methodology is used for two principal purposes; to provide a description of the response pattern in the region of the observations studied and to assist in finding the region in which the optimal response occurs. Our model is a straightforward extension of the sigmoidal concentration–response relation for individual drugs. We test the proposed model using data from a study of the interaction of midazolam, propofol, and alfentanil with loss of consciousness. 3This article only considers pharmacodynamic interactions, the type of interaction most relevant to the practice of anesthesia. Pharmacokinetic interactions are entirely different and will not be considered. Appendix 1 (which can be found on the Anesthesiology Web site at www.anesthesiology.com) reviews several commonly used pharmacodynamic models of drug interactions and shows areas in which existing models fail to meet the criteria in table 1.The effects of individual drugs are often modeled by relating drug effect (E) to drug concentration (C) using a sigmoid model:where E0is the baseline effect when no drug is present, Emaxis the peak drug effect, C50is the concentration associated with 50% drug effect, and γ is a “sigmoidicity factor” that determines the steepness of the relation.This relation is shown graphically in figure 2. The concentration term often is defined as the concentration at the site of drug effect, but the model can be generalized to any measure of exposure (e.g. , dose, plasma concentration, or area under the curve). For models of probability, such as the probability of moving in response to surgical incision, E0is 0 and Emaxis the maximal probability (usually assumed to be 1). Dividing the numerator and denominator of equation 1by C50γ, we obtain an alternate form:In this model, concentration has been normalized to the concentration that results in 50% of maximal drug effect. This is a natural way to think about drug concentration—as a fraction of some measure of potency. For example, anesthesiologists are accustomed to thinking about volatile anesthetics in terms of minimum alveolar concentration (MAC), rather than in absolute concentration terms. This is precisely the concept of normalizing drug concentration to potency.The basic concept of our proposed interaction model is simple. Consider two drugs, each of which has a sigmoidal concentration–response relation. We will think of any given ratio (i.e. , B/(A + B), called θ herein) of the two drugs as behaving as a new drug. This new drug, which is actually a fixed ratio of the two drugs, has its own sigmoidal concentration–response relation, as shown in figure 3. This is the basic premise of our interaction model. The mathematics are simply an extension of the model for a single drug to a model that considers each ratio of two drugs as a drug in its own right. We will express the concentrations of drugs A and B as [A] and [B]. As suggested by equation 2, we must first normalize each drug to its potency, C50, and express the results in units (U) of potency. where UAis the normalized concentration of drug A, and UBis the normalized concentration of drug B. We can define a family of “drugs,” each being a unique ratio of UAand UB. Each drug will be defined in terms of θ, where θ is defined as By definition, θ ranges from 0 (drug A only) to 1 (drug B only). The “drug concentration” is simply UA+ UB. We can extend equation 2to describe the concentration–response relation for any ratio, θ, of the two drugs in combination:where θ is the ratio of the two drugs, the drug concentration is UA+ UB, γ(θ) is the steepness of the concentration–response relation at ratio θ, U50(θ) is the number of units (U) associated with 50% of maximum effect at ratio θ, and Emax(θ) is the maximum possible drug effect at ratio θ. Because Emax, C50, and γ in equation 2have been replaced by functions of θ, each ratio has the potential to have its own Emax, C50, and γ. This allows each ratio of drug A and drug B to behave as its own drug, with its own sigmoidal concentration–response relation, which is the basic premise of the model.The term “U50(θ)” is the potency of the drug combination at ratio θ relative to the normalized potency of each drug by itself. This requires careful explanation. Let us assume that only drug A is present, in a concentration of C50,A. In this case, the drug effect is half of the maximal effect, UA= 1, UB= 0, θ= 0, and the drug concentration is UA+ UB= 1. Because we have 50% of the maximum drug effect, and 1 unit of drug, then the number of units associated with 50% drug effect when only drug A is present, U50(0), must be 1. Similarly, let us assume that only drug B is present and the concentration of drug B is C50,B. In this case, the drug effect is half of the maximal effect, UA= 0, UB= 1, θ= 1, and the drug concentration is UA+ UB= 1. Because we have 50% of the maximum drug effect, and 1 unit of drug, then the number of units associated with 50% drug effect when only drug B is present, U50(1), must again be 1. By definition, if only drug A or drug B is present, U50(θ) = 1.Now, let us assume that drug A and drug B both are present, each in exactly half of the concentration that would cause 50% of the drug effect when administered alone. In this case, UA= 0.5, UB= 0.5, θ= 0.5, and the drug concentration is UA+ UB= 1. If this causes 50% of maximum effect, then the drugs are simply additive at θ= 0.5, and U50(0.5) = 1. However, if this combination produces more than a half-maximal effect, then 1 unit of this combination, at θ= 0.5, is more potent than 1 unit of either drug alone (i.e. , synergistic). In this case, U50(0.5) < 1. Conversely, if this combination produces less than a half-maximal effect, then 1 unit of this combination, at θ= 0.5, is less potent than either drug alone (i.e. , infraadditive). In this case, U50(0.5) > 1. Thus, U50(θ) is the potency of the combination compared with the potency of either drug alone, which is 1 by definition.Thus, the units of U50(θ) are not concentration units, but rather the number of units, at ratio θ, associated with 50% of maximal drug effect. U50(θ) is 1 for θ= 0 and θ= 1. For all values of θ between 0 and 1 (i.e. , all possible ratios of the two drugs), U50(θ) assumes a value determined by the data. If this value is 1, then the interaction is additive at θ. If the value is less than 1, then the drug effect is synergistic at θ. If the value is greater than 1, then the interaction is antagonistic at θ.Figure 4shows the relation between a three-dimensional response surface and a conventional two-dimensional isobolographic analysis. The two-dimensional isobologram is a cut through the three-dimensional surface, generally taken at the 50% response level. In this particular example, synergy is evident in the three-dimensional model as a bowing of the surface toward the reader. This bowing causes the conventional isobologram to deviate toward the origin from the straight line of additivity. Much pharmacodynamic literature supports the sigmoid relation in equation 1, equation 2, and equation 5. There is only modest information specifying the functions Emax(θ), U50(θ), and γ(θ). Our choice is to use functions that are capable of taking a variety of shapes, so that good approximations to the true relations can be determined empirically. To provide these flexible functions we chose fourth-order polynomials of the form where f(θ) is Emax(θ), U50(θ), or γ(θ). The coefficients (β0, β1, β2, β3, β4) are model parameters that are either constrained by the model or estimated from the data. Fortunately, two of these terms, β0and β1, can be replaced by other terms already defined.We already defined the values Emax(θ), U50(θ), and γ(θ) when only drug A is present, Emax,A, U50,A, and γA, respectively. Note in equation 6that when θ= 0 (only drug A is present), f(0) =β0. Therefore, when f(θ) is Emax(θ), U50(θ), or γ(θ), β0must be Emax,A, U50,A, and γA, respectively.Similarly, we also defined the values Emax(θ), U50(θ), and γ(θ) when only drug B is present, Emax,B, U50,B, and γB, respectively. Referring again to equation 6, when θ= 1 (only drug B is present), f(1) =β0+β1+β2+β3+β4. We can rearrange this as β1= f(1) −β0−β2−β3−β4. Thus, when f(θ) is Emax(θ), U50(θ), or γ(θ), β1must be Emax,B− Emax,A−β2,Emax−β3,Emax−β4,Emax, U50,B− U50,A−β2, U50−β3,U50−β4,U50, or γB−γA−β2,γ−β4,γ, respectively.This permits us to develop models that incorporate the individual drug parameters for Emax(θ), U50(θ), and γ(θ) as functions of θ. The equation for Emax(θ), using the substitutions previously mentioned for β0and β1, is U50,Aand U50,B, [equivalent to U50(θ) and U50(1)], are both 1 by definition. Thus, when f(θ) = U50(θ), the values of β0and β1in equation 6are 1 and −β2−β3−β4, respectively. Therefore, the equation for potency as a function of θ can be simplified to Many isobolograms have a simple inward or outward curvature, which can be readily encompassed with a simple quadratic form of equation 8with just one coefficient:If β2,U50is 0, then the value of U50(θ) will be 1 for all values of θ. This means that the interaction will be additive. If β2,U50is a positive number, then U50(θ) will be less than 1 for all values of θ between 0 and 1. The effect is to magnify the term in equation 5, making it appear that there is more drug present. This will produce a greater than additive effect, i.e. , synergy. If β2,U50is a negative number, then U50(θ) will be greater than 1 for all values of θ between 0 and 1. This reduces the term in equation 5, making it appear that there is less drug present. This will produce a less than additive effect. This assumes that drugs A and B have the same maximal effect. It is possible for some approaches to synergy analysis to show apparent synergy if the maximal effects of drugs A and B are not identical, even if U50(θ) = 1 for all values of θ.The model for the steepness term, γ(θ), can similarly be described from equation 6, with appropriate substitutions for β0and β1. The resulting equation is Equations 6–10describe straight lines (simple additivity) when the coefficients (i.e. , β2, β3, β4) are 0. They are the equations for parabolas if the respective β2coefficient is nonzero, and β3and β4are 0. More complex shapes are generated when β3and β4are nonzero.Figure 5shows Emax, U50, and γ as functions of θ for the synergistic interaction seen in figure 4. Emaxand γ are constant, and thus have no interaction. U50is necessarily 1 at θ= 0 and θ= 1, but is less than one between these extremes. This increases the potency of the drugs when administered in combination, resulting in the synergy seen in figure 4. The model can be readily expanded to show the interaction of more than two drugs. In the case of three drugs (A, B, and C) the proportion of each drug present can be expressed by θA, θB, and θC, where We can define the ratio of three drugs from just two of these ratios because θA+θB+θC=1. For our purposes here, we will use θBand θC. We again assume that for any fixed value of θBand θC, there is a sigmoidal relation between concentration and response. Therefore, if the three drugs could be administered to the effect site in an exactly fixed proportion, they would show a sigmoidal total concentration–response relation, where the “concentration” was the sum of the three normalized concentrations. This is precisely the notion that underlies the two-drug model. The equation for the model the model the parameters of the sigmoidal relation, Emax, and U50, are functions of θBand θC. The functions and are described in Appendix (which can be found on the Anesthesiology Web site at The point is that of a as in equations when three drugs are present, the parameters of the sigmoidal relation are surfaces for functions of θBand θC. The response-surface model was in the by the and as a for for also the model for of at 3This is on to the using and for the use of our response-surface model, we data previously by data are also the Anesthesiology Web site relations intravenous doses of midazolam, propofol, and alfentanil administered and in combination in for as to the to administration and or alfentanil to peak effect an intravenous the combination being midazolam, it was administered before the other drugs. The doses of midazolam, propofol, and alfentanil used and the proportion of for each dose are shown in table 2. This data set was because it three two-drug combinations that could be used to In the data are for the number of and the of the it the to a interaction model, the of the proposed response-surface model. We assumed in the model that all when no drug was 0 by definition. In we assumed that each drug was capable of if administered in a a of equation and can be constrained to 0 and 1 with no interaction the Thus, the probability of for any combination is where UB, and the doses of midazolam, propofol, and respectively. The units are of each dose to cause in 50% of the based on equation the data for the single and combination of and the data for the single and combination of and alfentanil the data for the single and combination of and alfentanil and the data set for the and combinations modeled parameters and estimated using by the for all the response of the either 0 to or 1 to and is the probability of response to for each dose be expressed in as the sum of the natural of the of response in the and in the The of the coefficients to the model was by the coefficients one at a by the model ratio and by of probability of for each dose and The response surfaces for the interactions and the surface was used to the synergistic combinations of the and the interactions based on the from the analysis of the data The intravenous doses to achieve probability of in this for each drug alone, for each combination, and for the To the application of the response-surface model with the parameters of , , and used to the for midazolam, propofol, and respectively. This was as the concentration at the of the respective then used to the of effect of in the these synergistic doses of midazolam, propofol, and administered alone and in The the and the from in of the to in of the The of effect was using for for by and shapes of the response surfaces generated by the equations are not readily We used three-dimensional to the response surface for a variety of interactions between two drugs, by the model parameters of equation 5. interactions and antagonistic interactions between two and interactions between and to the data for all in the in to the used by , the of the data for and for the analysis of the three drug interactions are shown in table 3. and for the analysis of the data set are shown in table 4. There no in the of the three drugs, there drug interactions the The for each drug to be the of the combination being modeled and This is an Because the data for single administration was in the interaction the entirely determined from each drug alone. the response surfaces for each of the drug interactions synergy. The synergy in the model was not Appendix on the Anesthesiology Web site at This when all three drugs are present, there is not synergy that from the interactions of all three drugs. The surface is shown in figure The maximum in values for the combinations are represented by the of the three of the as a = = = The maximum in for the combination is found at the point of the surface, which is at and This in figure and where the point as a on the 5shows the doses for the and combinations for maximum synergy associated with probability of a of based on the parameters shown in figure The between probability of to probability of no for each combination was based on the shown in figure the synergistic combination administration of one the dose, this results in a in the for to alone is the drug of choice when the point is a of A of the and of other such as and is to the drug combinations for other our response-surface model for an additive interaction a synergistic interaction and an interaction It also shows the interaction between a and a a and a and a and an way to describe our model for two drugs, A and B, is that the drug A and the drug B there are two sigmoid 1). Our proposed model connects these two sigmoid curves functions of θ interactions are then as coefficients of the polynomials that the to each each value of θ can have its own Emax, C50, and the model assumes that the sigmoidal is for all values of θ. This concept of a fixed ratio of two drugs own is not each drug ratio to be to a single response could be described by a single two-dimensional concentration–response that when using combinations of combination should be as a new with individual rather than the of the individual use of functions to the parameters of drug A to drug B assumes that the response surface is and the basic model the parameters estimated in sigmoid the polynomials that U50(θ), Emax(θ), and γ(θ) are more The use of response functions to complex response surfaces is in However, models with the variable present at than the are not often used because it to the proposed a flexible model. of the response surface, or application of the could result in of parameters that provide a but when more an for the are not unique to this model and can be by the one is in the terms can be from the model. The statistical of the terms should be the models using the ratio In to of model such as of and the pattern of the model should also be by the response surface, and by the individual model parameters as functions of θ (e.g. , equations to that the pharmacodynamic parameters not to For it must be that U50(θ) and γ(θ) are positive in the of 0 1. In the case of three drugs, the surface should be as shown in figure a mathematical that if and only if the isobolograms are straight For this to be be with to θ. The case of γ(θ) is more is with to θ, there is if Emax(θ) and U50(θ) are also not equal to γB, there is no way to use our interaction model to test for defined by 1). we with of the surface, the description of an interaction as or antagonistic may be For example, a drug combination can be synergistic in and antagonistic in our the on drug interactions can be to simple such as or the The interaction has the potential to be and than about which to the relation, the should be to the response the surface one can the combination to produce the model is It no about the of interaction between the drugs. However, we assume that the concentration–response relation for each of the drugs is described by a pharmacodynamic model. We have not to describe interactions between drugs that and that we are not of any that our could not be combined with the more of model for each drug not have to be the sigmoid 1). For example, the model could be a or response The model could also be a response as seen with some the model can be any so as it has parameters that the individual models. Thus, the only is that the interaction model reduces to the model for drug A when θ= 0 and to the model for drug B when θ= the of response-surface can For example, the of effects the of data in a to the model parameters for one of the drugs. to specifying a administered function for the concentration–response relation is to use a as described by the use of flexible functions that are to example, a can be constrained to an they in the of antagonistic interactions, it can be to model additive and synergistic drug used our response-surface model to the drug interactions for the hypnotic point between midazolam, propofol, and on this a maximum effect of for all three drugs described the data the dose of and alfentanil the response to in of the dose of the response to in only of results not that alfentanil will or in response to a surgical they that doses of will response to in of the of our response-surface model to potential interactions of two or three drugs at the effect site We that these concentrations are based on information parameters and not possible interactions between the three drugs. this we to that the synergistic dose ratio is not necessarily if a hypnotic effect is the the three-dimensional may in and different used to study drug interactions, it not information that be by a of two-dimensional such as the isobologram of the response surface, of three-dimensional the response to concentration of one drug in the of fixed concentration of the other drug to one and the response to fixed concentration ratios of the two any of these a three-dimensional of the response surface can be if are In the case of three drugs, it is no possible to the response surface because it is a surface, the model parameters can be in three (fig. of using axes to be in the of the interactions between three or more drugs. the study of drug interactions in anesthesia has used isobolographic analysis or multiple approaches have In the multiple is so with described in Appendix 1 in the web with pharmacodynamic that it should be The application of response-surface methodology to the study of drug interactions has the potential to the of these models. We proposed a flexible model for drug interactions, which the relation between the concentrations of two or three drugs and drug effect. We our new model using previously data and that this model can also describe of interaction between an a a and an of response-surface methodology permits of the concentration–response relation and can be used to develop for optimal drug
This thesis examines tactical lessons learned from recent military operations other than war (MOOTW) for implications on leadership development for junior leaders in the United States Marine Corps. A doctrinal examination of MOOTW provides the context for the study. The research questions focus on unique leadership capabilities and competencies necessary for junior Marine Corps leaders in the MOOTW environment. The research involved analysis of recent tactical experiential lessons. These tactical lessons learned, coupled with the doctrinal examination, result in MOOTW specific junior leader competencies necessary for MOOTW organizational effectiveness. The results synthesize into three key competency areas: (1) ability to adapt leadership roles to diverse environments, (2) independent decision-making skills for decentralized operations, and (3) ability to develop leadership skills in team members. Theoretical leadership development frameworks are reviewed for insight into improving these junior leader competencies in the Marine Corps. Recommendations include focusing MOOTW training on the characteristics of: (1) highly politicized environment at all levels of command, (2) high ambiguity between combatants and non-combatants, (3) decision-making at the lowest tactical levels in a decentralized environment, (4) development of teams to operate autonomously in this decentralized environment, and (5) reinforcement that tactical decisions by junior leaders have operational and even strategic impact.
This paper discusses the movement toward self-sufficiency in vaccine supply in developing countries (and countries in transition to new economic and political systems) and explains special supply concerns about vaccine as a product class. It traces some history of donor support and programmes aimed at self-financing, then continues with a discussion about self-sufficiency in terms of institutional capacity building. A number of deficiencies commonly found in vaccine procurement and supply in low- and middle-income countries are characterized, and institutional strengthening with procurement technical assistance is described. The paper also provides information about a vaccine procurement manual being developed by the United States Agency for International Development (USAID) and the World Health Organization (WHO) for use in this environment. Two brief case studies are included to illustrate the spectrum of existing capabilities and different approaches to technical assistance aimed at developing or improving vaccine procurement capability. In conclusion, the paper discusses the special nature of vaccine and issues surrounding potential integration and decentralization of vaccine supply systems as part of health sector reform.
The goal of the US Department of Energy (DOE) Clean Coal Technology (CCT) Program is to provide the energy marketplace with a suite of advanced, cost-effective, highly efficient, and environmentally responsible coal-utilization technologies through cooperatively implementing a series of demonstration projects with industry stake holders. These projects seek to establish at scale the commercial viability of the most promising advanced coal technologies that have developed beyond the proof-of-concept stage. This document serves as DOE's post-project assessment of a project selected in CCT Round 2, SNOX{trademark} Flue Gas Cleaning Demonstration Project. DOE's participation in this project through Cooperative Agreement No. DE-FC22-90PC89655 is consistent with Public Law 100-202 as amended by Public Law 100-446. The SNOX process is a combination of catalytic processes that remove sulfur dioxide (SO{sub 2}), nitrogen oxides (NO{sub x}) and residual particulate matter (PM) from flue gas that has been pre-cleaned with particulate removal. The process generates salable sulfuric acid (H{sub 2}SO{sub 4}) meeting an industry wide standard (US Government Specification O-S-801E) from the SO{sub 2} and converts the NO{sub x} to harmless nitrogen and water vapor. The integrated design of the process enables high-pollutant-removal efficiencies, no significant waste production (only very low quantities of flue gas ash and catalyst degradation fines), and significant heat recovery potential that can be used in the commercial application of the technology to attain increased thermal efficiency of the system. The host site chosen for this CCT demonstration project was Ohio Edison's Niles Station located along the Mahoning River in Niles, Ohio, just northwest of Youngstown. There are two cyclone coal-fired, steam electricity-generating units at the plant. The performance objectives of this project were as follows: to demonstrate SO{sub 2}-removal efficiency greater than 95%; to demonstrate NOx-removal efficiency greater than 90%; to demonstrate the commercial quality of the by-product H{sub 2}SO{sub 4}; to satisfy all Environmental Monitoring Plan requirements; to perform a technical and economic characterization of the technology.
This thesis examines tactical lessons learned from recent military operations other than war (MOOTW) for implications on leadership development for junior leaders in the United States Marine Corps. A doctrinal examination of MOOTW provides the context for the study. The research questions focus on unique leadership capabilities and competencies necessary for junior Marine Corps leaders in the MOOTW environment. The research involved analysis of recent tactical experiential lessons. These tactical lessons learned, coupled with the doctrinal examination, result in MOOTW specific junior leader competencies necessary for MOOTW organizational effectiveness. The results synthesize into three key competency areas: (1) ability to adapt leadership roles to diverse environments, (2) independent decision-making skills for decentralized operations, and (3) ability to develop leadership skills in team members. Theoretical leadership development frameworks are reviewed for insight into improving these junior leader competencies in the Marine Corps. Recommendations include focusing MOOTW training on the characteristics of: (1) highly politicized environment at all levels of command, (2) high ambiguity between combatants and non-combatants, (3) decision-making at the lowest tactical levels in a decentralized environment, (4) development of teams to operate autonomously in this decentralized environment, and (5) reinforcement that tactical decisions by junior leaders have operational and even strategic impact.
I put forward a new theoretical framework to analyze the relationship between soft budget constraint syndrome and the economic performances of firms. It differs from the existing theoretical framework, à la Dewatripont and Maskin (1995), in the soft budget constraint literature. In this paper, soft budget constraint syndrome arises when firms that are expected to lose money are financed. The paper highlights a trade-off between hard and soft budget constraints. While soft budget constraints may compromise firms' incentives to improve performances, an all-out effort to harden budget constraints may put macro stability at risk, especially for economies suffering from allocative inefficiency. Based on this trade-off, the paper shows that a transition from centralized financing to decentralized financing in fact compromises firms' incentives to improve their performances, whereas a transition from centralized financing to a dual track system enhances efficiency. In the dual track system, budget constraints are soft in the centralized track but the macro stability of the economy is assured as a result. The macro stability enhances the disciplinary effect of hard budget constraints in the decentralized track, which in turn promotes firms' incentives to improve performances. The paper sheds light on a complementary relation between soft budget constraint syndrome in the state sector (i.e., the centralized track) and the remarkable growth of the non-state sector (i.e., the decentralized track) in China.
Michael Gillmann, Jeanine Weißenfels, German Shegalov, Wolfgang Wonner · 5 authors
The Mentor-lite prototype has been developed within the research project “Architecture, Configuration, and Administration of Large Workflow Management Systems” funded by the German Science Foundation (DFG). It has evolved from its predecessor Mentor [1], but aims at a simpler architecture. The main goal of Mentor-lite has been to build a light-weight, extensible, and tailorable workflow management system (WFMS) with small footprint and easy-to-use administration capabilities. Our approach is to provide only kernel functionality inside the workflow engine, and consider system components like history management and worklist management as extensions on top of the kernel. The key point to retain the light-weight nature is that these extensions are implemented as workflows themselves. The workflow specifications are interpreted at runtime, which is a crucial prerequisite for flexible exception handling and dynamic modifications during runtime. The interpreter performs a stepwise execution of the workflow specification according to its formal semantics. For each step, the activities to be performed by the step are determined and started. Mentor-lite supports a protocol for distributed execution of workflows spread across multiple workflow engines. This support is crucial for workflows that span large, decentralized enterprises with largely autonomous organizational units or even cross multiple enterprises to form so-called “virtual enterprises”. A communication manager is responsible for sending and receiving synchronization messages between the engines. In order to guarantee a consistent global state even in the presence of site or network failures, we have built reliable message queues using the CORBA Object Transaction Services. For administration, Mentor-lite provides a Java-based workbench for workflow design, workflow partitioning across multiple workflow servers, and a Java-based runtime monitoring tool.
Abstract In France, like in other Western European countries, the third sector has been on a steady increase during the last decades. Similar to the situation in Germany, the French Third Sector is predominately financed by public money that is concentrated on those subsections which form the core of the welfare state: education, health and social services. However, public funding is currently being reduced and against this background, government and nonprofit-organizations are looking for new ways of cooperation. In other words, in France the partnership of the Third Sector with government is changing as well as its position and role in the French welfare mix. Introduction In the following the results of the Johns Hopkins Nonprofit Sector Comparative Project for France will be presented, thus outlining: * the overall size of the Third Sector in France in 1995, * its composition, * its revenue sources, and * its recent evolution. Thereafter, the Third Sector's central role in labour market policies will be discussed. In France, many new jobs, new markets and new skills have initially been explored by volunteer work. Combined with a trend towards professionalisation this knowledge served as a blueprint for paid labour. Moreover, the changing role of the nonprofit organizations as partners in a new welfare mix will be analysed. The recent Assises de la Vie Associative - a major event which gathered in February 1999 more than 2,500 nonprofit leaders, many government representatives and eight ministers including the Prime Minister was a kind of celebration of the government nonprofit sector partnership. But beyond this temporary event the relationship is not so clearly defined and in some subfields it includes a newcomer: the for-profit sector. I. Dimension of the French Nonprofit Sector As stated elsewhere (Archambault 1997 a, 1997 b), the French nonprofit sector developed only quite recently, associations - the generic form for most nonprofit organizations - being illegal during the whole 19th Century until a nearly centenarian act legalized them. During the 1960s and the 1970s the French Nonprofit Sector slowly grew in a context of state-provided welfare. More recently the decentralization of 1982 broke with a millenary Jacobin tradition which was a major incentive for the Third Sector to contract with local authorities. Graph 1 shows this recent growth: today between 60,000 and 70,000 associations are created per year, more than three times the average of the 1960s. [GRAPH OMITTED] A. Overall Size of the French Third Sector In 1995 full-time-equivalent employment was 975,000 including religion and 960,000 excluding religion - that is 5 per cent of the total employment or the total agricultural employment or the total employment of all consumption-goods-manufacturing industries in 1995. In addition to this paid employment, millions of volunteers are working in the Third Sector. One French individual out of four declare to be a volunteer. The total operating expenditures of the Third Sector in 1995 was FF 290 billion (44.2 billion Euro), which is the equivalent of the turnover of the public utilities industry or the mechanical engineering industry. These figures do not include the estimated monetary value of volunteering which would raise the sum by some 70 per cent. Therefore, the economic activity of the French Third Sector - which is frequently a by-product of its social role - is significant and sizeable. In a comparative perspective France is a middle weight - graph 2 shows the nonprofit share of total employment by country. The French third sector ranks exactly at the average level among the 22 countries which were included in the statistical part of the project. Germany is in a similar position. Graph 2: Nonprofit share of total employment by country, 1995 Netherlands 12. …
Reduced reimbursements from the federal government and third-party payors have threatened the financial viability of many hospitals. An increasing number of hospitals are losing money from their primary mission of caring for patients. The hospital “industry” is still viewed by many as inefficient. Hospitals are generally not run like businesses, nor is it really possible for them to function in the same manner because they have to provide services, to some extent unpredictable, 24 h a day, 7 days a week. Unlike businesses, they cannot increase the charges to their clients to any significant extent when their costs increase because fees are largely dictated by the federal government. For no other business is there the equivalent of capitation or dictation of prices by outside organizations as there is in the medical business. It is perhaps easier for hospital administrations to assess the productivity of their clinical laboratories than of most other hospital services. The number of tests, the number of staff, and the cost of running the service as determined by the supply and salary budgets can be readily quantified. Furthermore, these factors can be bench-marked against the performance of other institutions. However, clinical laboratories also have to contend with the absurd concept of the “billed test” beloved by the federal government, insurance carriers, and consulting companies lacking laboratory expertise. The “billed” test assigns equal weight to a multitest outpatient panel as it does to a dipstick urinalysis or to an elaborate genetic test that is labor-intensive and may take days to complete. This ridiculous concept makes comparisons of productivity between institutions impossible. Indeed, the billed test concept hides increases in productivity because one billed outpatient test may generate as much work as 12 inpatient tests. Successful efforts by hospitals to reduce their inpatient testing, because of non-reimbursability, then mask any increase in revenue-generating outpatient tests. This dual objective of reducing unnecessary inpatient testing and capitalizing on the potential for outpatient revenue has become a major charge for the responsible clinical laboratory director. Clinical laboratories everywhere have been faced with the challenge of doing more tests at less cost, i.e., boosting their productivity. Many laboratories have reached the point at which it is impossible to increase productivity using the equipment that they have. Although each generation of “automated” analyzers usually provides some improvement in throughput and turnaround time for results, they do not have the ability to make the quantum improvements that are a prerequisite to significantly improving productivity. This has led to the concept of “total laboratory automation”, as much a misnomer as “automation” is for a single laboratory instrument. Total laboratory automation goes beyond the automation of analyses but includes automation of much of the important hitherto labor-intensive manual preanalytical phase in the process. The concept was conceived in Japan and has been widely accepted there, so that many large Japanese hospitals now include robotized specimen processing and delivery systems. In the United States, only a very small proportion of even the largest hospital and reference laboratories have installed such systems. Clearly, many laboratory directors have been waiting to learn of the success, or otherwise, of the automated systems in daily operation before they, too, embark on such a major investment. Many also remain uncertain as to whether maximum centralization, as represented by total laboratory automation, is to be preferred over maximum decentralization, as represented by point-of-care testing. The 1999 Clinical Chemistry Forum was designed to present the arguments as to why a fresh approach to laboratory testing was needed and to detail the steps necessary to make the decision whether to commit to total laboratory automation and how to identify the steps involved in a successful installation. The presentations began, appropriately, with discussions of alternative approaches to coping with rapidly escalating workloads. These included total laboratory automation for both individual hospitals and for networks of hospitals. Within the laboratory, alternative approaches were presented, including the use of modular components and automation of selected fixed tasks. The topics covered included a discussion of the components of the necessary overall planning process by a senior administrator from an integrated health system. Another paper dealt with the internal marketing of the concept by the laboratory to the administration and medical staff who would have a major, and vested, interest in the successful operation of a new system. Two of the critical areas that can make or break a robotic system are the layout of the facility with its attendant demands, which involves providing an appropriate environment for both the operators and the analytical systems, and the design and implementation of a superior information system. The latter is essential for capitalizing on the rapid generation of test results. The planning for an automated laboratory entails much more than the operation of the system once it is installed. One of the difficulties in many laboratories is maintaining the daily processing and testing of specimens while a large part of the laboratory’s space is taken out of service during construction. An especially difficult area to manage is ensuring the loyalty and productivity of staff. This is particularly true when they are aware that one of the objectives of installing a robotized laboratory is to reduce labor costs, which must inevitably impact some of the staff whose goodwill and cooperation are essential. This also is essential during all of the steps before the successful introduction of routine operation of the system on a daily basis. A majority of the forum papers are presented here in their full-length form. Four other papers are summarized below that address key problems in working toward an automated laboratory. We believe that the meeting achieved its objective of presenting all of the issues that need to be recognized by a laboratory director before embarking on the very challenging and expensive pathway leading to total laboratory automation. Although this concept has been well accepted in Japan, the small number of installations in the US to date means that those laboratory directors who have installed systems are still pioneers. We are grateful that they were willing to share their experience at the 1999 Clinical Chemistry Forum. In addition, the attendees and the readers of these Proceedings need to recognize the dedication and support given by Jean Rhame and Pamela Nash of the American Association for Clinical Chemistry’s staff, who made the meeting happen. Implementation of total automation of a laboratory is a formidable task. Not only does it ultimately require a large expenditure of money, it requires time and perseverance on the part of its proponents. Two of the papers presented at this forum addressed the very practical issues of getting buy-in from constituencies as diverse as a hospital administration to all of the individuals whose jobs may be threatened by an automated system. A third paper summarized the necessary steps for the overall planning process, and a fourth paper highlighted the critical importance of information handling in a successful robotic facility. These papers are summarized below. Julie A. Fisher, Mount Sinai Medical Center, New York City, discussed selling the concept of a totally automated laboratory to a hospital’s administration and other stakeholders. Successful selling is based on extensive communication and detailed financial and other justifications. There are eight essential elements to successfully selling an automation concept. These are defining goals, assessing needs, obtaining stakeholder buy-in, the decision-making process, vendor selection, the financial planing process, implementation, and metrics. Continuous communication is essential throughout all phases of the project. The wishes of the laboratory must be congruent with those of the administration. The process may be protracted; the cycle between initial concept and routine operation may be as long as 6 years. The trigger for a laboratory to consider automation usually is pressure to reduce costs and improve its efficiency. Automation has the potential to enhance the economic survival of a laboratory, reduce its operating costs, improve the quality of services, and provide a safer work environment. The need for automation should be assessed in the context of whether the institution is planning to expand or to just cut costs. Every ramification must be considered. For example, contractual arrangements with unions must be taken into account. This will become particularly important when the system is fully implemented because contracts may determine who may or may not be laid off. Additionally, needs for upgrading or changing the laboratory information system and analytical instruments must be assessed. A successful automation project depends on stakeholder buy-in. The stakeholders include the laboratory staff, the hospital administration and Board of Trustees, and hospital physicians. It is important to communicate to each of the groups what automation will do for them. Each of these constituencies has different interests and concerns. The laboratory staff are most concerned about job security, but it is important to let them know that automation is a tool to help them perform their jobs differently, and perhaps better. For the administration and Board of Trustees, the focus needs to be on the financial bottom line, with emphases on the opportunity for both revenue enhancement and expense reduction. Other selling points for the administration can include the potential to perform tests for other hospitals and develop group purchasing arrangements with other hospitals for which laboratory services can be provided. Physicians are primarily concerned with turnaround times of test results as well as enhanced information. The financial planning process requires projections of revenue and expenses. A break-even analysis is essential and must demonstrate that automation will reduce costs and/or enhance revenue. Various approaches may be used. A traditional return on investment (ROI) analysis relates net income to investment capital. The formula for calculating a ROI may be refined to take into account sales as well, as in a DuPont analysis. This approach recognizes that it might not be beneficial to tie up assets, thereby lowering profitability. The same formula can be used for an expense analysis by keeping sales constant. The net profit margin increases with a reduction in expenses, and with automation, the key expense reduction is in labor. Technical productivity can be calculated by dividing the number of tests performed by the total number of paid full-time employees or equivalents (FTEs). The calculation of labor savings should take into account how the number of employees will be reduced. With layoffs, there often will be severance and/or retraining expenses to equip the laid-off employees for other jobs. Different laboratory areas will be affected differently. Thus, the laboratories in which automation will be implemented will be more impacted than others. For each laboratory area, a separate projection of staffing needs to be done. Recently, there has been a trend away from justifying automation solely on an ROI analysis because not all of the benefits can be quantified in financial terms. Automation provides added value through improved efficiency coupled with reduction in processing errors, improved turnaround times, automated repeat and reflex testing, enhanced safety, and improved specimen tracking. The active participation of stakeholders in the planning process enhances the laboratory’s ability to sell the concept. Thus, an overall executive committee derives benefits when supported by laboratory management with information systems and instrumentation teams. It is advantageous to enlist stakeholders in vendor selection because acceptance of the system is critically dependent on the their involvement. The more people involved in different aspects of the planning process, the greater the probability of acceptance. Even during the implementation phase, it is important to involve the stakeholders, especially the staff who will be directly affected by the system. During the installation and after the system becomes operational, it is important to continue to communicate to the stakeholders. Information that should be communicated includes actual performance compared with projections, especially with regard to revenue projections and/or expense reductions, the quality of service, and whether a safer environment has been created. Patricia Abbott, Hospital of the University of Pennsylvania (HUP), Philadelphia, discussed the practical aspects of creating a robotized laboratory. Because acceptance of laboratory automation by a hospital’s administration is, to a great extent, dependent on perceived financial benefits, an accurate estimate of the number of employees needed to operate the system is required. The greatest financial returns are likely to arise from reduced labor costs. Unfortunately, the estimate of the number of staff needed to operate a robotized laboratory must be made before the laboratory has any experience with the system or its impact. One of the first steps in the planning process is to decide which tests will be performed in the automated laboratory and which will be performed elsewhere. This decision requires not only an analysis of which tests are performed at each existing bench station but the proportion of tests requested stat vs routine per shift, the number of tests per shift, and the number of technologists working on each shift on each day of the week. With automation, it becomes feasible to combine the stat and routine workbenches for the high-volume tests, but for precise planning of staffing needs, the time of receipt of specimens in the laboratory must be considered. It is also necessary to consider physician needs in deciding which instruments should be interfaced with the robotized and to assess whether greater can be through the test on different analytical the of the planning process, it is essential to assess the and interests of the laboratory staff. This is especially important the laboratory been to a of separate laboratories because there may be a need for extensive of existing on the of the staff in the laboratory at it was to staff the automated laboratory with a staff who would be to operate all of the instruments in the and who would be by staff from the areas working in their areas of expertise. this the laboratory for example, be to on the of of the technologists who would be to operate only the in the automated laboratory to become in operating technologists who been to the and laboratories would not have to the needed to operate a was to assess the of the for working in the automated laboratory, it was on a small number of staff. The for the technologists to assess their to new and for management to assess each potential for a successful to a environment with new for the individuals selected to work in the automated laboratory was each existing The not only on instruments but also on the clinical of the that were new to them and of the results of these tests. before all technologists were to the it was on a selected staff and by their before it was out to all the staff. The of the automated laboratory the laboratory to turnaround time to the the and the in as well as from a processing to a of benefits through of test results possible to the efficiency of testing by the automated laboratory. a the turnaround times for and high-volume tests between in the laboratory information system of the receipt of a specimen and its test results to is now for and for the tests. It is important to have a committee of technologists to at all of work including and in work A of the a of the planning committee once the decision to been made to that the interests of all of the staff were The planning committee has been after the system to Because the staff from different the senior management has with the management of the automated laboratory to their and has with the staff on a as well as on a to that the of the staff are and The senior management a many of the staff a and that problems were to be A committee was as a to and assess problems and The ROI for the project at was based on the of the impact of on the staff, staff were to for all even those not directly affected by the automated laboratory, so that those staff from the automated laboratory be to laboratory the and of these benefits were to them. In the number of that to be was less than been for because of a to tests from other hospitals and the A. the concept of project management as to the of a robotized laboratory. management is as the of and to project to or needs and from a project. Thus, it is a approach to the management of costs, and However, it has only been management requires of a to and manage people and other One individual is to the and is given and to manage the project to its areas of or function are involved in project and the project should have and some in all of them. The primary areas involve the management of cost, and These are by the management of and management is concerned with the of the the overall and of management involves of the necessary the of and the for the project. It is concerned with all aspects of and requires critical and/or as management planning and cost and management all of the of total quality management to that the of the project will the needs of the of the project. management the most use of the people involved in the project and includes and management includes the to the and services needed to the project. management is the function of and to The project must manage or communication so that all of the appropriate people are about the of the project at the appropriate time in the appropriate both and in Each project has a cycle which may have different of and There is no single to manage a but the approach involves the phases of implementation, and the of the concept phase, there usually is only a of a but the of this phase is the for the project. The or design phase usually is when the project is to the project and is the critical detailed planning with planning is the need to develop to and manage of the project. Two critical require the of the people who must the project and the that many individuals working on a project are not working on it The of the phase is a project which should not be The must identify all the necessary and their costs The costs must be to the individual work times and must be with to to the overall project For large such as for installation of a costs with should be as part of the overall project. for costs are of the for for for and of the for the service for the instrument. For large it is to a work which the project to identify the and to to them. A is the for the and of time and cost to be based on is now readily to identify the through the and to determine the of the project. In of the most there is the of with of the project beyond the initial This is not a as long as the project the the cost, and quality and this to the stakeholders. A potential is and to develop management must be a and one of the most to manage is through to can be to whether the can be the probability of is or The latter requires the of a the objectives of the project are it is and its to an Mount Sinai Medical Center, New York City, discussed the critical of a laboratory information system in an automated laboratory. automation involves much more than a robotic system a laboratory. The in an automated laboratory is involved in both analytical and The latter includes both preanalytical such as the processing of and specimen and such as and The provides to the quality and and results and them to the In an automated laboratory, the of the must be integrated with the of the robotic processing and the robotic The each specimen on the robotic system and the robotic process to the and to the specimen and its they might be the system. It and from the robotic system the quality of each primary specimen and the of specimen in the so that specimens may be as It is for tests to be directly into the Not only does this reduce errors, it also has the potential to improve turnaround of to the also and testing. Furthermore, it enhances and provides an accurate time of specimen Within the laboratory, from the to the robotic information and the and system However, such an approach requires or of specimens for which tests were but not on the robotic of the provides in testing and reflex specimen testing. of different of specimens on the but the need to cost and may also a in the testing process because all specimens must through a single An automated laboratory is critically dependent on a and its and system should be in to to of some part of the system. An supply by an is essential to the impact of or in The should have a of that usually share the but with each one of handling the are also needed to provide in one become or to and from the to and and other should be for rapid the system one or more and should also be Each the system should be up to This should be in the at the same time operation of the in the and of the must be with and of the a is it should be in the of the before to the part of the a with the the laboratory staff should to but then should enlist the vendor for The same should be a The staff should provide the laboratory staff with an estimate of the likely so that alternative may be In the of a the medical staff must also be function is this should be communicated to all in the same manner that the was The papers summarized when taken with the full-length papers that will provide the an of the of and with regard to laboratory automation.
Syaikhu Usman, M. Sulton Mawardi, Nina Toyamah, Vita Febriany · 6 authors
The central government of Indonesia is trying to accommodate demands for greater autonomy from the regions. As a result, provincial and kabupaten/kota level governments will soon have to cope with political, fiscal and administrative decentralization. Article 8 of Law 22/1999 states that decentralization must be accompanied with the hand-over and transfer of financing, facilities and infrastructure as well as resources in accordance with the authority delegated to a region. SMERU has outlined a four to five year study to monitor the process of decentralization and to test the impact of decentralization on the structure of the government and on the government's ability to deliver services in 12 kabupaten/kota.
From April 2000 to April 2001 SMERU proposes to monitor preparations and expectations in provincial, kabupaten/kota, kecamatan and village level administrations as well as prepare a survey instrument for evaluating decentralization in the future. The study will investigate how the sub-national governments are coping with the processes related to their new functions.
In the second year of the study, starting may 2001, the affect of decentralization on the performance of kabupaten/kota governments in service delivery will be measured. In this study a different methodology will be needed to test performance because it will involve a broad household survey, a census of service delivery points and expert interviews at the local level. As previously stated, SMERU plans to develop the survey instruments for this 2001 study using input and key indicators generated from this year's study.
Twelve kabupaten/kota will be surveyed with two villages covered in each kabupaten. Government, universities, NGOs, print media and village level representatives will be surveyed. Reports will be produced on one kabupaten/kota per month for 12 months with working papers comparing results across kabupaten/kota being published in November 2000 and again in May 2001.
Abstract Until a few years ago, the organizations belonging to the third sector were relatively unknown to a large share of the population, to the media and probably also to the legislator. This is not the case anymore; in fact, nonprofit organizations have gained wider public attention; they are playing a more significant and increasingly autonomous role in the Italian welfare state. Introduction Over the last decade, the Italian society devoted a great amount of attention to the so called Third Sector. Until a few years ago, the organizations belonging to this sector were relatively unknown to a large share of the population, to the media and probably to the legislator himself. This is not the case anymore; in fact, nonprofit organizations have gained wider public attention and now play a more significant (and increasingly autonomous) role in the Italian welfare state. Although statistical data are still missing, a common feeling is that nonprofit organizations are growing in number and strength, therefore gaining a more significant role in the Italian economic and social landscape. Several factors explain this new attitude toward nonprofit organizations: first of all, changes in the demographic, social, economic and legal environment have to be mentioned. Thanks to a significant increase in the average life expectancy and because of a rapidly declining birth rate, the Italian population is growing older. Moreover, while the country is still confronted with a very high unemployment rate, the number of women with a full-time job is now significantly higher than just a few years ago, especially in northern higher than just a few years ago, especially in northern Italy. These changes in the age structure of the population and in women's access to the labor market generated a whole set of new needs (from children's care to care of the elderly) that the public welfare system has not been able to tackle rapidly. These needs are now generating (although to a quite limited level) demand for new services that are provided neither by the 'state' nor the 'market'. Moreover, private (and public) demand for services is also growing in areas not closely related to the traditional welfare sector, such as the cultural and the recreational areas. Furthermore, the traditional structure of the Italian welfare state has been under attack because of its failure in providing services of good quality and because of its high costs; while criticism concentrated particularly on the pension and the health systems, public provision in the fields of social and educational services has not been immune against difficulties. These challenges to the Italian system of welfare service provision generated two different trends. The first one is a reduction of direct public expenditure in the welfare area (more relevant in the pension system, but quite evident in health and social services as well) and a tendency to decentralize service provision by transferring it onto the local authorities. The second one can be seen in a heavier reliance on private provision of services as a cost-effective way of serving social needs. These are some of the reasons why quite a lot of people, as well as many public authorities, started looking at nonprofit organizations as a possible cost-effective answer to new needs emerging in the sector of social and health services. Therefore quite a few new organizations (associations and especially social cooperatives) have been created to answer this new demand coming from local public authorities and, although to a far more limited extent, from private citizens. Scholars agree that the number of Italian nonprofit organizations is growing, that older organizations learn to deal with new markets and behave more and more as economic entities rather than as missionary's clubs. This attention has been accompanied by new legislation that deals with the Third Sector. A law passed in 1997 (d. …
Ran Canetti, Oded Goldreich, Shafi Goldwasser, Silvio Micali
We introduce the notion of Resettable Zero-Knowledge (rZK), a new security measure for cryptographic protocols which strengthens the classical notion of zero-knowledge. In essence, an rZK protocol is one that remains zero knowledge even if an adversary can interact with the prover many times, each time resetting the prover to its initial state and forcing it to use the same random tape. All known examples of zero-knowledge proofs and arguments are trivially breakable in this setting. Moreover, by definition, all zero-knowledge proofs of knowledge are breakable in this setting. Under general complexity assumptions, which hold for example if the Discrete Logarithm Problem is hard, we construct:
Article On zero-knowledge proofs (extended abstract): "from membership to decision" Share on Authors: Giovanni Di Crescenzo Telcordia Technologies Inc., 445 South Street, Morristown, NJ Telcordia Technologies Inc., 445 South Street, Morristown, NJView Profile , Kouichi Sakurai Dept. of Computer Science, Kyushu University, Fukuoka 812-8581, Japan Dept. of Computer Science, Kyushu University, Fukuoka 812-8581, JapanView Profile , Moti Yung CertCo, New York, NY CertCo, New York, NYView Profile Authors Info & Claims STOC '00: Proceedings of the thirty-second annual ACM symposium on Theory of computingMay 2000 Pages 255–264https://doi.org/10.1145/335305.335336Online:01 May 2000Publication History 3citation509DownloadsMetricsTotal Citations3Total Downloads509Last 12 Months8Last 6 weeks1 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteGet Access
The study identifies strategic priorities for restoring sound public finances, emphasizing the need to maintain fiscal sustainability under a constrained budget, the need to improve the processes for making budgetary allocations, and the need for budget implementation, towards greater fiscal transparency. It reviews Indonesia's public spending during the crisis and the unavoidable build-up of fiscal pressure, its indebtedness, and fiscal risks coupled with policy implications. Improvements to the budget allocation process are examined, focusing on budgetary management processes across levels of government, and on the impact of decentralization which could possibly reinforce civil society participation. A shift in fiscal policy focus towards maintaining fiscal sustainability and ensuring economic recovery is recommended. Nonetheless, certain risks may threaten fiscal sustainability, namely, macroeconomic fluctuations, contingent liabilities, and decentralization. To minimize these risks, the study suggests a combination of domestic revenue generation efforts, spending cuts, accelerated privatization, aggressive asset recovery, and external finance.
Jürgen U. Linder, Thomas Hoffmann, Ursula Kurz, Joachim E. Schultz
Paramecium has a 280-kDa guanylyl cyclase. The N terminus resembles a P-type ATPase, and the C terminus is a guanylyl cyclase with the membrane topology of canonical mammalian adenylyl cyclases, yet with the cytosolic loops, C1 and C2, inverted compared with the mammalian order. We expressed in Escherichia coli the cytoplasmic domains of the protozoan guanylyl cyclase, independently and linked by a peptide, as soluble proteins. The His6-tagged proteins were enriched by affinity chromatography and analyzed by immunoblotting. Guanylyl cyclase activity was reconstituted upon mixing of the recombinant C1a- and C2-positioned domains and in a linked C1a-C2 construct. Adenylyl cyclase activity was minimal. The nucleotide substrate specificity was switched from GTP to ATP upon mutation of the substrate defining amino acids Glu1681 and Ser1748 in the C1-positioned domain to the adenylyl cyclase specific amino acids Lys and Asp. Using the C2 domains of mammalian adenylyl cyclases type II or IX and the C2-positioned domain from the Paramecium guanylyl cyclase we reconstituted a soluble, all C2 adenylyl cyclase. All enzymes containing protozoan domains were not affected by Gαs/GTP or forskolin, and P site inhibitors were only slightly effective. Paramecium has a 280-kDa guanylyl cyclase. The N terminus resembles a P-type ATPase, and the C terminus is a guanylyl cyclase with the membrane topology of canonical mammalian adenylyl cyclases, yet with the cytosolic loops, C1 and C2, inverted compared with the mammalian order. We expressed in Escherichia coli the cytoplasmic domains of the protozoan guanylyl cyclase, independently and linked by a peptide, as soluble proteins. The His6-tagged proteins were enriched by affinity chromatography and analyzed by immunoblotting. Guanylyl cyclase activity was reconstituted upon mixing of the recombinant C1a- and C2-positioned domains and in a linked C1a-C2 construct. Adenylyl cyclase activity was minimal. The nucleotide substrate specificity was switched from GTP to ATP upon mutation of the substrate defining amino acids Glu1681 and Ser1748 in the C1-positioned domain to the adenylyl cyclase specific amino acids Lys and Asp. Using the C2 domains of mammalian adenylyl cyclases type II or IX and the C2-positioned domain from the Paramecium guanylyl cyclase we reconstituted a soluble, all C2 adenylyl cyclase. All enzymes containing protozoan domains were not affected by Gαs/GTP or forskolin, and P site inhibitors were only slightly effective. nitrilotriacetic acid heterotrimeric guanine nucleotide-binding protein, GTPγS, guanosine 5′-O-(3-thiophosphate) guanylyl cyclase fromParamecium Adenylyl and guanylyl cyclases are key proteins in intracellular signaling of essentially all eukaryotic cells. In the freshwater protozoans Paramecium and Tetrahymena cAMP and cGMP levels depend on the ion composition of the extracellular milieu. Whereas adenylyl cyclase activity in vivo is stimulated by membrane hyperpolarization (1.Schultz J.E. Klumpp S. Benz R. Schürhof-Goeters W. Schmid A. Science. 1992; 255: 600-603Crossref PubMed Scopus (128) Google Scholar, 2.Schultz J.E. Schönborn C. FEBS Lett. 1994; 356: 322-326Crossref PubMed Scopus (17) Google Scholar), cGMP formation is enhanced by a depolarizing Ca2+ inward current (3.Schultz J.E. Pohl T. Klumpp S. Nature. 1986; 322: 271-273Crossref Scopus (48) Google Scholar). Recently, we reported on a group of guanylyl cyclases of 280 kDa that is present in the ciliates Paramecium and Tetrahymena but also in the genome of the malaria parasite Plasmodium (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). This novel signal transduction protein is bifunctional. It has a 155-kDa N-terminal P-type ATPase-like domain and a 115-kDa C-terminal guanylyl cyclase domain. Both are linked by a cytosolic loop of about 110 amino acids (see Fig. 1 A). Surprisingly, the guanylyl cyclase domain is topologically identical to mammalian adenylyl cyclases,i.e. it is composed of two pseudosymmetric modules of six putative transmembrane spans (M1 and M2) that serve as membrane anchors for the cytosolic, catalytic segments C1 and C2 (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). The sequences of both cytosolic subdomains are similar to each other and resemble the catalytic regions of metazoan adenylyl and, to a lesser extent, guanylyl cyclases. Sequence comparisons show that the order of the protozoan C1a- and C2-positioned loops is reversed compared with the corresponding mammalian adenylyl cyclase loops (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). Data based on the crystal structure of a soluble adenylyl cyclase type VC1a/type IIC2 chimera demonstrated that Lys938 and Asp1018 in the catalytic pocket of the C2 domain (adenylyl cyclase type II numbering) are responsible for ATP substrate specificity (5.Zhang G. Liu Y. Ruoho A.E. Hurley J.H. Nature. 1997; 386: 247-253Crossref PubMed Scopus (326) Google Scholar, 6.Tesmer J.J.G. Sunahara R.K. Gilman A.G. Sprang S.R. Science. 1997; 278: 1907-1916Crossref PubMed Scopus (680) Google Scholar). In theParamecium guanylyl cyclase, those two amino acids have evolved as Glu1681 and Ser1748 in the C1-positioned domain, i.e. specify GTP as a substrate, whereas the surrounding amino acid residues are more akin to metazoan adenylyl cyclases (see Fig. 1 B for an abbreviated sequence alignment). The expressed membrane-bound Paramecium guanylyl cyclase domain uses MgGTP as a substrate; it accepts MnATP as a substrate only slightly and is inactive with MgATP (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). Following successful strategies by others to produce soluble heterodimeric adenylyl cyclases (7.Tang W.-J. Gilman A.G. Science. 1995; 268: 1769-1772Crossref PubMed Scopus (165) Google Scholar, 8.Whisnant R.E. Gilman A.G. Dessauer C.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6621-6625Crossref PubMed Scopus (117) Google Scholar, 9.Dessauer C.W. Gilman A.G. J. Biol. Chem. 1996; 271: 16967-16974Crossref PubMed Scopus (86) Google Scholar, 10.Dessauer C.W. Scully T.T. Gilman A.G. J. Biol. Chem. 1997; 272: 22272-22277Crossref PubMed Scopus (109) Google Scholar, 11.Dessauer C.W. Gilman A.G. J. Biol. Chem. 1997; 272: 27787-27795Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12.Scholich K. Barbier A.J. Mullenix J.B. Patel T.B. Proc. Natl. Acad. Sci. 1997; 94: 2915-2920Crossref PubMed Scopus (64) Google Scholar, 13.Tang W.-J. Stanzel M. Gilman A.G. Biochemistry. 1995; 34: 14563-14572Crossref PubMed Scopus (111) Google Scholar), we wished to assemble a protozoan heterodimeric guanylyl cyclase by expression inEscherichia coli of the catalytic domains either separately or covalently connected by a peptide linker. Here, we report on the expression and activity of such constructs. We then changed the purine nucleotide substrate specificity in this ciliate guanylyl cyclase with mammalian adenylyl cyclase topology by site-directed mutagenesis of two amino acids in the C1-positioned cytosolic loop. The inversion of the cytosolic loops was definitively proven by the successful generation of active adenylyl cyclase chimeras, which consisted only of cytosolic C2 cyclase domains, i.e. the mammalian adenylyl cyclase IIC2 or IXC2 and the C2-positioned domain of the Paramecium guanylyl cyclase. Radiochemicals were purchased from ICN or Amersham-Pharmacia Biotech; pQE vectors and nickel-NTA1 resin were from Qiagen. All enzymes were from Roche Molecular Biochemicals and New England Biolabs. To obtain the soluble constructs of theParamecium guanylyl cyclase cytosolic loops, we used a clone as a template in which all TAA/TAG-Gln codons had been mutated to the universal CAA/CAG-Gln triplets (GenBankTM accession numberAJ238859; Ref. 4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). For cloning purposes the C1a- (ParaGC-C1a) and C2- (ParaGC-C2) positioned cytosolic domains were fitted withSalI, MluI, and AscI restriction sites. The exact segment boundaries including the N-terminal His6-sequence and N- and C-terminal stuffer amino acids added to accommodate respective restriction sites are depicted in Fig.2 A. Conventional experimental protocols in molecular biology were followed to obtain the DNA constructs. A list of oligonucleotide sense and antisense primers and of synthetic mutagenic primers that were used in this study is available on request. The peptide linker AAGGPPAAGG in the construct ParaGC-C1aLParaGC-C2 was generated with two complementary oligonucleotide primers. The correctness of all constructs was verified by double-stranded DNA-sequencing. The constructs were cloned into a pQE30 expression vector that was modified to contain only a 5′-SalI and a 3′-AscI/HindIII cloning site. The C2 clone from rat type II adenylyl cyclase (GenBankTMaccession number M80550; IIC2) and a mouse type IX adenylyl cyclase clone (GenBankTM accession number Z50190) were kindly provided by Dr. C. Kleuss (Berlin) and Dr. F. Antoni (Glasgow), respectively. The C2 regions were cloned the with respective as and specific with and restriction sites for cloning of the into the pQE30 expression vector (see Fig. mutagenesis and was by the of and 1992; PubMed Scopus Google the site-directed mutagenesis and by to the C1a- and C2-positioned loops of the cyclase cloned into II as The constructs in the pQE30 expression were into the were in of containing and and with of were and in For C.W. Gilman A.G. J. Biol. Chem. 1996; 271: 16967-16974Crossref PubMed Scopus (86) Google were in of containing a of inhibitors from were and were and were and the was for was by The were in and of was the resin was into a and with A with A with and were with of C containing The of the recombinant proteins with to adenylyl and guanylyl cyclase was Using we were to the protozoan constructs active upon on or by The of activity affected all protozoan constructs and not from to and on adenylyl or guanylyl cyclase were and all were from the affinity of activity was not to the proteins as analyzed by but to The proteins were analyzed by a mouse or a mouse Molecular were for in a of either or and 1 of were used as an of recombinant and The recombinant cyclase domains were on for to the by of and were and chromatography S. Schultz J.E. J. PubMed Scopus Google Scholar, Y. C. M. PubMed Scopus Google Scholar). The membrane-bound guanylyl cyclase from the Paramecium of two domains 1 A). The 155-kDa N-terminal domain resembles a P-type ATPase, and the C-terminal for a guanylyl cyclase of kDa with a structure of canonical mammalian adenylyl cyclases yet with reversed cytosolic C1a- and C2-positioned loops (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). For soluble constructs of cytosolic adenylyl cyclase loops have been (7.Tang W.-J. Gilman A.G. Science. 1995; 268: 1769-1772Crossref PubMed Scopus (165) Google Scholar, 8.Whisnant R.E. Gilman A.G. Dessauer C.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6621-6625Crossref PubMed Scopus (117) Google Scholar, 9.Dessauer C.W. Gilman A.G. J. Biol. Chem. 1996; 271: 16967-16974Crossref PubMed Scopus (86) Google Scholar, 10.Dessauer C.W. Scully T.T. Gilman A.G. J. Biol. Chem. 1997; 272: 22272-22277Crossref PubMed Scopus (109) Google Scholar, 11.Dessauer C.W. Gilman A.G. J. Biol. Chem. 1997; 272: 27787-27795Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12.Scholich K. Barbier A.J. Mullenix J.B. Patel T.B. Proc. Natl. Acad. Sci. 1997; 94: 2915-2920Crossref PubMed Scopus (64) Google Scholar, 13.Tang W.-J. Stanzel M. Gilman A.G. Biochemistry. 1995; 34: 14563-14572Crossref PubMed Scopus (111) Google Scholar, W.-J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, R.K. Dessauer C.W. R.E. Kleuss C. Gilman A.G. J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar, C.W. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We wished to a soluble protozoan guanylyl cyclase from and C2-positioned loops and expressed the recombinant proteins in coli either or linked by a peptide in to W.-J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, R.K. Dessauer C.W. R.E. Kleuss C. Gilman A.G. J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar, C.W. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We used a construct with an molecular of kDa i.e. amino acid in of the which to a slightly for in C2 of rat type II adenylyl cyclase. The protozoan C2-positioned loop with an molecular of kDa consisted of the of the transmembrane A). of the recombinant a the as the proteins and only a of a was present in Guanylyl cyclase activity of catalytic loops was not whereas a of the C1a- and C2-positioned loops had activity either or MgGTP as substrate the protozoan guanylyl cyclase loops had a affinity for each other to a active This is in to with the catalytic domains from mammalian adenylyl cyclases of soluble adenylyl cyclase activity mixing of cytosolic domains from and the of C.W. Gilman A.G. J. Biol. Chem. 1996; 271: 16967-16974Crossref PubMed Scopus (86) Google and guanylyl cyclase of type and mutated constructs of Paramecium were with of the respective or and of each recombinant cytosolic domain or of the linked all affinity in were and in the C1-positioned domain and in the C2-positioned domain of the Paramecium guanylyl cyclase. not The of the was Data are from with similar The were of the C2-positioned in a were with of the respective or and of each recombinant cytosolic domain or of the linked all affinity in were and in the C1-positioned domain and in the C2-positioned domain of the Paramecium guanylyl cyclase. not The of the was Data are from with similar The were of the C2-positioned It was demonstrated that the activity of soluble constructs of mammalian adenylyl cyclases is or the catalytic loops are linked by a peptide (7.Tang W.-J. Gilman A.G. Science. 1995; 268: 1769-1772Crossref PubMed Scopus (165) Google Scholar). we linked the protozoan cytosolic domains a the order of the domains present in the reversed compared with mammalian adenylyl cyclases Fig. A). affinity the was by as a guanylyl cyclase activity was it not that in a of the expressed loops The of the of for MgGTP and were and and not from the with the linked construct and and to for the membrane-bound guanylyl cyclase domain expressed in or for the (4.Linder J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar, S. Schultz J.E. J. PubMed Scopus Google Scholar). of substrate were from to MgGTP and not from a substrate GTP The was to with the In with GTP as a substrate a of ATP guanylyl cyclase a specificity for GTP as a The of was A of was from the of an To the substrate specificity of the soluble guanylyl cyclase, we all constructs for adenylyl cyclase activity Using MgATP as a substrate, adenylyl cyclase activity was or of the respective guanylyl cyclase activity MnATP adenylyl cyclase activity was about of guanylyl cyclase and was similar to that with GTP as a substrate The crystal structure of a rat adenylyl cyclase type IIC2 and of a and rat to and and two or amino acids in the cyclases as responsible for purine nucleotide specificity (5.Zhang G. Liu Y. Ruoho A.E. Hurley J.H. Nature. 1997; 386: 247-253Crossref PubMed Scopus (326) Google Scholar, 6.Tesmer J.J.G. Sunahara R.K. Gilman A.G. Sprang S.R. Science. 1997; 278: 1907-1916Crossref PubMed Scopus (680) Google W.-J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hurley J.H. Hurley J.B. Proc. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). amino acids are all mammalian adenylyl and guanylyl cyclases and are In adenylyl cyclases Lys938 and the IIC2 catalytic domain with the and of the J.J.G. Sunahara R.K. Gilman A.G. Sprang S.R. Science. 1997; 278: 1907-1916Crossref PubMed Scopus (680) Google Scholar, Sunahara R.K. G. Gilman A.G. Sprang S.R. Science. 1999; PubMed Scopus Google Scholar). In guanylyl cyclases the corresponding amino acids are and to the of rat soluble guanylyl which with the and the of the guanine of amino acid residues the respective substrate of mammalian guanylyl and adenylyl cyclases R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hurley J.H. Hurley J.B. Proc. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). to the Paramecium guanylyl cyclase, the C1-positioned domain is the of the catalytic of soluble guanylyl cyclases. Glu1681 in the C1-positioned loop is to and Ser1748 is to 1 In the a that is in mammalian guanylyl cyclases 1 This not the specific of GTP in the a the of the guanine and the This was a mutation the guanylyl cyclase activity to the of the A. C. J. Schultz G. Biochemistry. 1997; PubMed Scopus Google Scholar). To the of Glu1681 and Ser1748 in theParamecium domain in substrate we mutated to the adenylyl cyclase specific residues Lys and In we generated the the was not The constructs were enriched by affinity chromatography and by All recombinant proteins the molecular and were more or of Ser1748 to all cyclase of ATP or GTP as with as a guanylyl cyclase activity was by more and adenylyl cyclase activity was by more the of the adenylyl and guanylyl cyclase was only which that substrate was The then that the with the amino acid corresponding to to the for ATP or GTP substrate and to substrate The was in a purine nucleotide cyclase. in of two amino acids in mammalian membrane-bound or soluble guanylyl cyclases and in the mammalian had all of cyclase activity R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hurley J.H. Hurley J.B. Proc. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In the guanylyl cyclase the nucleotide specificity was switched from GTP to of guanylyl cyclase were of type whereas adenylyl cyclase activity to and This demonstrated the inversion of the of the cytosolic loops in the ciliate guanylyl cyclase the amino acids were in the domain, whereas in mammalian adenylyl cyclases are in the C2 domain R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it demonstrated that which a that is in all mammalian guanylyl cyclases, is and a to had the In it the that the Paramecium guanylyl cyclase with a mammalian adenylyl cyclase membrane topology is a guanylyl cyclase we substrate specificity by site-directed mutagenesis of the protozoan domain as by the available of the mammalian adenylyl cyclase C2 (5.Zhang G. Liu Y. Ruoho A.E. Hurley J.H. Nature. 1997; 386: 247-253Crossref PubMed Scopus (326) Google Scholar, 6.Tesmer J.J.G. Sunahara R.K. Gilman A.G. Sprang S.R. Science. 1997; 278: 1907-1916Crossref PubMed Scopus (680) Google Sunahara R.K. G. Gilman A.G. Sprang S.R. Science. 1999; PubMed Scopus Google Scholar). A novel for a cyclase with a canonical mammalian adenylyl cyclase topology was the in purine nucleotide This has been only for mammalian guanylyl cyclases R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hurley J.H. Hurley J.B. Proc. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The to the substrate specificity of a soluble mammalian adenylyl cyclase in a purine nucleotide cyclase R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the C1 domain of adenylyl cyclases type adenylyl was as a of for substrate by and by (5.Zhang G. Liu Y. Ruoho A.E. Hurley J.H. Nature. 1997; 386: 247-253Crossref PubMed Scopus (326) Google Scholar, R.K. A. J.J.G. Sprang S.R. Gilman A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hurley J.H. Hurley J.B. Proc. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In adenylyl cyclases this is of a In soluble guanylyl cyclases the corresponding is an which to in the Paramecium C2-positioned loop. we mutated is in guanylyl in the ciliate C2-positioned domain to the adenylyl cyclase B and The construct was expressed in to a protein on a of the type with the guanylyl cyclase activity to and with MgGTP and the is adenylyl this have been it was to that also the adenylyl cyclase activity was to and with MgATP and MnATP as the of guanylyl to adenylyl cyclase that the of the C1-positioned loop is not all in substrate We that the was inactive which the The in which all residues and specific for were not cAMP formation that with the are in with substrate of the adenylyl cyclase chimera in which the Sunahara R.K. G. Gilman A.G. Sprang S.R. Science. 1999; PubMed Scopus Google Scholar). we the that a of the to substrate in other cyclase (see In theParamecium guanylyl cyclase the amino acid residues for substrate to for guanylyl cyclase adenylyl cyclase cyclase activity were with of the respective or Guanylyl cyclase activity was not with either All the domain were residues are in (see for in a were with of the respective or Guanylyl cyclase activity was not with either All the domain were residues are in (see for In the protozoan the molecular of the cytosolic and C2-positioned loops is reversed (see and J.U. Engel P. Reimer A. Krüger T. Plattner H. Schultz A. Schultz J.E. EMBO J. 1999; 18: 4222-4232Crossref PubMed Scopus (80) Google Scholar). To the of on we the of the C2-positioned domain for of cyclase activity with the catalytic C2 loop from mammalian adenylyl cyclases of rat type II and mouse type IX Fig. expression and IIC2 as a on a whereas the of IXC2 by of guanylyl cyclase activity was in protozoan C2 chimeras, whereas adenylyl cyclase were in with either IIC2 or IXC2 The were with MnATP as a substrate as compared with MgATP This was in the which was more active with MnATP the inversion of the cytosolic loops in the Paramecium guanylyl cyclase has been on an the C2-positioned domain from the ciliate guanylyl cyclase for a mammalian adenylyl cyclase domain. of the sequence theParamecium C2-positioned and mammalian domains, the which are to a were in the ciliate C2 loop. we used the for adenylyl cyclase with IIC2 or Whereas adenylyl cyclase activity was the for MnATP as a substrate was This that the to the of the C1 and C2 domains in adenylyl cyclases, not the domain not an active cyclase with mammalian domains not All membrane-bound mammalian adenylyl cyclases by the of and the forskolin, and by P site of M. 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The then of this was the The protein that is in for the of the group of the nucleotide in with the of two Sunahara R.K. G. Gilman A.G. Sprang S.R. Science. 1999; PubMed Scopus Google Scholar). The amino acids are of the C1 and in the domain and and IIC2 Sunahara R.K. G. Gilman A.G. Sprang S.R. Science. 1999; PubMed Scopus Google Scholar). from respective sequence all of amino acid residues are present in the corresponding C2- and C1-positioned domains of the protozoan guanylyl cyclase. are of the C2-positioned and in the C2-positioned loop and and in the catalytic C1-positioned loop (see the abbreviated in we that the amino acid for the site is present in the protozoan guanylyl cyclase and that the of of P site inhibitors has a In mammalian adenylyl cyclases loops a substrate ATP to a specific and active site and the heterotrimeric proteins either or such a which the substrate group and the catalytic residues Sunahara R.K. G. Gilman A.G. Sprang S.R. 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Kleuss and (Berlin) for a clone of the adenylyl cyclase type IIC2 and a of and Dr. F. for a clone of the mouse type IX adenylyl cyclase.
Kalevi Lauslahti, Risto P. Roine, Virpi Semberg, Martti Kekomäki · 6 authors
Finland has a long tradition of supporting social programs that promote equality and the welfare state. The healthcare system is financed mainly by taxation. Everyone is insured against illness. Each of Finland's five provinces is run by a provincial government that monitors the provision of social welfare and health care. However, the municipalities actually provide the services and regulate medical equipment and regionalization of services. During the early 1990s, gross domestic product (GDP) fell dramatically, and healthcare expenditure rose to 9.4% of GDP. Due to the economy's rapid recovery, the share of healthcare expenditure has again decreased and now matches the average level of OECD countries of approximately 7.7%. The former Finnish method of central planning and norm setting has guaranteed a fairly uniform development of necessary services throughout the country and free or low-cost access. Tight central planning did not, however, create incentives to contain costs. Therefore, in the beginning of the 1990s, decision-making power was largely decentralized to the municipalities, and the principles of state subsidies were reformed. In 1995, the Finnish Office for Health Care Technology Assessment (FinOHTA) was set up as a new unit of the National Research and Development Centre for Welfare and Health (STAKES). FinOHTA is intended to function as a national central body for advancing HTA-related work in Finland, with the ultimate goal of promoting the effectiveness and efficiency of Finnish health care. At present, the importance of HTA is widely recognized in Finland, especially in the face of rising healthcare costs.
Health Systems, Economic Evaluations, Quality of Life
The Austrian healthcare system relies mainly on physicians in private practice and on various services provided by hospitals. The social health insurance scheme is compulsory, covering 99% of the population. The system is very decentralized. While the federal state provides the framework, the nine autonomous provinces are responsible for administering health and social services. There is ongoing public discussion about centralizing the healthcare system to make it more efficient and to enforce structural reforms. Because of concerns about healthcare expenditures, in 1997 the Performance-Related Hospital Financing System (LKF), a system similar to the diagnosis-related group system, was introduced for hospitals, including a plan for large medical devices. It is too early to evaluate the success of this new system, although some effects of the LKF system that could have been anticipated, such as shortened lengths of stay and more hospitalizations, have been seen. Previously, health technologies have been almost uncontrolled in Austria. The evaluation of health technologies as an instrument to support or to control their dissemination and use or to help define policies is not institutionalized or systematically used. It seems clear that structural reforms of the Austrian healthcare system are needed. Health technology assessment should be part of such reforms.
Health Systems, Economic Evaluations, Quality of Life