Early structure models of crystals go back to the 17th century.1, 2 By studying the external regularity of the crystals and their optical properties, an arrangement of the fundamental particles as shown in Figure 1(a) was suggested without actual knowledge of their size and nature. It took about 200 years until the molecular details could be ascertained, as shown for NaCl in Figure 1(b).3 Note that this was before X-ray diffraction was available for precise crystal structure determination.8 At about the same time, thermodynamics reached the present-day precision.4, 9 It represents the macroscopic tool to describe phases. Thereafter, microscopic experimental crystal structures were amassed by X-ray diffraction. Parallel, large numbers of heat capacities (at constant pressure), Cp, were determined by adiabatic calorimetry, often covering the temperature region from close to absolute zero to beyond the equilibrium melting temperature, T. Tables of the integral thermodynamic functions enthalpy, H, free enthalpy, G, and entropy, S, were collected for many substances as a function of temperature.10, 11 On the basis of the macroscopic thermodynamics and the microscopic structure, the molecular motion within the crystals was assesses by approximation and in detail.12-14 (a–d) Development of the knowledge about crystal structure (a2 and b3), phase property and size (c4, 5, 6), and the 10 basic states of matter (d7). The next step involved the evaluation of the properties of smaller and disordered crystals. As the main change in property, experiments on small crystals showed a lower melting temperature, Tm. This change in Tm could be described by the Gibbs-Thomson equation based on their surface area and the specific surface free energies.5 The same treatment was useful later, when analyzing lamellar polymer crystals.6 Figure 1(c) summarizes the historical definitions of the thermodynamic properties of macrophases and microphases, with the former being, in at least one dimension, larger than 1000 nm (1 μm). The Gibbs-Thomson equation listed in Figure 1(c) applies to the melting point lowering, ΔT, of lamellar, microphase crystals (𝓁 < 1.0 μm). The earlier suggestion that microphases in the form of colloids where a “fourth state of matter” could be discarded after understanding the effects of surface free energy and surface charges. More recently, nanophases are of general interest for objects marginally larger than the limit of a few ångstroms, set by the homogeneity of the phase due to the atomic structure and the fluctuations of the thermodynamic properties because of a too small sampling volume.15 Experiments following the glass transition of unsupported polymer spheres of decreasing size16 suggested that as long as a small phase has unchanged bulk material within its center, there is no reason to apply a different name to a small microphase.17 As one, however, approaches a size so small that the opposing surfaces leave no unchanged bulk material, it was found that there is a size-range for an entirely new phase, a true “nanophase.”15, 17 An updated thermodynamic description of phases is given in Figure 1(d). It contains a list of the possible phase types when considering not only degrees of condensation and ordering, but also the differences in modes of molecular motion. Figure 1(d) expands the basic, classical states of matter to ten.7, 18 The phases known since antiquity, have been linked in the early 19th century to their newly proven atomic nature.19, 20 The expansion with intermediate phases (mesophases) was discovered over the last 150 years.21 On the left side of the figure, it is indicated that the mesophases become increasingly more “solid” when changing in order toward the crystal. Unfortunately, crystals may have a broad range of solidity, so that the term “solid” is not a scientific, operational definition22 for their state. Glasses, in turn, have an easily measured glass transition temperature, Tg, which can be identified as a solid/liquid transition.23 The mesophases often possess a Cp close to that of the melt. On quenching, they undergo a glass transition similar to liquids. This leads to the three mesophase glasses indicated (from top to bottom: liquid crystal glass, plastic crystal glass, and condis crystal glass). Recently, it was observed, that some polymeric crystals, like aliphatic nylons and polyoxides, may even approach liquid-like mobility on heating before melting or undergoing a disordering transition. This change in mobility causes a change in heat capacity as in a glass transition, that is, the crystal displays a glass transition.24 Crystals that remain “truly” solid up to Tm become a mobile liquid on fusion. Turning to the right side of Figure 1(d), one notes that only the gas connects to all condensed phases. The entropy change of a liquid to a gas without change in the molecular structure is expressed empirically by Trouton's rule.25 The disordering of a crystal to a liquid follows the empirical rule of Richards as long as the ordering species are spherical.26 Nonspherical species follow Walden's rule,27 and for conformational disordering, a similar empirical entropy increase was observed as for spheres.28 The possible transitions between the condensed phases are marked in Figure 1(d) and their overall entropy of fusion is expressed in terms of the three types of disorder by the boxed equation.29, 30 Today, this development of the knowledge about crystal structures, phase properties and sizes, and the states of matter are supported by a wide range of experiments. The macroscopic picture is supplied by the equilibrium and nonequilibrium thermodynamics, based on calorimetry, and is supported by direct experimental evidence about the microscopic structure as well as the molecular motion. Furthermore, the enormous increase in computational capability allows to simulate molecular structure and motion. The time scale of importance, the picosecond, however, is far removed from human experience. The present summary is to establish the needed developments to attain a base for the detection of flaws in the still incomplete description of the thermodynamics and kinetics of crystallization of flexible molecules and their phase structures. In the next three sections, the often neglected problems of nucleation of a new phase of increased order will be analyzed and the nanophase structure of macromolecules will be probed as to its influence across the interfaces. In the conclusions, a view towards the enormous job of supplying details about the resolution of the indicated problems is summarized. The development of the idea of primary and secondary nucleation as they were ultimately applied to the crystallization of semicrystalline macromolecules are described in this section.31 The classical concept of crystal nucleation was already suggested by Gibbs about 130 years ago.32 The description of small phases as a function of size was discussed in Figure 1(c) and led to the free enthalpy plots describing primary nucleation given in Figure 2(a). The curves are scaled to the free enthalpies of polyethylene crystals. The boxed numbers in the graph on the right of Figure 2(a) represent the free enthalpy in convenient units at an approximately 40 K supercooling. They indicate a saddle point (*), calculated by the given equations. The system must travel across it to become stable. Obviously, at T the size of the nucleus is infinity, that is, no nucleation is possible. The larger the supercooling, the lower is the barrier for a move into the region of negative ΔG. About 60 years ago, a mathematical expression for the nucleation rate was derived by Turnbull and Fisher33 written in Figure 2(b). This was fitted to experiments on homogeneous nucleation with sufficiently small polyethylene droplets in silicone oil, eliminating the effect of accidental, heterogeneous nuclei. The result is the graph in Figure 2(b), based on the two-dimensional plot of Figure 2(a).36 There is a region of about 30 K in polyethylene where primary, homogeneous nucleation is not observed, followed by increasingly fast nucleation which slows as the melt viscosity, η, increases and reaches zero when the glass transition at 250 K is approached.31 (a–d) Free enthalpy of primary nucleation of a tetragonal crystal of dimension i = a × a × 𝓁 and expressed by the equations (a31); rate of primary nucleation, calculated analogous to part a (b31, 33); and the basic surface effects leading to secondary nucleation (c,34 d35). To assess the further crystallization after homogeneous or heterogeneous nucleation, the Kossel model of a crystal was used.34 Figure 2(c) illustrates that on a cubic crystal there are five distinguishable locations of different surface free energy for crystallization or melting. Only position 3 has no change in surface free energy, that is, at position 3 crystallization (or melting) should occur at equal rates. Position 1 would require a secondary nucleation on the smooth crystal surface, and position 2, a tertiary nucleation of a new row on a step in the surface. Positions 4 and 5 would be stable and require a positive free enthalpy for removal from the crystal. This model was transferred 30 years later to the crystallization of polymers by Lauritzen and Hoffman35 by simplifying a polymer crystal as shown in Figure 2(d). It was the basis for the description of polymer crystallization for many years with numerous improvements and fine tunings,37 and is often still applied today. Figure 3(a) the for the secondary nucleation of analogous to homogeneous needed to be given for the observed crystallization in form of a but 𝓁 with a positive ΔG. Furthermore, it was that an of similar as for crystallization with a atomic step should the experiments on Early of the polymer as shown in Figure in a to the of the and from the of a molecular of one can that a with 𝓁 = nm which a crystal is only one of about In the in energy so that there is not only an but also an which of Figure temperature In present-day of secondary nucleation, the thermodynamic functions are as of temperature, the that of heat capacities are available for many for the heat capacity been measured by and was linked to its and by crystals of close to could be by crystallization in the condis phase of the condis phase to the phase by removal of the the equilibrium melting temperature was by to the from by and could be shown to the experimental equilibrium melting temperature = but the was leads to a 3 K a when small degrees of supercooling. Today, the contains and thermodynamic functions for 200 polymers and with the of the rate equation of Figure to secondary nucleation is the of the secondary polymer on a smooth crystal surface, as shown in Figure 2(d). as the on its molecular model of a surface a with new surface. This the or surface as the only to secondary It will be shown in the last of this that surfaces to to crystal Furthermore, and thermodynamic evidence of the of secondary nucleation will be in the next (a–d) and and experiments of possible secondary nucleation of all it was that for years the model for polymer crystallization was the to secondary at found The evidence for secondary nucleation was a large of on crystal as shown in Figure have an and could be fitted to nucleation rate as in Figure It was from the experimental of Figure that in the model would ultimately have to to a mathematical description of similar The direct experimental of the of secondary nucleation in polymers is about 40 years An of a of crystals of polyethylene is shown in Figure that should be for secondary nucleation can be on the surface. the was the was to melt some and to the surface with crystals. The area as in Figure is in Figure The on the surface should have secondary nucleation, but by following the crystal it is that not as crystal nucleation The crystals, however, are in indicated by their the of secondary surface of crystals of after heating to K for 3 to a small of crystals. indicate 1.0 from with from the crystallization of of was by experiments with the equilibrium phase by crystals were by up to a of about was The polymer was melting more than from the phase the of a solid This was to crystals from and from the at The after crystallization from can be and by were analyzed and the of is shown as 2 in Figure on crystallization from the melt are as 1 after the by K due to the increase of the melting temperature on of The melt was and so that the could only and were by calorimetry, was to the temperature and to on of the At the crystallization temperature, the curves up to far the by the phase as is this all curves approach the same limit at temperature, at there must be a for to the different the equilibrium melting or temperature of the given The that this is the equilibrium at the saddle point of secondary nucleation in Figure 3(a) is not Only one of many molecules could in this be by secondary On the basis of was molecular nucleation, similar to secondary nucleation was needed for of the molecular nucleation is as Figure It the step of nucleation by and the which sufficiently of the could at a different This nucleation of a could be followed by similar The in more than one form as were discovered earlier by On the molecules in different locations form a to the melting crystal. The are by after by This picture of the thermodynamics and kinetics of crystallization of flexible molecules is by years on the molecular of the of species their equilibrium melting temperature of molecular the of the of the nucleation and of and polyethylene crystals from the the description of the further developments must be In the in the of crystallization of flexible macromolecules a The possible of or at the lamellar surfaces of polymer crystals a It that were a could be found for by of the however, is based on with only by by all on it was from on to for polymer and interest It up only with a new of and new The is in the of more on the The new development with the of surface into the description of polymer crystals, or the secondary nucleation The of a was an early in the crystallization of small from the gas flexible were for the a model of was it no to the nonequilibrium of Figure suggestion of the a mesophase it is that the in Figure must intermediate order before the and a of polymers possess stable or for polyethylene (at and many mesophases are to be stable at the of following the molecular motion of of on a to a view of the crystallization in the to and follow possible in polymer crystals and to the motion involved in the of crystal but the time of to follow crystallization was still too could be To the to more was the many and the cubic an nucleation of nucleation and could be supported by the ultimately also the of molecular was in the as a new tool to and It is applied as calorimetry, Figure the limit of the of crystallization and melting of and experiments and were is a where the is about a temperature with a The were three of an of the and and broad The is to a of This limit of also with Figure where true is up to about It was that in the of glass or surfaces no in the crystallization of by homogeneous This found an by the of of long on by atomic The only K the bulk T. Figure also that the is not by the in the crystal with larger is by heating and as with Figure for As long as T is within the melting and crystallization are The and incomplete phase transitions due to time and a of the and 5 are indicated by the measured by the and the which to the and liquid heat The in Figure the of the of melting and crystallization with a of than the experimental limit of the heating rate to 30 K not change the of melting (at beyond the which was for in Figure 1 K 10 K The of in at larger than 10 K and reached a of 10 K at 30 K experiments a of the of crystallization by the enormous of possible of the in the to the no of crystal with the rate of after primary More on the kinetics of molecular nucleation and its influence on in the Turnbull and equation of Figure has not been as Today, with calorimetry, can be to as as K range of may a direct of molecular nucleation kinetics with changing molecular (a–d) of melting and crystallization of for a of melting in nucleation as step of crystallization after homogeneous or heterogeneous nucleation, in to an between crystal and the melt which must influence the This effect would in the Turnbull and equation of Figure and will be in the last On of the of semicrystalline it was found when the that the glass transition was to temperature and the increase in Cp at was often smaller than from the This in was the and is as the development of it possible to heat effects from the heat capacity in the temperature range between and Tm. from the of this it was found that many crystals a of of by the melting from Cp, a glass transition could be identified for a of polymers the of the phase, for the By a transition temperature, the of a that the not only of a but represents a phase between the crystal and the bulk phases. the influence on the heat capacity by melting and the it possible to the molecular motion within the crystals in this temperature It was found that polymer crystals an of conformational motion as the melting temperature is In many this molecular motion could also be and by solid state X-ray and molecular In of which is available as material, this increase in conformational mobility was discovered to at about In some this motion even reaches a glass transition of the crystal as in the of Figure 1(d). In a of polymer crystals, a transition to a mesophase as is long for for polyethylene at and To a semicrystalline material and to its it is to and three possible phase and more than one, The influence of phases on the overall thermodynamics and the kinetics of crystallization are analyzed in this The observed on is in Figure for It at the phase and is in the temperature range were melting is also observed, a close between the small of different surface melting was earlier by X-ray In this the at the surface over a wide temperature not the crystal and at a lower temperature than the By a larger of experiments on it was that only semicrystalline with and The melting is by the of to At lower temperature the is larger and it approaches zero at the of melting. The the the is the melting. It increases with and with The effect is in Figure on the of a and melting occur to the glass transition region and are at The crystallization in Figure on at 10 K a On with only of this because of to the by the of the is The broad melting is at a temperature than the main crystallization To be linked to the the melting must be a It can be by considering the molecular nucleation of Figure The of the are from the more of the so that melting can only occur at a The however, can as a molecular nucleus for the which within the of Crystals of macromolecules with or no of melting have also been Figure the for a without At this it is to crystals of and or of no (a–d) of the melting and crystallization of a of different polymers for melting of crystals of of different of polymers are or melting was observed for of Figure a of similar as in Figure similar melting was also observed for the crystal was determined by on from It of a lamellar structure as for of a to of within the The of the polymer was in this not to the homogeneous to like an their of than the limit of The polymeric was the that the crystallization and melting are close to that of a of similar The of of the different to influence the molecular nucleation and to be The has a influence on the crystallization of flexible in there is no of the as in there is a of the glass transition to temperature in all semicrystalline the intermediate phase was proven by on This intermediate phase was and on the top and of the This intermediate phase for of the and in solid state experiments it an intermediate mobility between that of the and This has also been by a between X-ray and The size of this intermediate phase was to be about nm for melt More is a of the but from the of the Figure for The Cp for the solid and the mobile could be calculated from of the The glass transitions can easily be from the K all polymer is and the indicated equation for the can be to represent of the and the of the all three phases must be when the by K no can be determined because glass and crystal have close to the same this for the and with it the of the crystallization not apply to by X-ray diffraction. is the of a phase the melting temperature, as for and in Figure experiments of this polymer by already that there was no glass transition the melting that is, the a the the melting the crystals as but it also the The of a is not far the melting temperature, but increases sufficiently when in the phase, as indicated by the experiments in Figure The melting rate is by the glass transition and the T is the of the but melting is at and the glass transition The melting kinetics could be followed and after some of the one of could melt for three units of Note that there is also no of melting in This an not by from the melt. The glass transition is sufficiently that nucleation leads to the of the its glass transition and further To the glass transition to be by the of a On one not only of the crystals, but also the On this is transferred to the the of it was possible to this by X-ray The of the that of a similar result was with The phase structure of semicrystalline polymers is a more system than for small On the basis of the updated phase description in Figure 1 of macroscopic and as well as molecular order and a arrangement of and nanophases was the classical model of Figure 2, one can the homogeneous nucleation of crystals of small as well as large the of the term may be to to this approach to the kinetics of polymer crystals the secondary nucleation of 2 and 3 4 and 5 supported the to a molecular (or nucleation to for direct of crystal without secondary nucleation, of of molecules the equilibrium temperature of their phase and the on of the limit of molecular nucleation a given set of experimental and the on melting and their They indicate that of sufficiently long molecules with a of the macromolecules are for and one can with the to heat capacities and to the thermodynamic functions in the temperature range between and Tm. to the picture that crystal in semicrystalline polymers is by an phase that has at least a glass transition from the phase, and in many leads to a with a glass transition a nanophase semicrystalline as and the may remain and on a structure which at their with a possible heat the of and that no one picture applies to all The details of must be before a description of the thermodynamics and kinetics of crystallization is an enormous which has by only The are available for this for evaluation of the thermodynamics, its and by even the of X-ray diffraction can the structure of all may assess the molecular and the The expression shown in Figure could still describe the experimental crystal as a function of temperature in Figure however, must a set of and the step of the crystallization can be by the of Figure The of may be from at fast the entropy and energy of the The of should into the by the because the of the in Figure are not to have the should be to represent all thermodynamic functions with their temperature In the this was supported by the of and the of and of of at and by for the of The a to or the form of this or to for
Thorsten Beck, Asli Demirgüç‐Kunt, María Soledad Martínez Pería
Using data from a survey of 91 banks in \n 45 countries, the authors characterize bank financing to \n small and medium enterprises (SMEs) around the world. They \n find that banks perceive the SME segment to be highly \n profitable, but perceive macroeconomic instability in \n developing countries and competition in developed countries \n as the main obstacles. To serve SMEs banks have set up \n dedicated departments and decentralized the sale of products \n to the branches. However, loan approval, risk management, \n and loan recovery functions remain centralized. Compared \n with large firms, banks are less exposed to small \n enterprises, charge them higher interest rates and fees, and \n experience more non-performing loans from lending to them. \n Although there are some differences in SMEs financing across \n government, private, and foreign-owned banks - with the \n latter being more likely to engage in arms-length lending - \n the most significant differences are found between banks in \n developed and developing countries. Banks in developing \n countries tend to be less exposed to SMEs, provide a lower \n share of investment loans, and charge higher fees and \n interest rates. Overall, the evidence suggests that the \n lending environment is more important than firm size or bank \n ownership type in shaping bank financing to SMEs.
Pulmonary vein (PV) isolation can be performed at different levels in the ostium. Initially, segmental isolation, targeting individual strands of atrial myocardial tissue in PV ostia, was performed using the combination of a circular mapping catheter and a standard ablation catheter.1 In most centres, clinical success rates were moderate. Soon, however, it was recognized that wider encircling improved success and reduced complications.2 Additional ablation lines and substrate modification may further increase success, but may also create a substrate for left atrial flutters.3–5 The creation of a long continuous ablation line around a PV antrum using a single ablation electrode is technically challenging. Kistler et al. described a prospective randomized study to investigate the contribution of image integration to catheter ablation of atrial fibrillation.6 The value of Cartomerge® was investigated on the basis of an incomplete Carto map. It is highly remarkable that even then, image integration did not affect the quality of the procedure. The study suggests that an anatomically correct geometry does not facilitate the creation of continuous transmural lesions. Such geometry definitively helps to outline the desired course of the ablation lines, but apparently it does not improve the continuity of that line. Use it if you like it, but don't expect any miracles. The ablation procedure was performed using an irrigated ablation electrode to create the long ablation lines around both pairs of PV ostia.6 Wall contact during ablation, precise catheter manipulation, and the delivery of sufficient radiofrequency (RF) power are the most important determinants of successful electrical isolation. While irrigated catheters are highly advisable to reduce the risk of blood clot formation during RF ablation, electrode cooling greatly eliminates the electrode temperature increase as feedback for tissue contact. This may have been the reason for the investigators using a remarkable irrigation protocol: the flow rate was maintained at 2 mL/min unless the 50°C target temperature was reached with <20 W. One should remember that a flow rate of 2 mL/min may only be sufficient to keep the irrigation holes open, not to prevent blood clot formation on the heated tissue surface.7 Even with standard non-irrigated electrodes, detection of wall contact and lesion formation on the basis of electrode temperature response remains difficult. A high electrode temperature increase at low power may be caused not only by intimate electrode–tissue contact, but also by low blood flow. Local electrogram characteristics and amplitude, impedance drop during ablation, fluoroscopic imaging, and intracardiac echocardiography (ICE) are alternative ways to judge wall contact, but they all have important limitations or add significant complexity. A combination of these methods and 3D mapping systems are used in most labs, but even then, multiple acute gaps in the lines are more the rule than the exception. Moreover, a large number of patients experience a recurrence after a first procedure because of resumed conduction through the antrum lines despite the fact that the observation time after isolation often is lengthened by additional ablations.8 Persistent continuity of ablation lines should be our main goal for future developments. A 30 W/50°C setting was originally used for segmental PV isolation where myocardial sleeves may be relatively thin. To prevent collateral damage, one should always try to limit RF power, but with low power it may sometimes be very difficult to achieve complete electrical isolation of the PV antrum that includes sections with thicker myocardium and the appendix ridge where catheter stability is a major challenge.9 Kistler et al. used an electrogram amplitude <0.1 mV or amplitude reduction >80% as endpoint during ablation.10 Reduction of the local unipolar electrogram clearly is an indicator for lesion formation. Often, however, electrograms <0.1 mV still can be found inside the PV ostia and some of these can be proven to be true local activations. Conversely, an electrogram >0.1 mV within PVs can be a remote signal from the bulk of the left or right atrium, left atrial appendage, or superior caval vein. The latter signals, very misleadingly, sometimes also show decremental properties with atrial extrastimuli. Consequently, a simple amplitude criterion is not sufficient to declare PVs electrically silent. If the goal is complete electrical isolation then one should meticulously investigate the origin of all electrograms distal from the ablation line and continue the search for leaks until all local signals have disappeared. Adenosine may reveal latent leaks, but mapping of those leaks can be very difficult.11 Kistler et al. speculate that image fusion in NavX could result in more reduction in fluoroscopy time than with Carto. With NavX, an accurate geometry can be created in 15 min, with only a few minutes of fluoroscopy. With image fusion, only these few minutes are at stake and it is unlikely that image fusion will reduce fluoroscopy time more than Cartomerge®. Reduction in radiation exposure, however, always remains a valid argument to investigate new technologies. Many electrophysiology (EP) labs are equipped with fluoroscopy systems that were originally designed to visualize tiny arteries and stents. EP procedures, however, do not require that image quality; we mainly have to see the contrasting catheters. Fluoroscopy systems in EP labs can therefore use extra primary beam filtration and lower pulse rates. In addition, one is obliged to use standard measures such as lower body-protecting lead flaps and an upper body-protecting glass screen. With a badge on the collar above the apron, the total annual dose of all operators performing catheter ablation procedures in a single EP lab can then stay below 5 mSv. Any team with a significantly higher total operator badge dose for catheter ablation procedures alone should seek advice from the fluoroscopy system manufacturer. Most modern systems have three different dose rate settings that are individually programmable by the manufacturer. Both electrophysiologists and interventional cardiologists can then be satisfied when they have to share the lab, and often operator and patient dose rates can be reduced by a factor of 5 or more without any impact on the quality of EP procedures. As a method for reducing fluoroscopy exposure, the application of advanced technologies, such as ICE, robotic or magnetic catheter navigation, image integration, and even 3D mapping systems alone, only makes sense when basic measures such as optimized fluoroscopy settings have been put in operation. Conflict of interest: F.H.M.W. is a consultant for St Jude Medical.
Complex business contracts are notoriously difficult to write and read. Certainly, when litigation arises, courts scarcely have an easy time interpreting them. Indeed, contracts don't look at all as though they are written to tell a court what the parties want. Why can't smart, well-motivated lawyers do a better job? My article argues that they rationally don't try. I argue for a view of contracting in which parties aren't principally trying to set forth an agreement for a court to enforce. Rather, by leaving inartful language and ambiguity in the agreement, parties are bonding themselves not to seek precipitous recourse to litigation. The agreement entered into provides each party with grounds to bring a lawsuit if it so desires. Thus, if one party sues, the other party will virtually always have grounds to countersue. The complex transacting community has a norm against litigation in any event; bonding encourages and bolsters this norm, as well as norms of appropriate conduct throughout the contracting relationship. The contracting process, and the contract that results, thus serves importantly to create the parties' relationship and to set the stage for dispute-resolution consistent with preserving the relationship, as well as to keep available the backstop of enforcement if needed.
This is part of an occasional series that recalls some of the stories reported 10 years ago in the News section of the Journal. In 1998, JNCI published a two-part feature about efforts to overcome multidrug resistance in cancer, which at the time was thought to be governed chiefly by a superfamily of molecular transporters, known as ATP-binding cassette (ABC) proteins. ABC transporters act as efflux pumps, which expel toxins and drugs from a cell. By reversing those transporters in cancer cells—particularly P-glycoprotein (Pgp), which was, and still is, the best-characterized among them—researchers hoped to overcome drug resistance, a primary cause of treatment failure. A decade later, efforts to reverse Pgp have proven futile, in part because the transport protein is also expressed by healthy tissues—leading to unacceptable side effects when its activity is knocked out. Furthermore, dozens of other ABC transport proteins identified within the last 10 years can take over for Pgp when its activity is reversed in cancer cells. Scientists are still studying clinical opportunities with ABC transporters, but drug resistance in cancer remains as much a problem now as it ever was. Even so, scientists have new leads to follow. Advances in molecular biology, driven by genomics and related fields, have revealed new resistance mechanisms and broadened opportunities to overcome it, said Michael M. Gottesman , M.D., head of the National Cancer Institute's molecular cell genetics section. “We just have to apply the mechanistic knowledge we’re gaining in the laboratory towards progress in the clinic.” Michael M. Gottesman, M.D. Today, those efforts are proceeding on dual fronts. Whereas scientists 10 years ago were concerned only with multidrug resistance against chemotherapy, those working today must also contend with single-drug resistance to newer, targeted therapies such as imatinib (Gleevec), a drug for chronic myelogenous leukemia (CML) and other cancers that inactivates a cancer-inducing protein called Bcr-Abl. Unlike chemotherapy—which kills rapidly dividing cells regardless of whether they’re cancerous—targeted therapies interfere with specific molecules involved in cancer and tumor growth. The new era of targeted therapy was supposed to leave chemotherapy behind and multidrug resistance behind with it. That's because researchers associated such resistance almost exclusively with efflux pumps, which act against a broad array of natural and synthetic toxins. By using nontoxic compounds targeted against specific molecules in carcinogenesis, scientists hoped that they could avoid resistance. But those expectations were dashed when clinicians found that although patients typically respond well to imatinib—among the first targeted drugs to reach the market—many also relapse within 3–5 years. Confronted with that distressing problem, scientists were reluctant to blame mechanisms like efflux, which were generally attributed to multidrug resistance and chemotherapy, for imatinib resistance. Instead, their explanations veered toward gene mutations that, by chance, might allow CML cells to survive imatinib exposure. In that scenario, most CML cells are killed by the drug, but those with mutations that favor survival multiply over time, leading to relapse. Scientists call this type of drug resistance “acquired.” To an extent, subsequent research has borne out this hypothesis, which was proposed when imatinib resistance was first observed, within a few years of the drug's approval by the U.S. Food and Drug Administration in 2001. More than a dozen gene mutations have since been implicated, of which the most effective is T315I, according to Susan Bates, M.D., director of the NCI's molecular therapeutics section. This simple variation alters Bcr-Abl's three-dimensional binding site, thus blocking imatinib's access to the target protein. But Bates argues that mutations alone can’t account entirely for imatinib resistance. Patients whose leukemic cells have identical mutations can vary with respect to the degree of resistance, she said, which suggests that other factors—including mechanisms linked to multidrug resistance—are also at play. “For example, interindividual variation has been found in the amount of Gleevec that winds up in the bloodstream, which could reflect differences in cellular absorption of the drug,” Bates explained. “We can’t rule out that ABC transporters might be involved, given that Gleevec is a substrate for at least two: Pgp and breast cancer resistance protein. In CML cells, those transporters reduce the amount of Gleevec that reaches the protein target, and that fosters resistance.” (However, variation in resistance among patients could also be due in part to behavioral factors, such as adherence to the drug regimen [ see JNCI 2008; 100: 912–3 ].) While researchers work to tease out resistance mechanisms against targeted therapies, efforts to overcome multidrug resistance to chemotherapy are making headway. Researchers in Gottesman's lab at NCI, who are among the leaders in this area, approach the problem by using three general strategies. Gottesman's research team collaborates with pharmaceutical companies to develop drugs that circumvent known resistance mechanisms. Compounds that evade ABC transporters—of which there are 48, according to current estimates—fall into that general category. Epothilones, for example, a new class of cytotoxic molecules identified as potential chemotherapy agents, aren’t recognized by Pgp. “This provides proof of concept that new classes of anticancer agents that don’t interact with multidrug transporters can be developed,” he said. This approach is currently in early developmental stages, with no compounds in clinical trials. Applying an alternate approach, the team strives to block resistance by inhibiting or reversing it. Clinical applications based on this approach would involve drug combinations: one drug to inhibit the resistance mechanism and another to kill the cancer cell. This strategy already has a long and unsuccessful history, exemplified by compounds such as PSC-833, a Pgp-reversing agent tested often in clinical trials. PSC-833 failed in part because of unpredictable pharmacokinetic interactions, leading to underdosing in some patients and overdosing in others. Scientists now hope to overcome that problem with third- and fourth-generation inhibitors designed for low pharmacokinetic interactions, as well as tight binding with target proteins. According to researchers in Gottesman's laboratory, promising candidates include tariquidar, a compound that offers extended Pgp inhibition, now in phase III clinical trials, and CBT-1, a plant alkaloid that inhibits Pgp in addition to an ABC transporter known as MRP1. The third strategy exploits certain unique features of multidrug-resistant cells, such as high surface expression of Pgp or a paradoxical hypersensitivity to a range of compounds. These features make it possible to target these cells directly, Gottesman said. For instance, thiosemicarbazones—a class of compounds with known antiviral, antimicrobial, and anticancer activity—kill resistant cells through Pgp-related mechanisms. This approach has not yet produced compounds for clinical trials. Scientists have also focused on the influx mechanisms that cells use to absorb certain compounds, including cancer drugs, instead of the efflux pumps that they use to expel them. Solute-carrier (SLC) protein transporters, recognized as the largest superfamily of membrane proteins, participate in these influx processes. Jeffrey Moscow, M.D., chief of pediatric hematology/oncology at the University of Kentucky Medical Center in Lexington, is now working to identify SLCs expressed uniquely by cancer cells. By harnessing these proteins, he hopes to pump drugs into a cancer cell faster than efflux transporters can pump them out. He's already identified an SLC expressed uniquely by lung and gastrointestinal malignancies, known as OATBIB3, and another expressed by leukemia, known as SLC22A16. “In these cases, the specificity of therapy would be determined by the expression of the solute carriers,” he said. Efforts to overcome single-drug resistance to targeted therapies differ from those applied to multidrug resistance. Instead of circumventing, inhibiting, or targeting mechanisms that cancer cells use to avoid poisons, scientists try to augment their treatment options with additional molecular targets, said Jeffrey Settleman, Ph.D., a professor at Harvard Medical School and scientific director of the Massachusetts General Hospital Cancer Center. Settleman's laboratory has accumulated the largest collection of human cancer cell lines in existence—more than 1,000 in all, representing all the major tissue types. With automated screening technology, he and his colleagues test putative targeted therapies until they find a positive hit in a sensitive cell line. Those lines are treated with the drug until only the resistant cells remain. By culturing those cells, Settleman's team can look for mutations that confer resistance, as well as for new targets to which the cells might be sensitive. The clinical strategy for managing resistance in targeted therapy, Settleman said, entails drug combinations to inhibit several targets sequentially. “The scenario could be that we convert cancer to a chronic disease by giving drugs in succession; as resistance develops to one drug, we shift to another,” he said. This approach is already being used now. For instance, CML patients who become resistant to imatinib can be treated with dasatinib (Sprycel). In a melanoma cell line, Settleman's laboratory recently modeled the acquisition of resistance to a candidate Raf kinase inhibitor. They found that resistant cells merely switched their metabolic dependency from Raf to another related kinase. “Raf kinase inhibitors are being tested clinically now,” Settleman said. “It's early days for these compounds, and we’re not sure they’re going to work. But if they do, we may have zeroed in on the resistance mechanism in advance.” The ability to switch from one kinase to another shows how adaptable cancer cells are in the face of drug pressure. But fortunately, it appears that cancer cells have at most three to four resistance mechanisms that they can direct against any particular compound, Settleman said. “And that shows we’re ultimately dealing with a manageable problem,” he said. “It indicates how important it is to tackle resistance from more than one angle. We’re faced with the same resistance mechanisms that infectious microbes use to evolve and mutate their way around a drug. We treat [human immunodeficiency virus] with multidrug cocktails, and we’ll be doing more of the same with cancer; our aim is to cut off the cells’ options to adapt.” So, although the previous 10 years revealed new mechanisms in cancer cell biology, including roles played by cancer stem cells that could offer the best therapeutic targets of all, accelerated research during the coming decade might bring the problem of resistance under better control. But doing that won’t be easy, Settleman admitted. “Cancer cells are crafty organisms in their own right,” he said. “And resistance is still the final frontier in treatment.”
Being able to make payments conveniently and securely is an essential ingredient in modern life and commerce. It enables economic livelihoods and supports many social relationships, communal support actions, and public welfare programs. Yet most people and micro enterprises in developing countries must rely on physical delivery of cash or actual goods to make payments. This imposes large costs and risks on those beyond the reach of modern payment networks. Access to payment facilities is a major enabler for achieving universal access to finance. In this paper the author further develop a broad vision for financial inclusion sketched out in Mas (2008), where payments can be easily made through an electronic network. What makes visioning such a payments utility possible is the technology author have today, which can be used to bridge distances, close information gaps, contain settlement risks, and generally reduce transaction costs. The author is confident that today's technology can do the job. Now the challenge is to develop attractive services that engage customers and workable business models that enable decentralized, largely private, and institutions to build this payments utility.
I wanted to like this book, and tried hard, but ultimately failed. I have recently written several papers on inappropriate corporate influences on the funding and conduct of epidemiological research, and have discussed several examples of hazards where the epidemiologic findings were strongly, and unethically, opposed by industry and by academic epidemiologists funded by industry.1–3 This book provides ‘the other side of the coin’ and discusses in depth four examples (environmental causes of breast cancer, electromagnetic fields and cancer, residential radon exposure and lung cancer and passive smoking) where, in the author's opinion, the health risks were low or non-existent, but were hyped by researchers and policy makers thus resulting in unnecessary research, inappropriate funding decisions and unjustified public concern. Such things certainly happen, and we need books like this which attempt to discuss them objectively, and which point out that academic researchers may also be affected by a range of influences including career and funding opportunities, even if they only accept peer-reviewed government funding and do not accept corporate funding. Thus, they may have incentives to overstate the evidence, just as industry and industry-funded epidemiologists may have incentives to negate or understate the evidence of health risks from environmental exposures. The book states its case well, is clearly written and discusses complicated issues in a relatively simple and readable way. It makes the case that ‘each side tends to cite the evidence that supports its point of view in order to influence public policy’ (p. 6) and that ‘the tendency to overstate the evidence, for whatever purpose, actually strengthens the opposing party's hand. It sanctions the partisan use of science that should be rejected, no matter who is engaging in it.’ (p. 7) The book also makes the important points that: (i) we have to some extent reached the limits of ‘risk factor’ epidemiology and have identified the strong risks (e.g. active smoking and lung cancer) and are now trying to assess weak risks (e.g. passive smoking and lung cancer), which are much more difficult to assess and much more prone to be overwhelmed by bias; (ii) for many of these risks (e.g. residential radon exposure and lung cancer) it is not possible to directly estimate the risks from low exposures, and it is necessary to make theoretical assumptions to interpolate from the findings of studies of highly exposed occupational populations (e.g. miners exposed to radon); and (iii) many of these risks are very small and have received perhaps excessive funding and scientific attention in comparison with other public health risks. So far so good. I agree with all of the above statements, and started reading the book in a positive frame of mind, with the expectation that it was an important book that would be an essential antidote to the writings of myself and others who have tended to emphasize the hazards of corporate influences. However, I became more frustrated and less impressed as I worked my way through the book, particularly when coming to discussions of issues that I had been involved in (e.g. electromagnetic fields and cancer). This probably reflects my own influences and prejudices. However, it became increasingly difficult, as I worked my way through the book, to avoid the conclusion that the discussions of these issues were, for want of a better word, ‘biased’, as well as being rather ‘grumpy’ and unpleasant in parts. It seems that no one can get it right. No single study is good enough or big enough, but meta-analyses should be discouraged because they combine studies from different exposure settings and with different methodologies. Researchers are criticized for arguing that ‘one must rely upon the evaluation of the data as a whole using expert judgement and the meta-analyses as a guide’ (p. 101), because this simply reflects their vested interests to continue researching a topic when an individual study is inconclusive. The findings of individual studies are dismissed because they are ‘not statistically significant’, even if they are consistent with previous findings. Significant associations are dismissed because they involved multiple comparisons, even if the specific associations were the a priori reason for the study and had been found previously [e.g. ‘the reported association [of EMFs with childhood] leukaemia was one of a very large number of comparisons made by the researchers and hence could well have arisen by chance’ (p. 100)]. Studies that show interesting dose-response associations verging on statistical significance, such as the National Cancer Institute childhood leukaemia study,4 are not only dismissed, but also researchers are condemned for not accepting the findings as proof of lack of risk (‘it is hard to escape the impression that the reluctance of the NIEHS working group to close the door on the possibility of EMF as a cause of leukaemia had more to do with its members’ stake in this area of research than with scientific rigor’ (p. 101). While every academic researcher who wants to study these issues apparently has a vested interest, even if their university salary is already funded, critics of the research are apparently unbiased, reasonable and objective, even if their criticisms are directly or indirectly funded by industry. Researchers into radon and lung cancer are biased because they do not repeatedly emphasize that tobacco smoking is the major cause of lung cancer, and that most cases of radon-induced lung cancer involve joint effects with smoking (the corollary that some cases of lung cancer in smokers are due to joint effects with radon exposure is never mentioned, nor is it mentioned that the same arguments could be applied to many other important lung carcinogens such as asbestos). The book gives particular emphasis to issues of biological plausibility, even though there are many historical examples of associations that were not biologically plausible when they were first discovered by epidemiologists, and the aetiological mechanisms involved were only subsequently discovered in laboratory-based studies. This is why, for example, all of the 30–40 known occupational causes of cancer (as classified by the International Agency for Research on Cancer) were first discovered in epidemiological studies, not in the laboratory. If it had been plausible that these substances caused cancer, then they would not have been used in the workplace. So epidemiology will always be in front of mechanistic research with regards to discovering new environmental and occupational causes of disease. The book also fails to mention that there are many historical examples of risks (dioxin and cancer is one example) where the evidence was initially weak and inconsistent but has strengthened over time (leading to the classification of dioxin as a carcinogen by the International Agency for Research on Cancer in 1997). So what are we supposed to do about ubiquitous environmental exposures that may carry weak risks, but which may account for a substantial number of cases of disease on a population level? Kabat's solution is nihilistic, namely that we simply should not study such exposures, or at least not attempt to quantify their effects: ‘it is entirely plausible that in some cases exposure to ETS may account for a few cases of lung cancer in nonsmokers, but … it is not possible to quantify the excess risk with any certainty’ (p. 150). The argument is essentially that the risks are too small to quantify accurately, and therefore should not be studied, or at least should not be estimated quantitatively. We are never told how we should decide if a risk is too ‘small’ to be concerned about if we do not first attempt to estimate its magnitude. And how are we supposed to tell the public that the risks are small (and their concerns are unimportant) without attempting to estimate them? And who decides what is a ‘small’ risk? The book finishes, literally on the last page, by advocating a ‘broader/integrative vision of epidemiology—one that can accommodate social, economic, and ecological/environmental realities … as well as rapidly evolving knowledge of the mechanisms of disease at the molecular level’ (p. 186).5–8 Such developments are to be encouraged, but they are intended to be inclusive, not exclusive, and we will have to continue to grapple with problems of studying weak risks from ubiquitous environmental exposures, even if they receive less attention than they have in the past. It is important to consider the influences on such research, including influences on academic researchers with regards to career opportunities and funding, even though these will continue to be relatively minor compared with the massive and pervasive influences of corporate funding of research and of critics of research.1–3 This book could have made a major contribution in this regard, but its lack of balance means that it fails to make such a contribution.
Huaxin Wang, Joris S. M. Vergeest, Jan Miedema, Frank Meijer · 6 authors
Synthetic environment equipped with user interfaces intuitive for direct 3D shape modification by non-designer stake-holders was proposed as a collaboration tool for design concept communication in dynamic prototyping of product design in early stages of the design process. After a survey of 3D user interaction techniques for SE, a simple user interface with hierarchical visual menu was proposed and a proof-of-concept implementation of it was tested to be intuitive with experiment, which serves as a base for further study to verify the hypothetical benefits of SE aided dynamic prototyping in terms of communication efficiency and accuracy.
Graeme Laver, one of Australia’s greatest influenza research scientists, died after collapsing en route to an influenza meeting in Portugal in September 2008. Graeme was born in Victoria, educated at Ivanhoe Grammar School and graduated from the University of Melbourne in biochemistry. He received his PhD in biochemistry at the University of London before returning to the John Curtin School of Medical Research at the Australian National University (ANU) in 1958. After the Burnet School at the Walter and Eliza Hall Institute in Melbourne changed its focus from influenza to immunology, the influenza research program moved with Frank Fenner’s group to ANU, where it was anchored by Stephan Fazekas de St. Groth. There the pioneering influenza work of Sir MacFarlane Burnet continued, with Graeme Laver as biochemist and Stephan Fazekas as the mathematical modeler of virus neutralization. I (Rob Webster) joined the group in 1959 to carry on the virus neutralization studies. To elucidate the subunit structure of influenza viruses, Graeme gently dissociated the lipid bilayer of the virus with the mild detergent sodium deoxycholate and established the basis for the first Australian subunit influenza vaccine. Before that accomplishment, only intact inactivated influenza vaccines had been used in Australia and they were considered undesirably reactogenic. Studies first in rabbits and then in children established the proof of principle for the vaccine. The ANU paid Laver and myself 10 shillings each for the patent rights. Australian subunit influenza vaccines have been further improved, but the fundamental principle established by Laver remains the same: that the proteins must be kept in their native conformation for the vaccine to be effective. Further studies with Robin Valentine of the National Institute of Medical Research at Mill Hill, London, established the morphology of the hemagglutinin (HA) and neuraminidase (NA) subunits by electron microscopy, and later work with Nick Wrigley produced the first electron microscopy images of antigen-antibody complexes. After the emergence of the Asian influenza pandemic in 1957 the influenza community, led by Martin Kaplan of the World Health Organization (WHO), began searching for the origins of influenza pandemics. During a fishing trip to the Southeast coast of Australia, near Bateman’s Bay, New South Wales, Laver and I found the beaches littered with dead mutton birds (Puffinus pacificus). Knowing that A/Tern/South Africa/61 (H5N3) influenza virus had been isolated from seabirds, we speculated that the mutton birds might have been killed by an influenza virus. In 1970, serological studies of mutton birds on the Great Barrier Reef of Australia found the first evidence of human N2 neuraminidase–inhibiting antibodies, and in 1973 influenza viruses were isolated for the first time from wild migratory seabirds. These findings provided the first links in the chain of evidence that subsequently showed that the migratory aquatic birds of the world are the natural reservoirs of all influenza A viruses. Studies on the structure of influenza virus neuraminidase began with Graeme’s keynote paper in 1978 on crystallization of the heads of the human N2 neuraminidase molecule (Virology 1978; 96: 78–87). These and subsequent studies culminated in the resolution of the three-dimensional structure of the neuraminidase, with Peter Colman and Jose Varghese. With this information, Mark von Itzstein was able to design the first structure-based anti-influenza drug, zanamivir (Relenza). Further development using NA crystals provided by Graeme led to the development of the orally available anti-influenza drug oseltamivir (Tamiflu). The WHO Global Influenza Surveillance Network was established in 1952 to keep up with antigenic drift in influenza viruses and to recommend changes in vaccine strains to stay abreast of antigenic variation. However, there was no fundamental understanding of the mechanisms involved until Graeme Laver began peptide mapping of the hemagglutinin (HA) molecule and provided evidence of multiple antigenic determinants on HA spikes (Virology 1974; 59: 230–244). The advent of monoclonal antibodies by Georges Kohler and Caesar Milstein and their use to select influenza virus escape mutants, together with sequence analysis of the HA molecules (Virology 1979; 98: 226–237), established that a single amino acid change in the HA would allow the influenza virus to escape neutralization. Antigenic mapping of the HA and NA molecules soon followed and, ultimately, establishment of the antibody binding domains and visualization of the epitopes on the NA subunits (Nature 1987; 326: 358–363). Thus, the mechanism of antigenic drift in influenza and the epitopes involved were elucidated thanks to the seminal work of the Laver laboratory. Graeme Laver had a sense of adventure in all aspects of his life, from family to friends to research, and was always a free spirit who was willing to challenge bureaucracy when they “got it wrong”. He was an avid skier, mountaineer, gardener and axeman. In later life, his scientific passion was the production of perfect crystals of NA through studies in zero gravity on the Russian MIR space station and crystallization chambers set up in every laboratory he visited. Some of the most beautiful crystals were the N9 neuraminidase of an influenza virus isolated from a noddy tern on the Great Barrier Reef. Photographs of these crystals appeared on the covers of many scientific journals, and Graeme and photographer Julie Macklin were awarded the Nikon “Small World” prize in 1987. In addition to influenza, Graeme made contributions to our knowledge about adenoviruses, sialidases and paramyxoviruses. His multiple scientific achievements were recognized by his election to the Royal Society of London in 1987 and by co-receipt of the Australia Prize with Peter Coleman, Mark von Itzstein and Paul Janssen in 1996. In its efforts to prepare for an influenza pandemic and to identify the best options for controlling seasonal influenza, the global community owes a very special debt to Graeme Laver. The current strategies for control of both pandemic and seasonal influenza, the stockpiles of anti-influenza drugs and prepandemic vaccines are products of his life’s work. His final mission was to have anti-influenza drugs made available over the counter so that every household could have an immediate supply in the face of a pandemic. He argued that this option would have no effect on the emergence of resistance and could save millions of lives in the event of infrastructure failure. New Zealand has taken the lead in following his visionary advice.
Autonomous Decentralized System (ADS) has been making progress in these 31 years since it was proposed in 1977. During these long years in the rapidly advancing computer and communication technologies, the ADS concept has not been changed but its technologies have been growing in accordance with the change and diversity of the social, economical and personal requirements and through the globalization of the market and the restructuring organizations. The ADS technologies are system-atized to cover all processes of system design, operation, maintenance and modification. This paper reviews the work done in fields of ADS in past 31 years from not only technological perspectives, but it also encompasses users requirements and value, system design, industrial activity, academic activity and standardization [1]-[26]. Moreover the new directions of the ADS are suggested.
The design of the decentralized co-operative governance system, conditioned and \nregulated by the South African constitution is of critical importance for policy design and \nimplementation. The division of powers falls within a unitary form of government. This \nstudy, which is about the processes, mechanisms and modalities of public policies \ndesign and implementation uses the public finance and health sectors, as a case study \nor lens through which policy design and implementation is examined within a \ndecentralized cooperative governance system. The study is per se not about the public \nhealth system, but rather a review and an analysis about how the decentralization and \ncooperative governance nature, practice and dynamic of government system, influences \nand condition the policy processes and practice on finance and health, separately and \ncollectively within the public health system. \nIn its attempt to unbundle the health function, but also reform the public health system, \ncentral and provincial governments have introduced a number of reforms. These reforms \nwere ostensibly driven by different policies and programmes originating either from the \npublic finance or public health sectors with significant consequences for the provinces. \nMoreover, these different policies also outlined structural and functional responsibilities \nand authority among the central and provincial government departments. The \nimplementation of these policies was at times based on different interpretations of policy \ndesign and implementation responsibilities and authority between the central and \nprovincial governments within co-operative governance system. \nThe argument of this study is that despite intentions implicit to public policy, co-operative \ngovernance system is contested at a central government level within the public health \nsystem, as well as between levels of government and the public health and finance \nsectors. This dissertation explores the nature of the relationship between the central and \nprovincial governments by exploring co-operative governance in the health sector on \npolicy and financing processes and mechanisms. The central question is how does \ndecentralized co-operative governance really work in the public health system? \nA case study method was used to conduct this research. Data was collected over a four \nand half year period using a variety of data collection methods, including semi-structured \nin-depth interviews; documents and reports analyses; policy content review and \nanalyses; and revenue and expenditure reviews and analyses. \nThe study’s findings are: \na) the functional and structural decentralization of policy-making and implementation \nwithin the co-operative governance system contributes to undermining the cooperative \ngovernance relationship between the public finance and health sector and \ncentral and provincial governments; \nb) the central government is using its overriding powers to “impose co-ordinated \nsolutions” to problems within the co-operative governance system, leading to \nsituations where ‘imposed co-ordination’ is considered as ‘co-operative governance’; \nc) the theory provides a classical distinction between state control, supervision and \ninterference models. This dissertation shows that, depending on the policy context \nand circumstances, the uniqueness of South Africa’s co-operative governance \nsystem allows the central government to mobilize any of these models to achieve its \npolicy intentions, whether written or unwritten; and \nd) the classical arguments of decentralization, particularly within a devolved system of \nco-operative governance where greater autonomy and authority are given to subnational \ngovernments, are found wanting within the South African governance \nsystem, given both the policy-making and fiscal resource strength of the central \ngovernment relative to the provinces. \nThis dissertation leads me to conclude that the South African practice of co-operative \ngovernance in the health system is actually imposed co-ordination and that provinces \nare de facto administration outposts of central government policies, programmes and \nservice delivery responsibilities. Therefore in reality there is no autonomy and \nindependence of the provinces from the central government as envisaged in the \nConstitution of the Republic of South Africa. In fact, provinces only exist, in terms of their \nconstitutional competencies as far the central government allows it to exist given its \nplenipotentiary powers over both micro and macro matters affecting institutions, fiscus \nand social policies.
Lu Li, Jinsong Han, Yunhao Liu, Lei Hu · 7 authors
Most of the current trust models in peer-to-peer (P2P) systems are identity based, which means that in order for one peer to trust another, it needs to know the other peer's identity. Hence, there exists an inherent tradeoff between trust and anonymity. To the best of our knowledge, there is currently no P2P protocol that provides complete mutual anonymity as well as authentication and trust management. We propose a zero-knowledge authentication scheme called pseudo trust (PT), where each peer, instead of using its real identity, generates an unforgeable and verifiable pseudonym using a one-way hash function. A novel authentication scheme based on zero-knowledge proof is designed so that peers can be authenticated without leaking any sensitive information. With the help of PT, most existing identity-based trust management schemes become applicable in mutual anonymous P2P systems. We analyze the security and the anonymity in PT, and evaluate its performance using trace-driven simulations and a prototype PT-enabled P2P network. The strengths of our design include (1) no need for a centralized trusted party or CA, (2) high scalability and security, (3) low traffic and cryptography processing overheads, and (4) man-in-middle attack resistance.
On January 8, 1997, the former President of Brazil, Fernando Enrique Cardoso signed the National Water Resource Policy into law (Law No. 9.433, 1997). The key principles of the National Water Policy include: an integrated approach with the river basin as the planning unit, water as a fragile and finite resource, water as an economic good, and finally, decentralized and participatory management of the resource (Formiga and Scatasta, forthcoming). The legislation provided for the implementation of bulk water pricing with the resulting revenues meant to finance the activities mandated by basin committees in the watershed area of Rio Paraíba Do Sul (in Rio de Janeiro and São Paulo, and also in the state of Minas Gerais, that basin committee is Comitê para Integraςão da Bacia Hidrográfica do Rio Paraíba Do Sul (CEIVAP) (Abers and Keck, 2004). To improve the sustainability of many different resources it is a widely accepted concept that charging a fee for something will spur sparing use by the target audience, particularly if the price is high. One-hundred percent of the collected monies have been invested within the basin; mainly designated to the following: non-structural institutional interventions, sediment control projects, and municipal wastewater treatment. Payments from agriculture and small hydroelectric plants have been mostly symbolic or non-existent and payments from other sectors have not been high enough to maintain a sustainable system. Convincing those that have not been actively participating is central to the success of this initiative: this paper will explain a framework called Social Marketing which is becoming more widely used throughout the globe to inspire behavior change. Social Marketing is a tool that can be used to persuade more users to pay the cobrança.
Open access
Water resources management and optimization
Conservation, Biodiversity, and Resource Management
Pursuant to the Local Self-Government Act adopted in February 2002, the fiscal decentralization has been carried out without the institutional decentralization of functions of the central tax administration, whereby only the affirmation of the self-government authorities has been done in the part of financing the budges of self-government units, but not in the part of administering the original local public revenues. The Local Self-Government Financing Act created a legal ground for decentralization of functions of the central tax administration (Tax Administration). Further concretization of competence of the local tax administration shall be done by the Amendment Act to the Tax procedure and Tax Administration Act.
A family of core extensions for cooperative TU-games is introduced. These solution concepts are non-empty when applied to non-balanced games yet coincide with the core whenever the core is non-empty. The extensions suggest how an exogenous regulator can sustain a stable and efficient outcome, financing a subsidy via individual taxes. Economic and geometric properties of the solution concepts are studied. When taxes are proportional, the proportional prenucleolus is proposed as a single-valued selection device. An application of these concepts to the decentralization of a public goods economy is discussed.
In 1936, 200 of the world's top medical scientists met in Brussels to address an emerging epidemic. Since the turn of the century, cancer had been steadily growing as a major cause of death. Naturally, researchers looked first to environmental factors, particularly agents of the Industrial Age, such as asbestos, road tar, ionizing radiation, and synthetic dyes. Since then, however, attention has been diverted away from such important environmental causes of cancer, especially where economic interests are at stake, according to Dr. Devra Davis in The Secret History of the War on Cancer (1). This expansive, ambitious book spans nearly a century and dozens of controversies, anecdotes, and personal stories. Davis devotes a chapter to describing the growth of the eugenics movement and Nazi medicine. Another chapter details the evolution of the nation's leading voluntary anticancer organization, from the grassroots anticancer advocacy of the American Society for the Control of Cancer's Women's Field Army to the corporate Lasker-era American Cancer Society. She describes how professional turf battles delayed the introduction of the Papanicolaou smear for over a decade. In subsequent chapters, she warns of the possible hazards to physician-researchers in working with novel compounds, the overselling of routine mammography, the role of paid experts in environmental tort litigation, the politics of establishing regulatory standards for environmental and occupational exposures, and the potential as-yet-unproven hazards of cell phones. A key theme running throughout the book is how financial interests, professional allegiances, and political ideology can manipulate the scientific process. Archives and court documents reveal how well-meaning scientists have at times become complicit in defending industrial interests at the expense of public health. There is no “secret history” here, however, as these histories are largely drawn from the work of other scholars. One exception is Davis's own study of the papers of Robert Kehoe, a key figure in the development of the occupational health field who conducted a wide range of toxicology research under contract for various industries. These documents provide a unique case study of how one academic laboratory functioned and interacted with its industry sponsors, and one wishes they were more fully explored here. Unsurprisingly, tobacco figures big in Davis's story. She touts German physician Franz H. Müller's 1939 case-control study of lung cancer and smoking (previously described in Robert Proctor's The Nazi War on Cancer (2)) as “the first irrefutable modern proof that smoking causes lung cancer in humans” (1, p. 61). This work was largely ignored by American and British researchers conducting their own case-control studies 10 years later. Davis faults these latecomers with failing to immediately denounce cigarettes, whereas Müller had definitively declared tobacco to be “the single most important cause of the rising incidence of lung cancer” (1, p. 53). Davis's argument here and repeated throughout the book is that, when the bar for medical proof is set too high, life-saving public health action is delayed. By the time of the 1964 Surgeon General's report (3), an unprecedented wealth of evidence had been amassed, including seven cohort studies and over 30 case-control studies implicating cigarettes as a cause of cancer. However, public health interventions often have to be taken on lesser evidence. Davis criticizes reliance on epidemiology as the “gold standard,” demanding an alternative to “waiting for enough bodies to drop or sicken before we decide we've got a problem” (1, pp. 399–400). Yet how much and what kind of evidence should be required to act? Unfortunately, Davis stops short of proposing any concrete answers to this question. There are a number of factual and historical errors in the book that detract from its force. For example, Davis devotes a page to describing Clarence C. Little's tenure as “the first Director of the fledgling National Cancer Institute” (1, pp. 120–121). In fact, he never held this post, although he did serve as one of six original members of the National Advisory Cancer Council. She claims that the Council for Tobacco Research gave money “directly” to Wilhelm Hueper and Tom Mancuso to study the environmental and occupational causes of cancer. However, the document she cites for this makes it clear that funds were given to Mancuso but not to Hueper (1, p. 153). She has both R. A. Fisher and Nathan Mantel working “directly” for the tobacco industry in 1967; this is unlikely as Fisher died in 1962 and Mantel was still at the National Cancer Institute (1, p. 189). Davis is at her strongest when telling her own story. She provides engaging, first-hand accounts of her early career in the 1980s as a junior epidemiologist tackling big issues, such as assessing the disease burden for victims of exposure to hazardous wastes and studying whether cancer rates were increasing. Davis began working on the latter question under the guidance of Abe Lilienfeld at The John Hopkins University. She found that the incidence of multiple myeloma and brain cancer in men over 45 years of age had grown by more than a third in less than two decades, and a resulting paper in the Lancet (4) drew major headlines. Davis describes an encounter with Richard Doll, in which he told her that she had made a “colossal error” and that her findings would be explained by improved diagnosis and record keeping for these particular cancers (1, p. 257). She held to her story and gathered the evidence to prove Doll's hypothesis wrong. She also incorporates personal stories and encounters with cancer, including her own brush with a suspicious mammography reading, her family's exposure to the legacy of environmental pollution in Pennsylvania, and the experiences of friends and colleagues facing difficult decisions and questions about treatment options. Throughout, she also raises questions about what might have been done differently to prevent these cancers. In the end, however, the book is frustrating for its lack of explicit conclusions or recommendations about how things should be done differently. After 480 pages describing many twists and turns in the politics of cancer research, there are no substantive conclusions to tie it all together. Davis offers broad statements—“we need to open a new front” in the war against cancer (1, p. xviii)—but she fails to offer concrete proposals. In the book's closing pages, she briefly suggests the need for an independent commission for the assessment of toxic hazards and medical monitoring programs for exposed populations, but these suggestions are not developed. “I am not smart enough,” she claims, “to know what kind of system will best identify and address the preventable causes of cancer in our environment” (1, p. 430). On this point, she is clearly wrong. As her own autobiographic accounts illustrate, there are few people privileged with the range of scientific and real-world policy experience Davis has to be in a better position to offer some potential solutions. Indeed, this is what makes her failure to do so, so disappointing. Conflict of interest: none declared.
提出了一种从3轮公开掷币的对任何NP语言的诚实验证者零知识证明系统到纯公钥模型下4轮(轮最优)对同一语言的具有并发合理性的并发零知识证明系统.该转化方法有如下优点:1) 它只引起O(1)(常数个)额外的模指数运算,相比Di Crescenzo等人在ICALP 05上提出的需要((n)个额外的模指数运算的转化方法,该系统在效率上有着本质上的提高,而所需的困难性假设不变;2) 在离散对数假设下,该转化方法产生一个完美零知识证明系统.注意到Di Crescenzo等人提出的系统只具有计算零知识性质.该转化方法依赖于一个特殊的对承诺中的离散对数的3轮诚实验证者零知识的证明系统.构造了两个基于不同承诺方案的只需要常数个模指数运算的系统,这种系统可能有着独立价值.;This paper shows how to efficiently transform any 3-round public-coin honest verifier zero knowledge argument system for any language in NP into a 4 round (round-optimal) concurrent zero knowledge argument for the same language in the bare public-key model. The transformation has the following properties: 1) incurs only O(1) (small constant, about 20) additional modular exponentiations. Compared to the concurrent zero knowledge protocol proposed by Di Crescenzo and Visconti in ICALP 2005, in which their transformation requires an overhead of ((n), the protocol is significantly more efficient under the same intractability assumptions; 2) yields a perfect zero knowledge argument under DL assumption. Note that the Di Crescenzo, et al.'s argument system enjoys only computational zero knowledge property. The transformation relies on a specific 3-round honest verifier zero knowledge proof of knowledge for committed discrete log. Such protocols that require only O(1) modular exponentiations based on different kinds of commitment scheme are developed and they may be of independent interest.
Dear Sir, In science, it is not surprising to have exciting claims later refuted by hard evidence – although it may even be harder to have them corrected in the same journal where they originally appeared (Don't challenge a winning paper: Bär, 2006). One of the main reasons why false claims could pass through peer reviewing and eventually appear in print is (i) limited knowledge about certain genetic markers in a newly emerging field at the time of submission or (ii) insufficient screening of the published data for comparison and (iii) inadvertent documentation and analysis of the novel data underlying such claims. It may then take some years before the true causes for a particular finding would come to light. This apparently applies to the remarkable claim made by Holyoake et al. (2001) that the mitochondrial DNA (mtDNA) mutations G9055A and G11719A would compromise the semen quality of those men who possess any of these mutations in their mtDNAs (leading to reduced sperm motility and/or low sperm count). This study won the 2nd Prize of the European Academy of Andrology in 2001 – a winning paper, thus. The results of this study were aptly challenged by Montiel-Sosa et al. (2002), who (i) pointed to the fact that site 11719 determines a basal European mtDNA haplogroup (nowadays referred to R0), (ii) hinted at the peculiar frequency of the 11719 polymorphism as reported by Holyoake et al. (2001), and (iii) argued that ethnic origins of samples in a mixed population would matter and that 'the control and low sperm motility group could be non-homogenous'. Indeed, no reference to haplogroups, constituting the major branches of the mtDNA phylogeny, was made in the study by Holyoake et al. (2001), although it was submitted at a time (September 2000) where the role of the two particular (G9055A and G11719A) and other mutations was already quite well understood. Holyoake et al. (2002) in their reply to Montiel-Sosa et al. (2002) emphasized that they were only 'interested in single nucleotide substitutions in relationship to poor semen quality'. This popular 'allelic' approach gleaned from the analysis of the nuclear genome, however, is patently unsuitable for a deeply hierarchical genetic system such as mtDNA. First, the allelic view ignores the tight link between different mutations in the mtDNA phylogeny (as between G9055A and G11719A). Clusters of mutations would show up together and could then not serve as independent indicators of a disease phenotype. Second, disregard for the mtDNA phylogeny leaves out the option of phylogenetic proof-reading of obtained mtDNA results in regard to potential errors (Bandelt et al., 2005a). Not unexpectedly, the detailed haplogroup analysis of Pereira et al. (2005) for a large Portuguese sample did not support the notion that men carrying an mtDNA from a specific haplogroup overall had an increased or a reduced risk of infertility. These authors also warned that the observation by Ruiz-Pesini et al. (2000) that 'haplogroups H and K are significantly more abundant in nonasthenozoospermic and asthenozoospermic populations, respectively' may have been caused by population stratification. As long as patients and controls are not controlled for ethnic background, geographical matrilineal ancestry and social stratum (which certainly matters in countries with a considerable record of recent immigration), mere correlation of a mutation/haplogroup with a disease phenotype may be spurious and thus cannot provide sufficient evidence for an association. The complete mtDNA data of Ingman et al. (2000) as well as the RFLP-based analysis of West Eurasian mtDNAs of Macaulay et al. (1999) would have provided the necessary background information for the SSCP analysis aimed at by Holyoake et al. (2001). Curiously, the Ingman et al. (2000) study was referred to in a later article (Gemmell & Sin, 2002) by the same senior author (F. Y. T. Sin), but apparently without reappraising the findings of his former paper. If the data by Ingman et al. (2000) had been inspected at the time, then it would have become clear that the frequencies of the mutations observed by Holyoake et al. (2001) are mutually inconsistent and thus cannot realistically correspond to real-world data. To see this, take a preview of the worldwide mtDNA phylogeny as seen from the early Ingman et al. (2000) data, but now enriched with the up-to-date information about the nesting of the corresponding haplogroups, as displayed in Figure 1 of Bandelt et al. (2006). Nucleotide A at site 8860 is shared by virtually all mtDNAs worldwide that are not closest relatives of the revised Cambridge reference sequence (rCRS; Andrews et al., 1999). In Table 3 of Holyoake et al. (2001) the frequencies are recorded as 2/102 and 1/59 instead of the expected frequency of (nearly) 100%! The other frequencies in that table do not fare much better. Virtually all mtDNAs not belonging to the basal West Eurasian haplogroup R0 (which encompasses the sister haplogroups R0a and HV) bear the characteristic mutation G11719A. Assuming the frequency for this mutation in 'normozoospermic' men reported by Holyoake et al. (2001), one would be forced to conclude that all 80 control mtDNAs are members of haplogroup R0 (Table 1). Such a population sample has never been observed anywhere in the world. Moreover, this zero frequency is at odds with the other mutation frequencies recorded, as there is evidence that the other two basal West Eurasian haplogroups, JT and U (including K), were observed in both, the 'normozoospermic' and the 'subnormozoospermic' men (Table 1). The two frequencies of G11719A, on their own, are thus far apart from any realistic value, indicating that the recognition of G11719A via SSCP analysis must have been strongly hampered by technical problems. There is, by the way, little evidence that Polynesian mtDNAs played a noticeable role, because the vast majority of them would fall into a specific branch of haplogroup B. This haplogroup would be pinpointed by the 9 base-pair (bp) deletion, which, however, was found at a meagre 2.8% in the total sample. Note that the 9-bp deletion is also seen sporadically on many haplogroup backgrounds other than B. Furthermore, potential Sub-Saharan African mtDNA mutations (possibly C7789A) or (South-)East Asian mtDNA mutations (possibly G7853A) are present (if at all) at similarly minor frequencies; thus, in particular, the suggestion of considerable African mtDNA ancestry (Montiel-Sosa et al., 2002) receives no support from the data. Therefore, the vast majority (perhaps >95%) of mtDNAs analysed by Holyoake et al. (2001) must have been of European descent. Table 4 of Holyoake et al. (2001), which provides the full haplotype information, indicates further problems. Mutations that would be expected to be linked with other mutations in view of the above inequalities are not just absent but show up in unexpected combinations, almost random-like, which would rather suggest sample mix-up. Moreover, the haplogroup K mutation G9055A should always entail the mutation G11719A specific to non-R0 lineages, but according to that table, both mutations are rather unlinked. In the present Table 2, some haplotypes from Table 4 of Holyoake et al. (2001) are listed that combine at least two mutations. In three cases, all from the 'subnormozoospermic' group, one observes potentially mosaic patterns (Table 2). The best explanation for the odd frequency spectrum as well as the incomplete and mosaic haplotypes is, in the first place, massive failure of the SSCP analysis carried out by Holyoake et al. (2001). Such a mis-analysis is not an infrequent phenomenon in medical genetics (see e.g. Bandelt et al., 2005b). But why would have 'subnormozoospermia' triumphed over 'normozoospermia' e.g. in the screening of G11719A? And why would the 11719 polymorphism, if deemed crucial for 'subnormozoospermia', have only been analysed in a meagre 33 instead of, say, 131 patients? And what about G9055A? A normal mtDNA sample of predominantly mixed European descent would hardly show so few (<1%) haplogroup K members (Behar et al., 2006). The consistent trend in identifying mutations at frequencies that are far too low, especially for the 'normozoospermic' group, could suggest that the SSCP analysis was biased and effectively carried out only for a minority of the samples. It then seems that the number of fully screened mtDNAs was smaller for the 'normozoospermic' group than for the 'subnormozoospermic' group. In summary, there is no solid evidence that primary mtDNA substitutions other than recognized pathogenic mutations, mainly in heteroplasmic state, which usually cause complex disease phenotypes, influence sperm motility in any way. Therefore, it would be premature to accept all hypotheses and interpretations put forward by Gemmell & Sin (2002) and St. John et al. (2005), who took the results of Ruiz-Pesini et al. (2000) and Holyoake et al. (2001) at face value. Before far-reaching implications are discussed, the underlying data should come under scrutiny first. It would certainly be desirable to re-study the mtDNA samples employed by Holyoake et al. (2001) by performing highest quality sequencing. In any case, there is an urgent need for a new start of mtDNA analysis of samples from men with idiopathic infertility (or subfertility) by complete mtDNA sequencing in order to provide a solid database to which any subsequent case studies could get compared and evaluated. The most recent work of Pereira et al. (2007) is a promising first step in this direction.
Keeping religion and politics apart is an idea with a history. That history is a Christian one, however, rooted in the experience of European Christendom and made possible because Christians, virtually from the beginning, viewed church and state as conceptually separate entities, with different jurisdictions and powers and even a different logic.1 It may be, as Mark Lilla recently argued, that the complex picture of the Christian triune God is inextricably caught up in this story.2 Divided sovereignty is more compatible with the picture of a divided God than a unified one. Other religious traditions may have different resources, however, enabling them to embrace or even stumble into the separation of religion and state. In the case of religions framed around legal traditions, pictures of the divine law are as important as pictures of God.3 Is the law imagined as a comprehensive system uniting all aspects of life under a single sacred framework, thus leaving no room for a separate political domain? Is the law imagined as primarily political, a blueprint for government; or as exquisitely ethical, taking into account only the rights of individuals and not societal needs or a collective such as the state? If so, what law regulates social need? Is there a universal law that has an origin outside of itself on which it can draw even in an internal context? These pictures of the divine law vary over time and among groups within the tradition, just as do pictures of secular law. Certain pictures of law, however, may assume mythic proportions over time, especially in the popular imagination, and this can be a potent obstacle to retrieving from within the tradition alternative images of the law more congenial to a separation of religion and state. It is in this spirit that two intellectual retrieval projects, both responding to the rise of modern nation-states in the Middle East, are taking place today. Muslim and Jewish thinkers are looking back on a wide variety of legal doctrines and theories, as well as historical experiences, in order to engage the question whether there are authentic warrants from within their respective traditions for separating religion and state. These two legal traditions begin with strong original visions of a unified religious polity in which the political authority both is subject to and enforces the divine law. 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