Equipoise, knowledge and ethics in clinical research and practice

It is widely maintained that a clinical trial is ethical only if some form of equipoise between the treatments being compared obtains. To be in equipoise between two treatments A and B is to be cognitively indifferent between the statement 'A is strictly more effective than B' and its negation. It is natural to claim that equipoise regarding A and B is necessary for randomised assignment to treatments A and B to be beneficent and non-maleficent and is sufficient for such an assignment to be fair. Cashing this out precisely is difficult, and various forms of equipoise have been discussed which consider whose equipoise is relevant to the decision. This is to make judgement of equipoise something to be managed socially, while its prima facie significance is supposedly cognitive. Recent reconstructions of equipoise-like concepts in epistemology give clues about how to understand equipoise cognitively. In this paper I examine some of this work and discuss how successful it has been. I suggest that while this work is promising, it still has far to go, and that while equipoise remains the best theory we have of the cognitive justification for clinical trials, it is nonetheless incoherent.     

Site of graviperception in roots: a re-examination

Two lines of evidence have been cited to support the assertion that the root cap is the sole site of graviperception in the root. The first evidence is based on surgical removal of the cap, which abolishes the response to gravity. This is sufficient to conclude that the cap is involved in gravitropism, but not to conclude that the cap is the site of graviperception. The second is based on the results of centrifugation experiments, in which different parts of the plant are subjected to different centrifugal forces. The data from such experiments have been cited to support the conclusion that the perception of gravity is limited to the rootcap. However, these data actually support the conclusion that gravity is perceived throughout the root tip, and not only in the root cap. We believe that the data support the conclusion that the root cap is involved in root gravitropism, but that there is inadequate evidence to conclude that the cap is the sole site of graviperception.     

Failure to Maintain Glycolysis in Anoxic Nerve Terminals

Synaptosomal glycolysis is stimulated eight- to 10-fold when the respiratory chain is inhibited by cyanide or by anoxia. However, the stimulation is transient and after 15 min declines toward the preanoxic rate. The decline is not seen when Ca2+ is absent or when the respiratory chain is inhibited by rotenone. The decline in glycolysis is reversible, is not due to substrate exhaustion, and is the cause, rather than the effect, of lowered synaptosomal ATP/ADP ratios. The failure to maintain glycolysis when the terminal oxidase of the respiratory chain is inhibited may have relevance to the sensitivity of the brain to anoxic damage.     

Analytical studies of injury criteria for the thorax

The viscous criterion is a recently developed criterion to assess injury severity of the human thorax. In the viscous criterion, the peak viscous response, which is defined as the maximum product of deformation velocity and compression of an object, is proposed as a predictor of injury risk. However, the physical meaning of the criterion is not very clear. In this paper, the mathematical properties of the viscous criterion are analyzed. A mechanical thorax model is then used to relate the criterion to the physical quantities of the model using energy concepts. It is found that the so-called peak viscous response is strongly related to the peak energy storing rate of the thorax which is not related to the viscosity of the thorax. It is also shown that the viscous response of the thorax is given by the integral of the velocity squared with respect to time. The analysis is further expanded to a more general case to result in four criteria based upon the energy concepts. A hypothesis for injury assessment is proposed by using the four criteria.     

Oxidation of glycine by Phaseolus leghaemoglobin with associated catabolic reactions at the haem.

Leghaemoglobin from the root nodules of kidney bean (Phaseolus vulgaris) reacts in alkaline glycine solutions as a glycine oxidase in a reaction that may also be regarded as a coupled oxidation. Leghaemoglobin is reduced to the ferrous form by glycinate, the oxygen complex is formed, and finally the haem is attacked to yield a green reaction product. Glycine is simultaneously oxidized to glyoxylate, and hydrogen peroxide is generated. The initial velocity of the formation of the green product is proportional to the concentrations of leghaemoglobin and glycine, and the optimum pH for the reaction is 10.2. The green product is not formed if carbon monoxide, azide of imidazole is bound to the haem, whereas oxidation of glycine to glyoxylate is not inhibited by azide and not essentially by carbon monoxide. Haem breakdown is activated by digestion of leghaemoglobin by carboxypeptidase, and partly inhibited by catalase and superoxide dismutase.     

The kinetics of hemolytic plaque formation. III. Inhibition of plaques by antigen.

Equations are presented which can be used to describe the inhibition of plaques by multifunctional antigen which binds γG antibody bivalently. The interaction is treated as a bimolecular reaction which is irreversible within the time of the experiment. It is shown that under these conditions the characteristics of the inhibition curve, and their relationship to kinetic and thermodynamic parameters are strongly dependent upon how antibody interacts with RBCs. When the epitope coating is dense, multivalent attachment of antibody is likely and the interaction is considered irreversible. When the epitope coating is sparse, only rapid, reversible univalent attachment is considered and local equilibrium is assumed to hold.The first case leads to an abrupt inhibition curve whose position is determined by the forward rate constant and RBC density. The second case leads to broad asymmetric curves. For this situation the relation between the extent of inhibition and the affinity of the population is generally complicated and reliable affinity information is difficult to obtain. This is contrasted to results obtained previously for unifunctional inhibitors from which reliable affinity information can, in principle, be obtained. The results emphasize the need for carefully designed experiments if affinity information is to be obtained from inhibition studies.     

马陆在森林生态系统物质转化中的功能研究

马陆是森林生态系统重要的分解者,在帽儿山林区,马陆摄食量随温度的升高而增加。据初步估算,马陆地对凋落物的分解量约占该地区年平均凋落物量的０．２１％。马陆对同一种、不同腐解程度的叶片摄食不同,对妆分解凋落物的摄食量大于对未分解凋落物的摄食量。在不同温度条件下,马陆的生态效率不同,其同化效率随温度升高而降低,而粪便率则随温度升高而增加。在不同林型下个体数量分布不均匀。通常、阔叶林＞针阔叶混交林＞针叶林。在土壤的垂直分布上,具有明显的表聚现象。马陆的个体数量季节变化明显,以夏末最多,冬末最少。     

The Medawar Lecture 2004 the truth about science

The attitudes of scientists towards the philosophy of science is mixed and includes considerable indifference and some hostility. This may be due in part to unrealistic expectation and to misunderstanding. Philosophy is unlikely directly to improve scientific practices, but scientists may find the attempt to explain how science works and what it achieves of considerable interest nevertheless. The present state of the philosophy of science is illustrated by recent work on the 'truth hypothesis', according to which, science is generating increasingly accurate representations of a mind-independent and largely unobservable world. According to Karl Popper, although truth is the aim of science, it is impossible to justify the truth hypothesis. According to Thomas Kuhn, the truth hypothesis is false, because scientists can only describe a world that is partially constituted by their own theories and hence not mind-independent. The failure of past scientific theories has been used to argue against the truth hypothesis; the success of the best current theories has been used to argue for it. Neither argument is sound.     

Aspects of the Clausius-Shannon Identity: Emphasis on the components of transitive information in linear,branched and composite physical systems

In this paper I consider how information is required to specify various systems. It is shown that the transitive information of any physical system, is distributed among three distinct components. One of these, the selective component, is required to specify the elemental parts of the system. Another, the connective component, is required to specify the macrostructure of the system; that is the way the parts are put together. And a third, the conformative component, is required to specify the intrinsic complexion or microstructure of the system. An interesting method for analyzing branched systems which takes account of connective ambiguity is described in some detail. The relationship between information and entropy, known as the Clausius-Shannon Identity, is then discussed with reference to selected thermodynamic models: and that aspect of information which is often overlooked, namely the distinction, between transitive and intransitive information is highlighted. The applications (or perhaps more correctly, the limitations of applying this treatment) to problems of biological interest are also indicated.     

Investigating the accessibility of the closed domain conformation of citrate synthase using essential dynamics sampling

A molecular dynamics study of pig heart citrate synthase is presented that aims to directly address the question of whether, for this enzyme, the ligand-induced closed domain conformation is accessible to the open unliganded enzyme. The approach utilises the technique of essential dynamics sampling, which is used in two modes. In exploring mode, the enzyme is encouraged to explore domain conformations it might not normally sample in free molecular dynamics simulation. In targeting mode, the enzyme is encouraged to adopt the domain conformation of a target structure. Using both modes extensively, it has been found that when the enzyme is prepared from a crystallographic open-domain structure and is in the unliganded state, it is unable to adopt the crystallographic closed-domain conformation of the liganded enzyme. Likewise, when the enzyme is prepared from the crystallographic closed liganded conformation with the ligands removed, it is unable to adopt the crystallographic open domain conformation. Structural investigations point to a common structural difference that is the source of this energy barrier; namely, the shift of alpha-helix 328-341 along its own axis relative to the large domain. Without this shift, the domains are unable to close or open fully. The charged substrate, oxaloacetate, binds near the base of this helix in the large domain and the interaction of Arg329 at the base of the helix with oxaloacetate is one that is consistent with the shift of this helix in going from the crystallographic open to closed structure. Therefore, the results suggest that without the substrate the enzyme remains in a partially open conformation ready to receive the substrate. In this way, the efficiency of the enzyme should be increased over one that is closed part of the time, with its binding site inaccessible to the substrate.     

Two types of hormone-responsive adenylate cyclase in the rat liver

We have demonstrated the existence of two types of hormone-responsive adenylate cyclase in the isolated perfused rat liver. One, less abundant, is linked to glycogenolysis and the other is not. Glucagon stimulates mainly the glycogenolysis-linked fraction and, to a lesser extent, the fraction which is not linked to glycogenolysis. The suppressive effect of insulin is specific for the glucagon-responsive adenylate cyclase and is inhibited by 3-isobutyl-1-methylxanthine (IBMX). However, this mechanism can explain only partly the ability of insulin to suppress glycogenolysis, and is not observed when cAMP is increased sufficiently by glucagon. Secretin-responsive adenylate cyclase is not linked to glycogenolysis and is suppressed specifically by oxymetazoline. The capacity of this suppressive effect is large and not inhibited by IBMX. These results suggest that there is a functional compartmentalization of cAMP within the hepatocyte or among hepatocytes.     

Risk avoidance and nesting strategies

Gillespie (1974,1975) has shown that selection will tend to minimize variance in offspring number. It is shown that this effect is due to selection maximizing the average number of surviving offspring when there is density-dependent survival, and that it is unnecessary to invoke principles such as minimizing the variability of fitness (Real, 1980). The effect of this principle of selecting for laying several small clutches rather than one large clutch when there is predation on whole clutches is investigated. It is found that the selection pressure is weak, contrary to the conclusion of Rubenstein (1982), and is unlikely to be of evolutionary importance.     

冷箭竹生殖特性研究

１９８１－１９９０年对冷箭竹（Ｂａｓｈａｎｉａｆａｎｇｅｎｉａ）开花、结实、种子萌发、幼苗更新复壮等生殖特性进行了观察。冷箭竹开花周期为４５－５５年,开花持续期约１０年,１９８３年盛花期测定茎秆上着生花序的长度平均为１７０．８ｃｍ,每１茎秆上的小花数为１２８０．３枚,每朵小花从开放至萎蔫的持续期约６天,花药持续开裂时间为０．７７天,花粉生活力达９６．７％,柱头承受花粉时间为２．３天,雌蕊子房发育为果实平均为３５８６粒／ｍ￣２,未受粉的瘪粒为１３９９４粒／ｍ￣２。种子生活力为２７．６％,种子发芽率为１５％－２０％,当年生幼苗成活率为７６％－９３％。     

Immunity to non-cerebral severe malaria is acquired after one or two infections

In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.     

Sequential allocation in clinical trials comparing two exponential survival curves.

The problem of comparing two medical treatments with respect to survival is considered. Treatment outcome is assumed to follow an exponential distribution. The ratio of expected survivals associated with the two treatments is the clinical parameter of interest. A nuisance parameter is present, but it is removed by an invariance reduction and a sequential probability ratio test is applied to the invariant likelihood ratio. A class of data-dependent treatment assignment rules is identified over which the probability of correct treatment selection at the termination of the trial is approximately constant. A cost function, the weighted sum of total patients in the trial and the number assigned to the inferior treatment is introduced, and a treatment allocation rule conjectured to minimize the expected cost is constructed. Both analytic and simulation results show that it is an improvement over rules previously proposed. The methodology contained herein can be used to construct near-optimal rules in other testing contexts.     

Role of physical activity in preventing and treating obesity.

There is an inverse relationship between physical activity and weight gain. However, additional research is needed to quantify the amount of physical activity required to prevent weight gain in different populations, improve the way we convey physical activity recommendations to the public, and help the individuals increase their physical activity. Although physical activity does not appear to contribute significantly to weight loss, it is critical for maintenance of weight loss. Available data are consistent in that 60-90 min/day of moderate-intensity physical activity is required to maintain a significant weight loss. Although there is agreement about the need for high levels of physical activity to maintain weight loss, there is a need for more research to understand why physical activity is critical for weight loss maintenance. Finally, additional research is needed to determine whether there is an optimal level of physical activity below which it is difficult for most people to achieve a balance between energy intake and expenditure at a healthy body weight. The increasing prevalence of obesity may reflect the fact that the majority of the population has fallen below such a level of physical activity.     

A transient histone hyperacetylation signal marks nucleosomes for remodeling at the PHO8 promoter in vivo.

Chromatin remodeling of the yeast PHO8 promoter requires the SAGA histone acetyltransferase complex. We report here that SAGA is necessary and sufficient to establish an activator-dependent hyperacetylation peak over the PHO8 promoter that is restricted to those nucleosomes that are remodeled upon activation. This local hyperacetylated state is observed upon activation in the absence of the SWI/SNF complex when the remodeling process is frozen subsequent to activator binding. Hyperacetylation is lost, however, if remodeling is permitted to go to completion. Thus, a transient histone hyperacetylation signal is shown to be a prerequisite for, and determinant of, the domain of nucleosome remodeling in vivo.     

Incorporation and replication of foreign metaphase chromosomes in cultured mammalian cells

It is shown that the dyes used to produce banding patterns on chromosomes, quinacrine and Giemsa, are bound to DNA, and not to non-histone protein, the other chromosomal component remaining after acetic acid fixation. Studies on fixed nuclei and on extracted DNA in gelatine films show that the amount of dye bound is not affected by whether the DNA is native or denatured, and is not directly related to the amount of DNA present. Quinacrine is bound to the DNA ionically. With Giemsa, a new magenta compound is formed in situ, consisting of two molecules of methylene blue and one of eosin; this compound is attached to the chromosome by hydrogen bonds. Both quinacrine and the magenta compound formed from Giemsa appear to be attached to DNA molecules at two separate points, and the available evidence suggests that the amount of dye bound is related to the concentration of the DNA. It is suggested that the dye molecules bridge longitudinally separated sites brought into close proximity by folding of the DNA, and that the spatial arrangement of sites in the chromosome is influenced by non-histone proteins. It is concluded that chromosome banding is thus a consequence of the reduction of dye binding in those regions where the DNA chains become sufficiently dispersed to prevent bridging by the dye molecules. Possible indirect effects of base composition and repetition on dye binding at certain chromosomal sites are discussed.     

Children as means and ends in large-scale medical research

This paper considers the often-expressed fear that medical research may use children merely as means, and not respect them as ends in themselves - especially insofar as they are deemed less able to consent than adults. The main focus is on large-scale genetic, socio-medical and epidemiological research. The theoretical starting point of the paper is that to be treated as an end in oneself is to be regarded as - and to act as - a participant in cooperative endeavours. This participatory status is certainly connected with individual authority to consent and dissent; and there is no doubt that consent plays an important role when adults participate in many research projects. However, insofar as consent is located within structures of human cooperation, the authority to consent is not a straightforward privilege. Rather, consent is bound up with responsibility for one's choices and commitment to shared terms of cooperation. Given this understanding, it is argued that consent should not be our principal concern when we involve children in research. This is not because of children's (possible) incompetence to consent as such, but rather because children are still learning how to respect and assess the cooperative terms involved in our institutional lives. Instead, our leading concern should be with the terms regulating their involvement in research. Given suitable safeguards, research is one way in which children may learn what it is to bear responsibilities and to act as an end in oneself - that is, to cooperate with others on reasonable terms and for worthy ends.