Fitting models for the joint action of two drugs using SAS(R)

Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of synergism, in which the joint action is greater than the actions of the individual drugs, or of antagonism, in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study. Copyright © 2007 John Wiley & Sons, Ltd.

Did pterosaurs feed by skimming? Physical modelling and anatomical evaluation of an unusual feeding method

Similarities between the anatomies of living organisms are often used to draw conclusions regarding the ecology and behaviour of extinct animals. Several pterosaur taxa are postulated to have been skim-feeders based largely on supposed convergences of their jaw anatomy with that of the modern skimming bird, Rynchops spp. Using physical and mathematical models of Rynchops bills and pterosaur jaws, we show that skimming is considerably more energetically costly than previously thought for Rynchops and that pterosaurs weighing more than one kilogram would not have been able to skim at all. Furthermore, anatomical comparisons between the highly specialised skull of Rynchops and those of postulated skimming pterosaurs suggest that even smaller forms were poorly adapted for skim-feeding. Our results refute the hypothesis that some pterosaurs commonly used skimming as a foraging method and illustrate the pitfalls involved in extrapolating from limited morphological convergence.

Managing threatened species: the ecological toolbox, evolutionary theory and declining-population paradigm

1. The management of threatened species is an important practical way in which conservationists can intervene in the extinction process and reduce the loss of biodiversity. Understanding the causes of population declines (past, present and future) is pivotal to designing effective practical management. This is the declining-population paradigm identified by Caughley. 2. There are three broad classes of ecological tool used by conservationists to guide management decisions for threatened species: statistical models of habitat use, demographic models and behaviour-based models. Each of these is described here, illustrated with a case study and evaluated critically in terms of its practical application. 3. These tools are fundamentally different. Statistical models of habitat use and demographic models both use descriptions of patterns in abundance and demography, in relation to a range of factors, to inform management decisions. In contrast, behaviour-based models describe the evolutionary processes underlying these patterns, and derive such patterns from the strategies employed by individuals when competing for resources under a specific set of environmental conditions. 4. Statistical models of habitat use and demographic models have been used successfully to make management recommendations for declining populations. To do this, assumptions are made about population growth or vital rates that will apply when environmental conditions are restored, based on either past data collected under favourable environmental conditions or estimates of these parameters when the agent of decline is removed. As a result, they can only be used to make reliable quantitative predictions about future environments when a comparable environment has been experienced by the population of interest in the past. 5. Many future changes in the environment driven by management will not have been experienced by a population in the past. Under these circumstances, vital rates and their relationship with population density will change in the future in a way that is not predictable from past patterns. Reliable quantitative predictions about population-level responses then need to be based on an explicit consideration of the evolutionary processes operating at the individual level. 6. Synthesis and applications. It is argued that evolutionary theory underpins Caughley's declining-population paradigm, and that it needs to become much more widely used within mainstream conservation biology. This will help conservationists examine critically the reliability of the tools they have traditionally used to aid management decision-making. It will also give them access to alternative tools, particularly when predictions are required for changes in the environment that have not been experienced by a population in the past.

Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes

This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log(10) transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log(10) cortisol concentration 2 h previously was detected. Analysis of the 'transport' stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log(10) ACTH secretion rate was related to log(10) vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log(10) cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate that corticosteroid negative-feedback is a significant control mechanism at both the pituitary and hypothalamus. The amplitude of HPA response may be related to stimulus intensity and corticosteroid negative-feedback, while duration depended on feedback alone.

Toughness & cutting: A new way of determining ductile fracture toughness and strength

A review is given of the mechanics of cutting, ranging from the slicing of thin floppy offcuts (where there is negligible elasticity and no permanent deformation of the offcut) to the machining of ductile metals (where there is severe permanent distortion of the offcut/chip). Materials scientists employ the former conditions to determine the fracture toughness of ‘soft’ solids such as biological materials and foodstuffs. In contrast, traditional analyses of metalcutting are based on plasticity and friction only, and do not incorporate toughness. The machining theories are inadequate in a number of ways but a recent paper has shown that when ductile work of fracture is included many, if not all, of the shortcomings are removed. Support for the new analysis is given by examination of FEM simulations of metalcutting which reveal that a ‘separation criterion’ has to be employed at the tool tip. Some consideration shows that the separation criteria are versions of void-initiation-growth-and-coalescence models employed in ductile fracture mechanics. The new analysis shows that cutting forces for ductile materials depend upon the fracture toughness as well as plasticity and friction, and reveals a simple way of determining both toughness and flow stress from cutting experiments. Examples are given for a wide range of materials including metals, polymers and wood, and comparison is made with the same properties independently determined using conventional testpieces. Because cutting can be steady state, a new way is presented for simultaneously measuring toughness and flow stress at controlled speeds and strain rates.

Technology trajectories, innovation, and the growth of biomimetics

Publication rate of patents can be a useful measure of innovation and productivity in science and technology. Patenting activity in new technological fields follows a sigmoid (S-shaped) path. Qualitative and quantitative models in management and economics literature explain why such patterns of productivity may occur. TRIZ analysis suggests that patents are generated in bursts during the evolution of a product and that they are at different levels of inventiveness. The tendency is for the inventiveness to reduce as the product is more mature. This makes it possible to guess at the lifetime stage of a product and gauge its maturity and profitability. An analysis of patenting activity and other measures of inventiveness in the emerging field of biomimetics was presented, and future trends in biologically-inspired innovation was discussed.

Did pterosaurs feed by skimming? Physical modelling and anatomical evaluation of an unusual feeding method

Similarities between the anatomies of living organisms are often used to draw conclusions regarding the ecology and behaviour of extinct animals. Several pterosaur taxa are postulated to have been skim-feeders based largely on supposed convergences of their jaw anatomy with that of the modern skimming bird, Rynchops spp. Using physical and mathematical models of Rynchops bills and pterosaur jaws, we show that skimming is considerably more energetically costly than previously thought for Rynchops and that pterosaurs weighing more than one kilogram would not have been able to skim at all. Furthermore, anatomical comparisons between the highly specialised skull of Rynchops and those of postulated skimming pterosaurs suggest that even smaller forms were poorly adapted for skim-feeding. Our results refute the hypothesis that some pterosaurs commonly used skimming as a foraging method and illustrate the pitfalls involved in extrapolating from limited morphological convergence.

How contractors price risk in bids: theory and practice

Formal and analytical models that contractors can use to assess and price project risk at the tender stage have proliferated in recent years. However, they are rarely used in practice. Introducing more models would, therefore, not necessarily help. A better understanding is needed of how contractors arrive at a bid price in practice, and how, and in what circumstances, risk apportionment actually influences pricing levels. More than 60 proposed risk models for contractors that are published in journals were examined and classified. Then exploratory interviews with five UK contractors and documentary analyses on how contractors price work generally and risk specifically were carried out to help in comparing the propositions from the literature to what contractors actually do. No comprehensive literature on the real bidding processes used in practice was found, and there is no evidence that pricing is systematic. Hence, systematic risk and pricing models for contractors may have no justifiable basis. Contractors process their bids through certain tendering gateways. They acknowledge the risk that they should price. However, the final settlement depends on a set of complex, micro-economic factors. Hence, risk accountability may be smaller than its true cost to the contractor. Risk apportionment occurs at three stages of the whole bid-pricing process. However, analytical approaches tend not to incorporate this, although they could.

Carbon reduction in buildings (CaRB) - Understanding the social and technical factors that influence energy use in UK buildings

Attempts to reduce the energy consumed in UK homes have met with limited success. One reason for this is a lack of understanding of how people interact with domestic technology – heating systems, lights, electrical equipment and so forth. Attaining such an understanding is hampered by a chronic shortage of detailed energy use data matched to descriptions of the house, the occupants, the internal conditions and the installed services and appliances. Without such information it is impossible to produce transparent and valid models for understanding and predicting energy use. The Carbon Reduction in Buildings (CaRB) consortium of five UK universities plans to develop socio-technical models of energy use, underpinned by a flow of data from a longitudinal monitoring campaign involving several hundred UK homes. This paper outlines the models proposed, the preliminary monitoring work and the structure of the proposed longitudinal study.

Probiotics and cancer: from in vitro to human studies

Studies in cell cultures and animal models provide evidence that probiotics can beneficially influence various stages in development of colon cancer including tumor initiation, promotion and metastasis. For example, oral administration of Lactobacillus and Bifidobacterium strains can prevent genotoxic damage to the colonic epithelium (considered to be an early stage of the carcinogenic process). Administration to rats of probiotics reduced the incidence of carcinogen-induced pre-cancerous lesions (aberrant crypt foci) in the colon. Furthermore a combination of Bifidobacterium longum and inulin (a prebiotic) was more effective than either treatment alone. In this latter study, the dietary treatments were given after exposure to the carcinogen, which suggests that the protective effects were being exerted at the promotional phase of carcinogenesis. L. acidophilus feeding has been shown to decrease the incidence of colon tumors in rats challenged with a carcinogen and B. longum reduced the incidence of carcinogeninduced colon, liver and mammary tumors. There is limited evidence from epidemiological studies for protective effects of products containing probiotics in humans, but a number of recent dietary intervention studies in healthy subjects and in polyp and cancer patients have yielded promising results on the basis of biomarkers of cancer risk and grade of colorectal tumors.

Diet, fecal water, and colon cancer - development of a biomarker

Colorectal cancer (CRC) is a leading cause of cancer incidence worldwide. Lifestyle factors, especially dietary intake, affect the risk of CRC development. Suitable risk biomarkers are required in order to assess the effect that specific dietary components have on CRC risk. The relationship between dietary intake and indicators of fecal water activity has been assessed using cell and animal models as well as human studies. This review summarizes the literature on fecal water and dietary components with a view to establishing further the potential role of fecal water as a source of CRC risk biomarkers. The literature indicates that fecal water activity markers are affected by specific dietary components linked with CRC risk: red meat, saturated fats, bile acids, and fatty acids are associated with an increase in fecal water toxicity, while the converse appears to be true for calcium, probiotics, and prebiotics. However, it must be acknowledged that the study of fecal water is still in its infancy and a number of issues need to be addressed before its usefulness can be truly gauged.

Green tea (Camellia sinensis) catechins and vascular function

The health benefits of green tea (Camellia sinensis) catechins are becoming increasingly recognised. Amongst the proposed benefits are the maintenance of endothelial function and vascular homeostasis and an associated reduction in atherogenesis and CVD risk. The mounting evidence for the influential effect of green tea catechins on vascular function from epidemiological, human intervention and animal studies is subject to review together with exploration of the potential mechanistic pathways involved. Epigallocatechin-3-gallate, one of the most abundant and widely studied catechin found in green tea, will be prominent in the present review. Since there is a substantial inconsistency in the published data with regards to the impact of green tea catechins on vascular function, evaluation and interpretation of the inter- and intra-study variability is included. In conclusion, a positive effect of green tea catechins on vascular function is becoming apparent. Further studies in animal and cell models using physiological concentrations of catechins and their metabolites are warranted in order to gain some insight into the physiology and molecular basis of the observed beneficial effects.

SORMA - business cases for an open grid market: concept and implementation

Economic mechanisms enhance technological solutions by setting the right incentives to reveal information about demand and supply accurately. Market or pricing mechanisms are ones that foster information exchange and can therefore attain efficient allocation. By assigning a value (also called utility) to their service requests, users can reveal their relative urgency or costs to the service. The implementation of theoretical sound models induce further complex challenges. The EU-funded project SORMA analyzes these challenges and provides a prototype as a proof-of-concept. In this paper the approach within the SORMA-project is described on both conceptual and technical level.

Evaluating forecasts of the evolution of the cloudy boundary layer using diurnal composites of radar and lidar observations

Observations of boundary-layer cloud have been made using radar and lidar at Chilbolton, Hampshire, UK. These have been compared with output from 7 different global and regional models. Fifty-five cloudy days have been composited to reveal the mean diurnal variation of cloud top and base heights, cloud thickness and liquid water path of the clouds. To enable like-for-like comparison between model and observations, the observations have been averaged on to the grid of each model. The composites show a distinct diurnal cycle in observed cloud; the cloud height exhibits a sinusoidal variation throughout the day with a maximum at around 1600 and a minimum at around 0700 UTC. This diurnal cycle is captured by six of the seven models analysed, although the models generally under-predict both cloud top and cloud base heights throughout the day. The two worst performing models in terms of cloud boundaries also have biases of around a factor of two in liquid water path; these were the only two models that did not include an explicit formulation for cloud-top entrainment.

Laboratory measurements of the water vapor continuum in the 1200–8000 cm−1 region between 293 K and 351 K

Laboratory Fourier transform spectroscopy of pure water vapor and water vapor mixed with air has been conducted between 1200 and 8000 cm−1 and at temperatures between 293 and 351 K with the purpose of detecting and characterizing the water vapor continuum. The spectral features of the continuum within the major water absorption bands are presented and compared where possible to those from previous experimental studies and to the commonly used MT_CKD and CKD models. It was observed that in the main, both models adequately capture the general spectral form of the continuum; however, there were a number of exceptions. Overall, there is no evidence to indicate that MT_CKD is an improvement upon the older CKD model in these spectral regions. There was generally good agreement between our results and those of other experimental investigators. The general mathematical forms of the self-continuum temperature dependence, given by both Roberts et al. (1976) and CKD/MT_CKD, fit well to the experimental continuum in these spectral regions. However, the range of temperatures over which we made measurements is not sufficient to discriminate between these two forms or to exclude the possibility of other forms of temperature dependence being more appropriate. At the same time, the actual parameters currently used in CKD/MT_CKD to describe the temperature dependence in many spectral regions cannot reproduce the observed strong spectral variation in the temperature dependence. It has not been possible to make definitive conclusions about the magnitude of the continuum absorption in the far wings of the absorption bands investigated here.