A study of general practitioners' reasons for changing their prescribing behaviour.

OBJECTIVES--To explore general practitioners'' reasons for recent changes in their prescribing behaviour. DESIGN--Qualitative analysis of semistructured interviews. SETTING--General practice in south east London. SUBJECTS--A heterogeneous sample of 18 general practitioners. RESULTS--Interviewees were able to identify between two and five specific changes that had occurred in their prescribing in the preceding six months. The most frequently mentioned changes related to fluoxetine, angiotensin converting enzyme inhibitors, and the antibiotic treatment of Helicobacter pylori. Three models of change were identified: an accumulation model, in which the volume and authority of evidence were important; a challenge model, in which behaviour change followed a dramatic or conflictual clinical event; and a continuity model, in which change took place against a background of willingness to change, modulated by other factors such as cost pressures and the comprehensible therapeutic action of a drug. Behaviour change was reinforced and sustained by experiences with individual patients. CONCLUSIONS--Multiple factors are involved in general practitioners'' decisions to change their prescribing habits. Three models of change can be identified which have important implications for the design and evaluation of interventions aimed at behaviour change.     

A long-lasting birefringence change recorded from a tetanically stimulated squid giant axon.

A long-lasting birefringence change (the delayed response) was found to be produced in a tetanically stimulated squid giant axon. The change was independent of the concurrent membrane potential change, summated on repetitive stimulation, and always had a sign representing a decrease in resting birefringence. The axons was placed between a polarizer and an analyzer with their polarizing axes crossed, making an angle of 45 degrees with the longitudinal direction of the axon. The light beam that passed through the axon and the other optical elements was received by a photodiode. The change in light intensity evoked by repetitive stimulation was composed of brief initial responses, which took place in response to individual stimuli, and a delayed response, which developed gradually and lasted for several hundred msec. It was necessary to differentiate the effect of birefringence change from that of turbidity change. Formulas were derived on the assumption that the optical properties of the axon could be represented by a model of a uniaxial crystal that was not only birefringent but also dichroic, its extinction coefficients and the angle of retardation being changed independently on excitation. Calculations with them yielded the resting retardation, which agreed well with those obtained by the Senarmont's method, and the change in birefringence, which agreed well with the other calculated value derived from experiments using a quarter-wave plate. The results of the calculation confirmed the existence of the long-lasting birefringence change in the tetanically stimulated axon.     

Changes in the fluorescence of bound nucleotide during the reaction catalysed by glucose-fructose oxidoreductase from Zymomonas mobilis.

The reduction of gluconolactone by glucose-fructose oxidoreductase containing tightly bound NADPH (enzyme-NADPH) is biphasic in nucleotide fluorescence. The initial rapid decrease, which represents quenching of the fluorescence by bound lactone, is followed by a slower decrease which corresponds to the change in absorbance. At low glucose concentrations, the oxidation of glucose by enzyme-NADP+ involves a single first-order process with similar rate constants in fluorescence and absorbance. At higher glucose concentrations, the apparent first-order rate constants for the fluorescence change are less than those for the absorbance change. This is consistent with a mechanism in which the fluorescence change occurs during the lactone dissociation step, which is slower than the hydrogen transfer step during which the absorbance change occurs. The rate constant for gluconolactone dissociation is 360 +/- 10 s-1 and this step is therefore rate-determining for the overall reaction. Reduction of fructose by enzyme-NADPH is first order with a limiting rate constant of at least 2000 s-1.     

The effect of density-dependent treatment and behavior change on the dynamics of HIV transmission

In this work, we propose a model for heterosexual transmission of HIV/AIDS in a population of varying size with an intervention program in which treatment and/or behavior change of the infecteds occur as an increasing function of the density of the infected class in the population. This assumption has socio-economic implications which is important for public health considerations since density-dependent treatment/behavior change may be more cost-saving than a program where treatment/behavior change occurs linearly with respect to the number of infecteds. We will make use of the conservation law of total sexual contacts which enables us to reduce the two-sex model to a simpler one-sex formulation. Analytical results will be given. Unlike a similar model with linear treatment/behavior change in Hsieh (1996) where conditions were obtained for the eradication of disease, we will show that density-dependent treatment/behavior change cannot eradicate the disease if the disease is able to persist without any treatment/behavior change. This work demonstrates the need to further understand how treatment/behavior change occurs in a society with varying population.     

A long-lasting birefringence change recorded from a tetanically stimulated squid giant axon

A long-lasting birefringence change (the delayed response) was found to be produced in a tetanically stimulated squid giant axon. The change was independent of the concurrent membrane potential change, summated on repetitive stimulation, and always had a sign representing a decrease in resting birefringence. The axon was placed between a polarizer and an analyzer with their polarizing axes crossed, making an angle of 45° with the longitudinal direction of the axon. The light beam that passed through the axon and the other optical elements was received by a photodiode. The change in light intensity evoked by repetitive stimulation was composed of brief initial responses, which took place in response to individual stimuli, and a delayed response, which developed gradually and lasted for several hundred msec. It was necessary to differentiate the effect of birefringence change from that of turbidity change. Formulas were derived on the assumption that the optical properties of the axon could be represented by a model of a uniaxial crystal that was not only birefringent but also dichroic, its extinction coefficients and the angle of retardation being changed independently on excitation. Calculations with them yielded the resting retardation, which agreed well with those obtained by the Sénarmont's method, and the change in birefringence, which agreed well with the other calculated value derived from experiments using a quarter-wave plate. The results of the calculation confirmed the existence of the long-lasting birefringence change in the tetanically stimulated axon.     

Climate change and habitat destruction: a deadly anthropogenic cocktail

Climate change and habitat destruction are two of the greatest threats to global biodiversity. Lattice models have been used to investigate how hypothetical species with different characteristics respond to habitat loss. The main result shows that a sharp threshold in habitat availability exists below which a species rapidly becomes extinct. Here, a similar modelling approach is taken to establish what determines how species respond to climate change. A similar threshold exists for the rate of climate change as has been observed for habitat loss-patch occupancy remains high up to a critical rate of climate change, beyond which species extinction becomes likely. Habitat specialists, especially those of relatively poor colonizing ability are least able to keep pace with climate change. The interaction between climate change and habitat loss might be disastrous. During climate change, the habitat threshold occurs sooner. Similarly, species suffer more from climate change in a fragmented habitat.     

Prostaglandin dependence of membrane order changes during myogenesis in vitro

Myogenic differentiation in vitro involves at least three events at the cell surface: binding of prostaglandin to cells, cell-cell adhesion, and fusion of the myoblast membranes into syncytia. Previous work has suggested that binding of prostaglandin is causal to the change in cell-cell adhesion and that both are accompanied by a characteristic reorganization of the myoblast membrane detected as a transient increase in membrane order by electron paramagnetic resonance. We show here that this membrane order change, which reaches a maximum at 38 h of development in vitro, was the last membrane order change before bilayer fusion which begins several hours later. This membrane order change, which accompanies the change in cell-cell adhesion, was dependent on the availability of prostaglandin. In myoblasts maintained in indomethacin, where further differentiation is known to be blocked at the prostaglandin binding step, the membrane order change did not occur. However, if myoblasts are provided with exogenous prostaglandin, the membrane order change occurred and differentiation proceeded. The results indicate that the basis of the membrane order change was the reorganization of myoblast membranes to allow increased adhesion and prepare the membrane for bilayer fusion. They also demonstrate that, like the increase in myoblast adhesion, the membrane order change was dependent on prostaglandin being available to bind to its receptor.     

Conformational aspects of the acid-induced fusion mechanism of influenza virus hemagglutinin. Circular dichroism and fluorescence studies

Circular dichroism and tryptophan fluorescence spectroscopy have been used to investigate the structures of the influenza virus membrane glycoprotein hemagglutinin, acid-treated hemagglutinin, and fragments of hemagglutinin derived by proteolysis. The conformational change in hemagglutinin which occurs at the pH of membrane fusion (pH 5-6) was associated with a significant change of the environment of tyrosine residues, a change in the environment of tryptophan residues, but no changes in secondary structure. Tryptic digestion of the hemagglutinin in its low pH conformation which releases one of the subunit polypeptides (HA1) caused minimal changes in tyrosine and tryptophan environments but a small secondary structural change in HA1. The secondary structure of the remainder of the molecule (HA2) was very similar to that predicted from the known x-ray crystallographic structure of the native molecule. However, fluorescence spectroscopy indicated a tertiary change in structure in the coiled coil of alpha-helices which form the fibrous central stem of the molecule. These results are consistent with a conformational change required for membrane fusion which involves a decrease of HA1/HA1, HA1/HA2 interactions and changes in tertiary structure not accompanied by changes in secondary structure.     

Waders in winter: long-term changes of migratory bird assemblages facing climate change

Effects of climate change on species occupying distinct areas during their life cycle are still unclear. Moreover, although effects of climate change have widely been studied at the species level, less is known about community responses. Here, we test whether and how the composition of wader (Charadrii) assemblages, breeding in high latitude and wintering from Europe to Africa, is affected by climate change over 33 years. We calculated the temporal trend in the community temperature index (CTI), which measures the balance between cold and hot dwellers present in species assemblages. We found a steep increase in the CTI, which reflects a profound change in assemblage composition in response to recent climate change. This study provides, to our knowledge, the first evidence of a strong community response of migratory species to climate change in their wintering areas.     

Single species dynamics under climate change

We propose a general mathematical model describing the growth and dispersal of a single species living in a 1-D spatially discrete array of habitat patches affected by a sustained and directional change in climate. Our model accounts for two important characteristics of the climate change phenomenon: (1) Scale dependency: different species may perceive the change in the environment as occurring at different rates because they perceive the environment at different scales, and (2) measure dependency: different species measure the environment differently in the sense that they may be sensible to or cue in on different aspects of it (e.g., maximum temperature, minimum temperature, accumulated temperature) which is associated with their physiological, ecological, and life history attributes, which renders some characteristics of the environment more biologically relevant than others. We show that the deterioration in the quality of habitable patches as a consequence of climate change drives the species to extinction when dispersal is not possible; otherwise, we proof and provide a numerical example that, depending on the velocity of climate change, the scale at which a species measures it, and the particular attribute of the environment that is more biologically relevant to the species under analysis, there is always a migration strategy that allows the persistence of the species such that it tracks its niche conditions through space, thus shifting its geographic range. Our mathematical analysis provides a general framework to analyze species’ responses to climate change as a relational property of a given species in interaction with a change in climate. In particular, we can analyze the persistence of species by taking into account the ways in which they measure and filter the environment. Indeed, one of our main conclusions is that there is not a single climate change but many, as it depends on the interaction between a particular species and climate. Thus, the problem is more complex than assumed by analytically tractable models of species responses to climate change.     

Normal modes of prion proteins: from native to infectious particle

Prion proteins (PrP) are the infectious agent in transmissible spongiform encephalopathies (i.e., mad cow disease). To be infectious, prion proteins must undergo a conformational change involving a decrease in α-helical content along with an increase in β-strand content. This conformational change was evaluated by means of elastic normal modes. Elastic normal modes show a diminution of two α-helices by one and two residues, as well as an extension of two β-strands by three residues each, which could instigate the conformational change. The conformational change occurs in a region that is compatible with immunological studies, and it is observed more frequently in mutant prions that are prone to conversion than in wild-type prions because of differences in their starting structures, which are amplified through normal modes. These findings are valuable for our comprehension of the conversion mechanism associated with the conformational change in prion proteins.     

A study on the enthalpy-entropy compensation in protein unfolding

A large number of thermodynamic data including the free energy, enthalpy, entropy, and heat capacity changes were collected for the denaturation of various proteins. Regression indicated that remarkable enthalpy-entropy compensation occurred in protein unfolding, which meant that the change in enthalpy was almost compensated by a corresponding change in entropy resulting in a smaller net free energy change. This behavior was proposed to result from the water molecule reorganization, which contributed significantly to the enthalpy and entropy changes but little to the free energy change in protein unfolding. It turned out that the enthalpy-entropy compensation could provide novel insights into the problem of enthalpy and entropy convergence in protein unfolding.     

Characterization of the folding and unfolding reactions of single-chain monellin: evidence for multiple intermediates and competing pathways

The mechanisms of folding and unfolding of the small plant protein monellin have been delineated in detail. For this study, a single-chain variant of the natively two-chain monellin, MNEI, was used, in which the C terminus of chain B was connected to the N terminus of chain A by a Gly-Phe linker. Equilibrium guanidine hydrochloride (GdnHCl)-induced unfolding experiments failed to detect any partially folded intermediate that is stable enough to be populated at equilibrium to a significant extent. Kinetic experiments in which the refolding of GdnHCl-unfolded protein was monitored by measurement of the change in the intrinsic tryptophan fluorescence of the protein indicated the accumulation of three transient partially structured folding intermediates. The fluorescence change occurred in three kinetic phases: very fast, fast, and slow. It appears that the fast and slow changes in fluorescence occur on competing folding pathways originating from one unfolded form and that the very fast change in fluorescence occurs on a third parallel pathway originating from a second unfolded form of the protein. Kinetic experiments in which the refolding of alkali-unfolded protein was monitored by the change in the fluorescence of the hydrophobic dye 8-anilino-1-naphthalenesulfonic acid (ANS), consequent to the dye binding to the refolding protein, as well as by the change in intrinsic tryptophan fluorescence, not only confirmed the presence of the three kinetic intermediates but also indicated the accumulation of one or more early intermediates at a few milliseconds of refolding. These experiments also exposed a very slow kinetic phase of refolding, which was silent to any change in the intrinsic tryptophan fluorescence of the protein. Hence, the spectroscopic studies indicated that refolding of single-chain monellin occurs in five distinct kinetic phases. Double-jump, interrupted-folding experiments, in which the accumulation of folding intermediates and native protein during the folding process could be determined quantitatively by an unfolding assay, indicated that the fast phase of fluorescence change corresponds to the accumulation of two intermediates of differing stabilities on competing folding pathways. They also indicated that the very slow kinetic phase of refolding, identified by ANS binding, corresponds to the formation of native protein. Kinetic experiments in which the unfolding of native protein in GdnHCl was monitored by the change in intrinsic tryptophan fluorescence indicated that this change occurs in two kinetic phases. Double-jump, interrupted-unfolding experiments, in which the accumulation of unfolding intermediates and native protein during the unfolding process could be determined quantitatively by a refolding assay, indicated that the fast unfolding phase corresponds to the formation of fully unfolded protein via one unfolding pathway and that the slow unfolding phase corresponds to a separate unfolding pathway populated by partially unfolded intermediates. It is shown that the unfolded form produced by the fast unfolding pathway is the one which gives rise to the very fast folding pathway and that the unfolded form produced by the slower unfolding pathway is the one which gives rise to the slow and fast folding pathways.     

Temperature dependence of cholesterol binding to cytochrome P-450scc of the rat adrenal. Effect of adrenocorticotropic hormone and cycloheximide.

A type I absorbance change is observed in suspensions of adrenal cortical mitochondria as the temperature is increased from 0-22 degrees. This "heat-generated" type I absorbance change is similar in magnitude to the pregnenolone-induced type II absorbance change of these mitochondria. Studies with inhibitors of cholesterol side chain cleavage indicate that the heat-generated type I absorbance change represents the specific interaction of cytochrome P-450scc with endogenous cholesterol in the mitochondria. This finding is confirmed by low temperature EPR spectroscopy on temperature-equilibrated, quick frozen adrenal mitochondrial samples. The EPR resonance at g = 8.2, which is that of the high spin cholesterol-bound cytochrome P-450scc, is absent in the samples incubated at 0 degrees and increases in magnitude with increasing temperature of incubation. Studies of the pH dependence of the heat-generated type I and pregnenolone-induced type II absorbance changes reveal that both are diminished by increasing pH over the range 6 to 8. Adrenocorticotropic hormone (ACTH) treatment of rats results in adrenal mitochondria which show a greatly increased heat-generated type I absorbance change. The latter correlates with an increased pregnenolone-induced type II absorbance change and increased EPR g = 8.2 signal. Prior treatment of animals with cycloheximide eliminated the ACTH-induced increase in the heat-generated type I absorbance change, the pregnenolone-induced type II absorbance change and the EPR g = 8.2 signal. We estimate that the hydrophobic bonding of cholesterol to cytochrome P-450scc occurs with a deltaH0' of approximately +15 kcal/mol and a deltaS0' of approximately +55 cal/mol deg. Our data support the concept of a labile protein which participates directly in this process.     

Attentive and pre-attentive processes in change detection and identification

In studies of change blindness, observers often have the phenomenological impression that the blindness is overcome all at once, so that change detection, localization and identification apparently occur together. Three experiments are described that explore dissociations between these processes using a discrete trial procedure in which 2 visual frames are presented sequentially with no intervening inter-frame-interval. The results reveal that change detection and localization are essentially perfect under these conditions regardless of the number of elements in the display, which is consistent with the idea that change detection and localization are mediated by pre-attentive parallel processes.In contrast, identification accuracy for an item before it changes is generally poor, and is heavily dependent on the number of items displayed. Identification accuracy after a change is substantially better, but depends on the new item's duration. This suggests that the change captures attention, which substantially enhances the likelihood of correctly identifying the new item. However, the results also reveal a limited capacity to identify unattended items. Specifically, we provide evidence that strongly suggests that, at least under these conditions, observers were able to identify two items without focused attention. Our results further suggest that spatial pre-cues that attract attention to an item before the change occurs simply ensure that the cued item is one of the two whose identity is encoded.     

气候变化背景下野生动物脆弱性评估方法研究进展

脆弱性评估是研究气候变化影响野生动物的重要内容,识别野生动物脆弱性,是适应和减缓气候变化影响的关键和基础。开展气候变化背景下野生动物的脆弱性评估工作,目的是为了确定易受气候变化影响的物种和明确导致物种脆弱性的因素,其评估结果有助于人类认识气候变化对野生动物的影响,为野生动物适应气候变化保护对策的制定提供科学依据。对野生动物而言(物种),脆弱性是物种受气候变化影响的程度,包括暴露度、敏感性和适应能力三大要素。其中,暴露度是由气候变化引起的外在因素,如温度、降雨量、极值天气等;敏感性是受物种自身因素影响,如种间关系、耐受性等;适应能力是物种通过自身调整来减小气候变化带来的影响,如迁移或扩散到适宜生境的能力、塑性反应和进化反应等。对近期有关气候变化背景下野生动物脆弱性评估方法予以综述,比较每种评估方法所选取指标的差异,总结在脆弱性评估中遇到的不确定性指标的处理方法,以及脆弱性评估结果在野生动物适应气候变化对策中的应用。通过总结野生动物脆弱性评估方法,以期为气候变化背景下评估我国野生动物资源的脆弱性提供参考方法。     

A multi-modeling approach to evaluating climate and land use change impacts in a Great Lakes River Basin

River ecosystems are driven by linked physical, chemical, and biological subsystems, which operate over different temporal and spatial domains. This complexity increases uncertainty in ecological forecasts, and impedes preparation for the ecological consequences of climate change. We describe a recently developed “multi-modeling” system for ecological forecasting in a 7600 km² watershed in the North American Great Lakes Basin. Using a series of linked land cover, climate, hydrologic, hydraulic, thermal, loading, and biological response models, we examined how changes in both land cover and climate may interact to shape the habitat suitability of river segments for common sport fishes and alter patterns of biological integrity. In scenario-based modeling, both climate and land use change altered multiple ecosystem properties. Because water temperature has a controlling influence on species distributions, sport fishes were overall more sensitive to climate change than to land cover change. However, community-based biological integrity metrics were more sensitive to land use change than climate change; as were nutrient export rates. We discuss the implications of this result for regional preparations for climate change adaptation, and the extent to which the result may be constrained by our modeling methodology.     

Visual processing levels revealed by response latencies to changes in different visual attributes.

Visual latencies, and their variation with stimulus attributes, can provide information about the level in the visual system at which different attributes of the image are analysed, and decisions about them made. A change in the colour, structure or movement of a visual stimulus brings about a highly reproducible transient constriction of the pupil that probably depends on visual cortical mechanisms. We measured this transient response to changes in several attributes of visual stimuli, and also measured manual reaction times to the same stimulus changes. Through analysis of latencies, we hoped to establish whether changes in different stimulus attributes were processed by mechanisms at the same or different levels in the visual pathway. Pupil responses to a change in spatial structure or colour are almost identical, but both are ca. 40 ms slower than those to a change in light flux, which are thought to depend largely on subcortical pathways. Manual reaction times to a change in spatial structure or colour, or to the onset of coherent movement, differ reliably, and all are longer than the reaction time to a change in light flux. On average, observers take 184 ms to detect a change in light flux, 6 ms more to detect the onset of a grating, 30 ms more to detect a change in colour, and 37 ms more to detect the onset of coherent motion. The pattern of latency variation for pupil responses and reaction times suggests that the mechanisms that trigger the responses lie at different levels in cortex. Given our present knowledge of visual cortical organization, the long reaction time to the change in motion is surprising. The range of reaction times across different stimuli is consistent with decisions about the onset of a grating being made in V1 and decisions about the change in colour or change in motion being made in V4.