The Equivalence Between Unit-Cell Twinning and Tiling in Icosahedral Quasicrystals.

It is shown that tiling in icosahedral quasicrystals can also be properly described by cyclic twinning at the unit cell level. The twinning operation is applied on the primitive prolate golden rhombohedra, which can be considered a result of a distorted face-centered cubic parent structure. The shape of the rhombohedra is determined by an exact space filling, resembling the forbidden five-fold rotational symmetry. Stacking of clusters, formed around multiply twinned rhombic hexecontahedra, keeps the rhombohedra of adjacent clusters in discrete relationships. Thus periodicities, interrelated as members of a Fibonacci series, are formed. The intergrown twins form no obvious twin boundaries and fill the space in combination with the oblate golden rhombohedra, formed between clusters in contact. Simulated diffraction patterns of the multiply twinned rhombohedra and the Fourier transform of an extended model structure are in full accord with the experimental diffraction patterns and can be indexed by means of three-dimensional crystallography. The alternative approach is fully compatible to the rather complicated descriptions in a hyper-space.

Chronic stress and Rosiglitazone increase indices of vascular stiffness in male rats.

Prolonged and/or frequent exposure to psychological stress responses may lead to deterioration of organs and tissues, predisposing to disease. In agreement with this, chronic psychosocial stress is linked to greater cardiovascular risk, including increased incidence of atherosclerosis, myocardial ischemia, coronary heart disease, and death. Thus the association between stress and cardiovascular dysfunction represents an important node for therapeutic intervention in cardiovascular disease. Here we report that 2weeks of chronic variable stress (CVS) increased indices of vascular stiffness, including increased collagen deposition in the aortic adventitia and increased resting pulse pressure, in male rats. Thus CVS may represent a useful rodent model for stress-associated CVD, especially for aging populations for which widening pulse pressure is a well-known risk factor. Additionally, we report that the thiazolidinedione Rosiglitazone (RSG) blunts chronic stress-associated increases in circulating corticosterone. Despite this, RSG was not protective against adverse cardiovascular outcomes associated with chronic stress. Rather RSG itself is associated with increased pulse pressure, and this is exacerbated by chronic stress-highlighting that chronic stress may represent an additional contributor to RSG-associated cardiovascular risk.

Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial.

Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]µg/l and 3.90 [10.1] µg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.

The medial prefrontal cortex: coordinator of autonomic, neuroendocrine and behavioural responses to stress.

Responding to real or potential threats in the environment requires the coordination of autonomic, neuroendocrine and behavioural processes to promote adaptation and survival. These diverging systems necessitate input from the limbic forebrain to integrate and modulate functional output in accordance with contextual demand. In the present review, we discuss the potential role of the medial prefrontal cortex (mPFC) as a coordinator of behavioural and physiological stress responses across multiple temporal and contextual domains. Furthermore, we highlight converging evidence from rodent and human research indicating the necessity of the mPFC for modulating physiological energetic systems to mobilise or limit energetic resources as needed to ultimately promote behavioural adaptation in the face of stress. We review the literature indicating that glucocorticoids act as one of the primary messengers in the reallocation of energetic resources having profound effects locally within the mPFC, as well as shaping how the mPFC acts within a network of brain structures to modulate responses to stress. Finally, we discuss how both rodent and human studies point toward a critical role of the mPFC in the coordination of anticipatory responses to stress and why this distinction is an important one to make in stress neurobiology.

Combined pituitary hormone deficiency: current and future status.

Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of POU1F1 human mutations responsible for a well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype-genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80-90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.

Novel aspects of glucocorticoid actions.

Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion.

Structural phase transition and related electronic properties in quasi-one-dimensional (NbSe4)(10/3)I.

The real crystal structure of the (NbSe4)(10/3)I charge density wave (CDW) compound is studied by simulation of the X-ray diffuse scattering. The average structure of the low-temperature twinned phase is determined and the phase transition is attributed to the formation of a CDW. The diffuse streaking, present in X-ray diffraction patterns above and below the transition at T = 282 K, is shown to be a projection of diffuse concentric rings perpendicular to the c* direction. The simulated patterns, based on a mismatch model between infinite NbSe4 chains, correlated by I atoms, are in good accordance with the experimental patterns. In addition to the experiments, the electronic properties of the high- and the low-temperature phases are calculated with the extended Hückel tight-binding method. The Fermi surfaces of the average structures above and below the phase transition appear very similar. Their shapes support a nesting instability and a CDW formation. The weak incommensurate CDW satellites, present below the phase transition, are at 100 K properly described by a modulation wavevector q = [0.06 (1), 0, 0.55 (1)].

Neural regulation of the stress response: glucocorticoid feedback mechanisms

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

Neural regulation of the stress response: glucocorticoid feedback mechanisms.

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback 'switch', control of the stress response requires a wide-reaching feedback 'network' that coordinates HPA activity to suit the overall needs of multiple body systems.

Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females.

Dysfunction in central glucocorticoid signaling is implicated in hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation and major depression. In comparison with men, women are twice as likely to suffer from depression and have heightened HPA axis responses to stress. We hypothesized that this striking increase in stress vulnerability in females may be because of sex differences in central glucocorticoid signaling. The current study tests the role of the forebrain type II glucocorticoid receptor (GR) on HPA axis function in female mice and depression-like behavior in both female and male mice. This was accomplished by using mice with selective deletion of GR in forebrain cortico-limbic sites including the prefrontal cortex, hippocampus, and basolateral amygdala (forebrain glucocorticoid receptor knockout mouse (FBGRKO)). In order to examine HPA axis function in female FBGRKO, we measured nadir, peak circadian and restraint-induced corticosterone concentrations in female FBGRKO. The data indicate that unlike male FBGRKO, basal and stress-induced corticosterone concentrations are not increased in female FBGRKO. Given the pronounced effect of central glucocorticoid signaling on mood, we also examined the necessity of corticolimbic GR on depression-like behavior with the sucrose preference and forced swim tests (FST) in male and female FBGRKO mice. Consistent with previous studies, male FBGRKO displayed increased depression-like behavior as indicated by greater immobility in the FST and decreased sucrose preference compared with littermate controls, effects that were not observed in females. Overall the findings indicate a marked sex difference in the function of forebrain GR on HPA axis regulation and depression-like behaviors, and may have implications for therapeutic approaches using GR-modulating drugs.

Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry.

Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress.

"Snacking" causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats.

A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n=10-13) with free access to water and chow were given additional twice-daily access to 4ml sucrose (30%) or water for 14days. Rats were subsequently tested for HPA responsiveness to an acute (20min) restraint stress at 1, 6 and 21days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala (BLA) and nucleus accumbens (NuAc). Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at 1day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the BLA and in the NuAc core. This HPA-dampening persisted through 21days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure.

Decreased glucose tolerance and plasma adiponectin:resistin ratio in a mouse model of post-traumatic stress disorder.

AIMS/HYPOTHESIS: Obesity and type 2 diabetes are among the most serious health pathologies worldwide. Stress has been proposed as a factor contributing to the development of these health risk factors; however, the underlying mechanisms that link stress to obesity and diabetes need to be further clarified. Here, we study in mice how chronic stress affects dietary consumption and how that relationship contributes to obesity and diabetes. METHODS: C57BL/6J mice were subjected to chronic variable stress (CVS) for 15 days and subsequently fed with a standard chow or high-fat diet. Food intake, body weight, respiratory quotient, energy expenditure and spontaneous physical activity were measured with a customised calorimetric system and body composition was measured with nuclear magnetic resonance. A glucose tolerance test was also applied and blood glucose levels were measured with a glucometer. Plasma levels of adiponectin and resistin were measured using Lincoplex kits. RESULTS: Mice under CVS and fed with a high-fat diet showed impaired glucose tolerance associated with low plasma adiponectin:resistin ratios. CONCLUSIONS/INTERPRETATION: This study demonstrates, in a novel mouse model, how post-traumatic stress disorder enhances vulnerability for impaired glucose metabolism in an energy-rich environment and proposes a potential adipokine-based mechanism.

Pinning of adsorbed cobalt atoms by defects embedded in the copper (111) surface.

Using a low-temperature scanning tunneling microscope (STM), we observe that Co adatoms are unusually strongly bound to a particular type of pinning centers on the Cu(111) surface. Using density-functional-theory calculations, the pinning centers are identified as Ag substitutional atoms embedded in the topmost atomic layer of the surface. These impurities are hardly detectable in the STM images as they have low topographic height and produce no standing-wave patterns. They do not affect the exchange coupling of the Co adsorbate with the substrate electrons; thus, the Kondo resonances measured on pinned and free Co adatoms show no detectable differences. Whereas free Co adatoms undergo significant surface diffusion already above 8 K, Ag-stabilized Co adatoms remain pinned up to 12.7 K.

Nongenomic actions of adrenal steroids in the central nervous system.

Mineralocorticoids and glucocorticoids are steroid hormones that are released by the adrenal cortex in response to stress and hydromineral imbalance. Historically, adrenocorticosteroid actions are attributed to effects on gene transcription. More recently, however, it has become clear that genome-independent pathways represent an important facet of adrenal steroid actions. These hormones exert nongenomic effects throughout the body, although a significant portion of their actions are specific to the central nervous system. These actions are mediated by a variety of signalling pathways, and lead to physiologically meaningful events in vitro and in vivo. We review the nongenomic effects of adrenal steroids in the central nervous system at the levels of behaviour, neural system activity, individual neurone activity and subcellular signalling activity. A clearer understanding of adrenal steroid activity in the central nervous system will lead to a better ability to treat human disease as well as reduce the side-effects of the steroid treatments already in use.

The medial amygdala modulates body weight but not neuroendocrine responses to chronic stress.

Stress pathologies such as depression and eating disorders (i.e. anorexia nervosa) are associated with amygdalar dysfunction, which are linked with hypothalamic-pituitary-adrenal axis (HPA) axis hyperactivity. The medial amygdaloid nucleus (MeA), a key output nucleus of the amygdaloid complex, promotes HPA axis activation to acute psychogenic stress and is in a prime position to mediate the deleterious effects of chronic stress on physiology and behaviour. The present study tests the hypothesis that the MeA is necessary for the development of maladaptive physiological changes caused by prolonged stress exposure. Male rats received bilateral ibotenate or sham lesions targeting the MeA and one half underwent 2 weeks of chronic variable stress (CVS) or served as home cage controls. Sixteen hours post CVS, all animals were exposed to an acute restraint challenge. CVS induced thymic involution, adrenal hypertrophy, and attenuated body weight gain and up-regulation of hypothalamic corticotrophin-releasing hormone mRNA expression. Consistent with previous literature, lesions of the MeA dampened stress-induced increases in corticosterone after 30 min of exposure to acute restraint stress. However, this effect was independent of CVS exposure, suggesting that the MeA may not be critical for modulating neuroendocrine responses after chronic HPA axis drive. Interestingly, lesion of the MeA modestly exaggerated the stress-induced attenuation of weight gain. Overall, the data obtained suggest that the MeA modulates the neuroendocrine responses to acute but not chronic stress. In addition, the data suggest that the MeA may be an important neural component for the control of body weight in the face of chronic stress.

Glial glucocorticoid receptors in aged Fisher 344 (F344) and F344/Brown Norway rats.

Glucocorticoid receptors (GR) regulate glial function, and changes in astrocyte gene expression are implicated in age-related pathology. We evaluated changes in astroglial GR expression in two strains of rats--Fisher 344 (F344; 4, 12 and 24 months) and F344/Brown Norway strain (F344/BN; 4, 12 and 30 months). In both strains basal levels of corticosterone were higher in the oldest groups of rats. Age-related increases in GR (+) astrocytes but not the percent of astrocytes expressing GR were observed in the hippocampus CA1 region in F344 rats. Age-related decreases in CA1 GR (+) astrocytes and the percentage of GR (+) astrocytes were observed in the F344/BN strain only. Similar strain-specific changes were observed in the dentate gyrus. In the hypothalamic paraventricular nucleus: (1) F344 rats exhibited significant decreases in the overall number of glial profiles with age, (2) F344/BN rats exhibited decreases in the numbers of GR (+) astrocytes with aging and (3) the proportion of GR (+) astrocytes decreased in older F344/BN, but not F344 rats. Overall, the data demonstrate age- and strain-related alterations in GR astrocytic expression that may explain unique phenotypic differences in brain function observed in both strains.

Chronic stress produces enduring decreases in novel stress-evoked c-fos mRNA expression in discrete brain regions of the rat.

Chronic stress produces numerous adaptations within the hypothalamic-pituitary-adrenal (HPA) axis that persist well after cessation of chronic stress. We previously demonstrated profound attenuation of HPA axis responses to novel environment 4-7 days following chronic stress. The present study tests the hypothesis that this HPA axis hyporesponsivity is associated with reductions in stress-evoked c-fos mRNA expression, a marker of neuronal activation, in discrete brain regions. Adult male Sprague-Dawley rats underwent 1 week of chronic variable stress (CVS), with unhandled rats serving as controls. Independent groups of control and CVS rats were exposed to novel environment at 16 h, 4 days, 7 days, or 30 days after CVS. Marked reductions of c-fos mRNA expression in the CVS group persisted for at least 30 days within the paraventricular nucleus of the hypothalamus, and for at least 1 week in rostroventrolateral septum and lateral hypothalamus. Lower levels of c-fos mRNA expression were observed at 16 h recovery in the ventrolateral medial preoptic area, basolateral amygdala, anterior cingulate cortex, and prelimbic cortex. The results demonstrate long-term alterations in neuronal activation within neurocircuits critical for regulation of physiological and psychological responses to stressors.

Ecological effects of diffuse mixed pollution are site-specific and require higher-tier risk assessment to improve site management decisions: a discussion paper.

Many Dutch ecosystems, whether terrestrial, aquatic or sediment-based, are diffusely polluted by mixtures of contaminants, whose concentrations often exceed regulatory Safe Values or other generic quality criteria. This situation has unclear consequences, especially when local authorities are confronted with such pollution. Water managers are frequently in doubt whether their water systems satisfy the criteria for 'Good Ecological Status' as defined in the EU's Water Framework Directive. In case of soils, soil users may wonder whether the soil is 'fit for use'. In case of nature conservation, the problem is that protected species might suffer from toxic stress. Official regulations in these cases call for appropriate action, but it is unclear whether the diffuse exposure causes adverse effects, and what the action should be. This paper proposes and discusses a site-oriented approach in the risk assessment of diffusely contaminated sites that can be used in addition to the compound-oriented policies from which the abovementioned generic quality criteria were derived. The site-oriented approach can be of help in reducing site-specific risks of diffuse contamination. Reflecting on the results of a large Dutch research effort in systems-oriented ecotoxicological effects, the conclusion is drawn that exposure and effects of diffuse pollution are site-specific in kind and magnitude, determined by the local combination of source-pathway-receptor issues, and often not clearly detectable (though often present). To assist in risk management, higher-tier methods can address various aspects, like addressing local mixture composition, bioavailability, and sensitivity of local species groups. Higher-tier risk assessment methods have as yet been developed mainly for cases of serious contamination, like for pesticide management and Risk-Based Land Management. For diffuse pollution, site-specific information can also be used to obtain site-specific exposure and impact information, while practical and ecology-based approaches can be introduced to obtain an integrated overview of the meaning of site contamination and to derive options for managing and reducing the local risks. These issues are discussed against the background of current major policy shifts, in The Netherlands and elsewhere, from a pollutant-oriented assessment to an additional ecological and site-oriented assessment. The latter is most clearly represented in the Good Ecological Status aim of the EU-Water Framework Directive. The paper assesses, integrates and discusses the results of the Dutch research effort in this policy context.