Generalized semiparametrically structured ordinal models

Semiparametrically structured models are defined as a class of models for which the predictors may contain parametric parts, additive parts of covariates with an unspecified functional form, and interactions which are described as varying coefficients. In the case of an ordinal response the complexity of the predictor is determined by different sorts of effects. Global effects and category-specific effects are distinguished; the latter allow the effect to vary across response categories. A general framework is developed in which global as well as category-specific effects may have unspecified functional form. The framework extends various existing methods of modeling ordinal responses. The Wilkinson-Rogers notation is extended to incorporate smooth model parts and varying coefficient terms, the latter being important for the smooth specification of category-specific effects.     

The assessment of pesticide hazards to birds: the problem of variable effects

The hazard presented to birds by the use of a particular pesticide is dependent on many factors and may therefore vary in its severity. Even effects which occur very infrequently may sometimes be sufficiently severe to warrant regulatory action. The potential for variability is illustrated by the effects of carbophenothion on geese and of fenitrothion on forest songbirds. Potential for the movements and behaviour of birds to vary their exposure to pesticides is illustrated using data on Tree Sparrows Passer montanus and Brent Geese Branta bernicla . Methods used in the assessment of pesticide effects are reviewed, and their ability to cope with variability is discussed. Further research is required to extend understanding of the mechanisms which cause variability, and to assess the sensitivity of methods for monitoring the effects of pesticides during commercial use.     

Environmental endocrine disrupters dysregulate estrogen metabolism and Ca2+ homeostasis in fish and mammals via receptor-independent mechanisms

Xenoestrogen endocrine disrupters (EDs) in the environment are thought to be responsible for a number of examples of sexual dysfunction that have recently been reported in several species. There is growing concern that these compounds may also cause abnormalities of the male reproductive tract and reduced spermatogenesis in man. Whilst some effects of EDs may be receptor-mediated, there is growing evidence that these compounds can exert potent effects in vivo by directly interacting with cellular enzyme targets. Here we report on, and review, the effects of alkylphenols and other EDs on two such enzymes: (1) sulfotransferases, which convert active estrogenic steroids to inactive steroid sulfates; and (2) Ca(2+)-ATPases, which are responsible for maintaining low, physiological, intracellular Ca(2+) concentrations. These enzymes are potently inhibited by EDs in both fish and mammalian species. The increased concentrations of active estrogens and the likely cytotoxic effects of elevated concentrations of intracellular Ca(2+) arising from these effects may underlie some of the endocrine disrupting potential of these widespread industrial pollutants.     

Change in maternal environment induced by cross-fostering alters genetic and epigenetic effects on complex traits in mice

The interaction between maternally provided environment and offspring genotype is a major determinant of offspring development and fitness in many organisms. Recent research has demonstrated that not only genetic effects, but also epigenetic effects may be subject to modifications by the maternal environment. Genomic imprinting resulting in parent-of-origin-dependent gene expression is among the best studied of epigenetic effects. However, very little is known about the degree to which genomic imprinting effects can be modulated by the maternally provided environment, which has important implications for phenotypic plasticity. In this study, we investigated this unresolved question using a cross-fostering design in which mouse pups were nursed by either their own or an unrelated mother. We scanned the entire genome to search for quantitative trait loci whose effects depend on cross-fostering and detected 10 of such loci. Of the 10 loci, 4 showed imprinting by cross-foster interactions. In most cases, the interaction effect was due to the presence of an effect in either cross-fostered or non-cross-fostered animals. Our results demonstrate that genomic imprinting effects may often be modified by the maternal environment and that such interactions can impact key fitness-related traits suggesting a greater plasticity of genomic imprinting than previously assumed.     

Climate change in size-structured ecosystems

One important aspect of climate change is the increase in average temperature, which will not only have direct physiological effects on all species but also indirectly modifies abundances, interaction strengths, food-web topologies, community stability and functioning. In this theme issue, we highlight a novel pathway through which warming indirectly affects ecological communities: by changing their size structure (i.e. the body-size distributions). Warming can shift these distributions towards dominance of small- over large-bodied species. The conceptual, theoretical and empirical research described in this issue, in sum, suggests that effects of temperature may be dominated by changes in size structure, with relatively weak direct effects. For example, temperature effects via size structure have implications for top-down and bottom-up control in ecosystems and may ultimately yield novel communities. Moreover, scaling up effects of temperature and body size from physiology to the levels of populations, communities and ecosystems may provide a crucially important mechanistic approach for forecasting future consequences of global warming.     

Growth hormone and glucose homeostasis

Patients with active acromegaly are insulin-resistant and glucose-intolerant, whereas children with growth hormone (GH) deficiency (GHD) are insulin-sensitive and may develop fasting hypoglycaemia. Surprisingly, however, hypopituitary adults with unsubstituted GHD tend to be insulin-resistant, which may worsen during GH substitution. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favourable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycaemia and GH substitution may cause hyperglycaemia. Such untoward effects should be minimized by carefully monitoring the individual patient.     

The toxicology of cannabis and cannabis prohibition

The acute side effects caused by cannabis use are mainly related to psyche and cognition, and to circulation. Euphoria, anxiety, changes in sensory perception, impairment of memory and psychomotor performance are common effects after a dose is taken that exceeds an individually variable threshold. Cannabis consumption may increase heart rate and change blood pressure, which may have serious consequences in people with heart disease. Effects of chronic use may be induction of psychosis and development of dependency to the drug. Effects on cognitive abilities seem to be reversible after abstinence, except possibly in very heavy users. Cannabis exposure in utero may have negative consequences on brain development with subtle impairment of cognitive abilities in later life. Consequences of cannabis smoking may be similar to those of tobacco smoking and should be avoided. Use by young people has more detrimental effects than use by adults. There appear to be promising therapeutic uses of cannabis for a range of indications. Use of moderate doses in a therapeutic context is usually not associated with severe side effects. Current prohibition on cannabis use may also have harmful side effects for the individual and the society, while having little influence on prevalence of use. Harm is greatest for seriously ill people who may benefit from a treatment with cannabis. This makes it difficult to justify criminal penalties against patients.     

Vasospasm and platelet deposition in human arteries: effects of topical methylene blue

Vasodilation of small blood vessels is controlled in part by the endothelium-derived relaxing factor (EDRF), which also inhibits platelet adhesion. Methylene blue (MB), which is occasionally applied directly to blood vessels during microsurgery to provide orientation and prevent torsion, is an irreversible inhibitor of the effects of endothelium-derived relaxing factor and may thereby augment both vasospasm and platelet responses. We have investigated the effects of the extravascular adventitial application of methylene blue on platelet deposition to human placental arteries (HPA) in the presence and absence of surgically induced vasospasm. A trend toward increased platelet deposition to human placental arteries was seen in each group but did not reach significance. The degree of platelet deposition to control human placental arteries suggests that the effects of methylene blue on platelet deposition may be dwarfed by the effects of surgical trauma and ischemia.     

Updating the side effects of the penicillins

Use of the penicillins in patients may result in a variety of side effects in addition to the well known occasional allergic reactions. Some of these side effects may be quite serious. Treatment with the various penicillins, expecially in the large amounts presently prescribed, may be attended by immunologic reactions, such as nephritis, and by direct toxic effects which may involve the blood platelets, the neurones of the central nervous system, and perhaps the parenchymal cells of the liver.     

Nutritional programming of adult disease

Intrauterine and early neonatal life is a period of physiological plasticity, during which environmental influences may produce long-term effects. Both undernutrition and overnutrition during this period have been shown to change disease risk in adulthood. These effects are influenced by the type, timing and duration of inappropriate nutrition and by the previous nutritional environment and may not be reflected in changes in body size. An understanding of the interaction between nutrient imbalance and alteration of gene expression is likely to be the key to optimising future health outcomes.     

慢波睡眠的激素与细胞因子调节

慢波睡眠（ＳＷＳ）是最重要的睡眠成分。近年来的研究揭示：腹外侧视前区－结节乳头核（ＶＬＰＯ－ＴＭＮ）可能是睡眠－觉醒的中枢发生部位。基底前脑吻端前列腺素Ｄ２（ＰＧＤ２）敏感性睡眠促进区（ＰＧＤ２－ＳＰＺ）参与睡眠的皖控。ＰＧＤ２延长ＳＷＳ;前列腺素Ｅ２（ＰＧＥ２）延长觉醒,抑制ＳＷＳ和快动眼睡眠（ＲＥＭＳ）。ＳＷＳ与下丘脑－垂体－肾上腺皮质轴的活动呈负相关,与生长激素的分泌呈正相关。褪黑素（ｍｅｌ     

Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action

Although the predominant mechanism of intra-articular hyaluronan (hyaluronic acid) (HA) and hylans for the treatment of pain associated with knee osteoarthritis (OA) is unknown, in vivo, in vitro, and clinical studies demonstrate various physiological effects of exogenous HA. HA can reduce nerve impulses and nerve sensitivity associated with the pain of OA. In experimental OA, this glycosaminoglycan has protective effects on cartilage, which may be mediated by its molecular and cellular effects observed in vitro. Exogenous HA enhances chondrocyte HA and proteoglycan synthesis, reduces the production and activity of proinflammatory mediators and matrix metalloproteinases, and alters the behavior of immune cells. Many of the physiological effects of exogenous HA may be a function of its molecular weight. Several physiological effects probably contribute to the mechanisms by which HA and hylans exert their clinical effects in knee OA.     

The importance of metacommunity ecology for environmental assessment research in the freshwater realm

Most bioassessment programs rest on the assumption that species have different niches, and that abiotic environmental conditions and changes therein determine community structure. This assumption is thus equivalent to the species sorting perspective (i.e. that species differ in their responses to environmental variation) in metacommunity ecology. The degree to which basing bioassessment on the species sorting perspective is reasonable is likely to be related to the spatial extent of a study and the characteristics of the organism groups (e.g. dispersal ability) with which the effects of anthropogenic changes are assessed. Recent findings in metacommunity research have stressed that community structure is determined not only by local abiotic environmental conditions but also by biotic interactions and dispersal‐related effects. For example, dispersal limitation may prevent community structure recovery from the effects of a putative stressor, as organisms may not be able to disperse to all sites in a region. Mass effects (i.e. the presence of species in environmentally suboptimal sites due to high dispersal rates from environmentally suitable sites) may, in turn, obscure the effects of a stressor, as dispersal from source sites (e.g. an unaltered site) allows persistence at sink sites (e.g. an anthropogenically altered site). Better bioassessment should thus take both niche‐ and dispersal‐related processes simultaneously into consideration, which can be accomplished by explicitly modelling spatial location as a proxy for dispersal effects. Such an integrated approach should be included in bioassessment programs using general multivariate approaches, predictive modelling, and multimetric indices.     

Biofeedback of Heart Rate Variability and Related Physiology: A Critical Review

Low heart rate variability (HRV) characterizes several medical and psychological diseases. HRV biofeedback is a newly developed approach that may have some use for treating the array of disorders in which HRV is relatively low. This review critically appraises evidence for the effectiveness of HRV and related biofeedback across 14 studies in improving (1) HRV and baroreflex outcomes and (2) clinical outcomes. Results revealed that HRV biofeedback consistently effectuates acute improvements during biofeedback practice, whereas the presence of short-term and long-term carry-over effects is less clear. Some evidence suggests HRV biofeedback may result in long-term carry-over effects on baroreflex gain, which is an area most promising for future investigations. On the other hand, concerning clinical outcomes, there is ample evidence attesting to efficacy of HRV biofeedback. However, because clinical and physiological outcomes do not improve concurrently in all cases, the mechanism by which HRV biofeedback results in salutary effects in unclear. Considerations for the field in addressing shortcomings of the reviewed studies and advancing understanding of the way in which HRV biofeedback may improve physiological and clinical outcomes are offered in light of the reviewed evidence.     

A Bayesian Hierarchical Model for Classification with Selection of Functional Predictors

Summary In functional data classification, functional observations are often contaminated by various systematic effects, such as random batch effects caused by device artifacts, or fixed effects caused by sample‐related factors. These effects may lead to classification bias and thus should not be neglected. Another issue of concern is the selection of functions when predictors consist of multiple functions, some of which may be redundant. The above issues arise in a real data application where we use fluorescence spectroscopy to detect cervical precancer. In this article, we propose a Bayesian hierarchical model that takes into account random batch effects and selects effective functions among multiple functional predictors. Fixed effects or predictors in nonfunctional form are also included in the model. The dimension of the functional data is reduced through orthonormal basis expansion or functional principal components. For posterior sampling, we use a hybrid Metropolis–Hastings/Gibbs sampler, which suffers slow mixing. An evolutionary Monte Carlo algorithm is applied to improve the mixing. Simulation and real data application show that the proposed model provides accurate selection of functional predictors as well as good classification.     

Accounting for the causal basis of collinearity when measuring the effects of habitat loss versus habitat fragmentation

Collinearity among metrics of habitat loss and habitat fragmentation is typically treated as a nuisance in landscape ecology, and it is the norm to use statistical approaches that remove collinear information prior to estimating model parameters. However, collinearity may arise from causal relationships among landscape metrics and may therefore signal the occurrence of indirect effects (where one model predictor influences the response variable by driving changes in another influential predictor). Here we suggest that, far from being merely a statistical nuisance, collinearity may be crucial for accurately quantifying the effects of habitat loss versus habitat fragmentation. We use simulation modelling to create datasets of collinear landscape metrics in which collinearity arose from causal relationships, then test the ability of two statistical approaches to estimate the effects of these metrics on a simulated response variable: 1) multiple regression, which statistically removes collinearity, and was identified in a recent study as the best approach for estimating the effects of collinear landscape metrics (although this study did not account for any indirect effects implied by collinearity among metrics); and 2) path analysis, which accounts for the causal basis of collinearity. In agreement with this previous study, we found that multiple regression gave unbiased estimates of direct effects (effects not mediated by other model predictors). However, it gave biased estimates of total (direct + indirect) effects when indirect effects occurred. In contrast, path analysis reliably identified the causal basis of collinearity and gave unbiased estimates of direct, indirect, and total effects. We suggest that effective research on the impacts of habitat loss versus fragmentation will often require tools that can empirically test whether collinear landscape metrics are causally related, and if so, account for the indirect effects that these causal relationships imply. Path analysis, but not multiple regression, provides such a tool.     

Wnt signaling involvement in beta-amyloid-dependent neurodegeneration

Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-beta peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC publication No. 13. The need for biological risk assessment in reaching decisions about carcinogens

The prudent assumption that carcinogen bioassays in rodents predict for human carcinogenicity is examined. It is suggested that in certain cases, as for example the induction of tumors against a high incidence in controls, or in situations in which high dose toxicity may be a critical factor in the induction of cancer, the probability that animal bioassays predict for humans may be low. The term 'biological risk assessment' is introduced to describe that part of risk assessment concerned with the relevance of specific animal results to the induction of human cancer. Biological risk assessment, which is almost entirely dependent on an understanding of carcinogenesis mechanisms, is an important addition to present mathematical modeling used to predict the effects of animal carcinogens that have been demonstrated after high dose exposure, to the effects of the much smaller doses to which humans are perceived to be exposed. Evidence for the conclusions reached by biological risk assessment may sometimes be supported by a careful review of human epidemiological data.     

Adrenoceptors and the pharmacology of affective illness: a unifying theory

Based on recent clinical and preclinical research, it is theorized that antimanic and antidepressant effects of clinically available drugs can be produced through their actions on alpha-1 adrenoreceptor-mediated neurotransmission in the central nervous system. The theory suggests that final effects on alpha-1 mediated neurotransmission may be produced not only by drugs which have direct effects on the alpha-1 receptor or its second messenger, but also by drugs having effects on neurotransmitter systems such as acetylcholine, GABA, and serotonin, among others, which modulate the activity of central norepinephrine neurons or, via feedback mechanisms, by drugs having effects on adrenergic receptors other than the alpha-1 receptor itself.     

Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations

The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme silent information regulator 2/sirtuin 1 (SIRT1), prolongs life span in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired the acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased reactive oxygen species production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. The smoking-induced upregulation of inflammatory markers (ICAM-1, inducible nitric oxide synthase, IL-6, and TNF-alpha) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-kappaB activation and inflammatory gene expression in CAECs. In CAECs, the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas the overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted antiapoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus resveratrol and SIRT1 exert antioxidant, anti-inflammatory, and antiapoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its antiaging action in mammals and may be especially beneficial in pathophysiological conditions associated with accelerated vascular aging.