Evidence-based decision making and asthma in the internet age: the tools of the trade

At the dawn of the Information Age, the practice of evidence-based decision making (EBDM) is still hindered by many important barriers related to the decision makers, to the evidence per se or to the health system. Some of these barriers, particularly those related to the distillation, dissemination and packaging of research evidence, could be overcome by recent and ongoing developments in portable/wearable computers, internet appliances, multimedia and wireless broadband internet traffic. This article describes specific EBDM-related tools, with emphasis on internet-enabled "how to" books; and tools to improve the quality of reporting research, to formulate questions; to search for evidence; to access journals, systematic reviews and guidelines; to interact with organizations promoting EBDM; and to tailor evidence to individual cases. However, thinking that all barriers to the practice of EBDM could be solved by fancy information technology is naïve. Barriers related to the generation, interpretation, integration and use of the evidence demand more complex and perhaps unfeasible solutions, as overcoming them will require substantial changes in the structure of the health system, in the politics of science and in the way in which humans think and behave.     

Mechanisms of the anorexia of aging in the Brown Norway rat

Aging is associated with a loss of the ability to maintain homeostasis in response to physiologic and environmental disturbances. Age-related dysregulation of food intake and energy balance appears to be the result of impaired responsiveness of hypothalamic integrative circuitry to metabolic cues, which can lead to lack of appropriate food intake (the anorexia of aging) and thus to inappropriate weight loss in response to acute or chronic illness or other stressors. Using the Brown Norway (BN) male rat model, we have shown that old animals fail to appropriately increase food intake after the metabolic challenge of a 72 h fast, resulting in the failure to re-gain lost body weight upon refeeding. Leptin levels increase with adiposity and age, and remain elevated above levels of young animals even after a 72 h fast, suggesting that hyperleptinemia may be influencing the energy balance dysregulation. It is unclear whether this age-related response is due to a failure of the network of hypothalamic neurons to appropriately integrate hormonal and neural inputs, or due to a failure of the neurons to produce the appropriate neuropeptides. We hypothesize that sequential, age-related alterations in the expression patterns of neuropeptides that maintain melanocortinergic tone, and in the hormone mediators that inform the system of the state of energy balance, result in a diminished ability to maintain energy homeostasis with increasing age. We have undertaken a number of interventional approaches to test this hypothesis, including manipulations of the hormones ghrelin, insulin and testosterone, and direct application of neuropeptides to the central nervous system in these animals.     

Allergic cross-reactions between cat and pig serum albumin

After observing a patient allergic to cat dander and pork but devoid of other allergies, we prospectively screened patients known to be allergic to cat for a second sensitization to pork. After collecting the sera of 10 young patients found to contain specific IgE to cat dander and pork, we undertook this study to detect the possible cross-reactive allergen, define its molecular characteristics, and evaluate its clinical relevance. Through immunoblotting techniques, cat and porcine serum albumin were found to be jointly recognized molecules. These findings were further analyzed by specific anti-albumin IgE titrations and cross-inhibition experiments. Cat serum albumin cDNA was obtained from cat liver, and the corresponding amino acid sequence was deduced and compared to the known porcine and human serum albumin sequences. Inhibition experiments showed that the spectrum of IgE reactivity to cat serum albumin completely contained IgE reactivity to porcine serum albumin, suggesting that sensitization to cat was the primary event. In two cohorts of cat-allergic persons, the frequency of sensitization to cat serum albumin was found to lie between 14% and 23%. Sensitization to porcine albumin was found to lie between 3% and 10%. About 1/3 of these persons are likely to experience allergic symptoms in relation to pork consumption. Sensitization to cat serum albumin should be considered a useful marker of possible cross-sensitization not only to porcine serum albumin but also to other mammalian serum albumins.     

Essentially Winnicott: Creating Psychic Health

The authors of this paper recognize the paradox of identifying with the body of work of D. W. Winnicott as it was essential to his view that each analyst has to become the analyst s/he is or can be. This is to avoid the dead hand of conformity and falsity. Nevertheless his work continues to inspire creative use with its concern with health and those conditions for its development. Both authors find themselves committed to history taking, to needing and taking time, to a willingness to wait before interpreting, to a recognition that the self derives originally from a bodily state of unintegration, that the body remains significant for the expression of self‐states, to an understanding of aggression as not primarily associated with destructiveness, to attending to the state of mind in the analyst that encourages the establishment and maintenance of the analytic setting. Clinically their intention is to maintain a continuity within which psychic change can be facilitated, through an attention to the ongoing exchanges between both parties of the analytic relation. Several clinical examples are given from different settings to illustrate the presence of these tenets in their work.     

Perturbed step initiation in cerebellar subjects 1. Modifications of postural responses

Recent experiments in healthy subjects have demonstrated that automatic postural responses can be suppressed when subjects are instructed to step instead of maintain stance in response to the surface translation. The aim of the present study was to investigate the role of the cerebellum in coordinating this interaction between the central command to step and peripherally triggered automatic postural responses. Eight subjects with cerebellar degeneration and eight control subjects were instructed to either maintain stance or step forward in response to a backward translation. In order to determine whether prediction of perturbation amplitude assisted suppression of postural responses, three platform translations were presented in both a serial (predictable) and a random (unpredictable) order. Cerebellar subjects were able to suppress their initial postural responses to the same amount as control subjects when instructed to step forward in response to backward translations, despite their hypermetria and inability to scale responses to predictable perturbation amplitudes. Control, but not cerebellar, subjects scaled the size of their postural responses to predictable perturbation amplitudes. The perturbation amplitude, however, had no effect on the size of early automatic responses when they were suppressed by instruction to step. The size of the suppressed postural response was independent of predictability of perturbation amplitudes in both control and cerebellar subjects. The dynamic interaction between automatic postural responses to an external perturbation and anticipatory postural adjustments for step initiation seems independent of prediction of perturbation amplitude and the integrity of the cerebellum. Although cerebellar subjects show larger-than-normal magnitude and variability of postural responses and an inability to scale the size of responses to predictable perturbation amplitudes, the cerebellum does not seem to be critical for suppression of the early postural response with a centrally intended movement. Received: 2 September 1996 / Accepted: 18 August 1997     

The impact of dementia on self and identity: A systematic review

There is much debate in the literature as to the extent to which self and identity persist in people with dementia. The aim of this systematic review was to examine methods currently used to investigate self and identity in people with dementia, and the resulting evidence as to the persistence of self and identity throughout the course of the disease. Thirty-three studies were reviewed, which showed that many approaches have been taken to studying aspects of self and identity in dementia, including both quantitative and qualitative methods. This appears to be partly due to the differing underlying concepts of self that have been used as a basis for these studies. Consequently, results obtained from these studies are somewhat disparate, although it is possible to draw some tentative conclusions from the available evidence. Almost all of the studies suggest that there is at least some evidence for persistence of self in both the mild and moderate to severe stages of the illness, although many studies record some degree of deterioration in aspects of self or identity. Further research is required to clarify existing evidence and to address outstanding questions regarding self and identity in dementia.     

Blood Cell Interactions and Segregation in Flow

For more than a century, pioneering researchers have been using novel experimental and computational approaches to probe the mysteries of blood flow. Thanks to their efforts, we know that blood cells generally prefer to migrate to the axis of flow, that red and white cells segregate in flow, and that cell deformability and their tendency to reversibly aggregate contribute to the non-Newtonian nature of this unique fluid. All of these properties have beneficial physiological consequences, allowing blood to perform a variety of critical functions. Our current understanding of these unusual flow properties of blood have been made possible by the ingenuity and diligence of a number of researchers, including Harry Goldsmith, who developed novel technologies to visualize and quantify the flow of blood at the level of individual cells. Here we summarize efforts in our lab to continue this tradition and to further our understanding of how blood cells interact with each other and with the blood vessel wall.     

Understanding the pathogenesis of psoriasis, psoriatic arthritis, and autoimmunity via a fusion of molecular genetics and immunology

The goal of my laboratory is to understand the molecular genetics basis of the inflammatory skin disease psoriasis and associated psoriatic arthritis. In performing these studies my colleagues and I have begun to identify common pathways leading to autoimmunity as well, because some of the defective pathways leading to autoimmunity are the same in different autoimmune diseases. Some of these pathways are involved in determining the activation status of inflammatory cells in the resting state. Other pathways are likely to determine target organ specificity and will be unique to a particular disease. Our approaches rely on genetic studies with cases and families to identify the causative variants, and then functional studies to identify the role of these variants in the predisposition to psoriasis and autoimmunity. The advantage of genetics approaches to understanding diseases such as those of the immune system is that one can identify novel genes and pathways that were not previously suspected as being involved in either the immune system or tolerance.     

Animal Models Relevant to Schizophrenia and Autism: Validity and Limitations

Development of animal models is a crucial issue in biological psychiatry. Animal models provide the opportunity to decipher the relationships between the nervous system and behavior and they are an obligatory step for drug tests. Mouse models or rat models to a lesser extent could help to test for the implication of a gene using gene targeting or transfecting technologies. One of the main problem for the development of animal models is to define a marker of the psychiatric disorder. Several markers have been suggested for schizophrenia and autism, but for the moment no markers or etiopathogenic mechanisms have been identified for these disorders. We examined here animal models related to schizophrenia and autism and discussed their validity and limitations after first defining these two disorders and considering their similarities and differences. Animal models reviewed in this article test mainly behavioral dimensions or biological mechanisms related to autistic disorder or schizophrenia rather than providing specific categorical models of autism or schizophrenia. Furthermore, most of these studies focus on a behavioral dimension associated with an underlying biological mechanism, which does not correspond to the complexity of mental disorders. It could be useful to develop animal models relevant to schizophrenia or autism to test a behavioral profile associated with a biological profile. A multi-trait approach seems necessary to better understand multidimensional disorders such as schizophrenia and autism and their biological and clinical heterogeneity. Finally, animal models can help us to clarify complex mechanisms and to study relationships between biological and behavioral variables and their interactions with environmental factors. The main interest of animal models is to generate new pertinent hypotheses relevant to humans opening the path to innovative research. Edited by Gene Fisch     

Function and interaction of on and off transients in vision II. Neurophysiology

Summary Neuronal responses to interruptions of light stimuli were studied in 58 X-type and 7 Y-type LGN relay cells with intra- and extracellular recording techniques. The responses to interruption were then compared with responses to either appearing or disappearing light stimuli which had the same luminance and size as the interrupted stimulus. The extent to which responses to interruption differed from those to appearance and disappearance was studied as a function of the interstimulus interval (ISI), the duration of the stimulus before the interruption (t₁) and after the interruption (t₂). Responses to stimuli appearing after interruptions of up to 500 msec were weaker than those to appearance and disappearance. This difference decreased with increasing ISI. The difference between responses to appearance and interruption increased as t₂ decreased, and decreased as t₁ decreased. The reverse was true for the difference between responses to disappearance and interruption. Stimulation of the mesencephalic reticular formation consistently reduced the difference between responses to appearance and disappearance compared with those to interruption for all stimulus conditions.These results are discussed in the context of the psychophysical study presented in the preceding paper. It is shown that the neuronal reactions are reflected in detail by the ability of humans to detect appearances and disappearances that occur during interruptions. EPSP sequences recorded from LGN relay cells and relay cell responses conditioned by reticular stimulation suggest that the differentiation of responses to interruption and change partially occurs already in the retina. This differentiation is subsequently enhanced by antagonistic inhibition in the LGN. It is proposed that these inhibitory interactions at peripheral sites of the visual pathway store visual information and serve to reduce the redundancy of responses to short interruptions of the visual input. Centrifugal modulation of LGN inhibition is proposed to control the trade off between temporal integration and temporal resolution.This work was partially supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 50, Kybernetik.     

To What Does the Terminal Orienting Response Respond?

Previous authors suggested that the electrodermal orienting response to stimulus onset (OR) reflects cognitive processes related to the content of a stimulus while responses to stimulus offset (TOR) reflect processes related to stimulus duration. Experiment 1 tested the hypothesis that the OR and TOR are special cases of Ss responding to whatever part of the stimulus contains information necessary to make the requested judgment. The results clearly supported this alternative hypothesis. The Ss responded to stimulus onset when asked to judge the pitch (content) of a constant tone and to stimulus offset when asked to judge the terminal pitch of a varying tone. They responded to both the onset and offset of a stimulus when asked to compare the onset and offset pitch and when asked to judge stimulus duration. Experiment 2 partially replicated Experiment 1 in an attempt to assess the OR-TOR phenomenon in a second sensory modality (vision) and with a second dependent measure. The patterns of both electrodermal and heart rate responses were similar to those of Experiment 1 and to those observed by other authors.     

The ramification and connections of retinal fibres in layer 7 of the domestic chick optic tectum: a Golgi impregnation, anterograde tracer and GABA-immunogold study

Layer 7 is one of the retinorecipient layers of the avian optic tectum. However, little information is available about the neuronal organization of this layer and its implications for visual function. Golgi impregnation was used to investigate the retinal input to and the neuronal architecture of layer 7 of the chick optic tectum, which forms a narrow band between the two cell‐dense layers 6 and 8. Anterograde tracers were also used to investigate the afferent and efferent connections of layer 7, in both the light and the electron microscope, together with GABA immunogold labelling. Three types of radial neuron were defined according to the origin and course of their axons. The perikarya of these neurons were situated in tectal layers 10–11. The principal dendrites of these radial neurons ascended to the tectal surface and gave rise to dendritic side‐branches in layer 7. These dendritic side‐branches received asymmetric synapses from the terminations of retinal fibre arborisations. Type 2 radial neurons, whose axons arose from the deep pole of the perikaryon or occasionally from a basal dendrite, were shown to project to the nucleus isthmi pars magnocellularis, which has previously been demonstrated to be GABAergic and to project to glomerulus‐like complexes in tectal layers 4–5. In these layers, the dendritic branches of layer 13 neurons that project to the nucleus rotundus have previously been shown to receive retinal fibre input. Therefore, the retinal input to layer 7 may be able to modulate the transmission of information to the visual thalamus, by way of a feedback loop to layers 4–5 of the tectum involving the nucleus isthmi pars magnocellularis.     

Distinguishing between adverse and non-adverse effects – Session summary: Session Report from the Joint STP/IFSTP International Symposium “Toxicologic Pathology in the New Millenium” June 24–28, 2001, in Orlando, Florida

We in toxicologic pathology have to make decisions on various levels: Firstly, we decide whether there is a lesion, secondly we have to diagnose it and give it the appropriate name, thirdly we have to find out whether it is induced, fourthly to judge whether the lesion is adverse or non-adverse, and lastly decide whether the induced lesion has relevance to man. In this session we are concerned with the characterization of adverse and especially of non-adverse effects. We have to be able to distinguish between the two in toxicity studies to determine the non-adverse effect level (NOAEL). The NOAEL is needed to set the initial dose in phase I studies with regard to drugs and to calculate the admissible daily intake of environmental chemicals.Thus, the topic of our session is important for hazard identification and risk assessment. There is, however, a paucity of references in the literature specifically dealing with this issue. Therefore, the chairmen of this session were pleased that our session topic was accepted in the overall program, since there appears to be an urgent need to present and discuss this issue in a large international forum. The objective of this session is to give some guidance to toxicologic pathologists, study directors, and their colleagues in governmental agencies, on how to define non-adverse effects and to establish the NOAEL in toxicity studies.     

Effect of heating and enzymatic hydrolysis on casein cow milk sensitivity in Moroccan population

The objectives of the present work were first to evaluate the sensitivity to cow raw milk of the population of Fez, and then to study the effect of heating and pepsin hydrolysis on the allergenicity of casein. A cross-sectional study was carried out in Fez Hospitals, in which 1000 patients were recruited to establish a sera bank used to evaluate specific IgE to cow milk and to casein. Then, we evaluated the reaction of human IgE to heated and pepsin-hydrolysed casein. The results showed that 11.5% of the population studied self-reported reactions to foods. From them, 3.6% reported allergy to milk. Evaluation of specific IgE to cow raw milk showed that 11.9% of patients presented higher specific IgE levels. The treatments of casein indicated that both heating and pepsin hydrolysis totally decreased its binding on the human IgE.     

Responses of calves to acute stress: individual consistency and relations between behavioral and physiological measures

The present study examined the consistency over time of individual differences in behavioral and physiological responsiveness of calves to intuitively alarming test situations as well as the relationships between behavioral and physiological measures. Twenty Holstein Friesian heifer calves were individually subjected to the same series of two behavioral and two hypothalamo-pituitary-adrenocortical (HPA) axis reactivity tests at 3, 13 and 26 weeks of age. Novel environment (open field, OF) and novel object (NO) tests involved measurement of behavioral, plasma cortisol and heart rate responses. Plasma ACTH and/or cortisol response profiles were determined after administration of exogenous CRH and ACTH, respectively, in the HPA axis reactivity tests. Principal component analysis (PCA) was used to condense correlated measures within ages into principal components reflecting independent dimensions underlying the calves' reactivity. Cortisol responses to the OF and NO tests were positively associated with the latency to contact and negatively related to the time spent in contact with the NO. Individual differences in scores of a principal component summarizing this pattern of inter-correlations, as well as differences in separate measures of adrenocortical and behavioral reactivity in the OF and NO tests proved highly consistent over time. The cardiac response to confinement in a start box prior to the OF test was positively associated with the cortisol responses to the OF and NO tests at 26 weeks of age. HPA axis reactivity to ACTH or CRH was unrelated to adrenocortical and behavioral responses to novelty. These findings strongly suggest that the responsiveness of calves was mediated by stable individual characteristics. Correlated adrenocortical and behavioral responses to novelty may reflect underlying fearfulness, defining the individual's susceptibility to the elicitation of fear. Other independent characteristics mediating reactivity may include activity or coping style (related to locomotion) and underlying sociality (associated with vocalization).     

53例慢性髓系白血病细胞遗传学和bcr/abl融合基因检测

目的了解我院慢性粒细胞白血病(慢粒)染色体变异及融合基因表达与临床诊断和分期间的关系。方法染色体制备采用骨髓或外周血短期培养法,G显带,分析核型;融合基因检测则用逆转录-聚合酶链反应法(PCR法)。结果发现慢粒急变期的染色体,除具典型的Ph染色体外,还有 8、 9、i(16)q、i(17)q、-18等其它染色体改变。bcr/ab l融合基因显示慢粒急变期的患者,同时具有165bp和90bp扩增带。结论我们宜将细胞遗传学和PCR法结合,对慢粒白血病进行检测,即有助于对其诊断、预测急变、判断疗效及预后情况的深入了解。     

Unilateral striatal lesions in the cat disrupt well-learned motor plans in a GO/NO-GO reaching task

 We examined the changes in learned and spontaneous motor behavior after a unilateral excitotoxin lesion of the neostriatum. Cats were trained to perform a sensory-cued GO/NO-GO reaching task. Success rate, reaction time, movement speed and kinematic patterns were used to characterize motor system properties. In addition, motor properties before and after the lesion were compared by clinical neurological examinations and video tape observations of free-range behavior. We found that in normal animals motor performance in the task was fluent, highly automatic and skillful with consistent patterns from trial to trial and day to day. The striatal lesion resulted in a marked impairment in the animals’ ability to perform the automatic response to the sensory cues in the motor task. In contrast, sensorimotor behavior in contexts apart from the task was altered minimally, with changes that were often difficult to detect. The animals recovered their ability to perform the task gradually, although they never reached prelesion performance levels in up to 24 weeks of evaluation. The animals had difficulty making reaching movements in GO trials and, in NO-GO trials failures to withhold movements were more frequent. Failures were due to a specific inability to execute previously well-learned movements in response to cues and not to an inability to recognize and interpret the cues. The lesion effects were restricted to the automatic motor response to the learned cues, as the animals could make reaching movements to the target without obvious impairment in response to novel stimuli. They also made similar spontaneous movements apart from the motor task that appeared to be unimpaired. The unique motor style and strategies that characterized the behavior of individual animals prior to the lesion were still evident after the lesion, even though they were superimposed on lower success rates and slower movement speeds. Our findings suggest that the basal ganglia facilitate the fluent and rapid execution of sequences of well-learned sensorimotor behavior, but the representations of motor plans are not stored in the basal ganglia. Received: 19 December 1995 / Accepted: 29 July 1996     

The role of macrophages in optic nerve regeneration

Following injury to the nervous system, the activation of macrophages, microglia, and T-cells profoundly affects the ability of neurons to survive and to regenerate damaged axons. The primary visual pathway provides a well-defined model system for investigating the interactions between the immune system and the nervous system after neural injury. Following damage to the optic nerve in mice and rats, retinal ganglion cells, the projection neurons of the eye, normally fail to regenerate their axons and soon begin to die. Induction of an inflammatory response in the vitreous strongly enhances the survival of retinal ganglion cells and enables these cells to regenerate lengthy axons beyond the injury site. T cells modulate this response, whereas microglia are thought to contribute to the loss of retinal ganglion cells in this model and in certain ocular diseases. This review discusses the complex and sometimes paradoxical actions of blood-borne macrophages, resident microglia, and T-cells in determining the outcome of injury in the primary visual pathway.     

The error-related negativity is related to risk taking and empathy in young men

We related self-report measures of risk taking and empathy to the error-related negativity (ERN) elicited during a flanker task in boys in late adolescence. We found that risk propensity (risk taking, sensation seeking, and sensitivity to reward) and empathy related to ERN amplitude (negatively and positively, respectively) but not to each other or to behavioral measures of response time, accuracy, and post-error slowing. They accounted for separate sources of variance in the ERN amplitude, suggesting that there are multiple routes to activation of its generator in the anterior cingulate. Impulsivity and sensitivity to punishment were unrelated to the ERN. The present study provides support that risk-taking traits and empathy affect anterior cingulate responsiveness to errors, and the ERN reflects the influence of the extent of individuals' concern with the outcome of events.     

Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis

Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors.