TNFA -308G>A and -238G>A polymorphisms and risk to systemic sclerosis: impact on TNF-α serum levels,TNFA mRNA expression,and autoantibodies

Clinical and Experimental Medicine - Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, characterized by chronic inflammation and fibrosis, which are processes associated...     

Chemotherapy of Chagas’ disease: the how and the why

Current developments in experimental chemotherapy of Chagas’ disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (inhibitors of sterol C14α demethylase), with particular selectivity against Trypanosoma cruzi and special pharmacokinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitological cure of this disease in its chronic phase. We also discuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas’ disease. Although previous studies have suggested an important autoimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed immunological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a positive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for chagasic cardiomyopathy and confirm the importance of specific etiological treatment in the management of chronic chagasic patients. Received: 30 March 1998 / Accepted: 6 November 1998     

Stephen Paget and the ‘seed and soil’ theory of metastatic dissemination

Abstract The outcome of cancer metastasis depends on multiple interactions between selected metastatic cells and homeostatic mechanisms unique to some organ microenvironments. The English surgeon Stephen Paget (1855–1926) is credited with being the first to postulate the important role played by microenvironment in metastasis formation. The concept of his ‘seed and soil’ theory has been supported and confirmed by numerous publications. This review article summarises the most important literature data about this matter.     

On the relations between affordance and representation of the agent’s effector

The present study aimed to determine whether the representation of object affordances requires specification of the effector potentially interacting with the object: specifically, in this study, vision of the interacting hand. In Experiment 1 we used an apparatus by which a fruit to be reached and grasped was identified by word reading, whereas another (interfering) fruit was visually perceived at the same location as the target. The apparatus allowed visual presentation of the agent’s interacting hand or prevented it. When visually presented, the hand was perceived as still at the start position even when it moved to grasp the fruit. An interference effect on the grasp congruent with the distractor size was observed only when the hand was visible. In Experiment 2, interference was observed also when a hand different from the agent’s own was visually presented. In both Experiments 1 and 2 the visible fruit interfered with the arm’s reach, but the effect was independent of its size and less dependent on the visually-presented hand. A control experiment (Experiment 3) enabled comparison of the interference of visual stimuli on targets identified by word reading (Experiments 1 and 2) with that of objects identified by word reading on visually-presented targets (Experiment 3). The interference induced by visual stimuli was stronger than the interference induced by objects identified by words (i.e. affordances evoked by visual stimuli were stronger than affordances evoked by semantics). Taken together, the results of the present study suggest that the specification of the agent’s effector is necessary for the elicitation of affordances. However, the elicitation of these affordances was observed for interactions between object and hand (grasp), rather than for interactions between object and arm (reach). Finally, our data confirm the influence of semantics on the control of arm movements, though less strong than that due to visual input.     

Oxidative stress and the pathogenesis of scleroderma: the Murrell’s hypothesis revisited

Systemic sclerosis (SSc, scleroderma) is a devastating, immune-mediated, multisystem disorder characterized by microvasculature damage, circulating autoantibodies, and fibroblast activation, leading to massive fibrosis of skin, vessels, muscles, and visceral organs. Scleroderma causes disability and death as the result of end-stage organ failure. At present, no specific diagnostic nor therapeutic tools are available to handle the disease. In spite of significant effort, the etiology and pathogenesis of SSc remain obscure and, consequently, the disease outcome is unpredictable. Several years ago, Murrell suggested a unifying hypothesis linking the pathogenesis of scleroderma to the generation of a large excess of reactive oxygen species. This hypothesis has been substantiated by several reports indicating the presence of an abnormal redox state in patients with scleroderma. This review will summarize the available evidence supporting the link between free radicals and the main pathological features of scleroderma.     

‘Alternate-goal bias’ in antisaccades and the influence of expectation

Saccadic performance depends on the requirements of the current trial, but also may be influenced by other trials in the same experiment. This effect of trial context has been investigated most for saccadic error rate and reaction time but seldom for the positional accuracy of saccadic landing points. We investigated whether the direction of saccades towards one goal is affected by the location of a second goal used in other trials in the same experimental block. In our first experiment, landing points (‘endpoints’) of antisaccades but not prosaccades were shifted towards the location of the alternate goal. This spatial bias decreased with increasing angular separation between the current and alternative goals. In a second experiment, we explored whether expectancy about the goal location was responsible for the biasing of the saccadic endpoint. For this, we used a condition where the saccadic goal randomly changed from one trial to the next between locations on, above or below the horizontal meridian. We modulated the prior probability of the alternate-goal location by showing cues prior to stimulus onset. The results showed that expectation about the possible positions of the saccadic goal is sufficient to bias saccadic endpoints and can account for at least part of this phenomenon of ‘alternate-goal bias’.     

Effects of the model’s handedness and observer’s viewpoint on observational learning

Observation promotes motor skill learning. However, little is known about the type of model and conditions of observation that can optimize learning. In this study, we investigated the effects of the model’s handedness and the observer’s viewpoint on the learning of a complex spatiotemporal task. Four groups of right-handed participants observed, from either a first- or third-person viewpoint, right- or left-handed models performing the task. Observation resulted in significant learning. More importantly, observation of same-handed models resulted in improved learning as compared with observation of opposite-handed models, regardless of the observer’s viewpoint. This suggests that the action observation network (AON) is more sensitive to the model’s handedness than to the observer’s viewpoint. Our results are consistent with recent studies that suggest that the AON is linked to or involves sensorimotor regions of the brain that simulate motor programming as if the observed movement was performed with one’s own dominant hand.     

Clinical communication and the ‘triangle of care’ in mental health and deafness: Sign language interpreters’ perspectives

Objective To explore the processes by which therapeutic alliance develops in mental health consultations with Sign Language interpreters.Method Semi-structured interviews with 7 qualified interpreters were transcribed and analysed with interpretative phenomenological analysis.Results Two key themes were generated: (1) Nurturing the triangle of care, where the therapeutic process relied on collaboration, continuity, and trust; and (2) Shared vision and knowledge, in which participants felt misunderstood and unsupported; there was a lack of deaf awareness and clinicians appeared to feel deskilled.Conclusions Interpreters should be viewed as valued members of clinical teams and have access to clinical supervision so that they can be supported in interpreting emotional distressing content. Clinicians can aim to be collaborative with interpreters and improve their knowledge of mental health issues that are relevant to deaf people.Practice Implications An aide-memoire of the role and practicalities of working with SL interpreters should be developed and disseminated to relevant services to support collaborative working with clinicians. A core competence in SL interpreter training is reflexivity. This should be embedded in educational curricula and facilitated through clinical supervision. Funding by commissioning services should be subject to services being deaf aware and interpreters being mental health aware.     

Why do Alzheimer’s disease and Parkinson’s disease target the same neurons?

The puzzle is to explain how cerebral involvement in the sporadic forms of Alzheimer’s disease (AD) and Parkinson’s disease (PD) can target the same population of vulnerable neurons. These neurons are poorly-myelinated projection neurons, lack of myelin being associated with high metabolic demand, high oxygen consumption, and high baseline oxidative stress. Yet the two diseases are clearly separable, with different intracellular markers, different risk factors, and different patterns of subcortical involvement.A theory is developed to show how two different pathophysiologies can preferentially affect the same neurons. In the case of AD, the hypothesis is as follows: the so-called vascular risk factors of AD, which include hypertension, diabetes, hyperlipidemia, and smoking, are all associated with increased systemic extracellular oxidative stress. High extracellular oxidative stress synergizes with high baseline intracellular oxidative stress to cause the disease. In the case of PD, mitochondrial failure associated with normal aging leads to diminished energy production and increased leakage of reactive oxygen species from mitochondria, a process which preferentially targets neurons with high baseline oxidative stress. In one case, the extra oxidative stress comes from outside the cell and, in the other case, it comes from inside the cell, i.e. from mitochondria. There is also evidence that neurofibrillary tangles are a protective mechanism against extracellular oxidative stress and that α-synuclein is a marker for mitochondrial failure. The basic pathophysiological difference is that AD is caused by oxidative stress alone, whereas PD is caused by oxidative stress plus failure of energy production.     

How organ-specific is the migration of ‘naive’ and ‘memory’ T cells?

The concept that ‘naive’ T cells (CD4⁺CD45RA^hi) selectively migrate into lymphoid organs and ‘memory’ T cells (CD4⁺CD45R0^hi) migrate into nonlymphoid organs has been enthusiastically taken up by the scientific community. However, even today, this premise is based mainly on indirect evidence obtained in one species. Here, Jürgen Westermann and Reinhard Pabst argue that, in the light of recent data, the generalization of this concept was too early.     

Urine melatonin and citrate excretion during the elite swimmers’ training season

The objectives of the study were to evaluate the influence of a whole training season on 6-sulfatoxymelatonin (αMT6s) and citrate excretion in 12 elite swimmers. Urine samples were obtained (before bedtime and after waking up) at the beginning of the season, basic training, macrocycle I, tapering and macrocycle II stages. For αMT6s, at basic training, mainly with aerobic training, the evening concentrations were significantly lower (P < 0.01; P < 0.05) than at the beginning, tapering and macrocycle II stages. At macrocycle II stage, with the maximal training workload, the total sum (evening plus morning) was significantly higher (P < 0.05) than at the beginning, basic training and macrocycle I stages. The ratio (morning/evening) that represents the capacity to produce melatonin at night depending on the evening values at the basic training stage and the nocturnal increment at the macrocycle II stage were significantly higher (P < 0.01) than at all other stages. Citrate morning values at basic training and tapering stages were significantly lower (P < 0.01) than in the evening indicating that a metabolic recuperation took place. The total sum significantly decreased (P < 0.05) as the aerobic training progressed from the beginning to macrocycle I. The basic training ratio (morning/evening) was significantly lower compared to the beginning and macrocycle II stages, and the nocturnal increment was significantly higher (P < 0.05) compared to the beginning. Melatonin and citrate represent complementary markers that could be used to evaluate the assimilation of the training workload by noninvasive methods.     

Effects of the Ebbinghaus illusion on children’s perception and grasping

We investigated the development of the Ebbinghaus illusion in children’s perception and grasping. A previous study (Hanisch et al. 2001) had reported negative illusion effects on 5- to 12-year-olds’ grasping as compared to their perception. We attempted to replicate this finding and to test different hypotheses based on a direct influence of the context elements on the trajectories of the fingers which could explain this reversal of the illusion effects. For 5- to 7- and 9- to 11-year-olds we observed the classical illusion effects in perception. Illusion effects were perfectly similar for perception and grasping in 9- to 11-year-olds, while there was a non-significant trend toward smaller illusion effects in grasping for the 5- to 7-year-olds. This could be due to a slightly different effect of the illusion on younger children’s grasping. However, it seems clear that there are no qualitative changes, as a reversal of the illusion effects in grasping of younger children. Finally, we show that our grasping data conform well to the motor literature for children’s grasping, thereby strengthening our conclusions.     

Agency and Ownership are Independent Components of ‘Sensing the Self’ in the Auditory-Verbal Domain

’Sensing the self’ relies on the ability to distinguish self-generated from external stimuli. It requires functioning mechanisms to establish feelings of agency and ownership. Agency is defined causally, where the subjects action is followed by an effect. Ownership is defined by the features of the effect, independent from the action. In our study, we manipulated these qualities separately. 13 right-handed healthy individuals performed the experiment while 76-channel EEG was recorded. Stimuli consisted of visually presented words, read aloud by the subject. The experiment consisted of six conditions: (a) subjects saw a word, read it aloud, heard it in their own voice; (b) like a, but the word was heard in an unfamiliar voice; (c) subject heard a word in his/her own voice without speaking; (d) like c, but the word was heard in an unfamiliar voice; (e) like a, but subjects heard the word with a delay; (f) subjects read without hearing. ERPs and difference maps were computed for all conditions. Effects were analysed topographically. The N100 (86–172 ms) displayed significant main effects of agency and ownership. The topographies of the two effects shared little common variance, suggesting independent effects. Later effects (174–400 ms) of agency and ownership were topographically similar, suggesting common mechanisms. Replicating earlier studies, significant N100 suppression was observed, with a topography resembling the agency effect. ‘Sensing the self’ appears to recruit from at least two very distinct processes: an agency assessment that represents causality and an ownership assessment that compares stimulus features with memory content.     

Visual and somatosensory processing in the macaque temporal cortex: the role of ‘expectation’

Summary The somatosensory and visual properties of cells in a polymodal region of temporal cortex were studied in 4 awake behaving macaque monkeys. When stimulated passively and out of sight, cells with tactile responses were found to have very large receptive fields covering most of the body surface and an apparent lack of selectivity for size, shape or texture of the tactile stimulus. These properties are equivalent to those described for the anaesthetized preparation (Bruce et al. 1981). Our study revealed that tactile responses were influenced by the degree to which stimuli could be expected. Tactile stimulation arising from active exploration of novel surfaces produced vigourous neuronal responses but equivalent stimulation of the skin arising when the monkey contacted expected surfaces such as itself or items with which it had become familiar produced no responses. The responses of cells to active or passive tactile stimulation were attenuated when the monkey could see the objects causing the stimulation. For cells responsive to more than one sensory modality, visual and somatosensory responses were associated in a compatible manner. Cells responsive to the onset of touch were selective for the sight of objects moving towards the monkey, whereas cells selective for the offset of touch were responsive to the sight of movements away from the monkey.     

Parkinson’s disease and immune system: is the culprit LRRKing in the periphery?

Background

Gold nanoparticles (AuNPs) are finding increased use in therapeutics and imaging. However, their toxic effects still remain to be elucidated. Therefore this study was undertaken to study the biochemical effects of AuNPs on rat brain and identify potential biomarkers of AuNP toxicity.

Methods

Male Wister rats weighing 150?C200 g were injected with 20 ??g/kg body weight of 20-nm gold nanoparticles for 3 days through the intraperitoneal route. The rats were killed by carbon dioxide asphyxiation 24 h after the last dose of gold nanoparticle injection. The parameters studied included lipid peroxidation, glutathione peroxidase, 8- hydroxydeoxyguanosine, caspase-3, heat shock protein70, serotonin, dopamine, gamma amino-butyric acid and interferon-??.

Results

In this study AuNPs caused generation of oxidative stress and a decrease of antioxidant enzyme, viz., glutathione peroxidase activity in rat brain. This was accompanied by an increase in 8-hydroxydeoxyguanosine, caspase-3 and heat shock protein70, which might lead to DNA damage and cell death. Gold nanoparticles also caused a significant decrease in the levels of neurotransmitters like dopamine and serotonin, indicating a possible change in the behavior of the treated animals. There was a significant increase in the cerebral levels of IFN-?? in treated animals.

Conclusion

This study concludes that AuNPs cause generation of oxidative stress and an impairment of the antioxidant enzyme glutathione peroxidase in rat brain. AuNPs also cause generation of 8-hydroxydeoxyguanosine (8OHdG), caspase-3 and heat shock protein70 (Hsp70), and IFN-??, which may lead to inflammation and DNA damage/cell death.     

The good,the bad,and the contingency: How patients’ treatment verification behaviors are linked to doctors’ reactions

ObjectiveThis article introducesTreatment Verification Behavior (TVB) to conceptualize patient proactivity. The article also aims to examine doctors’ responses to patients’ TVBs.MethodsA doctor-patient paired, two-wave data set was collected from eight hospitals in North China. We collected data from 304 doctor-patient dyads with each doctor rating, on average, three inpatients.ResultsThe results show that when patients consulted their doctors about information regarding a diagnosis or treatment (i.e.,consulting TVB), it improved doctors’ perception of the patients’ ability, which further increased doctors’ work engagement. Alternatively, when patients challenged doctors about information regarding a diagnosis or treatment (i.e., challenging TVB), it induced doctors’ perception of threat but without significantly decreasing doctors’ work engagement. In addition, when doctors felt respected by patients, this feeling moderated the effects of patients’ TVBs on doctors’ reactions.ConclusionBoth the content (the “what”) and the manner (the “how”) of patients’ proactive communications with their doctors will influence doctors’ responses.Practice implicationsThese insights suggest that patient and doctor communication training should include components that address both the content and performance of communication.     

The effect of widowhood on husbands’ and wives’ physical activity: the cardiovascular health study

This prospective study examined the effect of widowhood on physical activity by comparing widowed elders to health status-, age-, and sex-matched married controls. Participants included 396 married controls and 396 widows/widowers age 64–91 (M age = 72.7 years) who experienced the death of their spouse while participating in the Cardiovascular Health Study. Compared to married controls, widowed men, but not women, were more likely to increase their physical activity following the death of their spouse. However, this increased level of activity was not sustained and declines as time since spousal death passes. Moreover, during the year before spousal death, soon-to-be widowed men, but not women, increase their physical activity. Our results suggest that widowed men experience significant changes in physical activity and that the transition to widowhood contribute to these changes.