Surrogate tissue analysis: monitoring toxicant exposure and health status of inaccessible tissues through the analysis of accessible tissues and cells

Genomics and proteomics have made it possible to define molecular physiology in exquisite detail, when tissues are accessible for sampling. However, many tissues are not accessible for human diagnostic evaluations or experimental studies, creating the need for surrogates that afford insight into exposures and effects in such tissues. Surrogate tissue analysis (STA) incorporating contemporary genomic and proteomic technologies may be useful in determining toxicant exposure and effect, or disease state, in target tissues at the pre- or early clinical stage. We present here a discussion of STA based on presentations given at the Society of Toxicology's 2003 annual meeting's "Innovations in Applied Toxicology" symposium. Speakers at the symposium (Box 1) discussed various potential applications of STA, including the use of peripheral blood lymphocytes (PBLs) as a source of genetic biomarkers to monitor radiation exposure; the use of gene expression analysis of PBLs and hair follicles as a means to monitor the impact of toxicants on inaccessible organs; the characterization of disease-associated gene signatures in peripheral blood mononuclear cells (PBMCs) of renal cell carcinoma (RCC) patients; the use of sperm RNA to determine genetic and environmental effects on sperm development in the testis; and the use of serum protein profiles to monitor the development and progression of various cancers. Also discussed are some of the challenges that must be overcome if the utility of STA is to be proven, and thus permit researchers to move this concept from the laboratory to the clinical environment.     

Understanding of Thought Bubbles as Mental Representations in Children with Autism: Implications for Theory of Mind

Standard false belief tasks indicate that normally developing children do not fully develop a theory of mind until the age of 4 years and that children with autism have an impaired theory of mind. Recent evidence, however, suggests that children as young as 3 years of age understand that thought bubbles depict mental representations and that these can be false. Twelve normally developing children and 11 children with autism were tested on a standard false belief task and a number of tasks that employed thought bubbles to represent mental states. While the majority of normally developing children and children with autism failed the standard false belief task, they understood that (i) thought bubbles represent thought, (ii) thought bubbles can be used to infer an unknown reality, (iii) thoughts can be different, and (iv) thoughts can be false. These results indicate that autistic children with a relatively low verbal mental age may be capable of understanding mental representations.     

Sleep characteristics in the turkey Meleagris gallopavo

Electrophysiological and behavioral characteristics of the states of vigilance were analyzed in chronically implanted specimens of the turkey Meleagris gallopavo (M. gallopavo). Five different states of vigilance were observed throughout the nyctohemeral period: active wakefulness (AW), quiet wakefulness (QW), drowsiness (D), slow wave sleep (SWS) and rapid eye movement (REM) sleep.These states exhibit characteristics similar to those described in other bird species. Sleep periods displayed a polyphasic distribution; however, they showed the tendency to concentrate between 2100 and 0900 h in spite of the fact that the recordings were carried out under constant illumination. Sleep period occupied 45.71% of the nyctohemeral cycle, 43.33% corresponded to SWS, while 2.38% to REM sleep. The average duration of the REM sleep phase was very short, lasting 7.7+/-0.55 s (mean+/-S.D.). In contrast, its frequency was very high with an average recurrence of 268+/-63 phases throughout the nyctohemeral cycle. The short duration of REM sleep phase presented by the turkey as by other bird species studied up to now may be dependent upon genetic factors shared by this group of vertebrates.     

Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment

OBJECTIVE: To evaluate the evidence for and against androgen insufficiency as a cause of sexual and other health-related problems in women and to make recommendations regarding definition, diagnosis, and assessment of androgen deficiency states in women. DESIGN: Evaluation of peer-review literature and consensus conference of international experts. SETTING: Multinational conference in the United States. PATIENT(S): Premenopausal and postmenopausal women with androgen deficiency. INTERVENTION(S): Evaluation of peer-review literature and development of consensus panel guidelines. RESULT(S): The term "female androgen insufficiency" was defined as consisting of a pattern of clinical symptoms in the presence of decreased bioavailable T and normal estrogen status. Currently available assays were found to be lacking in sensitivity and reliability at the lower ranges, and the need for an equilibrium dialysis measure was strongly emphasized. Causes of androgen insufficiency in women were classified as ovarian, adrenal, hypothalamic-pituitary, drug-related, and idiopathic. A simplified management algorithm and clinical guidelines were proposed to assist clinicians in diagnosis and assessment. Androgen replacement is currently available in several forms, although none has been approved for treatment of sexual dysfunction or other common symptoms of female androgen insufficiency. Potential risks associated with treatment were identified, and the need for informed consent and careful monitoring was noted. Finally, the panel identified key goals and priorities for future research. CONCLUSION(S): A new definition of androgen insufficiency in women has been proposed along with consensus-based guidelines for clinical assessment and diagnosis. A simplified management algorithm for women with low androgen in the presence of clinical symptoms and normal estrogen status has also been proposed.     

Influence of regular voluntary exercise on spontaneous and social stress-affected sleep in mice

To investigate the impact of regular physical exercise on sleep, we assessed sleep-wake behaviour in male C57BL/6N mice with and without long-term access (i.e. 4 weeks) to a running wheel. We studied sleep-wake behaviour during undisturbed conditions as well as after social stress. The exercising mice ran approximately 4 km/day, which affected their physical constitution, their spontaneous sleep-wake pattern and their endocrine and sleep responses to stress. When compared with the control mice, exercising animals had more muscle substance, less body fat and heavier adrenal glands. At baseline, exercising mice showed fewer, but longer-lasting, sleep episodes (indicating improved sleep consolidation) and less rapid-eye-movement sleep. In both control and exercising mice, mild social stress (elicited by a 15-min social conflict) evoked elevated plasma levels of adrenocorticotrophic hormone and corticosterone, an increase in non-rapid-eye-movement sleep, an enhancement of low-frequency activity in the electroencephalogram within non-rapid-eye-movement sleep (indicating increased sleep intensity) and a decrease in wakefulness. However, as compared with the control animals, exercising mice responded to social stress with higher corticosterone levels, but not adrenocorticotrophic hormone levels, suggesting an increased sensitivity of their adrenal glands to adrenocorticotrophic hormone. Moreover, in control mice, social stress increased rapid-eye-movement sleep in parallel to non-rapid-eye-movement sleep, whereas this stressor selectively decreased rapid-eye-movement sleep in exercising animals. Corticosterone is known to decrease rapid-eye-movement sleep. Therefore, changes in the regulation of the hypothalamic-pituitary-adrenocortical axis as a result of the long-term exercise may contribute to the observed differences in spontaneous and social stress-affected sleep. In conclusion, regular exercise appears to increase sleep quality and reverses the effects of mild social stress on rapid-eye-movement sleep.     

On the societal value of health care: what do we know about the person trade‐off technique?

The person trade-off (PTO) technique has been suggested as a means of eliciting social preferences for health care, both the valuation of health care interventions and, more recently, to inform on the weights that society may attach to other decision-making criteria (e.g. the severity of a patients pre-treatment condition). Given the increased attention afforded to the PTO technique, this review examines the current evidence to inform on the ability of the PTO to provide a measure of social preference. Applying criteria of practicality, reliability and validity to empirical and theoretical contributions to the PTO literature, the review finds that the technique has limited empirical support. Applications of the PTO have been in a largely experimental setting, the reliability of the PTO is unproven and the empirical validity of the technique, in terms its ability to reflect actual preferences, remains unclear. In the broader context of the valuation of health states or outcomes, all techniques are open to criticism. Given this position, the review finds support for the potential of the PTO in the assessment of the societal value of health care, and it supports further empirical inquiry on the PTO.     

The maturation of respiratory patterns in normal full term infants during the first six postnatal months. I: Sleep states and respiratory variability.

ABSTRACT. Four term healthy infants had their respiratory pattern monitored during a 2-hour afternoon nap recording period at monthly intervals up to six months of age. The time spent asleep significantly decreased with a marked reduction in active sleep (66% to 10%) while maintaining one long epoch of quiet sleep (mean 31 mins). Mean breathing rate at one week was higher in active sleep than quiet sleep (47 vs 41 breaths/min.) and decreased by 6 months in both sleep states (31 breaths/min. in both). Variability of breathing rate at 1 week was significantly increased in active sleep compared to quiet sleep and both decreased by 6 months. These findings confirm a significant maturational change in the respiratory pattern and variability of normal infants in the afternoon nap from 1 to 6 months.     

Sleep induced PO2-changes in preterm infants

In seven healthy preterm infants the transcutaneous PO₂ was measured during different sleep states. The tcPO₂ is lower during active sleep than during quiet sleep and shows a higher variability in active sleep. The incidence of apneic spells, which occur predominantly during active sleep, was not found to be correlated to tcPO₂ levels.Supported by the Deutsche Forschungsgemeinschaft, SFB 33This is a part of the thesis     

Intravenous infusion of Diazemuls® in the control of status-like epileptic seizures of different etiology

This report concerns three patients in whom continuous intravenous infusion of Diazemuls (diazepam dissolved in soya bean oil and emulsified) diluted in 5.5% glucose was used for the controlling of epileptic seizures (status). Diazemuls infusion was effective in one patient with complex partial status epilepticus; in another patient with convulsion secondary to a brain stem infarct, the convulsions were abolished; while only reduced jerking was achieved in the third patient suffering from myoclonic jerks caused by anoxic brain damage. Infusion time ranged from 15 to 33 h. The serum concentrations of diazepam obtained during the infusions were higher than recommended in the literature for treatment of status epilepticus, but could not be correlated to either clinical efficacy or infusion rate.