PARE0019 Adherence to therapy: a comparison between three patients populations with autoimmune inflammatory diseases

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Reassessing the approach to informed consent: The case of unrelated hematopoietic stem cell transplantation in adult thalassemia patients

Introduction: The informed consent process is the legal embodiment of the fundamental right of the individual to make decisions affecting his or her health., and the patient's permission is a crucial form of respect of freedom and dignity, it becomes extremely important to enhance the patient's understanding and recall of the information given by the physician. This statement acquires additional weight when the medical treatment proposed can potentially be detrimental or even fatal. This is the case of thalassemia patients pertaining to class 3 of the Pesaro classification where Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment. Unfortunately, this kind of intervention is burdened by an elevated transplantation-related mortality risk (TRM: all deaths considered related to transplantation), equal to 30% according to published reports. In thalassemia, the role of the patient in the informed consent process leading up to HSCT has not been fully investigated. This study investigated the hypothesis that information provided by physicians in the medical scenario of HSCT is not fully understood by patients and that misunderstanding and communication biases may affect the clinical decision-making process.Methods: A questionnaire was either mailed or given personally to 25 patients. A second questionnaire was administered to the 12 physicians attending the patients enrolled in this study. Descriptive statistics were used to evaluate the communication factors.Results: The results pointed out the difference between the risks communicated by physicians and the risks perceived by patients. Besides the study highlighted the mortality risk considered to be acceptable by patients and that considered to be acceptable by physicians.Conclusions: Several solutions have been suggested to reduce the gap between communicated and perceived data. A multi-disciplinary approach may possibly help to attenuate some aspects of communication bias. Several tools have also been proposed to fill or to attenuate the gap between communicated and perceived data. But the most important tool is the ability of the physician to comprehend the right place of conscious consent in the relationship with the patient

Allopregnanolone modulation of HPA axis function in the adult rat

Rationale GABAergic neuronal circuits regulate neuroendo- crine stress response, and the most potent positive endogenous modulator of GABAA receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABAA receptors; in addition, it also induces long-lasting changes in the expres- sion of specific GABAA receptor subunits in various brain regions, with consequent changes in receptor function. Objective The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differ- ences in allopregnanolone levels can influence general resilience. Results The results showed that there is an apparent correla- tion between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity. Conclusion The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders

Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat

Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-TH PROG) and 3 alpha,5 alpha-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin ( ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+/- 86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis

Changes in expression of the neuropeptide YY1 receptor gene in the medial amygdala of transgenic mice during pregnancy and after delivery

Long-term administration of progesterone or allopregnanolone was previously shown to increase Y-1 receptor gene expression in the medial amygdala of Y1R/LacZ transgenic mice, which harbor a construct comprising the murine Y-1 receptor gene promoter and a lacZ reporter. We have now investigated the effects of physiological fluctuations in the cerebrocortical concentrations of neuroactive steroids during pregnancy on Y1R/LacZ transgene expression by quantitative histochemical analysis of beta-galactosidase activity. Cerebrocortical concentrations of progesterone and its metabolites allopregnanolone and allotetrahydrodeoxycorticosterone were increased on day 18 of pregnancy and had returned to control values 2 days after delivery. Transgene expression in the medial amygdala was also increased on day 18 of pregnancy and had returned to control values 2 days after delivery. Similar results were obtained after analysis of Y1R mRNA levels in the medial amygdala of pregnant mice by in situ hybridization. Administration of the 5alpha-reductase inhibitor finasteride to pregnant mice prevented both the increase in the cerebrocortical concentrations of neuroactive steroids as well as the increase in transgene expression. These data suggest that fluctuations in the brain concentrations of endogenous neuroactive steroids during pregnancy are associated with changes in Y-1 receptor gene expression in the medial amygdala, further supporting a functional interaction between the GABAergic and NPY-Y-1 receptor systems

Anticipation and consumption of food each increase the concentration of neuroactive steroids in rat brain and plasma

Stressful stimuli and anxiogenic drugs increase the plasma and brain concentrations of neuroactive steroids. Moreover, in rats trained to consume their daily meal during a fixed period, the anticipation of food is associated with changes in the function of various neurotransmitter systems. We have now evaluated the effects of anticipation and consumption of food in such trained rats on the plasma and brain concentrations of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-TH PROG) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-TH DOC), two potent endogenous positive modulators of type A receptors for gamma-aminobutyric acid (GABA). The abundance of these neuroactive steroids was increased in both the cerebral cortex and plasma of the rats during both food anticipation and consumption. In contrast, the concentration of their precursor, progesterone, was increased in the brain only during food consumption, whereas it was increased in plasma only during food anticipation. Intraperitoneal administration of the selective agonist abecarnil (0.1 mg/kg) 40 min before food presentation prevented the increase in the brain levels of 3 alpha,5 alpha-TH PROG and 3 alpha,5 alpha-TH DOC during food anticipation but not that associated with consumption. The change in emotional state associated with food anticipation may thus result in an increase in the plasma and brain levels of 3 alpha,5 alpha-TH PROG and 3 alpha,5 alpha-TH DOC in a manner sensitive to the activation of GABA(A) receptor-mediated neurotransmission. A different mechanism, insensitive to activation of such transmission, may underlie the changes in the concentrations of these neuroactive steroids during food consumption. (c) 2006 Published by Elsevier Inc

Changes in neuroactive steroid content during social isolation stress modulate GABA(A) receptor plasticity and function

Rats deprived of social contact with other rats at a young age experience a form of prolonged stress that leads to long-lasting alteration in their behavior profile. This chronic stress paradigm is thus thought to be anxiogenic for these normally gregarious animals and their abnormal reactivity to environmental stimuli, when reared under this condition, is thought to be a product of prolonged stress. Neurochemical, molecular, and electrophysiological evidences demonstrate that social isolation is associated with alteration in the structure and function of GABA(A) receptors and suggest that endogenous content of the progesterone metabolite 3 alpha,5 alpha-TH PROG may be an important determinant in regulating brain excitability and sensitivity to stimuli and point out its possible role in psychiatric and neurological disorder. (c) 2007 Elsevier B.V. All rights reserved