The antidepressant-like effect induced by the sigma(1) (sigma(1)) receptor agonist igmesine involves modulation of intracellular calcium mobilization

RATIONALE: Activation of the neuronal sigma(1) (sigma(1)) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, sigma(1) agonists modulate learning, response to stress and depression. In particular, the selective sigma(1) agonist igmesine reduced immobility in the forced swimming test. OBJECTIVES AND METHODS: We investigated the effect of modulators of Ca(2+) influx and mobilization, administered intracerebroventricularly at doses ineffective alone, on the igmesine effect. The tricyclic antidepressant desipramine was also studied for comparison. RESULTS: The calcium chelator EGTA blocked both igmesine and desipramine-induced decreases of immobility duration, indicating the importance of extracellular Ca(2+) influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the sigma(1) agonist effect. Verapamil, an L-type VDCC antagonist or omega-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (-)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca(2+) stores is involved selectively in the effect mediated by the sigma(1) receptor, since the membrane permeable intracellular Ca(2+) chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP(3)) receptor-sensitive Ca(2+) pools appeared primarily involved, rather than Ca(2+)/caffeine-sensitive Ca(2+) pools. Indeed, the InsP(3) receptor positive modulator bradykinin potentiated, whereas the InsP(3) receptor antagonist xestospongin C blocked the igmesine effect. The ryanodine receptor agonist caffeine failed to affect the efficacy of igmesine, whereas the antagonist ryanodine reduced it. CONCLUSIONS: The sigma(1) receptor-mediated behavioral effect is dependent not only on rapid Ca(2+) influx, as observed for a classical antidepressant, but also on intracellular Ca(2+) mobilization.     

Overcoming the limits of empathic concern: the case for availability and its application to the medical domain

Medicine, Health Care and Philosophy - Empathic concern is essential to our social lives because it motivates helping behavior. It has, however, well-known shortcomings such as its limitation in...     

The impact of left truncation of exposure in environmental case–control studies: evidence from breast cancer risk associated with airborne dioxin

European Journal of Epidemiology - In epidemiology, left-truncated data may bias exposure effect estimates. We analyzed the bias induced by left truncation in estimating breast cancer risk...     

General practitioners’ preferences with regard to colorectal cancer screening organisation Colon cancer screening medico-legal aspects

Objective

French health authorities put general practitioners at the heart of the colorectal cancer screening. This position raises organisational issues and poses medico-legal problems for the professionals and institutions involved in these campaigns, related to the key concepts of medical decisions and suitability of standards. The objective of our study is to reveal the preferences of general practitioners related to colorectal cancer screening organisation with regard to the medico-legal risk

Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes

Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific na?ve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.     

Migraine and quality of life

As there is a significant deterioration in the overall quality of life, i.e., a disruption in the professional and social life of migraine-prone subjects, it was decided that a study should be carried out to investigate this issue via specific and non-specific questionnaires. An analysis of the findings showed disturbances not only during but between migraine attacks, with evasive behavior patterns and relational problems. Current drug therapy does little to provide relief apart from the triptan group of drugs, which can be used in emergency situations, and the scores recorded for migraine are frequently noticeably lower than those for other chronic diseases such as diabetes, arthritis, or depressive disorders.     

Immunohistological localization of immunoglobulins in pneumocystosis of adults

We examined by direct immunofluorescence open lung biopsies from seven adult patients with Pneumocystis carinii pneumonia. In all of them, immunoglobulin deposits (especially IgA) were found in alveoli that exhibited by light microscopy the classical foamy exudate infested by Pneumocystis. These immunoglobulins were eluted at an acid pH and were able to fix complement fractions in vitro. Moreover, we could reproduce this fixation by incubating previously eluted tissue sections with concentrated immunoglobulins isolated from a bronchopulmonary lavage performed in another case of pneumocystis. This immunohistological pattern suggests the presence of a humoral response in pulmonary parenchyma of patients infected with Pneumocystis carinii, despite the consistent underlying immunocompromised status. Considering these results, we conclude that humoral immune mechanisms do not constitute the main barrier against the development of Pneumocystis carinii in human lungs.     

Species-specific inhibition of cerebral malaria in mice coinfected with Plasmodium spp

Recent epidemiological observations suggest that clinical evolution of Plasmodium falciparum infections might be influenced by the concurrent presence of another Plasmodium species, and such mixed-species infections are now known to occur frequently in residents of most areas of endemicity. We used mice infected with P. berghei ANKA (PbA), a model for cerebral malaria (CM), to investigate the influence of experimental mixed-species infections on the expression of this pathology. Remarkably, the development of CM was completely inhibited by the simultaneous presence of P. yoelii yoelii but not that of P. vinckei or another line of P. berghei. In the protected coinfected mice, the accumulation of CD8(+) T cells in the brain vasculature, a pivotal step in CM pathogenesis, was found to be abolished. Protection from CM was further found to be associated with species-specific suppression of PbA multiplication. These observations establish the concept of mixed Plasmodium species infections as potential modulators of pathology and open novel avenues to investigate mechanisms implicated in the pathogenesis of malaria.