Immunological parameters in girls with Turner syndrome

Disturbances in the immune system has been described in Turner syndrome, with an association to low levels of IgG and IgM and decreased levels of T- and B-lymphocytes. Also different autoimmune diseases have been connected to Turner syndrome (45, X), thyroiditis being the most common. Besides the typical features of Turner syndrome (short stature, failure to enter puberty spontaneously and infertility due to ovarian insufficiency) ear problems are common (recurrent otitis media and progressive sensorineural hearing disorder). Levels of IgG, IgA, IgM, IgD and the four IgG subclasses as well as T- and B-lymphocyte subpopulations were investigated in 15 girls with Turners syndrome to examine whether an immunodeficiency may be the cause of their high incidence of otitis media. No major immunological deficiency was found that could explain the increased incidence of otitis media in the young Turner girls

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP

Although extracellular ATP is abundant at sites of inflammation, its role in activating inflammasome signalling in neutrophils is not well characterized. In the current study, we demonstrate that human and murine neutrophils express functional cell-surface P2X(7)R, which leads to ATP-induced loss of intracellular K(+), NLRP3 inflammasome activation and IL-1β secretion. ATP-induced P2X(7)R activation caused a sustained increase in intracellular [Ca(2+)], which is indicative of P2X(7)R channel opening. Although there are multiple polymorphic variants of P2X(7)R, we found that neutrophils from multiple donors express P2X(7)R, but with differential efficacies in ATP-induced increase in cytosolic [Ca(2+)]. Neutrophils were also the predominant P2X(7)R-expressing cells during Streptococcus pneumoniae corneal infection, and P2X(7)R was required for bacterial clearance. Given the ubiquitous presence of neutrophils and extracellular ATP in multiple inflammatory conditions, ATP-induced P2X(7)R activation and IL-1β secretion by neutrophils likely has a significant, wide ranging clinical impact

Topoisomerase I inhibitors and drug resistance

DNA topoisomerase I is a nuclear enzyme which catalyzes the conversion of the DNA topology by introducing single-strand breaks into the DNA molecule. This enzyme represents a novel and distinct molecule target for cancer therapy by antitopoisomerase drugs belonging to the campthotecin series of antineoplastics. As many tumors can acquire resistance to drug treatment and become refractary to the chemotherapy it is very important to investigate the mechanisms involved in such a drug resistance for circumventing the phenomenon. This article describes the role of topoisomerase I in cell functions and the methods used to assess its in vitro catalytic activity. It reviews the mechanisms of cytotoxicity of the most specific antitopoisomerase I drugs by considering also the phenomenon of drug resistance. Some factors useful to drive the future perspectives in the development of new topoisomerase I inhibitors are also evidenced and discussed