SummarySex has a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Neuroinflammation is involved in the onset and progression of several neurological diseases, and the fact that estrogens have anti-inflammatory activity suggests that these hormones may be a determinant in the sex-dependent manifestation of brain pathologies. We describe significant differences in the transcriptome of adult male and female microglia, possibly originating from perinatal exposure to sex steroids. Microglia isolated from adult brains maintain the sex-specific features when put in culture or transplanted in the brain of the opposite sex. Female microglia are neuroprotective because they restrict the damage caused by acute focal cerebral ischemia. This study therefore provides insight into a distinct perspective on the mechanisms underscoring a sexual bias in the susceptibility to brain diseases.

Abstract-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2 R4496Cϩ/Ϫ ). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (nϭ20) in WT but induced DADs in 21 of 33 (63%) RyR2R4496Cϩ/Ϫ myocytes (Pϭ0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2R4496Cϩ/Ϫ myocytes (Pϭ0.001). DADs and triggered activity were abolished by ryanodine (10 mol/L) but not by K201 (1 mol/L or 10 mol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2R4496Cϩ/Ϫ mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2-FKBP12.6 interaction both in WT and RyR2R4496Cϩ/Ϫ either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2R4496Cϩ/Ϫ myocytes and ventricular arrhythmias in RyR2R4496Cϩ/Ϫ mice; and (3) RyR2-FKBP12.6 interaction in RyR2 R4496Cϩ/Ϫ is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex. Key Words: cardiac electrophysiology Ⅲ ryanodine receptor Ⅲ sudden death Ⅲ transgenic mice Ⅲ ventricular tachycardia C atecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated bidirectional or polymorphic ventricular tachycardia leading to syncope and/or sudden cardiac death in individuals without structural heart disease. 1,2 In 2001, we reported that the autosomal dominant form of CPVT is caused by mutations in the ryanodine receptor gene (RyR2). 3 Based on the evidence that the morphology of ventricular tachycardia observed in CPVT resembles that of digitalis induced ventricular tachycardia (VT), it had been suggested that arrhythmogenesis in CPVT could be mediated by delayed afterdepolarizations (DADs) and triggered activity. Although the discovery that CPVT is caused by mutations in the ryanodine receptor has substantiated this hypothesis, up to now no conclusive demonstration that DADs cause CPVT is available.Furthermore, although several authors have characterized in vitro the functional consequences of RyR2 mutations, 4 -6 the molecular and electrophysiological derangements leading to arrhythmias in CPVT patients are still uncl...

Heat shock triggers the assembly of nuclear stress bodies that contain heat shock factor 1 and a subset of RNA processing factors. These structures are formed on the pericentromeric heterochromatic regions of specific human chromosomes, among which chromosome 9. In this article we show that these heterochromatic domains are characterized by an epigenetic status typical of euchromatic regions. Similarly to transcriptionally competent portions of the genome, stress bodies are, in fact, enriched in acetylated histone H4. Acetylation peaks at 6 h of recovery from heat shock. Moreover, heterochromatin markers, such as HP1 and histone H3 methylated on lysine 9, are excluded from these nuclear districts. In addition, heat shock triggers the transient accumulation of RNA molecules, heterogeneous in size, containing the subclass of satellite III sequences found in the pericentromeric heterochromatin of chromosome 9. This is the first report of a transcriptional activation of a constitutive heterochromatic portion of the genome in response to stress stimuli.