Brain neurosteroid changes after paroxetine administration in mice.

Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine.     

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.     

Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.     

Warty dyskeratoma/focal acantholytic dyskeratosis--an update on a rare oral lesion

J Oral Pathol Med (2012) 41 : 261–267 Background: Warty dyskeratoma (WD) is an uncommon lesion of the skin that is considered to be associated with the pilosebaceous apparatus. Histologically similar lesions have been described in the oral region mainly by case reports and under the terms ‘WD’ or ‘focal acantholytic dyskeratosis (FAD)’. Owing to the paucity of reports, many aspects of the oral lesions remain unclear. The purpose of this study is to report a new case in an extremely rare location, the buccal mucosa, and to present a comprehensive updated review and analysis of the literature. Methods: We reviewed all cases of oral lesions that were diagnosed as WD and FAD and analyzed them according to their clinical and pathologic features. Results: The search yielded only 41 cases. The lesions usually appeared as asymptomatic, solitary, white nodules, papules, or patches on bone‐bound mucosa. They occasionally had a rough surface and depressed center. The lesions were most common in the fifth to seventh decades. Use of tobacco appeared to be the most prevalent predisposing factor. The histopathological differential diagnosis of the lesion included acantholytic squamous cell carcinoma, keratoacanthoma, and Darier’s disease. Conclusion: Warty dyskeratoma/FAD are uncommon oral lesions which are not encountered in the daily practice of oral pathologists. The absence of an association of oral lesions with the pilosebaceous apparatus suggests that they are probably distinctly different from cutaneous ones. As such, we suggest the histologic term isolated FAD for oral lesions, rather than WD.