Decreased NOX2 expression in the brain of patients with bipolar disorder: association with valproic acid prescription and substance abuse.

Neuroinflammation and increased oxidative stress are believed to contribute to the development of psychiatric diseases. Animal studies have implicated NADPH oxidases (NOX) as relevant sources of reactive oxygen species in the brain. We have analyzed the expression of NOX isoforms in post-mortem brain samples from patients with psychiatric disorders (schizophrenia, bipolar disorder) and non-psychiatric subjects. Two collections from the Stanley Medical Research Institute were studied: the Array Collection (RNA, 35 individuals per group), and a neuropathology consortium collection (paraffin-embedded sections, 15 individuals per group). Quantitative PCR analysis revealed expression of NOX2 and NOX4 in prefrontal cortex. No impact of psychiatric disease on NOX4 levels was detected. Remarkably, the expression of NOX2 was specifically decreased in prefrontal and cingulate cortices of bipolar patients, as compared with controls and schizophrenic patients. NOX2 expression was not statistically associated with demographic parameters and post-mortem interval, but correlated with brain pH. Immunostaining demonstrated that NOX2 was predominantly expressed in microglia, which was corroborated by a decrease in the microglial markers CD68 and CD11b in the cingulate cortex of bipolar disorder patients. The analysis of potentially confounding parameters showed association of valproic acid prescription and heavy substance abuse with lower levels of NOX2. Taken together, we did not observe changes of NOX2 in schizophrenic patients, but a marked decrease of microglial markers and NOX2 in the brain of bipolar patients. This might be an underlying feature of bipolar disorder and/or a consequence of valproic acid treatment and substance abuse.

NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology.

Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47(phox) was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47(phox) were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations.

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation.

Ret finger protein-like 1 (RFPL1) is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. However, its cellular activity remains elusive. In this article, we report that Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells can be enhanced by in vivo p53 binding to its promoter and therefore investigated the hypothesis that hRFPL1 regulates cell-cycle progression. Upon expression in these cells, hRFPL1 decreased cell number through a kinase-dependent mechanism as PKC activates and Cdc2 inhibits hRFPL1 activity. hRFPL1 antiproliferative activity led to an increased cell population in G(2)/M phase and specific cyclin B1 and Cdc2 downregulations, which were precluded by a proteasome inhibitor. Specifically, cytoplasm-localized hRFPL1 prevented cyclin B1 and Cdc2 accumulation during interphase. Consequently, cells showed a delayed entry into mitosis and cell-cycle lengthening resulting from a threefold increase in G(2) phase duration. Given previous reports that RFPL1 is expressed during cell differentiation, its impact on cell-cycle lengthening therefore provides novel insights into primate-specific development.

[Liver haemangioma: current surgical indications. Our experience]. / Gli angiomi epatici: attuali indicazioni al trattamento chirurgico. Revisione casistica.

Hemangiomas are the more frequent benign liver tumours. Therapeutic approach at these neoplasms is changed in the last years because has resulted that massive haemoperitoneum from a spontaneous rupture of the hemangiomas is a rare occurrence. From a personal review of 124 liver resection performed for traumatic and organic, benign and malignant, pathologies, the Authors present two cases of symptomatic liver haemangioma surgically treated Excluding emergency induced by tumour hemorrhage, actually indications to surgical treatment are controversial. In all patients the right approach is choice by the integrated evaluation of general conditions of the patient, liver functionality and from anatomical location of the neoplasm.

[Appendicectomy: laparoscopic versus open treatment. A case survey]. / Appendicectomia: laparoscopica versus laparotomica. Analisi della casistica.

AIM: Laparoscopy is actually the gold standard approach in many surgical procedures: this consideration is still controversial as to appendectomy. METHODS: From 2000 to 2004 we have performed 257 appendectomies: 51 (20%) in laparoscopic approach. Preoperative diagnosis has been formulated on blood parameters, abdominal or, sometimes, transvaginal ultrasonography. RESULTS: Two hundred and fifty-seven surgical operations, 62 laparoscopic, have been performed for suspicious appendicitis. In the laparoscopic procedures, 11 revealed various diseases without appendicitis. In the remaining 51 cases, appendectomy has been performed totally intra-abdominal and none case turned to laparotomic conversion. Operative times were between 27 and 105 min in the laparoscopic appendectomies (LA) and between 18 and 46 min in the laparotomic appendectomies (OA). In 7.3% of OA and in 3.9% of LA wall infections occurred, as well as abdominal abscesses in 1% of OA and in 4% of LA. Postoperative discharge was after 3.3 days and bowel canalization appeared at 10-18 hours from the surgery, in OA and in LA. CONCLUSIONS: On the basis of these results, the conclusion is drawn that, although discordant opinions in the literature, the advantages of the laparoscopic approach compared to laparotomic approach is still to be demonstrated, both in advantages for the patient and in costs. Laparoscopy is the better surgical technique when the preoperative diagnosis is not clear, particularly in young women or in elderly, in whom a colic neoplasm may be suspected.