Prefrontal cortical control of a brainstem social behavior circuit

The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER)

ZD6474 – a novel inhibitor of VEGFR and EGFR tyrosine kinase activity

Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in stimulating neovascular growth and survival. ZD6474 is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumour-induced angiogenesis. Consistent with inhibition of angiogenesis, once-daily oral dosing of ZD6474 produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, ZD6474 also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. This may be particularly relevant in tumours with a dependency upon EGFR signalling, for example in certain tumours harbouring activating mutations in EGFR. RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment

Cyclooxygenase-1 and -2 are expressed by human T cells

In vitro, prostaglandins (PG) have strong inhibitory effects on T cell activation and proliferation and inhibitors of PG synthesis (NSAID) increase proliferation and activation of T cells. Although most studies have failed to demonstrate cyclooxygenase (COX) activity in lymphocytes, there is contradictory evidence on the synthesis of different PG. We have studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot the expression of COX-1 and -2 mRNA and protein in resting and activated peripheral blood or Jurkat T cells. Cells were activated by T cell receptor triggering with OKT3 antibodies and activation confirmed by flow cytometric analysis of surface CD69. COX enzymatic activity was measured by determination of arachidonic acid (AA)-induced PG synthesis. Both peripheral blood and Jurkat T cells expressed COX-1 and -2 mRNA and protein. COX-1 was constitutively expressed and did not change after OKT3 stimulation. COX-2 was inducible upon OKT3-induced activation. In spite of the presence of COX mRNA and immunoreactive protein, AA-induced PG synthesis was not detected at the EIA detection (pm) level. The potential role of cyclooxygenases in T cells deserves further study, since no PG of the studied series seem to be synthesized by T cells

Capsular fixation limits graft extrusion in lateral meniscal allograft transplantation

Purpose: The main purpose of this investigation was to compare the amount of graft extrusion of lateral meniscal allograft transplantation (MAT) performed with a suture-only technique with or without a capsulodesis. Secondarily, the assessment of functional results was also covered. We hypothesized that capsular fixation reduces the post-operative degree of allograft extrusion and it does not affect the functional outcomes during the short-term follow-up period studied. Methods: Prospective series of 29 lateral MAT. Fifteen were fixed with a suture-only technique (group A). The remaining 14 cases (group B) also included arthroscopic lateral capsular fixation (capsulodesis). Functional results were assessed with Lysholm, Tegner, and VAS for pain. Magnetic resonance imaging (MRI) was performed to determine the degree of meniscal extrusion. Millimeters of extrusion and percentage of extruded meniscal tissue were calculated for both groups. The degree of extrusion was considered minor if it was 3 mm. Results: Group A had 11 cases (73.3%) of major extrusion and group B had 4 cases (28.6%) (p = 0.02). The percentage of extruded meniscal tissue was 35% in group A and 24.6% in group B (p = 0.04). At a mean 3.4 years (range 1-4) post-operatively, the Lysholm score had a mean 89.60 ± 6.93 and 91.43 ± 6.19 points in groups A and B, respectively (p < 0.001). The median follow-up Tegner score improved from 4 (range 3-5) to 7 (range 6-9) in group A (p < 0.001) and from 4 (range 3-5) to 7 (range 6-8) in group B (p < 0.001). VAS dropped 5 and 7.3 points in groups A and B, respectively (p < 0.001). There were no complications in this series. Conclusions: In lateral MAT with the suture-only fixation technique, the described capsulodesis minimized meniscal extrusion. In terms of functional results, there were no differences between the groups at a mean 3.4-year follow-up