Alterations of GABA(A) and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy

Traumatic brain injury (TBI) can result in the development of posttraumatic epilepsy (PTE). Recently, we reported differential alterations in tonic and phasic GABA(A) receptor (GABA(A)R) currents in hippocampal dentate granule cells 90 days after controlled cortical impact (CCI) (Mtchedlishvili et al., 2010). In the present study, we investigated long-term changes in the protein expression of GABA(A)R α1, α4, γ2, and δ subunits, NMDA (NR2B) and AMPA (GluR1) receptor subunits, and heat shock proteins (HSP70 and HSP90) in the hippocampus of Sprague-Dawley rats evaluated by Western blotting in controls, CCI-injured animals without PTE (CCI group), and CCI-injured animals with PTE (PTE group). No differences were found among all three groups for α1 and α4 subunits. Significant reduction of γ2 protein was observed in the PTE group compared to control. CCI caused a 194% and 127% increase of δ protein in the CCI group compared to control (p<0.0001), and PTE (p<0.0001) groups, respectively. NR2B protein was increased in CCI and PTE groups compared to control (p=0.0001, and p=0.011, respectively). GluR1 protein was significantly decreased in CCI and PTE groups compared to control (p=0.003, and p=0.001, respectively), and in the PTE group compared to the CCI group (p=0.036). HSP70 was increased in CCI and PTE groups compared to control (p=0.014, and p=0.005, respectively); no changes were found in HSP90 expression. These results provide for the first time evidence of long-term alterations of GABA(A) and glutamate receptor subunits and a HSP following CCI.     

Adaptation to conflict via context-driven anticipatory signals in the dorsomedial prefrontal cortex

Behavioral interference elicited by competing response tendencies adapts to contextual changes. Recent nonhuman primate research suggests a key mnemonic role of distinct prefrontal cells in supporting such context-driven behavioral adjustments by maintaining conflict information across trials, but corresponding prefrontal functions have yet to be probed in humans. Using event-related functional magnetic resonance imaging, we investigated the human neural substrates of contextual adaptations to conflict. We found that a neural system comprising the rostral dorsomedial prefrontal cortex and portions of the dorsolateral prefrontal cortex specifically encodes the history of previously experienced conflict and influences subsequent adaptation to conflict on a trial-by-trial basis. This neural system became active in anticipation of stimulus onsets during preparatory periods and interacted with a second neural system engaged during the processing of conflict. Our findings suggest that a dynamic interaction between a system that represents conflict history and a system that resolves conflict underlies the contextual adaptation to conflict.     

Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata

Cardiac glycosides, known ligands of the sodium pump, are widely used in the treatment of heart failure, such as digoxin and digitoxin. Besides this important activity, other biological activities, such as the antiviral activity, have been described for this group. HSV are responsible for many infections of oral, ocular and genital regions. Treatment with nucleoside analogs such as acyclovir is effective in most cases; however drug-resistance may arise due to prolonged treatment mainly in immunocompromised individuals. In this study, an antiherpes screening was performed with 65 cardenolide derivatives obtained from different sources, and one natural cardenolide, glucoevatromonoside, inhibited HSV-1 and HSV-2 replication at very low concentrations. This cardenolide showed viral inhibitory effects if added up to 12 h p.i. and these effects appear to take place by the inhibition of viral proteins synthesis (ICP27, U_L42, gB, gD), the blockage of virus release and the reduction of viral cell-to-cell spread. This compound also showed synergistic antiviral effects with acyclovir and anti-Na⁺K⁺ATPase activity, suggesting that cellular electrochemical gradient alterations might be involved in the mechanism of viral inhibition. These results suggest that cardenolides might be promising for future antiviral drug design.     

Salvage radiotherapy for biochemical relapse after complete PSA response following radical prostatectomy: outcome and prognostic factors for patients who have never received hormonal therapy

Background

Intraoperative Radiotherapy (IORT) is a method by which a critical radiation dose is delivered to the tumour bed immediately after surgical excision. It is being investigated whether a single high dose of radiation will impart the same clinical benefit as a standard course of external beam therapy. Our centre has four Photon Radiosurgery Systems (PRS) currently used to irradiate breast and neurological sites.

Materials and methods

The PRS comprises an x-ray generator, control console, quality assurance tools and a mobile gantry. We investigated the dosimetric characteristics of each source and its performance stability over a period of time. We investigated half value layer, output diminution factor, internal radiation monitor (IRM) reproducibility and depth-doses in water. The half value layer was determined in air by the broad beam method, using high purity aluminium attenuators. To quantify beam hardening at clinical depths, solid water attenuators of 5 and 10 mm were placed between the x-ray probe and attenuators. The ion chamber current was monitored over 30 minutes to deduce an output diminution factor. IRM reproducibility was investigated under various exposures. Depth-dose curves in water were obtained at distances up to 35 mm from the probe.

Results

The mean energies for the beam attenuated by 5 and 10 mm of solid water were derived from ICRU Report 17 and found to be 18 and 24 keV. The average output level over a period of 30 minutes was found to be 99.12%. The average difference between the preset IRM limit and the total IRM count was less than 0.5%. For three x-ray sources, the average difference between the calculated and actual treatment times was found to be 0.62% (n = 30). The beam attenuation in water varied by approximately 1/r³.

Conclusion

The x-ray sources are stable over time. Most measurements were found to lie within the manufacturer's tolerances and an intercomparison of these checks suggests that the four x-ray sources have similar performance characteristics.     

Preoperative external beam radiotherapy and reduced dose brachytherapy for carcinoma of the cervix: survival and pathological response

Background

To describe long-term changes in time of quality of life (QOL) and the relation with parotid salivary output in patients with head-and-neck cancer treated with radiotherapy.

Methods

Forty-four patients completed the EORTC-QLQ-C30(+3) and the EORTC-QLQ-H&N35 questionnaires before treatment, 6 weeks, 6 months, 12 months, and at least 3.5 years after treatment. At the same time points, stimulated bilateral parotid flow rates were measured.

Results

There was a deterioration of most QOL items after radiotherapy compared with baseline, with gradual improvement during 5 years follow-up. The specific xerostomia-related items showed improvement in time, but did not return to baseline. Global QOL did not alter significantly in time, although 41% of patients complained of moderate or severe xerostomia at 5 years follow-up. Five years after radiotherapy the mean cumulated parotid flow ratio returned to baseline but 20% of patients had a flow ratio <25%. The change in time of xerostomia was significantly related with the change in flow ratio (p = 0.01).

Conclusion

Most of the xerostomia-related QOL scores improved in time after radiotherapy without altering the global QOL, which remained high. The recovery of the dry mouth feeling was significantly correlated with the recovery in parotid flow ratio.