Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein

Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α⁺ isoform but not the α⁻ isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.     

Vestibular Function Measurement Devices

Vestibular function laboratories utilize a multitude of diagnostic instruments to evaluate a dizzy patient. Caloric irrigators, oculomotor stimuli, and rotational chairs produce a stimulus whose accuracy is required for the patient response to be accurate. Careful attention to everything from cleanliness of equipment to threshold adjustments determine on a daily basis if patient data are going to be correct and useful. Instrumentation specifications that change with time such as speed and temperature must periodically be checked using calibrated instruments.     

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

Cancer Chemotherapy and Pharmacology - CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize...     

Stability of transverse expansion in the mandibular arch.

This was a retrospective, longitudinal cephalometric and cast study of 29 white patients at pretreatment, posttreatment, and an average of 6 years 3 months postretention. The goal was to assess changes with treatment and retention with the expanding mandibular lingual arch appliance in conjunction with fixed edgewise treatment. Seven mandibular cast measurements were assessed, including arch crowding, arch perimeter, arch length, and arch width at the permanent canines, first premolars, second premolars, and first molars. Cephalometric radiographs were digitized, and 16 cephalometric measurements were made. Repeated-measures analysis of variance and 2-sample t tests were used to determine statistically significant changes. It was found that the expanding lingual arch used for less than 6 months with the mandibular fixed edgewise appliance caused an increase in both the transverse and sagittal dimensions of the mandibular dental arch. Transverse expansion was more stable in the posterior region of the mandibular dental arch than in the anterior region. Mandibular intercanine width increase could be maintained only by fixed retention. Although the maxillary and mandibular incisors were advanced and proclined, lip protrusion did not occur.     

Specification of the Dose to Organs at Risk in External Beam Radiotherapy

Reporting of the clinical relevant dose to organs at risk (OR) and other normal tissues is crucial in trials and protocols where the aim is to assess late complications and to increase the therapeutic ratio for external beam radiotherapy. The dose distribution in normal tissues and ORs are, however, most often heterogeneous, at least when more than two opposing beams are applied. To decide the most clinical relevant dose with respect to late occurring complications is therefore not a straight forward problem. In this work we discuss what parameters characterise the dose-volume-histogram (DVH) best by calculating normal tissue complication probabilities (NTCPs) by using the Lyman model and various sets of statistical parameters drawn out from the DVHs. These NTCPs are compared to NTCPs calculated from the full DVHs, when the sets of parameters are evaluated. Our calculations indicate that the NTCP based on the Lyman model is best correlated to the D_max value, for serially organised tissues such as the spinal cord. For organs, described largely as tissues organised in parallel, the D_median or D_mean of the DVH may be applied. Our calculations reveal that D_mean is the parameter of choice when D_meclian is quite small, but when the two parameters approach each other, D_mediarl will be a better choice, using a unity volume fraction. For ORs characterised by a mixed serial and parallel functional structure, as the heart, neither D_max, D_median, nor D_mi,_an may predict the actual NTCP.     

Rapid adenosine release in the nucleus tractus solitarii during defence response in rats: real-time measurement in vivo

We have measured the release of adenosine and inosine from the dorsal surface of the brainstem and from within the nucleus tractus solitarii (NTS) during the defence response evoked by hypothalamic stimulation in the anaesthetised rat. At the surface of the brainstem, only release of inosine was detected on hypothalamic defence area stimulation. This inosine signal was greatly reduced by addition of the ecto-5'-nucleotidase inhibitor α,β-methylene ADP (200 μM), suggesting that the inosine arose from adenosine that was produced in the extracellular space by the prior release of ATP. By placing a microelectrode biosensor into the NTS under stereotaxic control we have recorded release of adenosine within this nucleus. By contrast to the brainstem surface, a fast increase in adenosine, accompanied only by a much smaller change in inosine levels, was seen following stimulation of the hypothalamic defence area. The release of adenosine following hypothalamic stimulation was mainly confined to a narrow region of the NTS some 500 μm in length around the level of the obex. Interestingly the release of adenosine was depletable: when the defence reaction was evoked at short time intervals, much less adenosine was released on the second stimulus. Our novel techniques have given unprecedented real-time measurement and localisation of adenosine release in vivo and demonstrate that adenosine is released at the right time and in sufficient quantities to contribute to the cardiovascular components of the defence reaction.