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.     

The practical assessment and management of bladder outflow obstruction

The initial management of bladder outflow obstruction typically related to benign prostatic hyperplasia (BPH) falls to a large extent within the remit of general practice. Referral onwards to secondary care typically arises following the failure to respond to conservative measures or when complications have supervened; the most significant of which is urinary retention. In the hospital setting, anaesthesia, constipation and immobility are the common precipitants. What follows is a practical guide to the management of these situations and provides an overview of the conservative, medical, minimally invasive and surgical treatments available.     

Effect of bite tray impression technique on relocation accuracy in frameless stereotactic radiotherapy.

A previously developed method for achieving patient relocation in fractionated stereotactic radiotherapy (attachment of an infrared fiducial system to a bite tray) relies on the integrity of a bite tray system that incorporates moulding to the patient's upper dentition. Reproducible and accurate patient positioning requires stability of the bite tray and mould during the full treatment process, both during the time the bite tray is inserted in the patient's mouth, and between separate bite tray insertions. The optimum construction method for a stable reproducible tray has not been sufficiently investigated. We undertook a study to identify factors which might influence the integrity of the hard palate bite tray system. Reprosil Fast Set Putty was used to construct 3 impression conditions; teeth only; teeth and alveolar sulcus; and teeth, alveolar sulcus, and the hard palate. Reproducibility was assessed by volunteers inserting the impressions multiple times and recording the locations of 8 standard reference points. Our results showed the optimal impression technique (i.e., the one that led to the smallest ranges in positional and rotational errors) was that which incorporated the teeth, alveolar sulcus, and hard palate.     

Prevalence of total hip replacement: how much demand has been met?

OBJECTIVE--To determine the prevalence of completed elective total hip replacements in a defined elderly population. DESIGN--Cross sectional postal questionnaire survey with additional data and validation from general practice and hospital records. SETTING--Six general practices in the English counties of Avon, Somerset, and Oxfordshire. SUBJECTS--A total of 7806 patients aged 65 years and over (94.7% response). RESULTS--The overall prevalence (95% confidence intervals) of elective total hip replacement was 5.3 (4.8,5.8)% Age and sex specific prevalences were 2.7 (2.0,3.5)% in men and 4.1 (3.3,4.9)% in women aged 65-74 years, and 5.2 (4.0,6.5)% in men and 8.8 (7.6,10.0)% in women aged 75 years and over. Of the 415 patients who had received elective total hip replacement, 28.2% had required bilateral surgery, 20% had received at least one operation privately, and 13% had required revision surgery. CONCLUSION--Our results show an increased level of satisfied demand for total hip replacement in elderly people compared with earlier estimates. The increasing prevalence of hip replacement is an indicator of increasing potential demand for revision procedures. Population based surveys are required to establish the level of unmet demand for primary procedures. Differences in past surgical activity may be important in interpreting the wide variation in current surgical rates.     

The pharmacokinetics of 125I-atrial natriuretic factor in anaesthetized rats. Effects of neutral endopeptidase inhibition with candoxatrilat and of ANF-C receptor blockade.

The effects of candoxatrilat (cis-4-([2-carboxy-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarbonyla mino)- 1-cyclohexane carboxylic acid) and the ring-deleted atrial natriuretic factor (ANF) analogue C-ANF4-23 (des[Gln18, Ser19, Gly20, Leu21, Gly22]ANF4-23-NH2) on the clearance of (3-[125I]iodotyrosyl28)ANF (125I-ANF) were studied in both intact and nephrectomized anaesthetized rats. HPLC analysis was used to verify that the 125I-labelled material isolated by solid phase extraction of rat plasma was intact ANF. In intact animals, clearance of 125I-ANF was biphasic with a T1/2 alpha of 17 sec and T1/2 beta of 95 sec. Volume of distribution (Vd) was 564 mL/kg and plasma clearance (Clp) 248 mL/min/kg. Candoxatrilat, over the dose range 0.01-10 mg/kg i.v., increased T1/2 beta (by a maximum of 56%) and decreased Clp (by up to 52%) with no effect on T1/2 alpha or Vd. C-ANF4-23 (10 micrograms/kg+1 microgram/kg/min i.v.) reduced Vd (by 57%) and Clp (by 54%) with no effect on T1/2 beta, whilst abolishing the T1/2 alpha phase in over 50% of animals. Increasing the dose of C-ANF4-23 did not increase the effect on any of these parameters, apart from a small increase in T1/2 beta. Combining the two agents resulted in a substantial decrease in Clp (76%) whilst the reduction in Vd and increase in T1/2 beta were comparable to those seen with C-ANF4-23 and candoxatrilat alone, respectively. In nephrectomized rats, the pharmacokinetics of 125I-ANF and the changes induced by candoxatrilat were similar to those observed in intact animals, whilst the effects of C-ANF4-23 alone were greater than in intact animals. The combination of C-ANF4-23 and candoxatrilat again produced a substantial increase in T1/2 beta (153%) and decreases in Vd (55%) and Clp (78%) in nephrectomized animals, although these changes could not be distinguished from those seen in intact animals treated with the same combination. Our studies indicate that neutral endopeptidase and ANF-C receptors are both major, and approximately equal, clearance mechanisms for 125I-ANF, together accounting for at least 75% of the total clearance of this peptide in the rat.