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.     

Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function

Background

Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.

Sexual function in patients presenting to a urogynecology practice

The purpose of this study was to evaluate sexual function in women referred to a urogynecology practice. All new patients were mailed an optional female sexual function index (FSFI) in conjunction with their history forms; other sexual function information was obtained during the physician interview. Over 6 months, four hundred fifty new patients were enrolled. Of these, 243 (54%) were not sexually active. Reasons listed for sexual inactivity included partner problems/no partner (32%), low desire (14%), prolapse (10%), and pain (10%). There were several differences between sexually active and non-sexually active participants; however, after a multivariate analysis, only age, marital status, and stage/grade 1–2 of prolapse remained significant. One hundred nine sexually active patients completed the FSFI; the majority was sexually active two to four times per month. Female sexual dysfunction was noted in 70 (64%) patients. Lowest scores were noted for the domain of desire, followed by arousal, orgasm, lubrication, satisfaction, and pain. Reduced frequency of intercourse was the only factor significantly associated with dysfunction. Ninety-four percent were not embarrassed by the survey. Overall, sexual inactivity is common in patients presenting for urogynecologic care. Those that are sexually active report low rates of sexual activity and high rates of sexual dysfunction. Most sexually active patients will accept a sexual function questionnaire as part of their routine assessment.This research was presented at the American College of Obstetricians and Gynecologists annual clinical meeting, May 10, 2005, San Francisco, CA, USA.     

Impaired Lymphocyte Proliferative Response to Mitogen in Alcoholic Patients. Absence of a Relation to Liver Disease Activity

Concanavalin A-induced lymphocyte proliferation was studied in 25 patients with alcoholic hepatitis or compensated alcoholic cirrhosis. Nine alcoholics without evidence of liver disease were also evaluated. A nonlinear correlation equation, which was natural logarithmic, was applied to individual dose-response proliferation curves and permitted comparisons between patient groups and controls. The proliferative response in all patient groups was significantly lower when compared to healthy controls and was independent of the presence or absence of liver disease. This suggests that some changes in immune function observed in alcoholics may be linked to the direct effects of alcohol on the immune system rather than to the associated liver disease.     

Evaluation of bedside blood glucose monitoring by the phlebotomy team in an acute general care hospital

A feasibility study was undertaken to evaluate laboratory phlebotomists performing bedside glucose monitoring (BGM) over a 3-month period on a medical and surgical floor. Specific questions included: feasibility of providing testing on a 24-h basis, accuracy, appropriate utilization, effect on patient care, and an analysis of cost. In all, 1975 tests were performed on 114 patients. BGM results were within 15% of the laboratory's result 97% of the time. Patient and physician satisfaction was high. Although the cost of BGM is slightly higher than a laboratory glucose test, its use appeared to reduce the length of hospital stay by 0.47 days. Practical information on initiating a highly successful BGM program is provided.     

Global transcriptional profiling demonstrates the combination of type I and type II interferon enhances antiviral and immune responses at clinically relevant doses.

A role for type II interferon (IFN-gamma) in resolving viral infection is suggested by the correlation of hepatitis C virus (HCV) clearance with enhancement of IFN-gamma-producing activated T cells in the resolution of acute HCV infection. Using vesicular stomatitis virus (VSV), a synergistic direct antiviral effect was documented using IFN-gamma1b and a potent, consensus type I IFN (IFN alfacon-1). Global expression profiling following EC50 exposure to IFN alfacon-1, IFN-gamma1b, or a cocktail of the two allowed the antiviral state to be correlated with induction of a subset of IFN-stimulated genes (ISGs). Genes identified through this analysis corresponded to classic antiviral components, ISGs more recently associated with direct antiviral functions, as well as expressed sequence tags (ESTs) and hypothetical proteins. The magnitude of these antiviral EC50-correlated expression events in human hepatoma (Huh7) cells exposed to clinically relevant doses of IFN alfacon-1, IFN-gamma1b, or a cocktail of the two was also probed because the standard of care for patients with chronic hepatitis C is type I IFN-containing regimens. Relative to type I IFNs used alone, the addition of type II IFN caused enhanced expression not only of many of the genes correlated with the direct antiviral state but also of genes involved in (1) antigen presentation to cytotoxic T lymphocytes (CTLs), (2) macrophage, natural killer (NK), and T helper 1 (Th1) cell recruitment and activation, (3) complement system function, (4) apoptosis, and (5) ISGs with unknown functions. As many of these processes are correlated clinically with resolution of chronic HCV infection, the combined use of these IFNs could display a beneficial effect on viral clearance in patients infected with HCV and other viruses through enhancement of one of these processes or of the direct antiviral state.     

The role of the le fort I maxillotomy in the management of incompletely resected pituitary macroadenomas.

Objective: The options available for the treatment of a nonsecreting pituitary macroadenoma that has been incompletely resected include reoperation, fractionated radiation therapy, and radiosurgery. Reoperation in this setting may be hindered by the same obstacles that prevented a complete resection during the initial surgical procedure, and should prompt consideration of an alternate approach or exposure. Methods: Between January 1998 and December 2003, 10 consecutive patients were referred to the Department of Neurosurgery at the University of Texas Southwestern Medical Center for the evaluation of a nonsecreting pituitary macroadenoma that measured 3 cm or greater in diameter despite having undergone an attempt at a complete resection elsewhere. Each of these patients was reoperated using a Le Fort I maxillotomy to enhance the exposure provided by a traditional transsphenoidal approach. Results: A total or near total (> 95%) resection was achieved in each case. One patient required reoperation for the repositioning of a fat graft to treat a cerebrospinal fluid fistula and one patient experienced a worsening of anterior pituitary function postoperatively. Five patients noted improved vision and no patient experienced further visual loss. Three patients have required subsequent treatment of small foci of recurrent or progressing tumor with stereotactic radiation therapy. No patient has received fractionated radiation therapy. Conclusion: The added exposure provided by a Le Fort I maxillotomy facilitates the resection of pituitary macroadenomas that have been incompletely resected by a traditional transnasal, trans-sphenoidal approach.     

On the road to automatic: dynamic aspects in the development of expertise.

One of the important steps on the road to becoming expert in a motor skill occurs when the individual can perform the movements in a seemingly effortless and automatic fashion. The authors review two lines of investigations, namely, fMRI and mathematically guided studies of the dynamics of skill acquisition, that suggest that this road to automatic involves two steps: (1) an increasing reliance on the self-regulatory aspects of the motor task, and (2) a minimization of the role of mechanisms based on intentionally directed corrective movements. The interplay between these two mechanisms implies that, at a given skill level, performance decreases whenever intention intervenes. The observation that psychological factors may be as important as mechanical repetition for the development of expertise has important implications for the design of neurorehabilitative strategies.