Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats.

Administration of the neurosteroid progesterone (PROG) has been shown to be beneficial in a number of brain injury models and in two recent clinical trials. Given widespread vitamin D deficiency and increasing traumatic brain injuries (TBIs) in the elderly, we investigated the interaction of vitamin D deficiency and PROG with cortical contusion injury in aged rats. Vitamin D deficient (VitD-deficient) animals showed elevated inflammatory proteins (TNFα, IL-1ß, IL-6, NFκB p65) in the brain even without injury. VitD-deficient rats with TBI, whether given PROG or vehicle, showed increased inflammation and greater open-field behavioral deficits compared to VitD-normal animals. Although PROG was beneficial in injured VitD-normal animals, in VitD-deficient subjects neurosteroid treatment conferred no improvement over vehicle. A supplemental dose of 1,25-dihydroxyvitamin D(3) (VDH) given with the first PROG treatment dramatically improved results in VitD-deficient rats, but treatment with VDH alone did not. Our results suggest that VitD-deficiency can increase baseline brain inflammation, exacerbate the effects of TBI, and attenuate the benefits of PROG treatment; these effects may be reversed if the deficiency is corrected.

Continuing professional development and social accountability: a review of the literature.

The idea that health professionals should be accountable to the society they serve is not a new concept and by the 1990 s, the continuing professional development (CPD) of health professionals was being seen as one way in which Canadians' level of health could be improved. The public was, and is still today, increasingly demanding a system that is more responsive to regional and community needs. As a result, there is a need for more health professional education at all stages of the education continuum - undergraduate, postgraduate, and continuing professional development - that meets the health and social needs of the populations being served. The trend is now towards 'socially accountable' health care, meaning that the broader context of CPD must also include the personal, social, and political aspects of health care and as such, involve a widening of accountability to patients, the community, managers and policymakers. CPD planning must take into account local and national priorities as well as personal learning needs. However, the definition of social accountability and the stages at which it is addressed is sometimes vague and this added to the difficulty of identifying relevant studies in the literature. Nonetheless, there were some "best practices" evident via Canadian and American studies which focused on models of socially accountable CPD, as well as examples of interdisciplinary collaboration in Canada, the United States, Australia, Great Britain, and the United Arab Emirates. However, there is a definite need for increased research and publication of such "best practice" initiatives. There is also a need for Canadian health professional schools to facilitate this process by sharing their experiences and resources if possible. An extensive literature review was conducted between January and March 2004. Due to time constraints, it was limited to articles written in the English language. The databases/sources utilized included: Medline (now known as Pubmed), CINAHL, ERIC, PsychInfo, Canadian Business & Current Affairs (CBCA) Full-text Education (now known as CBCA Education), Research and Development Resource Base in Continuing Medical Education (RDRB/CME) at the University of Toronto, EMBASE (Excerpta Medica). This literature review was one of the first activities conducted under the auspices of "Issues of Quality and Continuing Professional Development: Maintenance of Competence", a national project funded by the Primary Health Care Transition Fund, Health Canada. The purposes of this review were to identify literature which focuses on aspects of continuing professional development, social accountability, and determinants of health; "best practices" of socially accountable CPD and inter/intra-disciplinary collaboration, and the critical success factors and challenges to implementing CPD, especially CPD that meets the needs of both health professionals and the populations they serve.

Progesterone and its metabolite allopregnanolone differentially regulate hemostatic proteins after traumatic brain injury.

Our laboratory has shown in numerous experiments that the neurosteroids progesterone (PROG) and allopregnanolone (ALLO) improve molecular and functional outcomes after traumatic brain injury (TBI). As coagulopathy is an important contributor to the secondary destruction of nervous tissue, we hypothesized that PROG and ALLO administration may also have a beneficial effect on coagulation protein expression after TBI. Adult male Sprague-Dawley rats were given bilateral contusions of the medial frontal cortex followed by treatments with PROG (16 mg/kg), ALLO (8 mg/kg), or vehicle (22.5% hydroxypropyl-beta-cyclodextrin). Controls received no injury or injections. Progesterone generally maintained procoagulant (thrombin, fibrinogen, and coagulation factor XIII), whereas ALLO increased anticoagulant protein expression (tissue-type plasminogen activator, tPA). In addition, PROG significantly increased the ratio of tPA bound to neuroserpin, a serine protease inhibitor that can reduce the activity of tPA. Our findings suggest that in a model of TBI, where blood loss may exacerbate injury, it may be preferable to treat patients with PROG, whereas it might be more appropriate to use ALLO as a treatment for thrombotic stroke, where a reduction in coagulation would be more beneficial.

Neurosteroids reduce inflammation after TBI through CD55 induction.

The inflammatory cascade that follows traumatic brain injury may lead to secondary cell death and can impede recovery of function. Complement factors and their convertases are increased in glia after brain injury and lead to the production of inflammatory products that kill vulnerable neurons. Progesterone and its metabolite allopregnanolone (5alpha-pregnan-3beta-ol-20-one) have been shown to reduce the expression of inflammatory cytokines in the acute stages of brain injury, although how they do this is not completely understood. In this study we show that both progesterone and allopregnanolone treatments enhance the production of CD55 following contusion injuries of the cerebral cortex in rats. CD55, a single-chain type 1 cell surface protein, is a potent inhibitor of the complement convertases which are activators of the inflammatory cascade. The increased expression of CD55 could be an important mechanism by which steroids help to reduce the cerebral damage caused by inflammation.

Progesterone improves acute recovery after traumatic brain injury in the aged rat.

Recent evidence has demonstrated that treatment with progesterone can attenuate many of the pathophysiological events following traumatic brain injury (TBI) in young adult rats, but this effect has not been investigated in aged animals. In this study, 20-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n = 4 per group) or sham operations received 8, 16, or 32 mg/kg of progesterone or vehicle. Locomotor activity was measured at 72 h to assess behavioral recovery. Brain tissue was harvested at 24, 48, and 72 h, and Western blotting was performed for inflammatory and apoptotic factors. Edema was assessed at 48 h by measuring brain water content. Injured animals treated with 8 and 16 mg/kg progesterone showed decreased expression of COX-2, IL-6, and NFkappaB at all time points, indicating a reduction in the acute inflammatory process compared to vehicle. The 16 mg/kg group also showed reduced apoptosis at all time points as well as decreased edema and improved locomotor outcomes. Thus, in aged male rats, treatment with 16 mg/kg progesterone improves short-term motor recovery and attenuates edema, secondary inflammation, and cell death after TBI.

The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury.

Previous work shows that neurosteroid enantiomers activate specific molecular receptors that relay neuroprotection. However, the actions of the enantiomer of progesterone (ent-PROG) at the PROG receptor (PR) are unknown. PR binding and transcriptional assays were performed to determine the actions of ent-PROG at the classical PR. Additionally, the neuroprotective effects of ent-PROG in traumatic brain injury (TBI) were investigated and compared to the actions of PROG and its metabolite allopregnanolone (ALLO), both of which have been shown to have neuroprotective properties when given after TBI. Binding studies performed in COS cells over-expressing the PR showed that ent-PROG inhibited PROG binding to the PR. In contrast, ent-PROG did not activate PR-mediated transcription. Rats received bilateral medial frontal cortex injury followed by treatments at 1, 6, 24 and 48h with PROG, ALLO or ent-PROG. Brains were processed for edema, protein and enzyme activity. ent-PROG treatment in vivo decreased cerebral edema, cell death mediators, inflammatory cytokines, and reactive gliosis, and increased antioxidant activity. These findings suggest that the progestin-mediated pro-survival response seen with TBI is regulated either independently of the classical PR or via nongenomic PR-regulated actions.

Slow-release and injected progesterone treatments enhance acute recovery after traumatic brain injury.

The benefits of continuous progesterone release via subcutaneous silastic capsule implants were compared to daily subcutaneous injections in a rat model of traumatic brain injury (TBI). Adult male Sprague-Dawley rats received either bilateral frontal cortex contusions or sham surgery. Rats were injected with progesterone or vehicle at 1 and 6 h post-injury, then once every 24 h for six days with tapering of the dose over the final two treatments. Progesterone-packed silastic capsules were implanted post-injury while the animals were anesthetized. Behavioral assays for anxiety and locomotor activity were evaluated pre- and post-TBI. Brains were extracted eight days post-TBI and prepared for molecular assays. Decreased GABAA-4 levels complemented a decrease in anxiety behaviors on the Elevated Plus Maze for capsule compared to progesterone-injected animals prior to daily injections. All groups with implanted capsules increased locomotor activity compared to those given progesterone injections. In conclusion, steady-state progesterone treatment after TBI decreases edema and anxiety and increases activity, thus enhancing behavioral recovery. A continuous mode of pharmacological administration may prove to be more beneficial in translational and clinical testing than bolus injections over the same period of time.

Tapered progesterone withdrawal promotes long-term recovery following brain trauma.

We previously demonstrated that after traumatic brain injury (TBI), acute progesterone withdrawal (AW) causes an increase in anxiety behaviors and cerebro-cellular inflammation compared to tapered progesterone withdrawal (TW). Our current study investigates the behavioral and cellular effects of AW two weeks after termination of treatments to determine the longer-term influence of withdrawal after injury. Adult, male Sprague-Dawley rats received either bilateral frontal cortex contusion (L) or sham (S) surgery. Rats were injected at 1 and 6 h post-injury, then every 24 h for six days. Vehicle (V)-treated rats were given 9 injections of 22.5% cyclodextrin, whereas AW rats received 9 injections of 16 mg/kg progesterone and TW rats received 7 injections of P at 16 mg/kg, followed by one at 8 mg/kg and one at 4 mg/kg. On day 8, sensory neglect and locomotor activity tests were initiated. Animals were killed 22 days post-TBI and the brains prepared for either molecular or histological analysis. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and heat shock protein 70 (HSP70) in TW vs. AW animals. P53 was increased in VL animals, whereas all progesterone-treated groups were equivalent to shams. TW animals had markedly decreased sensory neglect compared to AW animals and increased center time in locomotor activity assays. In addition, lesion reconstruction revealed a decreased lesion size for TWL over AWL over VL animals. Glial fibrillary acidic protein (GFAP) immunofluorescent staining followed this pattern as well. In conclusion, after TBI, AW affects select behaviors and molecular markers in the chronic recovery period.

Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury.

Systemic injections of the neurosteroid progesterone improve cognitive recovery after traumatic brain injury (TBI) and stroke, and decrease molecular indicators of neuronal damage. Suddenly withdrawing progesterone after repeated dosing (PW) exacerbates ischemia and causes increased anxiety, seizure susceptibility, and excitotoxicity. Adult male Sprague-Dawley rats received either bilateral medial frontal cortex contusions or sham surgery. Injections were administered at 1 and 6 h post-injury, then every 24 h for 7 days. Vehicle-treated rats received 2-hydroxypropyl-beta-cyclodextrin (HBC). Acute PW (AW) rats received a full 16 mg/ml of progesterone for 7 days, and tapered PW (TW) rats received 5 days at full dosage, then 2 days with progressively halved dosages. Anxiety behaviors were observed pre- and post-surgery, and compared to levels at the peak of withdrawal. AW rats with lesions exhibited significantly more anxiety than any other treatment group, while both lesion- and sham-operated TW rats were indistinguishable from vehicle-treated intact animals. After behavioral tests were complete, the brains were extracted and prepared for Western blotting. TNFalpha, cFos, Caspase-3, and NFkappaB, among others, were investigated. While all progesterone treatments resulted in improved molecular recovery, TW animals had significantly fewer active markers for apoptosis and inflammation than AW animals. In conclusion, although progesterone treatment decreases inflammation and apoptosis, acute withdrawal increases activity in some apoptotic and inflammatory pathways and increases anxiety behavior during the acute healing phase. A tapered withdrawal of the hormone further enhances short-term recovery after TBI.

Start out: building healthcare careers for minority teenagers.

BACKGROUND: The healthcare industry is currently experiencing a severe shortage of nurses and other allied healthcare professionals. To compound this crisis, the current workforce does not mirror the growing linguistic and cultural diversity of the population needing health care. This article describes a community partnership approach to creating educational and career opportunities in nursing and other health sciences for young, multicultural, bilingual teenagers. METHOD: Several community organizations joined together to design and implement an 8-week summer program entitled "Start Out," which served to integrate life planning, mentorship, nursing assistant training, and college application assistance while providing summer salary stipends and work scholarship opportunities. Twenty-seven students participated in the program. RESULTS: Twenty-four bilingual, economically disadvantaged teenagers 16 to 19 years old, from the greater Seattle metropolitan area, completed the first session of this innovative program and passed the certified nursing assistant examination. CONCLUSION: Culturally focused assistance programs may provide an avenue to meet the current nursing shortage and provide healthcare workers who can be sensitive to the cultural and linguistic needs of the growing ethnic population.

Engineering cell adhesive surfaces that direct integrin alpha5beta1 binding using a recombinant fragment of fibronectin.

Integrin receptors mediate cell adhesion to extracellular matrices and trigger signals that direct cell function. While many integrins bind to the arginine-glycine-aspartic acid (RGD) motif present in numerous extracellular proteins, integrin alpha(5)beta(1) requires both the PHSRN synergy site in the 9th and the RGD site in the 10th type III repeat of fibronectin (FN). Binding of alpha(5)beta(1) to FN is critical to many cellular processes, including osteoblast and myoblast differentiation. This work focused on engineering integrin-specific bioadhesive surfaces by immobilizing a recombinant FN fragment (FNIII(7-10)) encompassing the alpha(5)beta(1) binding domains of FN. Model hybrid surfaces were engineered by immobilizing FNIII(7-10) onto passively adsorbed, non-adhesive albumin. Homo- and hetero-bifunctional crosslinkers of varying spacer-arm length targeting either the cysteine or lysine groups on FNIII(7-10) were investigated in ELISA and cell adhesion assays to optimize immobilization densities and activity. FN-mimetic surfaces presenting controlled densities of FNIII(7-10) were generated by varying the concentration of FNIII(7-10) in the coupling solution at a constant crosslinker concentration. Cells adhered to these functionalized surfaces via integrin alpha(5)beta(1) and blocking with integrin-specific antibodies completely eliminated adhesion. In addition, adherent cells spread and assembled focal adhesions containing alpha(5)beta(1), vinculin, and talin. This biomolecular engineering strategy represents a robust approach to increase biofunctional activity and integrin specificity of biomimetic materials.