Effect of the glucocorticoid receptor antagonist Org 34850 on fast and delayed feedback of corticosterone release

We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c. cannula for Org 34850 administration. All experiments were conducted at the diurnal hormonal peak in the late afternoon. Rats were connected to an automated sampling system and blood samples were collected every 5 or 10 min. Org 34850 (10 mg/kg, s.c.) or vehicle (5% mulgofen in saline) was injected at 1630 h; 30 min later, rats received an injection of MPL (500 μg/rat, i.v.) or saline (0.1 ml/rat). We found that an acute administration of MPL rapidly decreased the basal corticosterone secretion and this effect was not prevented by acute pretreatment with Org 34850. However, blockade of GR with Org 34850 prevented delayed inhibition of MPL on corticosterone secretion measured between 4 and 12 h after MPL administration. Our data suggest an involvement of GR in modulating delayed, but not fast, inhibition induced by MPL on basal corticosterone secretion

Case-Based Study: From Prediabetes to Complications—Opportunities for Prevention

A 31-year-old man presents with central obesity, hypertension, and abnormal lipids. How would you manage this patient

Increased CD4 ؉ Expression and Decreased IL-10 in the Anterior Chamber in Idiopathic Uveitis

PURPOSE. To compare cell types and cytokines in aqueous humor from patients with uveitis either occurring in association with a systemic disease or apparently isolated and not associated with a systemic disease. METHODS. Cells were collected by centrifugation of fresh aqueous humor from uveitis and controls, and immunofluorescence techniques were performed with markers for T cells, B cells, and monocytes. Cytokines were measured in the aqueous supernatants, and serum samples were assayed for soluble interleukin-2 receptors. RESULTS. When aqueous samples from idiopathic uveitis were compared with those from uveitis associated with a systemic disease, there were increases in CD3 ϩ , CD4 ϩ (p ϭ 0.001), and activated CD4 ϩ T cells (p ϭ 0.02) and a decrease in B cells (p ϭ 0.0013). This was not reflected in the peripheral blood where there were no differences in the cell types or in soluble interleukin-2 receptor levels. No cells were obtainable from control aqueous. Interleukins-10 and -12, interferon-␥, and transforming growth factor-␤2 were detected in aqueous supernatants. Interleukin-10 was reduced (p ϭ 0.024) in uveitis in comparison with controls

Inflammatory eye disease:Pre-treatment assessment of patients prior to commencing immunosuppressive and biologic therapy: Recommendations from an expert committee

AIM: To outline recommendations from an expert committee on the assessment and investigation of patients with severe inflammatory eye disease commencing immunosuppressive and/or biologic therapy. METHOD: The approach to assessment is based on the clinical experience of an expert committee and a review of the literature with regard to corticosteroids, immunosuppressive drug and biologic therapy and other adjunct therapy in the management of patients with severe sight-threatening inflammatory eye disease. CONCLUSION: We recommend a careful assessment and consultative approach by ophthalmologists or physicians experienced in the use of immunosuppressive agents for all patients commencing immunosuppressive and/or biologic therapy for sight threatening inflammatory eye disease with the aim of preventing infection, cardiovascular, metabolic and bone disease and reducing iatrogenic side effects

Macrophages Inhibit Neovascularization in a Murine Model of Age-Related Macular Degeneration

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV. METHODS AND FINDINGS: We examined the role of macrophages in a mouse model of CNV. IL-10 (−/−) mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand). CONCLUSIONS: Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness

Interobserver Agreement Among Uveitis Experts on Uveitic Diagnoses:The Standardization of Uveitis Nomenclature Experience

• PURPOSE: To evaluate the interobserver agreement among uveitis experts on the diagnosis of the specific uveitic disease. • DESIGN: Interobserver agreement analysis. • METHODS: Five committees, each comprised of 9 individuals and working in parallel, reviewed cases from a preliminary database of 25 uveitic diseases, collected by disease, and voted independently online whether the case was the disease in question or not. The agreement statistic, κ, was calculated for the 36 pairwise comparisons for each disease, and a mean κ was calculated for each disease. After the independent online voting, committee consensus conference calls, using nominal group techniques, reviewed all cases not achieving supermajority agreement (> 75%) on the diagnosis in the online voting to attempt to arrive at a supermajority agreement. • RESULTS: A total of 5766 cases for the 25 diseases were evaluated. The overall mean κ for the entire project was 0.39, with disease-specific variation ranging from 0.23 to 0.79. After the formalized consensus conference calls to address cases that did not achieve supermajority agreement in the online voting, supermajority agreement overall was reached on approximately 99% of cases, with disease-specific variation ranging from 96% to 100%. • CONCLUSIONS: Agreement among uveitis experts on diagnosis is moderate at best but can be improved by discussion among them. These data suggest the need for validated and widely used classification criteria in the field of uveitis

Implementation of a health care policy: An analysis of barriers and facilitators to practice change

BACKGROUND: Governments often create policies that rely on implementation by arms length organizations and require practice changes on the part of different segments of the health care system without understanding the differences in and complexities of these agencies. In 2000, in response to publicity about the shortening length of postpartum hospital stay, the Ontario government created a universal program offering up to a 60-hour postpartum stay and a public health follow-up to mothers and newborn infants. The purpose of this paper is to examine how a health policy initiative was implemented in two different parts of a health care system and to analyze the barriers and facilitators to achieving practice change. METHODS: The data reported came from two studies of postpartum health and service use in Ontario Canada. Data were collected from newly delivered mothers who had uncomplicated vaginal deliveries. The study samples were drawn from the same five purposefully selected hospitals for both studies. Questionnaires prior to discharge and structured telephone interviews at 4-weeks post discharge were used to collect data before and after policy implementation. Qualitative data were collected using focus groups with hospital and community-based health care practitioners and administrators at each site. RESULTS: In both studies, the respondents reflected a population of women who experienced an "average" or non-eventful hospital-based, singleton vaginal delivery. The findings of the second study demonstrated wide variance in implementation of the offer of a 60-hour stay among the sites and focus groups revealed that none of the hospitals acknowledged the 60-hour stay as an official policy. The uptake of the offer of a 60-hour stay was unrelated to the rate of offer. The percentage of women with a hospital stay of less than 25 hours and the number with the guideline that the call be within 48 hours of hospital discharge. Public health telephone contact was high although variable in relation to compliance the guideline that the call be within 48 hours of hospital discharge. Home visits were offered at consistently high rates. CONCLUSION: Policy enactment is sometimes inadequate to stimulate practice changes in health care. Policy as a tool for practice change must thoughtfully address the organizational, professional, and social contexts within which the policy is to be implemented. These contexts can either facilitate or block implementation. Our examination of Ontario's universal postpartum program provides an example of differential implementation of a common policy intended to change post-natal care practices that reflects the differential influence of context on implementation

Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis.

BACKGROUND: RPE65 is specifically expressed in the retinal pigment epithelium and is essential for the recycling of 11-cis-retinal, the chromophore of rod and cone opsins. In humans, mutations in RPE65 lead to Leber congenital amaurosis or early-onset retinal dystrophy, a severe form of retinitis pigmentosa. The proof of feasibility of gene therapy for RPE65 deficiency has already been established in a dog model of Leber congenital amaurosis, but rescue of the cone function, although crucial for human high-acuity vision, has never been strictly proven. In Rpe65 knockout mice, photoreceptors show a drastically reduced light sensitivity and are subject to degeneration, the cone photoreceptors being lost at early stages of the disease. In the present study, we address the question of whether application of a lentiviral vector expressing the Rpe65 mouse cDNA prevents cone degeneration and restores cone function in Rpe65 knockout mice. METHODS AND FINDINGS: Subretinal injection of the vector in Rpe65-deficient mice led to sustained expression of Rpe65 in the retinal pigment epithelium. Electroretinogram recordings showed that Rpe65 gene transfer restored retinal function to a near-normal pattern. We performed histological analyses using cone-specific markers and demonstrated that Rpe65 gene transfer completely prevented cone degeneration until at least four months, an age at which almost all cones have degenerated in the untreated Rpe65-deficient mouse. We established an algorithm that allows prediction of the cone-rescue area as a function of transgene expression, which should be a useful tool for future clinical trials. Finally, in mice deficient for both RPE65 and rod transducin, Rpe65 gene transfer restored cone function when applied at an early stage of the disease. CONCLUSIONS: By demonstrating that lentivirus-mediated Rpe65 gene transfer protects and restores the function of cones in the Rpe65(-/-) mouse, this study reinforces the therapeutic value of gene therapy for RPE65 deficiencies, suggests a cone-preserving treatment for the retina, and evaluates a potentially effective viral vector for this purpose