A comparison of undergraduate teaching of psychiatry across medical schools in the Republic of Ireland.

OBJECTIVES: To examine the delivery and assessment of psychiatry at undergraduate level in the six medical schools in the Republic of Ireland offering a medical degree programme. METHODS: A narrative description of the delivery and assessment of psychiatry at undergraduate level by collaborative senior faculty members from all six universities in Ireland. RESULTS: Psychiatry is integrated to varying degrees across all medical schools. Clinical experience in general adult psychiatry and sub-specialities is provided by each medical school; however, the duration of clinical attachment varies, and the provision of some sub-specialities (i.e. forensic psychiatry) is dependent on locally available resources. Five medical schools provide 'live' large group teaching sessions (lectures), and all medical schools provide an array of small group teaching sessions. Continuous assessment encompasses 10-35% of the total assessment marks, depending on the medical school. Only one medical school does not provide a clinical examination in the form of an Objective Structured Clinical Examination with viva examinations occurring at three medical schools. CONCLUSIONS: Many similarities exist in relation to the delivery of psychiatry at undergraduate level in Ireland. Significant variability exists in relation to assessment with differences in continuous assessment, written and clinical exams and the use of vivas noted. The use of e-learning platforms has increased significantly in recent years, with their role envisaged to include cross-disciplinary teaching sessions and analysis of examinations and individual components within examinations which will help refine future examinations and enable greater sharing of resources between medical schools.

Electronic communication based interventions for hazardous young drinkers: A systematic review.

Previous reviews have specifically looked at computer-based or Internet-based approaches. However, there has been no systematic review focused upon electronic communication based interventions for hazardous young drinkers. Out of 3298 relevant citations, 13 papers consisting of 11 studies met the inclusion criteria. Effectiveness of intervention delivery was assessed using behavioural outcomes. Eight papers delivered interventions using the Web, three implemented text messaging, one used a mobile phone app and the remaining paper used a social networking site. The ability to provide personalized electronic feedback resulted in a reduction in alcohol consumption, frequency of binge drinking, and drinking in a non-risky way. However, intervention length did not appear to have an impact on overall effectiveness. Usage of text messaging and Social Network Sites (SNS) increased accessibility and ease of engaging in an intervention that is appealing and acceptable for young adults.

Diagnostic accuracy of a brief screening tool for attention deficit hyperactivity disorder in UK prison inmates.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is overrepresented in prison, making it imperative to identify a screening tool that can be quickly applied to efficiently detect the disorder. We explored the discrimination ability of a widely used ADHD screen, the Barkley Adult ADHD Rating Scale (BAARS-IV), against a clinical diagnostic interview. A brief version of the screen was then developed in order to simplify its use in the prison context, and maximize its diagnostic properties. METHOD: A cross-sectional study of 390 male prison inmates was performed in the UK, all participants were screened and interviewed via the Diagnostic Interview for ADHD in Adults 2.0 (DIVA-2). RESULTS: A total of 47 (12.1%) inmates screened positive for ADHD using the full BAARS-IV, and 96 (24.6%) were clinically diagnosed, for a sensitivity of 37.9 and a specificity of 96.3. Our models identified the six items that most predicted ADHD diagnosis, with adjusted odds ratios ranging from 2.66 to 4.58. Sensitivity, specificity and accuracy were 0.82, 0.84 and 0.84, respectively, for the developed brief scale, and 0.71, 0.85 and 0.81 for its validation. Weighted probability scores produced an area under the curve of 0.89 for development, and 0.82 for validation of the brief scale. CONCLUSIONS: The original BAARS-IV performed poorly at identifying prison inmates with ADHD. Our developed brief scale substantially improved diagnostic accuracy. The brief screening instrument has great potential to be used as an accurate and resource-effective tool to screen young people and adults for likely ADHD in the criminal justice system.

TNF-alpha and leptin activate the alpha-isoform of class II phosphoinositide 3-kinase.

The class II PI 3-kinases are known to be activated by growth factors and chemokines but to date there are no reports of cytokine mediated regulation. Further, the intracellular signalling mechanisms regulating the class-II PI 3-kinases are poorly understood. We investigated the effects of the cytokines TNFalpha and leptin on the activity of the alpha isoform of the class II PI 3-kinase (PI3K-C2alpha) and find that these stimulate the enzyme 2-fold and 3-fold, in CHO cells and J774.2 macrophages, respectively. The stimulation by leptin was not accompanied by recruitment of any tyrosine phosphorylated proteins to PI3K-C2alpha and no shift in electrophoretic mobility was noted. Furthermore, we demonstrate that the actions of both cytokines are blocked by the MEK inhibitor PD98059. These findings indicate that the cytokines activate PI3K-C2alpha and do so by a mechanism that requires activation of the ERK pathway and thus differs from the mechanism used by insulin to activate the enzyme.

Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways.

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.

Reduced leukocyte migration, but normal rolling and arrest, in interleukin-8 receptor homologue knockout mice.

PURPOSE: To determine the role of the murine interleukin-8 receptor homologue (mIL-8Rh, neutrophil chemokine CXC receptor 2) in leukocyte migration using intravital microscopy in a standardized model of eye inflammation, endotoxin-induced uveitis (EIU). METHODS: Two hundred fifty nanograms of E. coli endotoxin was injected into the vitreous of knockout mIL-8Rh(-/-) (n = 7) mice or heterozygous littermate mIL-8Rh(+/-) controls (n = 7). Intravital microscopic examination of iris microvasculature was performed at baseline and 6 and 24 hours after endotoxin injection. The numbers of rolling (cells/mm2 endothelial surface/min), sticking (cells/mm2 endothelial surface), and infiltrating cells (cells/mm2 iris tissue) were evaluated by digital off-line quantification. RESULTS: The number of infiltrating cells was significantly reduced in mIL-8Rh(-/-) mice: 406 +/- 77 cells/mm2 at 6 hours and 242 +/- 50 cells/mm2 at 24 hours in mIL-8Rh(+/-) mice versus 14 +/- 4 cells/mm2 at 6 hours and 38 +/- 11 cells/mm2 at 24 hours in mIL-8Rh(-/-) mice (P < 0.001). In contrast, the absence of the IL-8 receptor homologue did not reduce rolling or sticking. CONCLUSIONS: Iris rhodamine angiography allows precise quantification of leukocyte-endothelial dynamics in the absence of surgical trauma. IL-8 and its homologues are known to be potent signals for leukocyte migration. Although IL-8 has previously been implicated in cell adhesion, video imaging in vivo demonstrated that deletion of the IL-8 receptor homologue had minimal effect on rolling or arrest in this model of inflammation.

Anti-rat ICAM-1 antibody does not influence the course of experimental melanin-induced uveitis.

PURPOSE: Experimental melanin-induced uveitis (EMIU) is a T cell-mediated rat model of acute anterior uveitis. We investigated the possibility of preventing the inflammation with monoclonal antibody directed against rat intercellular adhesion molecule 1 (ICAM-1). METHODS: To induce EMIU, Lewis rats were immunized with bovine ocular melanin extract (250-500 microg). Each day from day 6 post-immunization, rats were injected intraperitoneally with anti-ICAM-1 monoclonal antibody (IA29) or normal mouse serum, and examined with a slit-lamp biomicroscope. On the first day of clinical inflammation, intravital microscopy of iris vasculature was performed on each animal following intraperitoneal injection of rhodamine 6G. At the peak of clinical inflammation, rats were killed, and eyes were examined histologically. Binding potency of IA29 was tested by flow cytometry using concanavalin A-stimulated rat T cells. Immunohistochemical staining was used to detect IA29 on rat uveal vascular endothelium. RESULTS: The ability of IA29 to bind T cell blasts was present to a 1:2000 dilution, and IA29 was readily detectable on uveal vascular endothelium following systemic administration. However, there was no significant difference (p > 0.05) in incidence, time of onset, or severity or histological appearance of EMIU for the rats treated with IA29 when compared with the control rats. Intravital microscopy revealed sticking of leukocytes in the iris vasculature in both groups. CONCLUSIONS: We were unable to demonstrate an inhibitory effect of anti-rat ICAM-1 antibody on the outcome of EMIU. Our observations may reflect a redundancy in the adhesion molecule profile responsible for this uveitis.

IL-1 and TNF receptor-deficient mice show decreased inflammation in an immune complex model of uveitis.

PURPOSE: To determine the role of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the induction of uveitis by a reverse passive Arthus reaction (RPAR). METHODS: Human serum albumin (HSA) antiserum was injected into the vitreous of "knockout" or "double knockout" mice genetically deficient in IL-1 receptor type I (IL-1RI-/-), TNF receptors p55 and p75 (TNFR p55-/-/p75-/-), IL-1RI and TNFR p55 (IL-1RI-/-/TNFR p55-/-), and controls. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were enucleated 4 hours after antigen challenge, and inflammation was quantitated by counting cells on histologic sections. Interleukin-6 in aqueous humor was measured with a B9 cell bioassay. The distribution of immune complexes in eyes was observed by immunohistochemical staining for IgG and complement component C3. RESULTS: Four hours after antigen challenge, immune complexes were localized at the ciliary body and iris of receptor-deficient mice. A transient uveitis was most severe at this time. A significant reduction in the median number of infiltrating cells was found in TNFR p55-/-/p75-/- mice (4.8, n = 15), compared with controls (14.2, n = 20, P < 0.05). The median number of infiltrating cells was significantly reduced in IL-1RI-/- mice (knockout 2.6, n = 11; controls 7.4, n = 8, P < 0.005). Interleukin-1RI-/-/TNFR p55-/- mice had a strong reduction in infiltrating cells (knockout 1.6, n = 11; controls 27.3, n = 12, P = 0.002). Interleukin-6 activity in aqueous humor was reduced in IL-1RI-/-/TNFR p55-/- mice (P = 0.03) but not in TNFR p55-/-/p75-/- (P = 0.40) mice. Most IL-1RI-/-mice had no detectable aqueous humor IL-6, but this group was not statistically different from controls. CONCLUSIONS: In contrast to endotoxin-induced uveitis, both IL-1 and TNF appear to have critical roles in RPAR uveitis. When receptors for these cytokines were deleted, the severity of immune complex-induced uveitis was profoundly reduced.

Murine endotoxin-induced uveitis, but not immune complex-induced uveitis, is dependent on the IL-8 receptor homolog.

PURPOSE: To determine the roles of the murine interleukin-8 receptor homolog (mIL-8Rh, neutrophil chemokine CXC receptor 2) and macrophage inflammatory protein-1alpha (MIP-1alpha, a CC chemokine) in two eye inflammation models: endotoxin-induced uveitis (EIU) and immune complex-induced uveitis (reverse passive Arthus reaction (RPAR) uveitis). METHODS: For the EIU model, 250 ng E.coli endotoxin was injected into the vitreous of mIL-8Rh-/- mice or heterozygous littermate mIL-8Rh+/- controls and into MIP-1alpha-/- mice or congenic MIP-1alpha+/+ controls. Eyes were harvested after 24 h for histologic characterization of infiltrating cells and IL-6 bioassays. For the RPAR model, mouse antiserum against human serum albumin (HSA) was injected into the vitreous of mIL-8Rh-/-, mIL-8Rh+/-, MIP-1alpha-/-, and MIP-1alpha+/+ mice. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were harvested after 4 h for analysis. RESULTS: RPAR resulted in the deposition of immune complexes at the ciliary area and iris with the subsequent development of uveitis. Genetic deficiency of mIL-8Rh reduced the median number of infiltrating cells in EIU by 63% (p < 0.01) but had no effect on RPAR-induced inflammation. In the EIU model, macrophages comprised a much higher percentage (45%) of infiltrating cells in mice lacking mIL-8Rh than in controls (17%). Loss of the MIP-1alpha gene had no apparent effect on RPAR uveitis and a 39% reduction of infiltrating cells in EIU that was not statistically significant. IL-6 activity in aqueous humor was much less in mice with RPAR uveitis than in those with EIU. Neither gene deletion had a significant impact on IL-6 levels in either disease model. CONCLUSIONS: Chemokines acting via mIL-8Rh have a significant role in the induction of neutrophil infiltration during EIU but not during RPAR uveitis. MIP-1alpha is not critical for either EIU or RPAR-induced uveitis. The differential dependence on IL-8-like chemokines is in accord with the two forms ofuveitis having different etiologies and, therefore, potentially different optimal therapies.

The effect of genetic deficiency of adhesion molecules on the course of endotoxin-induced uveitis.

PURPOSE: Multiple adhesion molecules of the selectin, integrin, and immunoglobulin-like families are involved in the migration of leukocytes out of the bloodstream into inflamed tissues. This study addresses the question of which adhesion molecules are specifically involved in endotoxin-induced uveitis. METHODS: Mice genetically deficient in p-selectin, ICAM-1, beta2-integrin, or controls received intravitreal injections of endotoxin. Eyes were harvested 24 h later and inflammation was evaluated by histologic and immunohistochemical assays of infiltrating cells. RESULTS: Mice lacking either P-selectin or beta2-integrin had less inflammation than controls (median cells/section: 64 for P-selectin knockout vs 130 for controls, p=0.02, n=17 per group: 244 for beta2-integrin knockouts, n=14, vs 355 for controls, n=17, p=0.05). Neither gene deletion significantly changed the ratio of infiltrating neutrophils to macrophages. ICAM-1 knockouts tended to have fewer infiltrating cells (median 22 cells/section) compared to controls (median 132 cells/section), but this difference was not statistically significant (p=0.25, n=9 per group). CONCLUSIONS: P-selectin, beta2-integrin, and possibly ICAM-1 are involved in the ocular inflammatory response to endotoxin. The lack of complete inhibition of leukocyte infiltration with the complete loss of each adhesion molecule is in accord with the notion that alternative adhesion molecules also participate in this process.

CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav.

CD19 is a coreceptor that amplifies signaling by membrane immunoglobulin (mIg) to promote responses of the B lymphocyte to T-dependent antigens. Vav is a guanine nucleotide exchange factor for the Rho, Rac, Cdc42 family of small GTPases. We found that coligating mIg and CD19 causes a synergistic increase in the tyrosine phosphorylation of CD19. Phosphorylated tyrosine-391 of CD19 binds Vav to mediate a sustained increase in intracellular Ca2+ concentration. This response correlates with activation by the CD19-Vav complex of phosphatidylinositol 4-phosphate 5-kinase for the synthesis of phosphatidylinositol 4,5-bisphosphate. Interaction of CD19 with Vav also mediates the synergistic activation of the mitogen-activated protein kinase JNK. Therefore, CD19 is a membrane adaptor protein that recruits Vav for the activation of lipid and protein kinases.

Co-receptors of B lymphocytes.

The past year has seen advances in our understanding of accessory membrane proteins that modulate the B cell response to antigen-receptor stimulation. The generation of complement receptor deficient mice has reinforced our appreciation of the importance of complement receptors in the B cell response to antigen. The association of inositol polyphosphate 5-phosphatase with FcgammaRIIB suggests another mechanism, in addition to recruitment of the phosphotyrosine phosphatase SHP-1, by which secreted immunoglobulin can limit further response to antigen. The in vivo function of CD22 in regulating the threshold of antigen-receptor signalling has been shown using CD22-deficient mice. Lastly, B cell receptor signalling in the B-1 subset of B lymphocytes has been demonstrated to be negatively regulated by CD5.

Time course of growth factor staining in a rabbit model of traumatic tractional retinal detachment.

BACKGROUND: This study examined the relationship between growth factor expression and cellular proliferation during the evolution of traumatic tractional retinal detachment (TRD) in a rabbit model. METHODS: TRD was induced in 15 pigmented rabbits by treating the inferior retina with cryopexy and making a scleral incision superiorly. Sections from varied time points were stained in the same assay with mouse monoclonal antibodies (MAb) specific for basic fibroblastic growth factor (bFGF) and platelet-derived growth factor (PDGF-BB/AB). RESULTS: Initially, the eyes exhibited intense vitritis; discrete membranes were present at 7 days and progressed to tractional retinal detachment at 17 and 28 days, after which there was no clinical change. At 6 and 24 h, bFGF, PDGF, and proliferating cell nuclear antigen (PCNA) were not detectable in membranes or wound sites (except for PDGF-positive inflammatory cells). On days 7, 17, 28, and 52, bFGF and PDGF were readily detectable in most membranes. Cellular proliferation as detected by PCNA staining was also present on days 7, 17, and 28, but was absent by day 52 despite growth factor staining. At all times, PCNA staining, which was most intense at the wound site, showed only limited correlation with staining for either growth factor for individual cells. Müller cells stained positively for PDGF-BB/AB in 13 of the 15 TRD eyes, but in none of the normal eyes. CONCLUSIONS: Since cellular proliferation correlated incompletely with the staining for bFGF and PDGF, these growth factors may not account exclusively for cellular proliferation within the membrane. Their distribution, however, including PDGF staining of Müller cells and bFGF staining at the vitreous-membrane interface, suggests that they may have roles in the pathogenesis of TRD.

Immunolocalization of integrins in the human retina.

PURPOSE: Integrins are cell surface proteins that participate in interactions between cells and with extracellular matrix. Binding of integrins to their ligands influences cell activities including proliferation, migration, and differentiation. Expression of integrin subunits from three different subfamilies were examined in human retina. METHODS: Integrins were detected in frozen sections of two human retinas with an avidin-biotin-complex immunohistochemical technique, using nine different monoclonal antibodies specific for alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha v, beta 1, beta 2, and beta 3. One retina was from a patient who had conjunctival squamous cell carcinoma, and the other was from uninvolved regions of an eye with a choroidal melanoma. RESULTS: All integrins tested were detectable in consistent patterns in two retinas. All except alpha 2 and alpha 4 were stained vibrantly in retinal and choroidal vessels. All alpha subunit staining of vessels showed overlap or close proximity to beta 1 staining. In addition to vessels, beta 1 was also present in the internal limiting membrane; alpha 2, alpha 3, alpha 4, alpha 5, and beta 2 were all found throughout much of the neural retina, albeit with distinctive staining patterns. Other than in association with vessels, alpha 6 and alpha v were not detected in neural retina, and beta 3 was only weakly detected in the nerve fiber layer; alpha 4 and beta 2 were expressed in the retinal pigment epithelium; beta 1 and beta 2 were strongly expressed in drusen present in one of the eyes. CONCLUSION: Nine integrin subunits have been found to have unique distributions in adult human retina. An understanding of the distribution in normal retina can serve as a useful contrast to patterns of staining associated with retinal diseases.

Immunolocalization of integrins in proliferative retinal membranes.

PURPOSE: Integrins are cell surface adhesion molecules that serve as receptors for extracellular matrix components or for other cells. Integrins help regulate processes such as cell proliferation, migration, and differentiation. These processes are thought to have fundamental roles in the pathogenesis of proliferative retinal membranes in diseases such as proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Therefore, the authors sought to determine the expression pattern of integrins in human proliferative membranes. METHODS: Tissue was obtained from two patients with PVR, two with PDR, and one subretinal neovascular membrane from a patient with presumed ocular histoplasmosis. Integrins were detected with an avidin-biotin-complex immunohistochemical technique using nine different monoclonal antibodies specific for alpha subunits 2, 3, 4, 5, 6, and V, and beta subunits 1, 2, and 3. RESULTS: All integrin subunits studied were detectable to varying degrees in proliferative membranes. beta 1 and alpha 6 were especially prominent at the edges of most PVR and PDR membranes. Pigmented cells expressed up to nine different integrin subunits, in contrast to normal RPE cells, which immunostained for only alpha 4 and beta 2. Proliferative diabetic retinopathy vessels expressed all nine integrin subunits examined, including alpha 4, which was poorly expressed in vessels of nondiabetic retinas. CONCLUSIONS: Integrin subunits are readily detectable in pathologic membranes. Both PVR and PDR are associated with altered integrin expression in vascular endothelium and pigmented cells. The distribution of integrins at the edge of a membrane suggests a role in the growth or contraction of the membrane, presumably by participating in the interaction between cells and substances such as vitreous collagen. Therefore, integrin antagonists may hold promise for the treatment of proliferative retinopathies.

Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining.

OBJECTIVE: To test the hypothesis that local proliferation contributes significantly to the hyperplasia of rheumatoid synovium. METHODS: Immunohistologic and chemical staining was used to identify 3 markers of cell proliferation: proliferating cell nuclear antigen, c-myc proto-oncogene, and nucleolar organizer regions. Synovium from 21 patients with rheumatoid arthritis, 34 with degenerative joint disease, and 7 with joint trauma was examined. RESULTS: All 3 markers indicated substantial, active proliferation of synovial lining cells in synovium with hyperplasia. Proliferating cells showed type I procollagen immunoreactivity but were negative for CD68, a monocyte/macrophage marker. Proliferation was greater in rheumatoid arthritis than in the other conditions evaluated. CONCLUSION: In situ proliferation of fibroblast-like synoviocytes in the synovium lining contributes considerably to the increase in cell numbers in rheumatoid synovium.