Global perspectives on the provision of diabetic retinopathy screening and treatment: Survey of health care professionals in 41 countries.

AIM: To assess the level of awareness and provision of screening and treatment for Diabetic Eye Disease (DED) comprising Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) among health care professionals. METHODS: The study was conducted in two phases. The first phase consisted of a qualitative study, based on semi-structured face-to-face and telephone interviews in 8 countries. The second phase used a quantitative approach utilising online surveys in 41 countries. The survey for health care professionals comprised of 43 questions covering provider information, practice characteristics, management of adults with diabetes and specific information from ophthalmologists on screening and treatments for DR. RESULTS: There were 2329 health care professionals who participated in the online survey. More than one third of diabetes specialists surveyed reported that they did not discuss eye care with their diabetes patients. Nearly two-thirds of all health care professionals surveyed reported that they had written information about diabetes for patients available in their practice. Only one in five (22%, n = 58) primary care providers reported they had material that contained sufficient information on eye complications, and 37% (n = 252) of ophthalmologists reported that they had sufficient information on eye complications. Sixty-five percent (n = 378) of ophthalmologists reported that most of their patients presented when visual problems had already occurred. Six percent (n = 36) stated that most of their patients presented when it was already too late for effective treatment. The most substantial barriers to eye health mentioned by health care professionals responding to the survey were: a patients' lack of knowledge and/or awareness about eye complications (43%), followed by lack of importance given to eye examinations by patients (33%), and the high cost of care (32%). Ophthalmologists also reported late screening (66%), and lack of patient education materials (55%) as obstacles for improving eye health outcomes. CONCLUSION: Health care professionals need to be appropriately supported and trained so they can provide adults with diabetes with information about the risks of DR, support them in reducing their risk, and advocate for the provision of affordable DR screening and treatment as required

The Molecular Signature Underlying the Thymic Migration and Maturation of TCRαβ+CD4+CD8- Thymocytes

BACKGROUND: After positive selection, the newly generated single positive (SP) thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate autoreactive T cells and functional maturation to acquire immune competence and egress capability. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the genetic program underlying this process, we analyzed changes in gene expression in four subsets of mouse TCRαβ(+)CD4(+)CD8(-) thymocytes (SP1 to SP4) representative of sequential stages in a previously defined differentiation program. A genetic signature of the migration of thymocytes was thus revealed. CCR7 and PlexinD1 are believed to be important for the medullary positioning of SP thymocytes. Intriguingly, their expression remains at low levels in the newly generated thymocytes, suggesting that the cortex-medulla migration may not occur until the SP2 stage. SP2 and SP3 cells gradually up-regulate transcripts involved in T cell functions and the Foxo1-KLF2-S1P(1) axis, but a number of immune function-associated genes are not highly expressed until cells reach the SP4 stage. Consistent with their critical role in thymic emigration, the expression of S1P(1) and CD62L are much enhanced in SP4 cells. CONCLUSIONS: These results support at the molecular level that single positive thymocytes undergo a differentiation program and further demonstrate that SP4 is the stage at which thymocytes acquire the immunocompetence and the capability of emigration from the thymus

Maturation-Dependent Licensing of Naive T Cells for Rapid TNF Production

The peripheral naïve T cell pool is comprised of a heterogeneous population of cells at various stages of development, which is a process that begins in the thymus and is completed after a post-thymic maturation phase in the periphery. One hallmark of naïve T cells in secondary lymphoid organs is their unique ability to produce TNF rapidly after activation and prior to acquiring other effector functions. To determine how maturation influences the licensing of naïve T cells to produce TNF, we compared cytokine profiles of CD4+ and CD8+ single positive (SP) thymocytes, recent thymic emigrants (RTEs) and mature-naïve (MN) T cells during TCR activation. SP thymocytes exhibited a poor ability to produce TNF when compared to splenic T cells despite expressing similar TCR levels and possessing comparable activation kinetics (upregulation of CD25 and CD69). Provision of optimal antigen presenting cells from the spleen did not fully enable SP thymocytes to produce TNF, suggesting an intrinsic defect in their ability to produce TNF efficiently. Using a thymocyte adoptive transfer model, we demonstrate that the ability of T cells to produce TNF increases progressively with time in the periphery as a function of their maturation state. RTEs that were identified in NG-BAC transgenic mice by the expression of GFP showed a significantly enhanced ability to express TNF relative to SP thymocytes but not to the extent of fully MN T cells. Together, these findings suggest that TNF expression by naïve T cells is regulated via a gradual licensing process that requires functional maturation in peripheral lymphoid organs

The why and how of thymocyte negative selection.

The generation of T cell receptor (TCR) sequence diversity is the strength of adaptive immunity, yet is also the Achilles' heel. To purge highly self-reactive T cells from the immune system, generation of diversity has coevolved with a mechanism of negative selection. Recent studies have revealed new insights addressing the why and how of negative selection by examining situations in which negative selection has failed in human and animals models of autoimmunity. Both thymocyte extrinsic and intrinsic mechanisms are required to restrict the TCR repertoire to a non-autoreactive set. Negative selection also ensures that T cells emerge with receptors that are focussed on the peptide moiety of MHC-peptide complexes