Disruption of TGF-β Signaling Improves Ocular Surface Epithelial Disease in Experimental Autoimmune Keratoconjunctivitis Sicca

TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Expression of transforming growth factor-beta 1 (TGF-beta 1) in the developing periodontium of rats

Transforming growth factor-beta 1 (TGF-beta 1) has been reported to be expressed within several tissue compartments of developing molar crowns and therefore is implicated in tooth development. Additionally TGF-beta 1 may also play a crucial role in tissue repair and regeneration. The aim of this study was to determine the distribution of TGF-beta 1 in the developing periodontal attachment apparatus (cementum, periodontal ligament, and alveolar bone) in Lewis rats. Animals aged 3; 6, and 12 wks were killed, their mandibles removed, fixed; demineralized, and processed in paraffin. The localization of TGF-beta 1 in tissues was detected by polyclonal goat antibodies against human TGF-beta 1 by means of immunoperoxidase techniques. TGF-beta 1 messenger RNA was detected by in situ hybridization with a cocktail oligonucleotide probe. Cell counts were determined for analysis of the percentage of cells stained positive for TGF-beta 1 Results revealed that TGF-beta 1 was expressed in the developing alveolar bone, periodontal ligament, and cementum at all stages of tissue development studied. Staining was stronger at sites of cementum and alveolar bone compared with the periodontal ligament. Intensity of the positive staining, based on 3 grades, indicated a similarity between the tissues obtained from different ages, but varied between several cell types. Cementoblasts and osteoblasts stained more strongly than fibroblasts. Large numbers (similar to 90%) of the osteocytes in developing bone expressed TGF-beta 1; however, in mature bone, fewer osteocytes stained for TGF-beta 1. The percentages of positively stained cementoblasts, osteoblasts, and fibroblasts in the periodontal space were greater at the apical portion than at the cervical portion of the root. TGF-beta 1 mRNA was expressed in osteoblasts, some bone marrow cells, cementoblasts, and fibroblasts, This study indicates that TGF-beta 1 may play an important role in the modulation of tissue formation and development of the periodontium