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Purpose: In the lacrimal gland (LG) acinar cells, signaling regulates the release of secretory vesicles through specific Rab and SNARE exocytotic proteins. In diabetes mellitus (DM), the LGs are dysfunctional. The aim of this work was to determine if secretory apparatus changes were associated with any effects on the secretory vesicles (SV) in diabetic rats as well as the expression levels of constituent Rab and members of the SNARE family, and if insulin supplementation reversed those changes. Methods: DM was induced in male Wistar rats with an intravenous dose of streptozotocin (60 mg/kg). One of the two diabetic groups was then treated every other day with insulin (1 IU). A third control group was injected with vehicle. After 10 weeks, Western blotting and RT-PCR were used to compared the Rab and SNARE secretory factor levels in the LGs. Transmission electron microscopy evaluated acinar cell SV density and integrity. Results: In the diabetes mellitus group, there were fewer and enlarged SV. The Rab 27b, Rab 3d, and syntaxin-1 protein expression declined in the rats with diabetes mellitus. Insulin treatment restored the SV density and the Rab 27b and syntaxin expression to their control protein levels, whereas the Vamp 2 mRNA expression increased above the control levels. Conclusions: Diabetes mellitus LG changes were associated with the declines in protein expression levels that were involved in supporting exocytosis and vesicular formation. They were partially reversed by insulin replacement therapy. These findings may help to improve therapeutic management of dry eye in diabetes mellitus.Keywords: Diabetes mellitus/chemically induced; Lacrimal apparatus; Exocytosis; secretory vesicles; R-SNARE proteins; Animals; Rats RESUMO Objetivo: Células acinares da glândula lacrimal (GL) sinalizam a regulação da liberação através de vesículas secretórias específicas Rab proteínas exocitóticas SNARE. No diabetes mellitus (DM), as glândulas lacrimais são disfuncionais. O objetivo deste trabalho foi determinar se em ratos diabéticos, alterações dos aparatos secretórios estão associados a efeitos sobre vesículas secretoras (VS) e sobre os níveis de expressão do constituinte Rab, bem como membros da família SNARE, e se a suplementação de insulina reverte as alterações. Métodos: DM foi induzido em ratos Wistar machos com uma dose intravenosa de estreptozotocina (60 mg/kg). Um dos dois grupos diabéticos foi então tratado a cada dois dias com insulina (1 UI). Um terceiro grupo controle foi injetado com o veículo. Após 10 semanas, western blot e RT-PCR comparou níveis de fatores secretórios de

The aims of this study were (1) to determine the efficacy of adenovirus vector serotype 5 (Ad) encoding human soluble VEGF receptor 1 (s-VEGFR1) gene transfer to the lacrimal gland (LG); (2) to investigate whether expression of s-VEGFR1 prevents corneal neovascularization (CNV) induced by alkali burns; and (3) to evaluate the safety of the procedure. METHODS. AdVEGFR1 vectors (25 lL, 1 3 10 10 pfu/mL) were injected in the right LGs of rats and were compared with AdNull vector (25 lL, 1 3 10 10 pfu/mL) or 25 lL of saline (Control) before cornea alkali burns with 1 M NaOH. After 7 days, CNV was documented at the slit lamp. Tear secretion was measured with phenol red threads. The animals were tested for s-VEGFR1 mRNA and protein in the LG by quantitative (q)PCR and immunohistochemistry staining, respectively. qPCR was used to compare the mRNA levels of IL-1b, IL-6, and TNF-a in the LG and ipsilateral trigeminal ganglion (TG). RESULTS. Ad-VEGFR1 transfected 83% (10/12) of the rats. VEGFR1 was present in LG acinar cells. CNV was prevented in 9 of 12 animals in the Ad-VEGFR1 group, compared with the Ad-Null (3:10) and Control groups (1:10) (P ¼ 0.0317). The tear secretion and cytokine mRNA levels in the LG and TG were similar in all three groups (P > 0.05). CONCLUSIONS. Adenoviral vector gene transfer was safe for LG structure and function. The LG as the target tissue showed local expression of human s-VEGFR1, and CNV was prevented in most of the eyes exposed to alkali burns.

Objective: To summarize characteristics, complications and success rates of different catheter-directed thrombolysis (CDT) protocols for the treatment of lower extremities (LE) deep venous thrombosis (DVT). Methods: A systematic review using electronic databases (MEDLINE, Scopus and Web of Science) was performed to identify randomized controlled trials and observational studies related to LE-DVT treated with CDT. A random-effect model meta-analysis was performed to obtain the pooled proportions of early complications, post-thrombotic syndrome (PTS) and venous patency. Results: Forty-six studies met the inclusion criteria reporting 49 protocols (n=3,028 participants). In studies that addressed the thrombus location (n=37), LE-DVT had iliofemoral involvement in 90±23% of the cases. Only 4 series described CDT as the solely intervention for LE-DVT, while 47% received additional thrombectomy (manual, surgical, aspiration or pharmaco-mechanical) and 89% used stenting. Definition of venogram success was highly variable, being the Venous Registry Index the most used method (n=19). Among those, minimal thrombolysis rate (<50% lysed thrombus) was 0-53%, partial thrombolysis (50-90% lysis) was 10-71% and complete thrombolysis (90-100%) was 0-88%. Pooled outcomes were 8.7% (95%CI 6.6-10.7) for minor bleeding, 1.2% (95%CI 0.8-1.7%) for major bleeding, 1.1% (95%CI 0.6-1.6) for pulmonary embolism and 0.6% (95%CI 0.3-0.9) for death. Pooled incidences of PTS and of venous patency at up to 1 year of follow-up were 17.6% (95%CI 11.8-23.4) and 77.5% (95%CI 68.1-86.9), respectively. Conclusions: Assessment of the evidence is hampered by the heterogeneity of protocols, which may be reflected in the variation of PTS rates. Despite this, CDT is a low-risk treatment for LE-DVT.

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