Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

Purpose: To measure prothrombin fragments (F1+2) and thrombin-antithrombin complex (TAT) in vitreous and subretinal fluid (SRF) of rhegmatogenous retinal detachment (RRD) patients and to validate and further specify our earlier finding of increased thrombin activity in patients with proliferative vitreoretinopathy (PVR). Methods: F1+2 and TAT were measured in 31 vitreous and 16 SRF samples using the Enzygnost® immunoassays. Results: We found significant levels of F1+2 and TAT in the vitreous of all patients with RRD compared to patients with macular hole or macular pucker. However, there was no significant difference between patients who would develop PVR in the future, had established PVR, and patients with uncomplicated RRD both in vitreous concentrations of F1+2 (Kruskal-Wallis p = 0.963) and TAT (p = 0.516). Conclusion: The analysis of F1+2 and TAT confirmed significant thrombin generation in both vitreous and SRF of patients with RRD. An imbalance between the thrombin regulation mechanisms TAT and α2-macroglobulin possibly explains the difference from our previous findings

The Role of Thrombin in Proliferative Vitreoretinopathy

PURPOSE. To determine the role of thrombin in the development of proliferative vitreoretinopathy (PVR). METHODS. Vitreous was collected from patients undergoing a vitrectomy (macular holes and puckers, n ¼ 11 [controls]; retinal detachment without PVR development following vitrectomy, n ¼ 15 [RRD1]; retinal detachment with PVR development within 6 months after vitrectomy, n ¼ 11 [RRD2]; and established PVR, n ¼ 14 [PVR]). Thrombin activity in vitreous was determined using a thrombin-specific chromogenic substrate. ARPE-19 cells were stimulated with 83 diluted vitreous samples in the presence and absence of hirudin. The samples were analyzed at t ¼ 0 and t ¼ 24 hours for the presence of 27 cytokines/ chemokines and growth factors using a multiplex approach. In comparable studies, ARPE-19 cells were stimulated for 2 hours, and mRNA expression levels for CCL2, CXCL8, GMCSF, IL6, and PDGFB were determined by real-time quantitative (RQ)-PCR. RESULTS. Thrombin activity was significantly (P < 0.05) higher in vitreous of the PVR group compared to the other groups. Proliferative vitreoretinopathy vitreous stimulated the production of chemokine (C-C motif) ligand (CCL)2, chemokine (C-X-C motif) ligand (CXCL)8, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and plateletderived growth factor (PDGF)-BB by ARPE-19 to significantly (P < 0.05) higher levels than vitreous from the RRD1 and RRD2 groups. These effects of PVR vitreous were significantly (P < 0.05) reduced by hirudin. These data were confirmed by mRNA studies. CONCLUSIONS. Thrombin activity is increased in vitreous of patients with established PVR and is involved in the activation of proinflammatory and profibrotic pathways in RPE cells. Inhibition of thrombin activity may therefore represent a potential treatment option for proliferative vitreoretinopathy

The immunopathology of ANCA-associated vasculitis.

The small-vessel vasculitides are a group of disorders characterised by variable patterns of small blood vessel inflammation producing a markedly heterogeneous clinical phenotype. While any vessel in any organ may be involved, distinct but often overlapping sets of clinical features have allowed the description of three subtypes associated with the presence of circulating anti-neutrophil cytoplasmic antibodies (ANCA), namely granulomatosis with polyangiitis (GPA, formerly known as Wegener's Granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (eGPA, formerly known as Churg-Strauss syndrome). Together, these conditions are called the ANCA-associated vasculitidies (AAV). Both formal nomenclature and classification criteria for the syndromes have changed repeatedly since their description over 100 years ago and may conceivably do so again following recent reports showing distinct genetic associations of patients with detectable ANCA of distinct specificities. ANCA are not only useful in classifying the syndromes but substantial evidence implicates them in driving disease pathogenesis although the mechanism by which they develop and tolerance is broken remains controversial. Advances in our understanding of the pathogenesis of the syndromes have been accompanied by some progress in treatment, although much remains to be done to improve the chronic morbidity associated with the immunosuppression required for disease control

Clonidine as an adjuvant to prolong local analgesia in conventional scleral buckle surgery

UNLABELLED: Abstract Purpose: The aim of this study was to determine the effect of a single dose of 150 μg of clonidine as an adjuvant to levobupivacaine (Chirocaine(®)) in retrobulbar block on postoperative safety and analgesia. METHODS: This was a prospective, randomized, controlled, double-blind trial. One hundred twenty patients with a rhegmatogenous retinal detachment scheduled to undergo external buckling surgery and cryocoagulation were asked to participate. Participants were randomly assigned either to receive 3-5 mL Chirocaine (22.5-37.5 mg) or 3-5 mL Chirocaine and 1 mL clonidine (150 μg) before surgery. Main outcome measures were postoperative pain, use of analgesics, blood pressure, and plasma clonidine concentration. Nine nonrandomized patients consented to give blood samples for pharmacokinetic analysis. RESULTS: There was no significant difference in pain score between both groups. On average, the use of analgesic medication occurred later in the clonidine group (P=0.0004), but there was no statistical difference in the first time that postoperative medication was taken (P=0.13). Blood pressure was reduced by clonidine (systolic: P=0.02, diastolic: P=0.006). Clonidine levels could be demonstrated during the 24-h postoperative period, with an average half-life of 22 h. CONCLUSIONS: Administration of clonidine as an adjuvant to conventional retrobulbar block is safe, and delays the postoperative use of analgesics. The reduction of postoperative pain and the time of first use of analgesic medication, however, were not significantly different between groups. Further, pain scores in both study groups remained low. Therefore, the beneficial effect of clonidine in conventional scleral buckle surgery appears to be limited

Massive ingestion of cardiac drugs: Toxicokinetic aspects of digoxin and sotalol during hemofiltration

Case. We present the case of a 75-year-old patient admitted to the emergency department after ingesting a large amount of several cardiac drugs, among which were digoxin and sotalol. Because of renal insufficiency, cardiogenic shock, and high serum digoxin levels, the patient received continuous venovenous hemofiltration (CVVH) and digoxin-specific Fab fragments. Digoxin and the digoxin-specific Fab fragments are normally cleared by the kidneys. Methods. Serum-free and total digoxin and serum sotalol concentrations were monitored for several days. Results. Less than 10 of the estimated ingested dose of digoxin was cleared by CVVH within 5 days. Conclusion. CVVH has little influence on the clearance of Fab-bound digoxin from the body. In contrast, sotalol is efficiently cleared by CVVH

Postoperative aqueous humour flare as a surrogate marker for proliferative vitreoretinopathy development

Purpose: As some surgical procedures have been shown to increase postoperative flare values and thus contribute to blood-ocular barrier breakdown, retinal reattachment surgery might influence the risk of developing proliferative vitreoretinopathy (PVR). Therefore, we investigated whether postoperative aqueous flare values are a surrogate marker for the development of postoperative PVR. Methods: We prospectively included 195 patients with primary rhegmatogenous retinal detachment (RRD) and measured aqueous laser flare preoperatively, and at 2 and 6 weeks postoperatively. Postoperative PVR was defined as reoperation for redetachment due to PVR membranes, within 6 months of initial surgery. Logistic regression and receiver operating characteristic (ROC) analysis determined whether higher postoperative flare values were associated with an increased risk of developing PVR later on. Results: Reoperation for postoperative PVR was needed in 12 (6.2%) patients; in 18 (9.2%), reoperation was not related to PVR. The median flare value for patients who would develop PVR was significantly higher than that of patients who would not develop PVR, both at 2 weeks (p = 0.001) and 6 weeks (p < 0.001) postoperatively. Logistic regression analyses showed that a higher flare value significantly increased the odds of developing PVR, either at 2 weeks [odds ratio (OR) 1.027; 95% CI: 1.010-1.044] or 6 weeks (OR 1.076; 95% CI: 1.038-1.115). Conclusion: Flare values both at 2 and 6 weeks postoperatively seem a good surrogate marker in terms of sensitivity and specificity for the development of postoperative PVR but have only a modest positive predictive value. The 2-week value would be more useful in terms of early recognition of high-risk patients and hence give the possibility to better study effects of treatment methods