Interaction of the cyanobacterial thiazoline-containing lipid curacin A with bovine brain tubulin

Curacin A is a thiazoline-containing lipid from the marine cyanobacterium Lyngbya majuscula. Despite being a potent inhibitor of microtubule assembly and of colchicine binding to tubulin, curacin A bears little or no structural resemblance to colchicine or to any other tubulin ligand. We investigated the interaction of curacin A with bovine brain tubulin using three different approaches. We first examined its effect on the intra-chain formation of a cross-link in β-tubulin by N,N′- ethylenebis(iodoacetamide). Formation of this cross-link, between cys²³⁹ and cys³⁵⁴, is blocked by colchicine and its A-ring analogues as well as by various other inhibitors of colchicine binding; C-ring analogues do not inhibit its formation. Curacin A strongly inhibited formation of this cross-link. Second, we examined the effect of curacin A on the time-dependent exposure of sulfhydryl groups on tubulin as measured by alkylation with iodo[¹⁴C]acetamide. Curacin A inhibited this very strongly, more so than either colchicine or podophyllotoxin. Last, we investigated the effect of curacin A on the time-dependent exposure of hydrophobic areas on the tubulin molecule. We found that curacin A had only a small effect on this process, comparable in magnitude to that of podophyllotoxin. Curacin A thus appears to have an unusual interaction with tubulin. Its binding site on tubulin is likely to overlap with that of the A-ring of colchicine. Drug Dev. Res. 40:223–229, 1997. © 1997 Wiley-Liss, Inc.     

Comparison of broadband and monochromatic photopic negative response in eyes of patients with diabetes with no diabetic retinopathy and different stages of diabetic retinopathy

Purpose:To evaluate the change in broadband (W/W), red on blue (R/B), and blue on yellow (B/Y) photopic negative response (PhNR) in patients with diabetes mellitus with no diabetic retinopathy (no DR) and different stages of DR and compare it with age-matched controls. This study was performed to provide a single PhNR protocol that can be used for early diagnosis of DR.Methods:It was a cross-sectional case-control study done in a hospital setup. Patients with diabetes with no DR and different stages of DR with no other associated ocular pathologies were included. Age-matched controls with no retinal pathologies were also included for comparison. All subjects underwent detailed ophthalmic examination and W/W, R/B, and B/Y electroretinography. Fifty control eyes and 52 treatment naïve eyes of 52 patients with diabetes [no DR = 11, mild nonproliferative diabetic retinopathy (NPDR) =11, moderate NPDR = 10, severe NPDR = 9, and proliferative DR = 11] were included in the study.Results:On comparing the ERG responses in patients with diabetes and age-matched controls, a significant reduction (P < 0.05) was noted in the amplitudes of a-wave (39.78 ± 11.34 μV vs. 67.28 ± 12.88 μV), b-wave (116.25 ± 45.25 vs. 134.39 ± 28.78 μV), W/W PhNR (33.86 ± 17.33 vs. 67.18 ± 15.99 μV), R/B PhNR (28.77 ± 15.85 vs. 53.48 ± 14.15 μV), and B/Y PhNR (55.04 ± 32.63 vs. 104.79 ± 24.37 μV). Post hoc analysis revealed that all the eyes in the diabetic group, including those with no DR, had a significantly reduced PhNR amplitude (P < 0.05) when compared with controls. PhNR was found to reduce in amplitude with increasing severity of DR (P < 0.05), with more significance in B/Y. Receiver operating characteristic showed highest area under the curve in B/Y PhNR (94%, P < 0.001), with maximum sensitivity and specificity of 88% and 87%, respectively.Conclusion:Changes in the amplitude and implicit time of ERG can reflect the severity of DR. PhNR amplitudes, especially B/Y PhNR, appear to be significantly reduced even in eyes with no DR.     

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti‐tumor necrosis factor treatment. Part 2: Management

Because anti‐tumor necrosis factor (anti‐TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti‐TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti‐TNF treatment. Twenty‐three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web‐based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti‐TNF therapy, (4) monitoring during anti‐TNF therapy, and (5) management of an active TB infection after anti‐TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti‐TNF treatment.     

Update in the Percutaneous Management of Coronary Chronic Total Occlusions

Percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been rapidly evolving during recent years. With improvement in equipment and techniques, high success rates can be achieved at experienced centers, although overall success rates remain low. Prospective, randomized-controlled data regarding optimal use and indications for CTO PCI remain limited. CTO PCI should be performed when the anticipated benefit exceeds the potential risk. New high-quality studies of the clinical outcomes and techniques of CTO PCI are needed, as is the expansion of expert centers and operators that can achieve excellent clinical outcomes in this challenging patient and lesion subgroup. In the current review the authors summarize the latest publications in CTO PCI and provide an overview of the current state of the field.     

Challenges in managing proximal hypospadias: A 17-year single-center experience

BackgroundThere are only a few publications in the medical literature reporting on complication rates in proximal hypospadias surgery, particularly with regard to long-term follow-up.MethodsOver a 17.5-year period, we operated 100 patients with penoscrotal, scrotal and perineal hypospadias. Sixty-four had a single-stage repair, including 15 who received a buccal mucosa inlay “Snodgraft” repair. Thirty-six had a two-stage Bracka repair of which 19 received buccal or lower lip grafts and 17 had preputial grafts. Overall, 34 patients received buccal grafts. The median follow-up was eight years (range 1–16 years). Three patients were operated for residual chordee years later.ResultsUrethral fistulae occurred in a total of 26/100 (26.0%) cases, meatal stenosis in 16/100 (16.0%), wound breakdown in six (6.0%) and graft failure in one (1.0%). The fistula rate after the single-stage approach was 15/64 (23.4%), whereas it was 11/36 (30.6%) following two-stage repair (P = 0.4811).ConclusionsProximal hypospadias remains a challenging condition to treat. It is possible to perform a single-stage repair in 64.0% of cases. This brings down the median number of operations to only two. Lower lip grafts were used in 34.0% but are now used in redo-surgeries only. Our fistula rate was 26.0% but has decreased significantly in recent years.Level of evidenceLevel III.