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Scutellariae radix (SR, roots of Scutellaria baicalensis Georgi), a popular Chinese medicine, contains plenty of flavonoids such as baicalin, wogonoside, baicalein, and wogonin. Methotrexate (MTX), an important immunosuppressant with a narrow therapeutic index, is a substrate of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). This study investigated the effect of SR on MTX pharmacokinetics and the underlying mechanisms. Rats were orally administered MTX alone and with 1.0 or 2.0 g/kg of SR. The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. Cell models were used to explore the involvement of MRP2 and BCRP in the interaction. The results showed that 1.0 g/kg of SR significantly increased Cmax, AUC(0-30), AUC(0-2880), and mean residence time (MRT) of MTX by 50%, 45%, 501%, and 347%, respectively, and 2.0 g/kg of SR significantly enhanced the AUC(0-2880) and MRT by 242% and 293%, respectively, but decreased AUC(0-30) by 41%. Cell line studies indicated that SR activated the BCRP-mediated efflux transport, whereas the serum metabolites of SR inhibited both the BCRP- and MRP2-mediated efflux transports. In conclusion, SR ingestion increased the systemic exposure and MRT of MTX via modulation on MRP2 and BCRP., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease., Methods: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809., Findings: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events., Interpretation: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality., Funding: AbbVie Pharmaceuticals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To compare the long-term efficacy of intraoperative 5-fluorouracil (5-FU) and mitomycin C (MMC) in primary trabeculectomy., Design: Comparative case series and extension of a prospective, randomized controlled trial., Participants: One hundred fifteen eyes of 103 subjects undergoing primary trabeculectomy with either intraoperative 5-FU or MMC., Methods: This study is an extension of a 12-month, prospective, double-masked, randomized trial that previously was reported. Subjects were randomized to receive either intraoperative 5-FU (50 mg/ml for 5 minutes) or MMC (0.2 mg/ml for 2 minutes) during primary trabeculectomy. Follow-up data were collected from patient medical records after informed consent was obtained from the study patient. Attempts were made to contact subjects who had been lost to follow-up, and some consented to reexamination., Main Outcome Measures: The primary measure was Kaplan-Meier survival function, with failure defined as intraocular pressure (IOP) of more than 21 mmHg or less than 6 mmHg on 2 consecutive visits, less than 20% reduction from baseline IOP, loss of light perception vision, or additional glaucoma surgery to lower IOP (except bleb revision). Secondary measures included IOP, number of glaucoma medications, visual acuity, additional surgeries, and number and type of complications., Results: Mean follow up was 53.4+/-31.4 months (interquartile range, 34-82 months) in the 5-FU group and 45.3+/-28.0 months (interquartile range, 19-70 months) in the MMC group (P = 0.15, t test). Kaplan-Meier success was 0.83 at 3 years and 0.76 at 5 years in the 5-FU group and 0.79 at 3 years and 0.66 at 5 years in the MMC group (P = 0.18, log-rank test). Bleb leakage was the most common complication in each group and developed in approximately 4% of subjects in each group per year (P = 0.33, log-rank test)., Conclusions: There were no significant differences between topical 5-FU and topical MMC in reducing IOP of eyes undergoing primary trabeculectomy. Both antifibrosis agents may contribute to the development of bleb leakage., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Long-term outcomes after kidney transplantation remain suboptimal, despite the great achievements observed in recent years with the use of modern immunosuppressive drugs. Currently, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the cornerstones of immunosuppressive regimens in many centers worldwide, regardless of their well described side-effects, including nephrotoxicity. In this article, we review recent CNI-minimization strategies in kidney transplantation, while emphasizing on the importance of long-term follow-up and patient monitoring. Finally, accumulating data indicate that low-dose CNI-based regimens would provide an interesting balance between efficacy and toxicity.

Purpose: To assess the long-term success rate and to determine factors that predict survival after 5-fluorouracil-augmented needling revision of poorly functioning trabeculectomy blebs., Design: Prospective observational cohort study., Participants: Eighty-one consecutive patients undergoing bleb needling., Methods: Survival analysis was performed after a minimum of 2 years' follow-up. Cox proportional hazards regression analysis was used to test the association between survival and study variables, including bleb morphology., Main Outcome Measures: Intraocular pressure (IOP) reduction by >20% and to 20% and to

Objective: To characterize and understand, at the cellular level, the aqueous humor pathways after filtering surgery, using in vivo confocal microscopy and impression cytology (IC)., Design: Observational case series., Participants: Thirty-two blebs of 29 patients after trabeculectomy were retrospectively evaluated., Methods: In vivo confocal microscopy and immunofluorescence staining of IC samples taken on and around the bleb area were performed. Impression cytology samples were examined under confocal microscopy after goblet cell and inflammatory cell immunostaining with anti-MUC5AC and antivimentin antibodies, respectively. Eyes were classified into 3 groups: (1) functioning blebs (11 eyes), (2) nonfunctioning blebs (10 eyes), and (3) functioning blebs after mitomycin C application (12 eyes). Impression cytology specimens and in vivo confocal microscopy images were analyzed and compared in a masked manner., Main Outcome Measures: Conjunctival epithelium changes of each type of bleb were analyzed using both impression cytology specimens and in vivo confocal microscopy and correlated to clinical outcomes., Results: In all IC specimens, numerous MUC5AC-positive cells were observed outside the edges of the blebs. Few MUC5AC-positive cells were observed at the surface of nonfunctioning blebs. Numerous goblet cells with immunostaining that was weak or limited to the membrane were clearly visible morphologically at the surface of functioning blebs (with and without adjunctive mitomycin C). Using in vivo confocal microscopy, all functioning blebs showed numerous intraepithelial optically empty microcysts, whereas nonfunctioning blebs had none or only a few. All blebs contained dendritiform inflammatory cells, especially after mitomycin C application., Conclusion: Impression cytology and in vivo confocal microscopy provide a new approach to filtering blebs. Microcysts observed at the surface of functioning blebs seemed to correspond to goblet cells, mostly containing aqueous humor instead of highly hydrophilic gel-forming mucins. Although this hypothesis requires further confirmation, the transcellular pathway of the aqueous humor could be hypothesized to occur at the level of goblet cells toward the ocular surface.

The aim of this review is to examine clinical aspects of the use of the hypouricemic drug allopurinol. Allopurinol is a moderately active hypouricemic drug. Its activity is largely the result of the inhibition of xanthine oxidoreductase by oxypurinol, the active metabolite of allopurinol. The activity of allopurinol may be limited by oxypurinol, reducing the renal clearance of urate. Optimal use of allopurinol involves individualization of dose to attain a sufficient decrease in plasma urate concentrations. This may require a dose greater than recommended based on creatinine clearance. The initial use of an anti-inflammatory drug or low-dose colchicine decreases but does not eliminate the development of acute attacks of gout during the initiation of therapy with allopurinol. Monitoring of oxypurinol concentrations has shed some light on the efficacy of allopurinol but more data are required particularly in patients with renal impairment. Probenecid increases the hypouricemic effect of allopurinol but the favorable interaction may be significant only in patients with glomerular filtration rates greater than about 50 mL/min.

Purpose: To study, through endoscopy, the postoperative structural changes of the intranasal ostium following external dacryocystorhinostomy and to evaluate the influence of saline solution and 5-fluorouracil., Methods: Fifty patients were distributed into the following groups: Group SS-dacryocystorhinostomy and an injection of saline solution during surgery (13 patients); Group 5--FU1-dacryocystorhinostomy and an injection of 5 fluorouracil during surgery (17 patients); Group C--dacryocystorhinostomy only (11 patients); Group 5--FU3-dacryocystorhinostomy and 3 injections, 1 during surgery and 1 on the third and fifth postsurgical days (9 patients)., Results: Pair-wise group comparisons using the nonparametric Mann-Whitney test revealed that there was a significant reduction of the ostium area only in Group 5-FU1 vs. Group SS on the 60th postoperative day (P <.01); however, a comparative study among the 4 groups using the Kruskal-Wallis test showed no significant changes in the ostium area on the 60th postoperative day. The ostium area within groups at the 30th vs 60th postoperative day was significantly reduced for Group C (P < .05; Mann-Whitney test); no significant changes were found for the other groups., Discussion: These results suggest that the use of 5-fluorouracil in external dacryocystorhinostomy does not significantly influence the final size of the surgical fistula as determined 2 months postsurgery.

Background: Poststroke depression (PSD) leads to impaired functional recovery and increased mortality, yet physiological mechanisms are unknown. The present study investigates the roles of glucocorticoids and interleukin-1 (IL-1) in poststroke anhedonia., Methods: Adult male mice underwent middle cerebral artery occlusion (MCAO), and were recovered 7 days. Mice were treated with metyrapone (100 mg/kg intraperitoneally), mifepristone (50 mg/kg subcutaneously), or vehicle injections on reperfusion days 4-7. A separate cohort of mice was implanted with cannulae and was administered IL-1 receptor antagonist (IL-1ra) or vehicle (6 microg intracerebroventricularly) on reperfusion days 6 and 7. After the final injection or infusion, sucrose consumption was recorded for 6 hours., Results: Mice in the sham-treated group consumed significantly more sucrose solution than water, whereas MCAO-treated mice consumed similar amounts of each, suggesting anhedonia among MCAO-treated mice. A separate experiment assessed whether stroke-induced increases in corticosteroids or IL-1 contribute to anhedonia. Only IL-1ra restored sucrose consumption in MCAO-treated mice. Vehicle-MCAO-treated mice drank significantly less sucrose solution than did both IL-1ra and vehicle-sham treatment groups, whereas IL-1ra-MCAO-treated mice drank similar amounts to both sham-treated groups., Conclusions: Poststroke anhedonia, a symptom of depression in human beings, can be reproduced in a mouse model of stroke and appears to involve altered IL-1 transmission in the brain.

Background: To describe the results of a novel postoperative management approach for patients undergoing combined cataract and glaucoma surgery supplemented with early needle revision and antimetabolites., Methods: Consecutive retrospective chart review identified 66 patients who had undergone combined cataract and glaucoma surgery with early needling and antimetabolite injections between January 2002 and May 2003; 8 patients were excluded from analysis because of missing data or inadequate follow-up time. Single-site phacotrabeculectomy was performed followed by subconjunctival antimetabolite injections of 5-fluorouracil (5-FU). Needling was performed as an office procedure if early evidence of subconjunctival scarring was observed 2-6 weeks after surgery. Additional subconjunctival 5-FU injections were administered after needling, and repeat needling was performed with 5-FU or mitomycin-C if subconjunctival scarring recurred. A complete success was defined as a reduction in intraocular pressure (IOP) to <18 mm Hg without the use of antiglaucoma medications or further surgical procedures to control IOP. The outcome was considered a qualified success when antiglaucoma medications were required to achieve the same result., Results: The mean preoperative IOP was 21.9 (SD 6.3) mm Hg, and the mean postoperative IOP at 6 months was 13.0 (SD 6.7) mm Hg. The mean number of medications was reduced from 2.9 (SD 1.3) preoperatively to 0.5 (SD 0.9) postoperatively at 6 months. Needling was performed because of early evidence of subconjunctival scarring in 34 patients. The 6-month outcomes of 37 patients (64%) were a complete success and of 47 patients (81%) were a complete or qualified success. A longer follow-up of 10-23 months was attained in 25 of the 58 patients. At latest visit, the mean postoperative IOP of this group was 13.0 (SD 5.5) mm Hg, the mean number of postoperative medications was 0.7 (SD 1), and 21 of the 25 (84%) had achieved a complete or qualified success. The most common complication for all 58 patients was an early, self-limited postoperative wound leak that was unrelated to the needling intervention and was observed in 26 patients (45%)., Interpretation: Phacotrabeculectomy supplemented with early needle revision and antimetabolites may improve outcomes of combined cataract and glaucoma surgery.

Jagged1-mediated Notch signaling has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. Unexpectedly, we report here that inducible Cre-loxP-mediated inactivation of the Jagged1 gene in bone marrow progenitors and/or bone marrow (BM) stromal cells does not impair HSC self-renewal or differentiation in all blood lineages. Mice with simultaneous inactivation of Jagged1 and Notch1 in the BM compartment survived normally following a 5FU-based in vivo challenge. In addition, Notch1-deficient HSCs were able to reconstitute mice with inactivated Jagged1 in the BM stroma even under competitive conditions. In contrast to earlier reports, these data exclude an essential role for Jagged1-mediated Notch signaling during hematopoiesis.

Objective: To evaluate the effect of temporal corneal phacoemulsification on intraocular pressure (IOP) in eyes after primary trabeculectomy with intraoperative fluorouracil (5-FU) or mitomycin C (MMC)., Design: Retrospective case-control study., Patients: Twenty-nine patients who were participants in a prospective randomized double-masked trial comparing the efficacies of intraoperative 5-FU and MMC and who underwent temporal corneal phacoemulsification after the primary trabeculectomy were matched to 29 patients enrolled in the same study who did not undergo cataract surgery. The 2 groups were matched for length of follow-up after the trabeculectomy and the antimetabolite used at the time of trabeculectomy., Methods: Comparisons of IOP, visual acuity (VA), and the number of glaucoma medications were made between the 2 groups and within the groups at various follow-up intervals to detect any statistically significant differences., Main Outcome Measures: Intraocular pressure before phacoemulsification and at various times postoperatively were compared with IOP in the control group at the matched follow-up times., Results: The mean of all IOP measurements beyond 3 months after phacoemulsification for each subject was significantly higher than the prephacoemulsification IOP (11.8+/-4.2 vs. 8.7+/-4.5 mmHg; P = 0.00003, paired t test). In contrast, the mean IOP remained stable in the control group during the equivalent time period (9.6+/-3.5 vs. 9.1+/-3.1 mmHg; P = 0.42, paired t test). Postphacoemulsification IOP was significantly higher than the corresponding IOP in the time-matched control group (P<0.003, analysis of covariance). Mean VA improved significantly after the phacoemulsification (P = 0.0002) but remained stable in the control group., Conclusion: Temporal corneal phacoemulsification can affect long-term IOP control after trabeculectomy with 5-FU or MMC.

Objective: We previously showed that treatment with liposomally encapsulated dichloromethylene bisphosphonate reduces intimal hyperplasia development and macrophage accumulation in a rat epigastric vein to femoral artery model of intimal hyperplasia. Our objective in this study was to determine the effect of liposomally encapsulated dichloromethylene bisphosphonate on the expression of two cytokines essential to neointimal development, monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-beta)., Methods: We injected rats both 2 days preoperatively and 2 weeks postoperatively with liposomally encapsulated dichloromethylene bisphosphonate (Lip-Clod), liposomally encapsulated phosphate-buffered saline solution (Vector), or phosphate-buffered saline solution (PBS), and harvested the grafts at 1 and 4 weeks. In the perianastomotic region, MCP-1 and TGF-beta protein expression in the total graft cross-section and in the neointima was determined with immunohistochemistry. In whole-graft lysates, MCP-1 and TGF-beta protein were determined with an enzyme-linked immunosorbent assay, and messenger RNA expression was determined with reverse transcription quantitative polymerase chain reaction., Results: Lip-Clod treatment reduced intimal hyperplasia when compared with Vector or PBS treatment. These reductions were significant (P<.05) at both time points. When compared with the PBS treatment, at 1 week but not at 4 weeks Lip-Clod reduced both MCP-1 and TGF-beta protein (P< or =.01 and P< or =.006) in the perianastomotic region of vein grafts. In whole-graft lysates, no significant difference was seen in MCP-1 protein at either time point; however, TGF-beta protein expression was significantly reduced at both 1 and 4 weeks (P=.02 and P=.004). Message analysis in whole-graft lysates at 1 week showed that MCP-1 message expression increased in the Lip-Clod group compared with the PBS group (P=.02), but no significant differences among groups for TGF-beta message levels. Results with Vector were often intermediate to results with Lip-Clod and PBS., Conclusion: The major effect of Lip-Clod treatment on TGF-beta and MCP-1 protein levels in the perianastomotic region is observed at 1 week, and macrophage depletion with Lip-Clod inhibits graft neointimal hyperplasia and TGF-beta protein expression in whole-graft lysates at 1 and 4 weeks. These results support the concept that the infiltrating macrophages contribute a significant portion of the cytokines that facilitate intimal hyperplasia and that reducing these cytokines early after grafting influences the development of intimal hyperplasia at later time points., Clinical Relevance: All vascular surgeons have patients who have undergone a technically satisfying vein graft, only to have the bypass fail during the first year due to perianastomotic intimal hyperplasia (IH). We hypothesize that vein graft IH is analogous to aberrant wound healing. Central to wound healing is the recruitment of macrophages with their cytokines. This work raises the question whether clinical strategies designed to either decrease macrophages or the cytokines released by macrophages at the time of vein graft placement will be efficacious for limiting the development of IH.

Background and Aims: The efficacy of azathioprine in the treatment of chronic active Crohn's disease is well established. However, this drug has a long onset of action. Methotrexate has also been shown to be effective in chronic active Crohn's disease. The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine, and to establish whether methotrexate has a shorter onset of action in this setting., Methods: Patients with chronic active Crohn's disease were admitted to this investigator-blind study. Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months, with at least one attempt to discontinue treatment. The disease had to be clinically active at entry, with a Crohn's Disease Activity Index of > or = 200. Six patients treated with azathioprine and methotrexate, respectively, were found to have enterocutaneous and perianal fistulas. At entry, all patients received prednisolone (40 mg once a day) which was tapered over a period of 12 weeks unless their clinical condition deteriorated. All patients were randomised to receive i.v. methotrexate 25 mg/week, or oral azathioprine 2 mg/kg per day, for a 6-month follow-up period. After the first 3 months, methotrexate was switched to oral administration maintaining the same dose. The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy. Clinical remission was defined as the lack of need for steroid treatment and a Crohn's Disease Activity Index score of < or = 150 points at each scheduled visit., Results: In the 54 patients (26 F, 28 M, mean age 34 years, range 18-60) randomly assigned to methotrexate (n=27) or azathioprine (n=27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 (methotrexate 44%, azathioprine 33%, p=0.28, (95% CI, 0.369-0.147), and 6 months (methotrexate 56%, azathioprine 63%, p=0.39, 95% CI, 0.187-0.335), respectively. Six patients withdrew from therapy due to adverse events: 3/27 (11%) in methotrexate and 3/27 (11%) in azathioprine. Drug-related adverse events (asthenia, nausea and vomiting) that did not require withdrawal from therapy were more frequent in the methotrexate group (azathioprine: 2/27 (7%); methotrexate: 12/27 (44%), p=0.00009). The frequency of these adverse events was comparable during the intravenous or oral administration of the drug., Conclusions: This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohn's disease, therapeutic efficacy being comparable, but not faster, than that of azathioprine.

Purpose: To study the long-term results (1-14 years) of trabeculectomies with 5-fluorouracil injections that were successful at 1 year., Design: A retrospective noncomparative case series. INTERVENTION/PARTICIPANTS: We identified 87 patients (87 eyes) who had trabeculectomies with 5-fluorouracil injections from 1984 to 1989 that were successful at 1 year and had a follow-up range of 1.0 to 14.7 years (mean, 8.1, standard deviation of 4.4 years). All patients had previously failed glaucoma surgery (66.7%), cataract surgery (47.1%), or other diagnoses making them at high risk for failure., Main Outcome Measures: Successful control of intraocular pressure (IOP) was defined as IOP less than 21 mmHg or a reduction of 33% if preoperative pressure was less than 21 mmHg. Statistical analysis was performed using Kaplan-Meier life table analysis., Results: If an eye is considered successful by IOP at 1 year, the probability of successful control is 61% at 5 years, 44% at 10 years, and 41% at 14 years., Conclusions: Despite successful IOP control at 1 year, trabeculectomies with 5-fluorouracil injections show a continual loss of IOP control over time.

To elucidate the relationship between 5-fluorouracil (5-FU) distribution and 5-FU-induced apoptosis and/or cell cycle arrest, microautoradiography was applied to murine intestinal crypts exposed to [14C] 5-FU by intravenous infusion. The histologic location of apoptotic cells in the crypt did not correlate to that of 5-FU. The temporal profiles of apoptotic and/or mitotic indexes corresponded to those of orally administered 5-FU in a previous study. Two cell cycle-related proteins, p21(WAF/Cip1) and bax, were also investigated in the present study. With time, p21(WAF/Cip1)-positive nuclei apparently migrated up the crypt. Bax-positive cytoplasm was observed throughout the crypt epithelial cells, accompanied by the occurrence of apoptosis, and remained until 48 h when the control level recovered. The findings demonstrate that 5-FU mainly exerts an apoptotic effect and/or cell cycle arrest by systemic exposure, and p21 and bax expression determine an individual cell's fate.

Purpose: To determine the effect of intraoperative application of 5-fluorouracil (5-FU) on the long-term outcome of trabeculectomy in uveitis-related glaucoma., Design: An open, prospective, noncomparative case study to evaluate the use of intraoperative application for 5 minutes of 25 mg/ml 5-FU in primary trabeculectomy for uveitis-related glaucoma., Participants: Fifty eyes of 43 consecutive patients were enrolled in the study., Methods: Data were recorded prospectively on specifically designed forms at visits every 3 months after surgery., Main Outcome Measures: The intraocular pressure, need for additional medication, and the need for repeat surgery were the criteria that determined the outcome of surgery., Results: No significant intraoperative, postoperative, or late complications of 5-FU administration were noted. Successful filtration was achieved in 82% of eyes at 1 and 2 years after surgery. The success rate was 67% at 5 years. Failure was significantly more common and occurred earlier in patients of black ethnic origin. No deleterious effect on control of uveitis in relation to surgical intervention was observed., Conclusions: Intraoperative application of 5-FU appears to be a long-term, safe, and effective adjunct to trabeculectomy in uveitis-related glaucoma.

Background: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans., Methods: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day., Results: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity., Conclusions: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

Purpose: Needling revision is an accepted method of management of poorly functioning trabeculectomy blebs. The authors present the outcome of the analogous needling revision of poorly functioning filtering blebs over glaucoma drainage device (GDD) reservoirs., Methods: Review of 20 patients (21 eyes) who underwent needling to the bleb overlying the GDD reservoir, with or without adjunctive 5-fluorouracil injection., Results: In the nine eyes (43%) that were considered successes (defined as intraocular pressure [IOP] less than or equal to 21 mmHg and decrease in IOP greater than or equal to 20% with no additional medication or glaucoma surgery), the mean IOP fell from 28.3 +/- 6.4 mmHg to 13.9 +/- 2.7 mmHg at last follow-up, after a mean of 1.7 needlings (range, 1-3 needlings) with mean follow-up of 14.6 months (range, 5-35 months [corrected]). Needling success was associated with larger GDD surface area (mean, 267 +/- 95 mm2 vs. 179 +/- 79 mm2 in eyes needled unsuccessfully, P = 0.04) and use of Baerveldt implants (six of eight eyes needled successfully). Minor complications were few. Endophthalmitis developed in one patient (5% of all eyes) after needling., Conclusions: Needling revision can be useful in the management of poorly functioning GDD blebs, although the risk for severe complications exists.

Background/aims: The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis., Methods: The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil., Results: Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7)., Conclusions: In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.

The agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS) induces acute polyuric renal failure which is attenuated by pretreatment with the glutathione depletors, diethyl maleate or buthionine sulfoximine (BSO). In the present study, the temporal aspects of BSO attenuation of NDPS nephrotoxicity were investigated. In addition, the ability of BSO to alter the renal accumulation of selected organic ions was examined as a possible mechanism for BSO's ability to attenuate NDPS nephrotoxicity. In the first set of experiments, NDPS (0.2 or 0.4 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg) was administered intraperitoneally (i.p.) to groups of male Fischer 344 rats (4-8 rats/group) 0.25 or 2 h prior to BSO (890 mg/kg, i.p.) and renal function was monitored at 24 and 48 h. NDPS (0.4 mmol/kg) nephrotoxicity was markedly attenuated by administration of BSO at 0.25 h post-NDPS, but was not substantially altered by injection of BSO at 2 h post-NDPS. NDPS (0.2 mmol/kg)-induced renal effects were not potentiated by BSO injected at 0.25 h post-NDPS, and only 1 of 8 rats exhibited marked nephrotoxicity when BSO was administered at 2 h post-NDPS. In the second set of experiments, rats (4/group) were administered BSO (890 mg/kg, i.p.) or vehicle (0.9% saline, 10 ml/kg) and kidneys harvested at 2 or 5 h post-treatment. The ability of renal cortical slices to accumulate organic ions (p-aminohippurate [PAH], alpha-aminoisobutryic acid [AIB] or tetraethylammonium [TEA]) during a 90 min incubation was studied. Only TEA accumulation by renal cortical slices prepared from the 2 h post-treatment group was reduced. Studies were also conducted to examine the in vitro effects of BSO (10(-7)-10(-4) M) on the accumulation of PAH, AIB and TEA by renal cortical slices following 5, 15 or 90 min co-incubations of BSO and an organic ion BSO had no significant effects on the accumulation of any organic ion studied at any time point. These results indicate that BSO can still attenuate NDPS nephrotoxicity when administered at 0.25 h post-NDPS, but BSO loses effectiveness when given 2 h post-NDPS. These results also suggest that BSO is attenuating NDPS nephrotoxicity via glutathione depletion rather than altering renal accumulation of NDPS metabolites via renal PAH, TEA or AIB transporters.

Purpose: To test the effect of postoperative subconjunctival 5-fluorouracil (5-FU) on the pressure outcome in combined procedure (limbus-based trabeculectomy + clear-cornea phacoemulsification)., Methods: Prospective randomized, controlled clinical trial; n = 24 eyes (24 patients) with concurrent open-angle glaucoma and cataract; 12 eyes per treatment group; sample size adjusted for a minimal expected difference in the event rate between the 2 treatment groups = 50%, control rate = 20%; type I error = 0.05; power = 95%. Uncomplicated limbus-based trabeculectomy + uncomplicated clear-cornea phacoemulsification + posterior chamber intraocular lens. The 5-FU group = five subconjunctival injections of 5 mg 5-FU, starting from day 8 after surgery, one injection per week. Control group = no injections. The groups were matched for age, preoperative intraocular pressure (IOP), duration of preoperative antiglaucoma treatment, preoperative pilocarpine and adrenergics, preoperative laser trabeculoplasty, and beta-blockers in the fellow eye. The IOP less than or equal to 15 mmHg without treatment 1 year after surgery (IOP = average of the two highest values measured in the diurnal curve, 8 AM to 6 PM, one reading every 2 hours)., Results: Each patient completed a 1-year follow-up. Ten of 12 eyes of the 5-FU group showed an IOP less than or equal to 15 mmHg at the end of follow-up versus 1 of 12 eyes in the control group (Fisher's exact test, P = 0.00064). The IOP range was 10 to 17 mmHg in the 5-FU group and 14 to 22 mmHg in the control group., Conclusion: Postoperative 5-FU may improve the 1-year success rate of trabeculectomy combined with clear-cornea phacoemulsification.

Purpose: The authors studied the effects of trabeculectomy on the time course of central 30 degrees visual field performances in progressive normal-tension glaucoma (NTG)., Methods: Patients with NTG who had clear ocular media and were adequate performers on the 30-2 program of Humphrey Perimeter were prospectively followed with periodic field testing. Trabeculectomy using an antimetabolite was indicated when the slope of a line fitted to the time course of the mean deviation (MD), MD slope, was significantly negative. The time courses of MD and mean of total deviations (mean TD) in four subfields, superior and inferior arcuate and superior and inferior cecocentral fields, were analyzed using the mixed linear model., Results: In progressive NTG, 21 eyes of 21 cases with postoperative follow-up of 2 years or more, intraocular pressure averaged 16 mmHg, MD averaged -13.5 dB, and MD slope averaged -1.48 dB/year preoperatively; 2 years after surgery, they averaged 9.2 mmHg, -13.6 dB, and +0.13 dB/year, respectively. Trabeculectomy had a significant beneficial effect on the time course of MD and mean TD in the superior and inferior arcuate and superior cecocentral fields, which showed significant preoperative deterioration. The mean TD in the inferior cecocentral field showed no significant time change during the period studied., Conclusion: For patients with NTG in whom the MD slope is significantly negative, trabeculectomy may have beneficial and diffuse effects on further deterioration of the visual field.

To determine whether cytomegalovirus (CMV) antigenemiaguided ganciclovir treatment may be as effective, may require less treatment, and thus may cause less marrow toxicity than ganciclovir administered at engraftment, 226 marrow transplant recipients were randomized at engraftment to receive placebo (antigenemia-ganciclovir group) or ganciclovir (ganciclovir group) until day 100 in a double-blind study. In patients with antigenemia of 3 or more positive cells in 2 slides and/or viremia, study drug was discontinued and ganciclovir was started for at least 3 weeks or until negative CMV antigenemia and resumed only if antigenemia recurred. More patients in the antigenemia-ganciclovir group developed CMV disease before day 100 after transplantation compared with the ganciclovir group (14% v 2.7%, P = .002). Of the 16 patients with CMV disease before day 100 in the antigenemia-ganciclovir group, 10 (8.8%) had disease before or during the first episode of antigenemia and 6 (5.3%) developed disease after discontinuation of ganciclovir. Untreated low-grade antigenemia progressed to CMV disease in 19% of patients with grade 3-4 compared with 0% of patients with grade 0-2 acute graft-versus-host disease (P = .04). There was no significant difference in CMV disease by day 180 after transplantation and thereafter. CMV-related death, transplant survival, and neutropenia were not significantly different between the groups. In the ganciclovir group, more invasive fungal infections occurred (P = .03) and more ganciclovir was used (P < .0001). Thus, delaying the start of ganciclovir until highgrade antigenemia and discontinuing ganciclovir based on negative antigenemia results in more CMV disease by day 100 than ganciclovir administered at engraftment. However, ganciclovir at engraftment is associated with more early invasive fungal infections and more late CMV disease resulting in similar survival rates.