Search

To compare the relative efficacy of trabeculectomy surgery with 90-s and 5-min intraoperative exposure time to 5-fluorouracil. This was a retrospective, non-randomized comparative study. 41 eyes of 33 consecutive patients in the study group were compared to 40 eyes of 30 consecutive patients in the historical control group. Both groups were exposed to 5-fluorouracil (50 mg/ml) during trabeculectomy surgery. The exposure time was 90 s for the study group and 5 min for the control group. Three criteria were used to define surgical success: IOP (intraocular pressure) less than 21 mmHg; IOP less than 21 mmHg with more than 30% reduction in pressure; and IOP less than 15 mmHg with more than 30% reduction. The number of antiglaucoma medications, visual acuity, complications, and interventions were recorded at regular intervals. Mean preoperative IOP was 21.6 +/- 4.8 in the 90-s group and 21.2 +/- 4.9 in the 5-min group. Mean follow-up was 28.2 +/- 5.1 months in the 90-s group and 48.0 +/- 4.9 months in the 5-min group. During the first 30 postoperative months, there were no statistically significant differences in IOP and requirement for antiglaucoma medications between the two groups. The 90-s group had shorter survival rates using the 1st success criteria, but no significant difference was detected when the more stringent 2nd and 3rd criteria were applied. Choroidal effusions were significantly less common in the 90-s group (P = 0.0076). The results of this small study suggest that a 90-s application of 5-fluorouracil may be as effective as a 5-min one in trabeculectomy.

We investigated effects of age and glutathione synthesis inhibition on the oxidative stress status of tibialis anterior muscles from young and old Fisher 344 x Brown Norway male rats after chronic administration of stretch-shortening contractions. Oral supplementation of L: -buthionine-(S,R)-sulfoximine (BSO) inhibited glutathione synthesis. Dorsiflexor muscles in the hindlimb were exposed to 80 maximal stretch-shortening contractions (SSCs) three times per week for 4.5 weeks. We measured malondialdehyde, hydrogen peroxide (H(2)O(2)), and free isoprostanes to determine oxidative stress. Glutathione peroxidase activity was measured as an indicator of H(2)O(2) scavenging. Glutathione measurements confirmed the effectiveness of BSO treatment. In young rats, the SSC exposure protocol prevented oxidative stress and enhanced H(2)O(2) scavenging. In old rats, malondialdehyde was increased in the exposed muscle and a BSO-induced increase in H(2)O(2) was not alleviated with SSC exposure as seen in young rats. In addition, glutathione peroxidase activity and total glutathione were increased in old rats relative to their young counterparts. All comparisons were significant at the 0.05 level. Overall, BSO administration was effective in decreasing total glutathione levels and increasing H(2)O(2) levels in old and young rats exposed to SSCs. In addition, effects of chronic exposure to high-force resistive loading SSCs in active muscle from old animals are: (1) antioxidant capacity is enhanced similar to what is seen with endurance training and (2) oxidative stress is increased, probably as a consequence of the enhanced vulnerability due to aging.

Risks that glaucoma medications pose to the fetus and neonate must be balanced against the risk of vision loss in the mother. There is no high level evidence for harmful effects on the fetus and neonate of medications used to treat glaucoma. All topical and systemic glaucoma medication should be avoided during the first trimester of pregnancy. Systemic carbonic anhydrase inhibitors, topical prostaglandin analogues and antimetabolites during surgery should be avoided absolutely. Some topical medications are deemed compatible with lactation by the American Academy of Pediatrics, however, caution should still be practiced.

Background: Topical 5-fluorouracil has been reported to reduce adhesions in animal models of tenolysis. The purpose of this study was to investigate the effects of topical 5-fluorouracil on adhesion formation after tendon repairs were subjected to immediate postoperative rehabilitation in a canine model in vivo., Methods: Sixty dogs were randomly assigned to either a 5-fluorouracil treatment (thirty dogs) or a control group (thirty dogs). Each treatment group was then divided into three survival time points: ten days, twenty-one days, and forty-two days. The second and fifth flexor digitorum profundus tendons from each dog were fully lacerated at the zone-II area and then were repaired. Passive motion therapy started at day 5 postoperatively and continued until the dogs were killed. The repaired tendons were evaluated for normalized work of flexion, gliding resistance, repair strength, gene expression for type-I and type-III collagen and transforming growth factor-beta1, and histological appearance., Results: The normalized work of flexion of the repaired tendons treated with 5-fluorouracil was significantly lower than that of the repaired tendons without 5-fluorouracil treatment at ten days. However, there was no significant difference between treated and untreated tendons at twenty-one and forty-two days. There was also no significant difference in gliding resistance, repair failure strength, or stiffness between treated and untreated tendons at any time point, or in the gross or histological appearance of adhesions at the time of killing. The expression of types-I and III collagen and transforming growth factor-beta1 of the repaired tendon with 5-fluorouracil treatment was significantly lower than that of the tendons without treatment at ten days postoperatively, but not at twenty-one or forty-two days., Conclusions: Although 5-fluorouracil treatment can reduce adhesions in in vivo models of tenolysis, this treatment had only a transient effect in an in vivo model of tendon repair that included passive motion.

Purpose: To assess the changes in optic nerve head (ONH) structure and visual field (VF) sensitivity over time in a cohort of patients with glaucoma after trabeculectomy., Methods: The MoreFlow Medical Research Council 5-Fluorouracil (5-FU) study was an 80-month prospective randomized controlled trial of per-operative 5-FU versus placebo on the outcomes of primary trabeculectomy. Before surgery, patients had ONH imaging with a retinal tomograph and full-threshold visual field testing. After surgery, ONH imaging was performed annually and VF testing at 4-month intervals. This analysis included only patients with a minimum of 3 years' postoperative ONH and VF data. ONH images were analyzed by linear regression of sector rim area (RA) over time with change defined as a significant slope >1% of baseline RA per year in any sector. VFs were analyzed with point-wise linear regression analysis (PLRA) techniques with the stringent three-omitting criteria used. Eyes were classed as progressing or not based on analysis with either technique. Patients' median IOP level, intervisit IOP fluctuation, and percentage reduction in IOP over the follow-up period were also determined., Results: Two hundred fifty eyes of 250 patients were suitable for analysis. Of these, 70 (28%) eyes were deemed to show glaucoma progression approximately 5 years after surgery: 20 eyes by ONH alone, 35 by VF alone, and 15 by both methods. Of the 15 shown to be progressing by both ONH and VF analysis, only 7 (3% total cohort) showed congruity in the location of change. Eyes showing changes in both ONH and VF sensitivity had slightly higher median follow-up IOP (median IOP [interquartile range; IQR] nonprogressors 14.0 mm Hg [11.8-16.0 mm Hg], progressors 15.1 mm Hg [12.7-17.0 mm Hg]; Mann-Whitney U test [MWU]; P = 0.03) and lower degrees of IOP reduction from baseline (percentage IOP reduction [IQR]: nonprogressors -38.4% [-51.8% to -26.4%]; progressors -31.4% [-43.1% to -21.5%]; MWU P = 0.01) compared with eyes showing no progression., Conclusions: The study demonstrates that approximately one third of eyes continued to show progression of glaucoma at five years after trabeculectomy, as determined by trend-based analysis of ONH structural changes and VF sensitivity over time. The study suggests that the degree of IOP reduction after trabeculectomy may play an important role in the progression of glaucoma as detected by both functional and structural methods.

Exercise training (EX) following percutaneous transluminal coronary angiography (PTCA) reduces progression to restenosis and increases event-free survival rates. Our aim was to determine whether EX inhibits lesion development and/or alters the extracellular matrix (ECM) composition of the neointima (NI) in a porcine PTCA model. Miniature Yucatan swine were assigned to cage confinement (SED) or EX for 20 wk. After 16 wk, all animals underwent a PTCA procedure of the left anterior descending artery (LAD) and left circumflex artery (LCX), with subsequent placement of an externalized jugular catheter. Animals recovered for 2 days and then resumed the previous protocol of SED or EX. Twelve days following PTCA, all animals received an intravenous bromodeoxyuridine (BrdU) injection to label proliferating cells. At 28 days following PTCA, the animals were euthanized, the LAD and LCX excised, and underwent standard histological processing for total collagen, type I collagen, fibronectin, BrdU, and Verhoeff-van Gieson stain. Our results demonstrate that EX significantly decreased lesion size and NI proliferation (-48%) in the LAD (P < 0.05) but not the LCX. Furthermore, EX attenuated type I collagen expression only in LAD, whereas total collagen was increased (5.9%) and fibronectin was decreased (-7.9%) in the NI of both vessels (P < 0.05). In conclusion, EX following PTCA may increase event-free survival rates following PTCA by decreasing lesion size and altering ECM composition.

2-Deoxy-d-glucose (2-DG) administration causes transient depletion of glucose derivates and ATP. Hence, it can be used in a model system to study the effects of a mild glycoprivic brain insult mimicking transient hypoglycemia, which often occurs when insulin or oral hypoglycemic agents are administered for diabetes control. In the present study, the effect of a single 2-DG application (500mg/kg, a clinically applicable dose) on glial reactivity and neurogenesis in adult rat hippocampus was examined, as well as a possible temporal correlation between these two phenomena. Post-insult (PI) glial reactivity time course was assessed by immunoreaction against glial-fibrillary acidic protein (GFAP) during the following 5 consecutive days. A clear increase of GFAP immunoreactivity in hilus was observed from 48 to 96h PI. Moreover, enhanced labeling of long radial processes in the granule cell layer adjacent to hilus was evidenced. On the other hand, a transient increase of progenitor cell proliferation was detected in the subgranular zone, prominently at 48h PI, coinciding with the temporal peak of glial activation. This increase resulted in an augment of neuroblasts double labeled with 5-bromo-deoxyuridine (BrdU) and with double cortin (DCX) at day 7 PI. Around half of these cells survived 28 days showing matured neuronal phenotype double labeled by BrdU and a neuronal specific nuclear protein marker (NeuN). These findings suggest that a transient neuroglycoprivic state exerts a short-term effect on glial activation that possibly triggers a long-term effect on neurogenesis in hippocampus.

Purpose: To evaluate the effects of radial conjunctival incision during fornix-based trabeculectomy, and conjunctival scarring associated with previous ocular surgeries, for the restriction of bleb formation., Methods: Digital photo-slit lamp images of filtering blebs, which had undergone fornix-based trabeculectomy with mitomycin C previously, were analysed. The area and the height of the bleb in the conjunctivae with radial incision (Ain and Hin, respectively) were compared with the area and the height of the bleb in the conjunctivae without radial incision (Ano and Hno, respectively). We compared the parameters of bleb area (total bleb area, Ain and Ano) and bleb height (the bleb height at the centre of the scleral flap; Hc, Hin and Hno) in eyes without previous ocular surgeries, with those in eyes that underwent previous ocular surgeries., Results: The study population consisted of 51 eyes. The Ano and the Hno were significantly larger than the Ain (p < 0.001) and the Hin (p < 0.001) respectively. Subgroup analyses in eyes without previous ocular surgeries and eyes with phacoemulsification cataract surgery also showed that the Ano was significantly larger than the Ain. However, there was no significant difference between the Ano and the Ain in eyes with previous trabeculectomy. A comparison of bleb formation between eyes without previous ocular surgeries and eyes with cataract surgery showed no significant differences in each of the bleb area and bleb height parameters. By contrast, the total bleb area (p = 0.021), the Ano (p = 0.017) and the Hc (p = 0.045) were significantly smaller in eyes with previous trabeculectomy than in eyes without previous ocular surgeries., Conclusions: Our data demonstrate that bleb formation depends on radial conjunctival incision during fornix-based trabeculectomy and surgical conjunctival scarring from previous trabeculectomy.

Purpose: To evaluate the long-term morphologic changes in the anterior segment structures after nonpenetrating filtering surgery (NPFS) supplemented with 5-fluorouracil (5-FU) and no scleral implant using ultrasound biomicroscopy (UBM)., Methods: Thirteen eyes of 13 consecutive patients who underwent NPFS with intraoperative 5-FU under the conjunctiva and the scleral flap and no implant were evaluated in an observational nonrandomized, consecutive case series study conducted 2 years postoperatively. Patients were assessed for the presence of a subconjunctival filtering bleb, the volume of an intrascleral cavity, and a suprachoroidal hypoechoic area. The intraocular pressure(IOP) was measured preoperatively and postoperatively at the time of UBM., Results: The IOP decreased significantly (p=0.01) from 24-/+7.6 mmHg to 13.7-/+4.1 mmHg. In most patients (69.2%), the postoperative IOP decreased at least 30% from the preoperative value without medications and in 84.6% with medication. UBM showed a subconjunctival empty space in 92.3% of eyes. In 84.6% of patients, an intrascleral cavity was seen, the mean volume of which was 1.68 mm(3) (range, 0-4.07). We found a negative correlation between the height, width, and volume of the intrascleral lake and the IOP. In 92.3% of eyes, a hypoechoic area in the suprachoroidal space also was seen., Conclusions: UBM showed a filtering intrascleral cavity, subconjunctival filtering bleb, and a suprachoroidal space after NPFS supplemented with 5-FU under the conjunctiva and the scleral flap without an implant.

Metyrapone is a glucocorticoid synthesis inhibitor known to induce a stress-like biological syndrome, but also to limit stress-related behaviours. Since stress is usually associated to an increased locomotion, the aim of the study was to determine whether metyrapone will increase, decrease or respect locomotion. Forty rats were placed in infrared actimeters to study spontaneous locomotion before and after injecting 150 mg kg(-1) of either metyrapone (n=20) or saline (n=20). Two hours after injection, half of each treatment group animals were tested in an open field to study test-evoked locomotion. Stress-induced analgesia was quantified using plantar test just before blood sampling. Immediately after injection, metyrapone decreased drastically horizontal and vertical locomotion. During the open field test, metyrapone-treated rats remained less active with slower movement execution than saline-treated rats. Metyrapone did not modify plantar test performances but blunted stress-induced corticosterone and ACTH increases. Mechanisms by which metyrapone induced these effects on locomotion are further discussed.

Glutathione (GSH) exists in mammalian tissues in vivo at high concentrations and plays an important protective role against oxidatively induced damage to biological molecules, including DNA. We investigated oxidatively induced damage to DNA by GSH depletion in different organs of rabbits in vivo. Rabbits were treated subcutaneously with buthionine sulfoximine (BSO), an effective GSH-depleting compound. GSH levels were measured in heart, brain, liver, and kidney of animals. BSO treatment significantly reduced GSH levels in heart, brain, and liver, but not in kidney. DNA was isolated from these tissues to test whether GSH depletion causes oxidatively induced DNA damage in vivo. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry with isotope dilution methods were applied to measure typical products of oxidatively induced damage in isolated DNA samples. Several such products were identified and quantified in all organs. BSO treatment caused significant formation of 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 8-hydroxyadenine, and (5'S)-8,5'-cyclo-2'-deoxyadenosine in DNA of organs of rabbits. Animals were fed with the semiessential amino acid 2-aminoethanesulfonic acid (taurine) during BSO treatment. Taurine significantly inhibited GSH depletion and also formation of DNA products. Depletion of GSH correlated well with formation of DNA products, indicating the role of GSH in preventing oxidatively induced DNA damage. Our findings might contribute to the understanding of pathologies associated with DNA damage, oxidative stress, and/or defective antioxidant responses and improve our understanding of the effect of BSO in increasing the efficacy of anticancer therapeutics.

Background: The drug eluting stents have been shown to play a substantial role in preventing in-stent restenosis. This study was initiated to determine the efficacy of 2-deoxy-D-glucose (2-DG) in an in-stent restenosis model for reducing neointimal hyperplasia after coronary stent placement., Methods: In a porcine overstretch model, three kinds of stents were investigated (n = 12 per group): bare metal stents (BMS), rapamycin-eluted stents (RES), and BMS after intracoronary short-term application of 2-DG (DGS). After 42 days histomorphometric and histopathological analyses were performed., Results: Neointimal thickness (BMS: 0.38 +/- 0.08, RES: 0.24 +/- 0.11, DGS: 0.15 +/- 0.01), area stenosis (BMS: 47.39 +/- 2.76, RES: 32.2 +/- 2.08, DGS: 29.30 +/- 2.98) did not differ after 42 days between the RES and DGS but were significantly lower as compared to BMS only. Lumen area (BMS: 3.15 +/- 1.53, RES: 4.37 +/- 1.72, DGS: 4.77 +/- 2.14) was significantly higher in the DGS group in comparison to the BMS group. The calculated injury and inflammation scores were similar and re-endothelialization was confirmed in all groups., Conclusions: This study could demonstrate that in porcine stent model neointimal hyperplasia and re-endothelialization after application of 2-DG are comparable to those seen in RES. Thus, 2-DG might be a promising clinical application for coronary stent coating.

Background: Immunological demyelination is a proposed strategy to improve nerve regeneration in the peripheral nervous system. To investigate the remyelinating potential of Schwann cells in vivo in the peripheral nervous system, the authors have reproduced and expanded upon a novel model of immunological demyelination in the adult rat sciatic nerve. The authors demonstrate (1) the peripheral nervous system's quantitative, regenerative response to immunological demyelination and (2) whether Schwann cells within a region of demyelination are induced to divide in the presence of demyelinated axons., Methods: The sciatic nerves of female Sprague-Dawley rats were exposed and injected with demyelinating agent bilaterally. At 3 days (n = 3), 7 days (n = 3), and 14 days (n = 3), the animals were euthanized for histological evaluation. A second group of animals (n = 3) was similarly injected with demyelinating agent and then exposed to bromodeoxyuridine between 48 and 72 hours after the onset of demyelination. These animals were euthanized soon after the last injection of bromodeoxyuridine. The tissue was analyzed for Schwann cells (labeled with antibodies to S100) and bromodeoxyuridine assay., Results: A single epineural injection of complement proteins plus antibodies to galactocerebroside resulted in demyelination followed by Schwann cell remyelination. At 3 days after injection, peripheral nerve demyelination and Schwann cell proliferation were evident. Maximum demyelination was seen at 7 days; however, Schwann cell proliferation and remyelination peaked at 14 days after injection., Conclusions: These studies demonstrate an immunological model of demyelination and remyelination in the peripheral nervous system and quantitatively measure regenerative potential. This model will be used to isolate nerve segments and to measure their regenerative potential when given demyelinating agent after acute contusion and transection injuries.

Warts are a common pediatric skin disease. Most treatments show only modest benefit, and some are poorly tolerated because of pain. 5-fluorouracil interferes with deoxyribonucleic acid and ribonucleic acid synthesis, and is used to treat genital warts in adults. Efficacy, safety, and tolerability of topical 5% 5-fluorouracil for treatment of common warts were examined in an open-label pilot study with pediatric patients. Thirty-nine children who have at least two hand warts applied 5% 5-fluorouracil cream (Efudex, Valeant Pharmaceuticals International) once or twice daily, under occlusion for 6 weeks. Assessment of treatment response and side effects was performed at baseline, treatment completion, and 3- and 6-month follow-ups. Hematology measures, liver function tests, and medication blood levels were reassessed at treatment completion. Eighty-eight percent of treated warts improved after 6 weeks of treatment, and 41% of subjects had complete resolution of at least one wart. Treatment response did not differ between once or twice daily applications. Tolerability and patient satisfaction were excellent. No subject had clinically significant blood levels of 5-fluorouracil. At 6 month follow-up, 87% of complete responders had no wart recurrence. Topical 5% 5-fluorouracil is a safe, effective, and well-tolerated treatment for warts in children.

Background: Hepatic oval cells, progenitor cells in the liver, can differentiate into hepatocytes and bile duct cells both in vitro and in vivo. Although hepatic stellate cells are another important cell component in the liver, less attention has been focused on the relationship between hepatic oval cells and hepatic stellate cells., Methods: Hepatic oval cells were isolated from rats fed a choline-deficient diet supplemented with 0.1% ethionine for 6 weeks and characterized by electron microscopy, flow cytometry, reverse transcription polymerase chain reaction, Western blot and bi-direction differentiation. After treatment with transforming growth factor-beta1 (TGF-beta1), changes in cell viability, morphology, extracellular matrix (ECM) expression and immune phenotype were analysed in these cultured and adherent hepatic oval cells., Results: The primary cultured hepatic oval cells were positive for the oval cell-specific markers OV-6, BD-1/BD-2 and M2PK as well as the hepatocyte markers albumin and alpha-foetoprotein. These hepatic oval cells differentiated bipotentially into hepatocytes or bile duct-like cells under appropriate conditions. It is noteworthy that these bipotential hepatic oval cells expressed ECM genes stably, including collagens, matrix metalloproteinases and tissue inhibitor of mellatoproteinase. Furthermore, except for growth inhibition and morphological changes in the hepatic oval cells after exposure to TGF-beta1, there was an increased expression of ECM genes, the onset expression of snail and loss expression of E-cadherin. During this process, TGF-beta1 treatment induced an upregulation of marker genes for hepatic stellate cells in hepatic oval cells, such as desmin and GFAP., Conclusion: Except for the expression of ECM, the cultured hepatic oval cells could induce an increased expression of hepatic stellate cell markers by TGF-beta1 through an epithelial-mesenchymal transition process, which might indicate the contribution of hepatic oval cells to liver fibrosis.

Purpose: To investigate, by transmission electron microscopy (TEM), the effect on the posterior capsule of a young rabbit eye of 5-fluorouracil (5-FU) or thapsigargin in a sealed-capsule irrigation device., Setting: St Erik's Eye Hospital, Stockholm, Sweden., Methods: Clear lens extraction was performed unilaterally in eight 4-week-old rabbits. A sealed-capsule irrigation device was irrigated for 2 min with 20 ml of one of the following: balanced salt solution (BSS; n=2), thapsigargin 300 muM (n=2), 5-FU 50 mg/ml (n=2), or 5-FU 25 mg/ml (n=2). The substances were washed out for 10 s with BSS. The eyes were left aphakic. Six weeks postoperatively, the animals were killed, and the posterior capsule was extracted and fixed for TEM. As a control, we also evaluated the capsules from the two fellow eyes in the BSS group that did not undergo surgery., Results: The ultrastructure of the posterior capsule in eyes irrigated with 5-FU or thapsigargin did not differ from that in the eyes irrigated with BSS or in the eyes that did not have surgery. The membranes had the same ultrastructure with thin collagen fibres on the anterior and posterior face of the posterior capsule and an amorphic matrix., Conclusion: Thapsigargin or 5-FU used in a sealed-capsule irrigation device does not seem to harm the posterior capsule, which appeared similar to when the capsule is irrigated with BSS.

We present the 12-month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 +/- 11 years) patients were enrolled at a mean interval of 45.5 +/- 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%-per-week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient- and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus-RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 +/- 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl (P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl.

Previous human studies have shown that excess cortisol sufficient to fully occupy central nervous system (CNS) corticosteroid receptors may reduce startle eye blink. The present study tested whether cortisol depletion and the resulting reduction in activity of CNS corticosteroid receptors has the opposite effect. In a single-blind, placebo-controlled, randomized study, eye blink EMG responses to 105 dB acoustic startle stimuli were assessed in 25 healthy subjects who received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. As expected, metyrapone significantly reduced salivary cortisol, indicating effective endogenous cortisol suppression. Startle eye blink responses were significantly increased in the metyrapone group. Short-term habituation of the startle reflex was not different between groups. Our results suggest that startle is enhanced during depletion of cortisol. This effect may be mediated by CNS mechanisms controlling cortisol feedback.

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.

Conditioned cue-induced relapse to drug seeking is a major challenge to the treatment of drug addiction. It has been proposed that D-cycloserine might be useful in the prevention of relapse by reducing the conditioned reinforcing properties of drug-associated stimuli through facilitation of extinction. Here we show that intrabasolateral amygdala infusions of D-cycloserine in fact potentiate the reconsolidation of stimulus-cocaine memories to increase cue-induced relapse to drug seeking in rats with an extensive drug self-administration history. This elevation of cocaine seeking was correlated with an increase in the expression of the reconsolidation-associated gene zif268.

Background: The thiopurine drugs azathioprine and 6-mercaptopurine are well established in the treatment of inflammatory bowel disease (IBD). However, great interpatient variability exists in the efficacy and toxicity of the drugs, and this results from thiopurine methyltransferase (TPMT) gene polymorphisms. The aim of this study was to identify the TPMT gene polymorphisms in Chinese IBD patients and to study the relationship between TPMT status and thiopurine-related toxicity in these patients., Materials and Methods: A total of 189 IBD patients, 87 with Crohn's disease and 102 with ulcerative colitis, and 273 healthy controls were enrolled. All subjects were from the Han Chinese ethnic group. Polymorphisms in TPMT*2, *3A, *3B and *3C were analyzed using allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Direct sequencing was used to confirm the mutation results. Exons of the TPMT gene from patients who suffered from azathioprine-induced toxicity were amplified and sequenced to detect TPMT mutations., Results: No TPMT*2, *3A or *3B mutant alleles were detected. The allele frequency of TPMT*3C in the IBD group was 1.59%, which was similar to that of the healthy control group (1.59 vs. 1.47%, p = 1.000). Forty-three patients were treated with azathioprine therapy, 4 experienced myelotoxicity, and 1 experienced hepatotoxicity, so the incidence of drug toxicity was 11.7% (5/43). No TPMT*2, *3A, *3B or *3C polymorphisms were detected in these 5 patients. After directly sequencing the exons of the TPMT gene in these 5 patients, a synonymous single-nucleotide polymorphism (TPMT*1S), which does not alter the encoded amino acid, was found in 3 patients., Conclusion: TPMT*3C seemed to be a unique variant allele in this Han Chinese population. The overall frequencies of variant TPMT alleles in this population were lower than those in Caucasians, but thiopurine toxicity in Han Chinese IBD patients is not low. Factors other than TPMT polymorphisms may be responsible for the development of toxicity.

Background: The application of weekly doses of D-cycloserine (DCS) to the enhancement of exposure-based treatments has been a particular achievement of translational research. It is not known, however, whether this enhancement effect can be extended to other forms of learning. In this study, we investigated the relative benefit of DCS versus placebo for enhancing nonemotional verbal and nonverbal memory across weekly trials., Methods: We randomized healthy participants to weekly doses of 50 mg DCS or placebo, with 33 participants completing a 5-week protocol. Participants completed baseline neuropsychological evaluation and then 4 subsequent weeks of repeated learning tasks., Results: No improvement was found in immediate or delayed memory following single doses of DCS for the memory tasks repeated on a weekly basis. Trends for an advantage of DCS were evident for novel word lists given each week., Conclusions: The learning tasks in our study were particularly distinct from the extinction learning paradigms that have shown strong DCS effects, and we were unable to demonstrate useful DCS effects with these nonemotional stimuli. Additional research is needed to elucidate the bounds of DCS augmentation effects on therapeutic learning., (2008 S. Karger AG, Basel.)

Carbon monoxide (CO) is generated during incomplete combustion of carbon-containing compounds and leads to acute and chronic toxicity in animals and humans depending on the concentration and exposure time. In addition to exogenous sources, CO is also produced endogenously by the activity of heme oxygenases (HOs) and the physiological significance of HO-derived CO has only recently emerged. CO exerts vasoactive, anti-proliferative, anti-oxidant, anti-inflammatory and anti-apoptotic effects and contributes substantially to the important role of the inducible isoform HO-1 as a mediator of tissue protection and host defense. Exogenous application of low doses of gaseous CO might provide a powerful tool to protect organs and tissues under various stress conditions. Experimental evidence strongly suggests a beneficial effect under pathophysiological conditions such as organ transplantation, ischemia/reperfusion, inflammation, sepsis, or shock states. The cellular and molecular mechanisms mediating CO effects are only partially characterized. So far, only a few studies in humans are available, which, however, do not support the promising results observed in experimental studies. The protective effects of exogenous CO may strongly depend on the pathological condition, the mode, time point and duration of application, the administered concentration, and on the target tissue and cell. Differences in bioavailability of endogenous CO production and exogenous CO supplementation might also provide an explanation for the lack of protective effects observed in some experimental and clinical studies. Further randomized, controlled clinical studies are needed to clarify whether exogenous application of CO may turn into a safe and effective preventive and therapeutic strategy to treat pathophysiological conditions associated with inflammatory or oxidative stress.

Aim: To investigate the effect on after-cataract and synechiae formation after clear lens extraction and irrigation with different substances in a sealed-capsule irrigation device., Setting: St Erik's Eye Hospital, Stockholm, Sweden., Methods: Clear lens extraction was performed in one eye of 42 4-week-old rabbits. The sealed-capsule irrigation device was applied and the sealed system was irrigated for 2 min with 20 ml of one of four substances: balanced salt solution (BSS), thapsigargin, 5-fluorouracil (5-FU) 50 mg/ml, or 5-FU 25 mg/ml. The substance then was washed out for 10 s with BSS. The eyes were left aphakic. Formation of after-cataract and synechiae was evaluated during two clinical examinations 3.5 and 5.5 weeks postoperatively, by photographs 5 weeks postoperatively, and by histologic evaluation of haematoxylin-eosin-stained slides after the 6-week end point postoperatively. After-cataract and synechiae were graded on a scale from 0 to 4. Kruskal-Wallis analysis of variance with multiple comparisons was used for statistical analyses., Results: 5-FU 50 mg/ml prevented after-cataract and synechiae formation best when compared with all other substances at all evaluations. 5-FU 25 mg/ml was not as effective, and thapsigargin was ineffective in this animal model., Conclusion: 5-FU 50 mg/ml used in the sealed-capsule irrigation device satisfactorily prevents after-cataract and synechiae. Thapsigargin was ineffective in this animal model.

There are challenges for diagnosis and treatment of idiopathic pulmonary hemosiderosis (IPH). This clinical trial was to review the diagnosis and evaluate the efficacy of maintenance therapy with dose-adjusted 6-mercaptopurine (6MP) in IPH children. Fifteen children were enrolled. Prednisone was administered at 2 mg/kg/day for 4 weeks in acute phase of the disease followed by taper. 6MP was also started at 60 mg/m(2)/day simultaneously and continued for 3 years in outpatient. The delay in diagnosis of IPH is common and probably due to a lack of classical triad of IPH in most children. All the patients exhibited response to the initial treatment. Only one of eight patients with relative leukopenia on 6MP maintenance recurred while 5 of 7 others recurred (P < 0.05) during median 4.5-year follow-up. Of the latter five patients who recurred, 4 remained recurrence-free after adjusting the dose of 6MP upwards to keep relative leucopenia. It suggests that children with IPH could achieve steroid-free long term remission on 6MP maintenance therapy, and relative leukopenia on 6MP might be a simple maker of predicting clinical response in most IPH children., ((c) 2008 Wiley-Liss, Inc.)

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 compare the long-term efficacy and safety of intraoperative 5-fluorouracil (5-FU) versus mitomycin-C (MMC) used adjunctively with primary trabeculectomy in a Black West African population., Design: Retrospective comparative study supplemented with cross-sectional follow-up data., Methods: Review of 68 eyes of 68 Black West African subjects that underwent primary trabeculectomy with the use of intraoperative 5-FU or MMC between January 1, 1988 and January 1, 2002 and had at least 3 years postoperative follow-up. Postoperative outcome measures included intraocular pressure (IOP) control, number of glaucoma medications, visual acuity, and complications., Results: Thirty-eight of sixty-eight eyes received 5-FU and 30 received MMC. Mean postoperative follow-up was 7.5 and 6.5 years in the 5-FU and MMC groups, respectively (P=0.17). A higher proportion of eyes in the MMC group achieved "qualified" (with or without medical therapy) success with varying IOP targets relative to the 5-FU group, but the differences were not statistically significant. "Complete" (without medical therapy) postoperative success was greater in the MMC group with a significantly higher proportion achieving an IOP <21 mm Hg (P=0.02). MMC use was also associated with a lower likelihood of receiving IOP-lowering medications postoperatively (P=0.01). Baseline demographic characteristics, preoperative and postoperative IOP, visual acuity, and complications did not differ significantly between the 2 groups., Conclusions: Intraoperative MMC use is associated with a lower likelihood of requiring postoperative medications and a greater likelihood of achieving IOP lowering without medications relative to the use of 5-FU in a Black West African population.

Aim: To determine the release characteristics of a 5-fluorouracil-loaded poly (lactic acid) disc (5-FU-PLA-DS) and the effect of sustained drug delivery on the success of glaucoma filtration surgery in rabbit eyes., Methods: A method of microspheres accumulated by excessive carriers was used in the preparation of the 5-FU-PLA-DS. The disc was characterized for drug loading, entrapment efficiency, in vitro release, and external morphology. It was then implanted subconjunctivally into rabbit eyes with trabeculectomy. Intraocular pressure, ocular inflammatory reaction, filtration bleb appearance, and persistence were evaluated up to postoperative d 90. A quantitative analysis of 5-fluorouracil (5-FU) was performed in the aqueous humor. Ultrasound biomicroscopy was used to assess the appearance of the filtering fistula., Results: The 5-FU-PLA-DS was produced with the drug-loading of 3.07+/-0.08 mg (mean+/-SD). 5-FU was released for 91 d with suppressive concentrations. The decrease in intraocular pressure from baseline was significantly more marked in the 5-FU-PLA-DSimplanted eyes during postoperative d 3-90, and the persistence of bleb and filtration fistula was longer than the control eyes (P<0.05). Corneal toxicity and hyperemia triggered by 5-FU was lower in the 5-FU-PLA-DS-implanted eyes than those exposed to 5-FU intraoperatively. The 5-FU concentration in the aqueous humor was insufficient for corneal endothelial damage. No evidence of toxic reaction was found in the conjunctival biopsy., Conclusion: 5-FU-PLADS displaying sustained intraocular release of 5-FU, reduced intraocular pressure, and prolonged bleb persistence, while significantly reducing 5-FU 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 huge improvement in the therapeutic arsenal for HIV infection has led to HIV becoming a chronic disease. Like us, our patients are aging and their life expectancy is close to that of the general population. Consequently, we need safe, easily administered drugs with interactions that can be controlled and the least possible impact on highly prevalent comorbidities such as atherosclerosis or coinfection with hepatotropic viruses. Drugs should fit the patient's lifestyle without affecting quality of life and, above all, be free of effects leading to stigma, such as lipoatrophy, a major concern for most recently diagnosed patients. The choice of the two nucleoside analogue reverse transcriptase inhibitors used at the start of antiretroviral therapy should be based on careful evaluation of the abundant data accumulated on all these determining factors which are heralding a new era in the control of HIV infection. Thus, in this scenario, thymidine analogues have been relegated to alternative use. Fixeddose combinations of tenofovir and emtricitabine (TDF/FTC) or abacavir and lamivudine (ABC/3TC) are the backbone of choice when initiating antiretroviral therapy. Direct comparative data are still scarce but suggest similar virological efficacy, with highly preliminary data suggesting some disadvantages associated with the use of ABC/3TC. After excluding patients at risk of hypersensitivity to ABC, both combinations are well tolerated, but TDF/FTC is associated with a better lipid profile. Recent data from the Data Collection on Adverse Events of Anti-HIV drugs (DAD) study show an unexpected association of ABC with increased cardiovascular risk and thus more detailed studies are required.

The use of nucleoside analogues, especially that of thymidine analogues, depletes mitochondrial DNA, which is the cause of many of the adverse effects of this family of antiretroviral drugs, among them lipodystrophy. The absence of a specific treatment for lipoatrophy and its direct association with stavudine and zidovudine exposure has led several authors to examine the development of lipoatrophy and of other secondary effects of antiretroviral therapy after substituting a thymidine analogue with tenofovir DF. Prospective observational studies and randomized clinical trials including more than 2000 patients have demonstrated that substituting thymidine with tenofovir increases total body fat, especially in the face and extremities, improves lipid and metabolic profiles in patients, and increases hemoglobin levels when zidovudine is discontinued. These changes are accompanied by maintenance or even an increase of the antiviral and immunological efficacy of antiretroviral therapy. Because of the wealth of scientific data supporting the improvement in lipoatrophy when zidovudine or stavudine are substituted by tenofovir, this strategy can be strongly recommended in antiretroviral therapy.

Background: Cardiopulmonary bypass (CPB) is associated with pulmonary inflammation and dysfunction. This may lead to acute lung injury and acute respiratory distress syndrome with increased morbidity and mortality. The authors hypothesized that inhaled carbon monoxide before initiation of CPB would reduce inflammatory response in the lungs., Methods: In a porcine model, a beating-heart CPB was used. The animals were either randomized to a control group, to standard CPB, or to CPB plus carbon monoxide. In the latter group, lungs were ventilated with 250 ppm inhaled carbon monoxide in addition to standard ventilation before CPB. Lung tissue samples were obtained at various time points, and pulmonary cytokine levels were determined., Results: Hemodynamic parameters were largely unaffected by CPB or carbon monoxide inhalation. There were no significant differences in cytokine expression in mononuclear cells between the groups throughout the experimental time course. Compared with standard CPB animals, carbon monoxide significantly suppresses tumor necrosis factor-alpha and interleukin-1beta levels (P < 0.05) and induced the antiinflammatory cytokine interleukin 10 (P < 0.001). Carbon monoxide inhalation modulates effector caspase activity in lung tissue during CPB., Conclusions: The results demonstrate that inhaled carbon monoxide significantly reduces CPB-induced inflammation via suppression of tumor necrosis factor alpha, and interleukin-1beta expression and elevation of interleukin 10. Apoptosis induced by CPB was associated with caspase-3 activation and was significantly attenuated by carbon monoxide treatment. Based on the observations of this study, inhaled carbon monoxide could represent a potential new therapeutic modality for counteracting CPB-induced lung injury.

Standard antiretroviral therapy (ART) consists of a combination of three active drugs. The selection of these drugs varies considerably according to the clinical scenario. The "gold standard" in patients initiating ART is tenofovir (TDF)/emtricitabine (FTC)/efavirenz. TDF/FTC is also considered a combination of choice when, for various reasons, ART is initiated with a boosted protease inhibitor. Abacavir and lamivudine (ABC/3TC) is also considered a combination of choice in most clinical practice guidelines. HLA-B*5701 determination minimizes the possibility of hypersensitivity of ABC and is a positive datum for the use of ABC/3TC. However, negative findings from the data collection on Adverse Events of Anti-HIV drugs (DAD) and ACTG5202 studies on this combination should be bourne in mind. TDF can also be a good choice for substituting another nucleoside analogue to avoid or reverse certain toxicities in patients with good virological control. Substituting thymidine analogues for TDF improves lipid profile and produces partial recuperation of subcutaneous fat. Because of the profile of resistance to TDF, this drug continues to be active in most patients with one, or even several, therapeutic failures. TDF plays and especially important role in patients coinfected with hepatotrophic viruses. In summary, TDF is a widely used drug in clinical practice due to its excellent combination of effectiveness, durability and tolerability, in addition to its ease of administration in a single daily dose, whether in its individual formation (Viread), or associated with FTC (Truvada), or with FTC and efavirenz (Atripla).

Background: 5-Fluorouracil is an antimetabolite that has been known to be effective for the treatment of common warts., Objective: The objective was to evaluate the efficacy of a combination of 5-fluorouracil, lidocaine, and epinephrine (5-FU+LE) for the treatment of common warts., Materials and Methods: Of the 40 patients initially enrolled, 34 patients with at least 68 verruca vulgaris (one pair for each subject) completed the study. The selected warts were randomized into two treatment groups, with one wart on each patient receiving intralesional 5-FU+LE (4 mL of 50 mg/mL 5-fluorouracil and 1 mL of a mixture of 20 mg/mL [2%] lidocaine and 0.0125 mg/mL epinephrine) and the other receiving intralesional normal saline placebo using a Mantoux needle. Patients received up to four injections at weekly intervals and were followed at 1 and 6 months after the initial injection., Results: Complete response was observed in 64.7% of the warts treated with 5-FU+LE compared to 35.3% in the warts treated with placebo (p<.05). Systemic reaction or treatment-related adverse medical events and recurrence rate did not differ significantly between two groups., Conclusion: The results show that intralesional 5-FU+LE is a safe and effective approach for common warts with high success rate.

As a by-product of heme catabolism by the heme oxygenase system, carbon monoxide (CO) has been neglected for many years, and only recently has its role as an essential signaling molecule been appreciated. In the past decade, the use of CO gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. However, the inherent toxic nature of CO cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. From a clinical perspective, a key question is whether a safe and therapeutically effective threshold of CO can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. The advent of CO-releasing molecules (CO-RMs), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, appears a plausible alternative in the attempt to overcome the limitations of CO gas. Although in its infancy and far from being used for clinical applications, the CO-RMs technology is supported by very encouraging biological results and reflected by the chemical versatility of these compounds and their endless potential to be transformed into CO-based pharmaceuticals.

Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of alpha-smooth muscle actin (alpha-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-beta(1)-induced expression of alpha-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

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.

In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer.

Background: At least one-third of patients with inflammatory bowel disease do not respond or are intolerant to therapy with 6-mercaptopurine (6-MP). A subgroup fails to attain optimal levels of 6-thioguanine nucleotide (6-TGN) and instead shunts to 6-methylmercaptopurine nucleotide (6-MMPN)., Patients and Methods: A retrospective chart review was conducted, and four patients are described who had been previously unable to achieve optimal 6-TGN metabolite levels until allopurinol was added to their treatment., Results: All four patients achieved optimal 6-TGN levels and undetectable 6-MMPN with a mean 6-MP dose of 0.49 mg/kg. Three achieved steroid-free clinical remission. Two of those three patients had normalization of liver enzymes; one patient had baseline normal liver enzymes despite an initial 6-MMPN level of 27,369 pmol/8 x 10(8) red blood cells. Two patients experienced reversible leukopenia., Conclusions: Combination allopurinol and low-dose 6-MP is an effective means to achieve optimal metabolite levels and steroid-free clinical remission in previously refractory patients. Caution is advised.

A two-phase cross-over therapeutic study was performed with 19 green iguanas (Iguana iguana) maintained within a preferred optimum temperature range of 26 to 37 degrees C. During phase 1, they were fed a normal vegetarian diet and medicated orally with either allopurinol or a placebo control once a day for seven days. Uric acid concentrations, total protein, packed-cell volumes (pcv) and bodyweights were recorded from each lizard before and after treatment to determine the effects of allopurinol. In phase 2, after a 10-day washout period, the iguanas were fed a high protein diet to induce hyperuricaemia. Normo- and hyperuricaemic iguanas that received 24.2 (3.2) mg/kg allopurinol had significantly lower mean (sd) uric acid concentrations (100.3 [53.1] micromol/l) than the controls (159.3 [100.3] micromol/l). There were no detectable interactions between the doses of allopurinol or placebo, and the iguanas' diet, weight, pcv or total protein. The allopurinol was well tolerated, and there was no significant clinical, gross or histological evidence of hepatic or renal toxicity in the iguanas that received the drug. However, in the kidneys of the hyperuricaemic iguanas that did not receive allopurinol there were proliferative changes in the glomeruli and degeneration of tubular epithelia. Allopurinol given orally at 25 mg/kg daily is able to reduce plasma uric acid levels by 41 to 45 per cent, and is therefore recommended for the treatment of hyperuricaemia in the green iguana.

We have investigated whether long-term oral administration of the nucleoside reverse transcriptase inhibitor (NRTI) stavudine affects nociception in Sprague-Dawley rats, and whether any changes of nociception are accompanied by deterioration in activity and appetite. Stavudine (50 mg kg(-1)) was administered to rats orally once daily for six weeks in gelatine cubes. Mechanical hyperalgesia of the tail was assessed using a bar algometer, and thermal hyperalgesia by tail immersion in 49 degrees C water. Withdrawal latencies were compared to those of rats receiving placebo gelatine cubes. Withdrawal latencies to the noxious thermal challenge were not affected by stavudine, but those to the mechanical challenge were significantly decreased in rats receiving stavudine, compared to rats receiving placebo, from week three to week six of drug administration (P<0.05, ANCOVA with Newman Keuls post-hoc comparisons). The overall condition of the rats was assessed by recording daily voluntary wheel running distance and maximum running speed, food intake and body mass. Daily stavudine administration did not adversely affect voluntary running activity, appetite or growth. We have shown that long-term daily oral administration of the NRTI stavudine results in mechanical hyperalgesia in rats within three weeks without affecting appetite, growth and physical activity.

Background: Primary open angle glaucoma (POAG) is one of the leading causes of avoidable blindness. Unlike blindness from cataracts, glaucomatous optic nerve damage is irreversible, and prevention of glaucoma is one of the priorities of World Health Organization (WHO) Vision 2020 program. POAG is the commonest type of glaucoma and affects about 33.1 million people worldwide. This study is a five year review of 71 eyes of 63 patients who had trabeculectomy. The study evaluates the pattern of presentation and modality of surgical treatment in our environment., Methods: Records of all patients with primary open angle glaucoma operated over a five year period was retrieved. Information extracted included patients bio data, visual acuity, gonioscopic findings, intra ocular pressure as measured with applanation tonometer before and after surgery, and recorded in mmHg. Perimetry was done with 2 m tangent screen and recorded in a perimetry chart. All the patients had trabeculectomy with application of antimetabolite (5-fluorouracil). Extra capsular cataract extraction with or, without posterior chamber intra ocular lens implantation was done on 13 patients. Biometry was not done on patients with cataract. Surgery was done on better eye first in all patients., Results: There were 71 eyes of 63 patients. The male to female ratio was 3:1. The age ranged between 18 to 75 years. 8 patients were below the age of 30 years. One third of the patients were between the ages of 50 to 59 years. At presentation 12 patients (19%) had normal vision (WHO vision category O), 26 patients (41%) were visually impaired, 12 patients (19%) were severely visually impaired and 13 patients (21%) were blind (from co existing cataracts). The cup disc(c: d) ratio assessed before surgery was 0.5 in 9 eyes (13%), 31 eyes (53%) had c: d ratio 0.6 to 0.8 and 18 eyes had c: d ratio of 0.9. All the patients had open anterior chamber angles (Schafer grade 3 and 4). Perimetric changes were; mild peripheral constriction in 5 eyes (8%), peripheral constriction with arcuate scotoma in 19 eyes (26%), constricted fields of 300 or less in 34 eyes (48%), and in 13 eyes there was inability to fixate on target. IOP before surgery was 21 to 30 mm Hg in 12 eyes (17%), and above 31 mm Hg in 69 eyes (83%). Post operative IOP of 10 to 15 mm Hg was obtained in 58 eyes (82%) and 11 eyes (15%) had IOP of 16 to 20 mm Hg. Only 2 eyes (3%) had IOP in the lower twenties., Conclusion: Primary open angle glaucoma is characterized by late presentation. Trabeculectomy with application of 5FU is the surgical treatment of choice in our environment and give good intra ocular pressure control. There is need to increase public awareness on glaucoma to limit this type of avoidable blindness.

Background: Capsule formation around breast implants, development of tendon adhesions after tendon repair, intestinal brits after laparatomies, hypertrophic scars in skin incisions all are the results of excessive collagen synthesis to the extracellular matrix by fibroblasts. Any intervention that leads to cessation of collagen synthesis in these clinical situations may help to prevent these untoward results of wound healing. Although 5-fluorouracil (5-FU) is used mainly as a cytotoxic drug in chemotherapy protocols, it decreases cellular metabolism and blocks protein synthesis only at lower concentrations. Findings have shown that 5-FU downregulates fibroblast proliferation and differentiation in vitro. It has been used to treat fibroproliferative disorders of the eye and skin and is thought to inhibit thymidylate synthetase, blocking DNA replication., Methods: This study used five treatment groups: (1) gelatin only, (2) silicone only, (3) silicone + gelatin, (4) silicone + gelatin containing 1 mg of 5-FU, and (5) silicone + gelatin containing 5 mg of 5-FU. The release kinetics of 5-FU from gelatin have been investigated by means of ultraviolet spectrophotometric analysis. Specimens were obtained on postoperative day 30. Gross evaluation and histopathologic examination were conducted for capsule formation and the development of inflammation., Results: The silicone group had the most prominent capsule formation among all the groups. The gelatin group was second, and the silicone + gelatin group was third. As compared with the other groups, the 5-FU-containing groups had the least capsule formation. The 5-mg 5-FU-containing group had the most inflammation. The silicone + gelatin group was second in inflammation. Although the silicone, gelatin, and 1-mg 5-FU-containing groups had the same means, the results of the silicone group showed the most divergent data within the group., Conclusions: Because 5-FU loaded to a gelatin carrier for its slow release seems to prevent capsule formation around silicone blocks, it may be used to prevent capsule formation around silicone breast implants.

Purpose: To study the safety of irrigation with 5-fluorouracil (5-FU) in the Perfect Capsule sealed-capsule irrigation device (Milvella, Ltd., Epping, Australia)., Setting: St. Erik's Eye Hospital, Stockholm, Sweden., Methods: Thirty 8-week-old rabbits were divided into 4 groups. Clear lens extraction was performed and the Perfect Capsule was applied in 1 eye in Groups 1, 2 and 3. The sealed system was flushed with balanced salt solution (BSS) in Group 1, 5-FU 50 mg/mL in Group 2, and 5-FU followed by BSS in Group 3. In Group 4, the Perfect Capsule was not applied; instead, 0.2 mL of 5-FU was instilled in the capsule and left there for 30 seconds. An endothelial cell count and pachymetry were performed preoperatively and 24 hours postoperatively. At 24 or 48 hours (half of each group at each time point), the rabbits were killed and the retina and trabecular meshwork histopathologically examined. The endothelial cell count and pachymetry were compared between the Perfect Capsule eye and the control eye in Group 1., Results: There was no difference between the groups in endothelial cell count (P = .96) or pachymetry (P = .32). Histologic evaluation showed no damage from the 5-FU. The comparison between eyes in Group 1 showed that the use of the Perfect Capsule did not cause more endothelial cell loss (P = .86) or increase pachymetry more (P = .28) than in the control eye., Conclusion: Irrigation with 5-FU 50 mg/mL in the sealed-capsule irrigation device was safe and caused no apparent damage to the adjacent intraocular tissues.