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Purpose: To evaluate the outcomes of uveitic macular edema at 6 and 12 months in patients treated with methotrexate or mycophenolate mofetil., Design: Subanalysis of a block-randomized, observer-masked, multicenter clinical trial., Participants: Patients were enrolled in the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial between August 2013 and August 2017., Methods: Patients were randomized to oral methotrexate 25 mg weekly or mycophenolate mofetil 1.5 g twice daily for 12 months, along with a corticosteroid taper. In addition to standardized clinical examination, all patients underwent spectral-domain OCT imaging at each visit. At the 6-month primary end point, patients who achieved treatment success continued the same treatment for a subsequent 6 months, and treatment failures switched to the other treatment group., Main Outcome Measures: Prespecified 6-month primary outcome and 12-month outcomes of central subfield thickness and visual acuity., Results: Of 216 patients in the FAST Trial, 42 eyes (30 patients) in the methotrexate group and 55 eyes (41 patients) in the mycophenolate group had uveitic macular edema. Baseline median central subfield thickness was 359 μm and 342 μm in the methotrexate and mycophenolate groups, respectively. At 12 months, for those who stayed on the same treatment, macular thickness decreased from baseline by 30.5 μm (interquartile range [IQR], -132.3 to 4.0) and 54 μm (IQR, -95.5 to -4.5) in the methotrexate and mycophenolate groups, respectively (P = 0.73). In patients who switched treatment at 6 months, macular thickness decreased from baseline by 12.5 μm (IQR, -32.3 to -0.5) and 50 μm (IQR, -181.0 to -10.0) in the methotrexate and mycophenolate groups, respectively (P = 0.34). At 12 months, 7 of 19 eyes (37%) on methotrexate had resolution of macular edema compared with 15 of 25 eyes (60%) on mycophenolate (P = 0.10). For those who switched treatments, 8 of 17 eyes (47%) on methotrexate and 6 of 11 eyes (55%) on mycophenolate had resolution of macular edema (P = 0.92)., Conclusions: Treatment with methotrexate or mycophenolate mofetil for uveitic macular edema results in similar improvements in macular thickness at 6 and 12 months. At 12 months, approximately half of eyes in each antimetabolite group still had persistent macular edema., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 μmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 μmol/L in dialyzed and 283 μmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. CONCLUSION: MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

The essential roles of eukaryotic translation initiation factor 4E (eIF4E) have been shown in various cancers, including ovarian cancer. In this work, we demonstrate that eIF4E inhibition in ovarian cancer can be achieved by ribavirin, a FDA-approved antiviral drug. We show that ribavirin at clinically relevant doses significantly inhibits growth and survival in multiple ovarian cancer cell lines, regardless of morphological and molecular subtypes. Mechanistically, ribavirin suppresses Akt/mTOR and eIF4E/p70S6K signaling pathways in ovarian cancer cells. We confirm that eIF4E is the critical molecular target of ribavirin, and furthermore that this is dependent on phosphorylation at S209. Notably, using both in vitro cell culture system and in vivo xenograft mouse model, we show that the combination of ribavirin with cisplatin (standard of care for patients with ovarian cancer) results in significantly greater efficacy than cisplatin alone in ovarian cancer. Interestingly, the sensitivity to ribavirin varies among a panel of ovarian cancer cell lines, mostly likely due to their differential expression level of eIF4E and dependency to eIF4E inhibition. The differential expression level is further observed in ovarian cancer tissues, with the higher level of eIF4E in the majority of ovarian cancer tissues compared to normal ovary tissues. Our work suggests that eIF4E expression varies among ovarian cancer. Additionally, ribavirin is a useful addition to ovarian cancer treatment, particularly to those with high dependency on eIF4E., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There has been relatively little attention focused on treatment strategies for smokers with panic attacks despite their increased risk of relapse. Panic and Smoking Reduction Treatment (PSRT) integrates standard smoking cessation treatment with an exposure-based intervention targeting the mechanisms underlying panic-smoking relations. Building upon emerging evidence supporting the efficacy of d-cycloserine (DCS) for augmenting exposure-based therapy, we are conducting an initial test of the efficacy of DCS for enhancing PSRT outcomes. Utilizing a randomized, double-blind trial comparing PSRT+DCS to PSRT+placebo, we will obtain initial effect sizes for short-term and long-term smoking cessation outcomes and perform an initial test of putative mechanisms., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Despite advances in individual and combined treatments for major depression, issues with non-response and partial-response remain relatively common, motivating the search for new treatment strategies. This study aims to develop one such novel treatment. In this proof-of-concept study, we are investigating whether the treatment enhancing effects of d-cycloserine (DCS) administration can be extended outside the extinction-learning paradigms where they have been primarily examined. Using uniform delivery of cognitive behavioral therapy (CBT) content via computer-administered interventions for depression, we are assessing the value of pre-session administrations of DCS for retention of therapeutic learning. Recall of this information is evaluated in conjunction with performance on standardized tests of memory recall with both emotional and non-emotional stimuli. Specifically, in a randomized, double-blind trial we will compare the benefits of two pre-session administrations of DCS augmentation to those achieved by similar administrations of modafinil or placebo. Because modafinil is associated with a number of discriminable effects in addition to cognitive enhancement (e.g., feelings of vigor, alertness, positive mood); whereas these effects would not be expected with DCS, we will assess drug context effects in relation to memory augmentation effects., (Copyright © 2016. Published by Elsevier Inc.)

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice., (Copyright © 2015 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.)

Background & Aims: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH., Methods: Wild-type mice, ATP receptor 2x7 (P2rx7)-KO mice, or mice overexpressing uricase were fed Lieber-DeCarli ethanol or control diet. We also implemented a pharmacological approach in which mice were treated with probenecid or allopurinol., Results: The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was achieved in mice treated with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling. We found that alcohol-damaged hepatocytes released uric acid and ATP in vivo and in vitro and that these sterile danger signals activated the inflammasome in LPS-exposed liver mononuclear cells., Conclusions: Our data indicate that the second signal in inflammasome activation and IL-1β production in ASH results from the endogenous danger signals, uric acid and ATP. Inhibition of signaling triggered by uric acid and ATP may have therapeutic implications in ASH., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

About half of patients with sarcoidosis will need systemic therapy for their disease. Oral glucocorticoids are the standard first-line treatment for sarcoidosis. With time, patients might develop substantial morbidity from long-term use of high doses of these drugs. We propose a step-wise approach to the management of pulmonary disease in sarcoidosis and provide details about how and when to use alternatives to glucocorticoids. The antimetabolites, such as methotrexate, azathioprine, leflunomide, and mycophenolate, are often used as alternatives to steroids. For patients who cannot be treated with low-dose glucocorticoids and an antimetabolite, anti-tumour necrosis factor (TNF) monoclonal antibodies have been shown to control disease. Unfortunately, anti-TNF drugs are associated with substantial toxic effects and in some cases are ineffective. The next step in treatment includes new strategies such as rituximab. A new regimen combining four antibiotics (levofloxacin, ethambutol, azithromycin, and rifamycin) has shown some promise in preliminary studies; however, the mechanism of action is unknown. Non-inflammatory effects of sarcoidosis, such as pulmonary hypertension and bronchiectasis, might also contribute to an increase in pulmonary symptoms. In those cases, alternative treatment strategies have to be considered., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To ascertain whether patients on long-term systemic immunosuppressive therapy for inflammatory eye disease (IED) are at increased risk of malignancy., Design: A single-center, retrospective cohort study., Participants: We included 190 adults with IED treated with corticosteroids only (n = 58) or systemic immunosuppression (n = 132) for ≥6 months between 1985 and 2007. Immunosuppressed patients were treated with antimetabolites, T-cell inhibitors, and/or alkylating agents., Methods: Incident malignancies were ascertained by self-report and confirmed by medical record review. Multiple malignancies in a single patient were counted, except for nonmelanoma skin cancer (NMSC), where only the first was counted. Standardized incidence ratios (SIRs) were calculated by malignancy type. Cox regression models were used to compare malignancy incidence by treatment type., Main Outcome Measures: Risk of malignancy relative to the general population and within the cohort., Results: During a median 7.34 years of follow-up, 25 malignancies were observed in 17 patients, namely, 2.10 per 100 person-years and 0.43 per 100 person-years in the immunosuppressed and corticosteroid only groups, respectively. In the immunosuppressed group, the most common malignancies were NMSC (n = 11) and non-Hodgkin's lymphoma (NHL; n = 4) and malignancy risk was significantly increased compared with the general population for any malignancy (SIR, 4.39; 95% CI, 2.78-6.59) and for any malignancy excluding NMSC (SIR, 4.16; 95% CI, 1.67-8.57). Significantly elevated SIRs were observed for NMSC and NHL in those treated with immunosuppressive agents. Compared with the corticosteroid treatment-only group, the immunosuppressed group was at an increased risk of any malignancy (adjusted hazard ratio, 4.36; 95% CI, 1.02-18.7), but not first malignancy (n = 17; adjusted hazard ratio, 2.56; 95% CI, 0.57-11.5). No cancer-related deaths were observed., Conclusions: Our findings suggest that patients with IED treated with systemic immunosuppressive therapy are at increased risk of malignancy; however, the increase in absolute risk was modest. The types of malignancies observed at excess risk are similar to those observed in solid organ transplant recipients and patients with autoimmune diseases treated with systemic immunosuppression. Immunosuppressive therapy remains an important treatment modality in IED; however, patients may benefit from targeted malignancy-prevention strategies and long-term clinical follow-up. These findings require validation by a prospective, long-term, population-based cohort study., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Infliximab withdrawal in patients with Crohn's disease on concomitant antimetabolite therapy is considered to be superior if obtained after a maintenance therapy period compared to induction alone., Methods: We retrospectively analyzed the outcome of Crohn's disease patients treated with infliximab and an antimetabolite after infliximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy. The time to relapse was analyzed using univariate and multivariate analyses. The model was adjusted according to the period of infliximab withdrawal., Results: A total of 92 patients were included, 54 in the induction alone group. The patient characteristics were identical in the two groups except for the period of infliximab withdrawal. After a median follow-up period of 47.1 (interquartile range=4.4-110.2) months, 66 patients (72%) experienced a relapse. After a year-adjustment, no significant difference was observed between the two groups. Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking, previous antimetabolite failure, and perianal disease. After relapse, 53 patients (80%) were retreated with infliximab. After infliximab retreatment, clinical remission was observed in 47 patients (89%) at weeks 8-10., Conclusion: In Crohn's disease patients, the probability of relapse on antimetabolite therapy after infliximab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918., (© 2014 by The American Society of Hematology.)

Morphoea is a localized scleroderma. Since the 1990s, it is described as a complication after irradiation for breast cancer. This complication is unrecognized and underdiagnosed. Irradiation seems to be a factor inducing an autoimmune process. Clinicians should be aware in case of an erythema in a treated area, appearing on average one year after the end of the irradiation. Histology alone can prove the diagnosis and rule out differential diagnoses: principally mastitis (carcinomatous, infectious), chronic radiodermatitis or radiation recall. Treatment of this rare complication is not consensual; it is most often topical steroids. The evolution is marked by a gradual decrease from the initial inflammation. Sclerosis persists, more or less substantially., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Objective: To compare the efficacy of transconjunctival needling revision with 5-fluorouracil versus medical treatment in glaucomatous eyes with uncontrolled intraocular pressure due to encapsulated bleb after trabeculectomy., Methods: Prospective, randomized, interventional study. A total of 40 eyes in 39 patients with elevated intraocular pressure and encapsulated blebs diagnosed at a maximum five months after primary trabeculectomy with mitomycin C were included. The eyes were randomized to either transconjunctival needling revision with 5- fluorouracil or medical treatment (hypotensive eyedrops). A maximum of two transconjunctival needling revisions per patient was allowed in the needling arm. All patients underwent follow-up for 12 months. Successful treatment was defined as an intraocular pressure ≤ 18 mmHg and a 20% reduction from baseline at the final follow-up. Clinicaltrial.gov: NCT01887223., Results: Mean intraocular pressure at the final 12-month follow-up was lower in the transconjunctival needling revision group compared to the medical treatment group. Similar numbers of eyes reached the criteria for treatment success in both the transconjunctival needling revision group and the medical treatment group., Conclusions: Despite similar success rates in eyes randomized to transconjunctival needling revision with 5-fluorouracil compared to eyes receiving medical treatment, there was a significantly lower mean intraocular pressure at 12 months after transconjunctival needling revision.

Background: The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with d-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence., Methods: Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training., Results: Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not., Conclusions: Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To report the 8-year outcomes of Asian subjects who underwent trabeculectomy augmented by intraoperative 5-fluorouracil (5-FU) or placebo., Design: Retrospective review of a randomized controlled trial., Participants: Subjects with primary open-angle or angle-closure glaucoma., Methods: Study subjects were prospectively followed up for 3 years. After the last subject recruited had completed 8 years of follow-up, the charts of all subjects were reviewed to capture data from the year 3 visit onward. Kaplan-Meier survival function with Cox regression was performed to identify risk factors associated with trabeculectomy failure at 8 years., Main Outcome Measures: The primary outcome was trabeculectomy failure defined as intraocular pressure (IOP) >21 or <6 mmHg on 2 consecutive occasions after the first 6 weeks after surgery, repeat glaucoma surgery, or loss of light perception. Further end points were defined at IOP levels >17 and >14 mmHg. Secondary outcomes included IOP at 8 years and number of glaucoma medications. Complete success was defined using IOP end points ≤ 21, ≤ 17, or ≤ 14 mmHg at 8 years without medications., Results: Of the 243 enrolled subjects, 170 (70.0%) completed 8 years follow-up, 86 in the 5-FU and 84 in the placebo group. There was no significant difference in failure rates at 8 years for the failure definitions of IOP >21 mmHg (11.6% of the 5-FU group vs. 16.7% of the placebo group; P = 1.00), IOP >17 mmHg (23.3% of the 5-FU group vs. 31% of the placebo group; P = 0.78), and IOP >14 mmHg (46.5% of the 5-FU group vs. 58.3% of the placebo group; P = 0.37). Mean IOP at 8 years was 13.7 mmHg in the 5-FU versus 14.4 mmHg in the placebo group (P = 0.24). Mean number of medications was 0.65 drops in the 5-FU versus 0.93 drops in the placebo group (P = 0.06). Complete success with IOP ≤ 21 mmHg at 8 years was achieved in 48 subjects (55.8%) in the 5-FU and 33 subjects (39.3%) in the placebo group (P = 0.09). Absence of bleb microcysts at 1 year, preoperative IOP, and number of bleb needlings performed within the first year were significantly associated with failure., Conclusions: There was no significant difference in IOP between the 5-FU and the placebo group at 8 years., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Posttraumatic stress disorder (PTSD) is a complex and debilitating anxiety disorder, and, although prolonged exposure therapy has been proven effective, many patients remain symptomatic after treatment. In other anxiety disorders, the supplementary use of D-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, showed promise in enhancing treatment effects. We examined whether augmentation of prolonged exposure therapy for PTSD with DCS enhances treatment efficacy., Methods: In a randomized, double-blind, placebo-controlled trial we administered 50 mg DCS or placebo 1 hour before each exposure session to 67 mixed trauma patients, recruited from regular referrals, with a primary PTSD diagnosis satisfying DSM-IV criteria., Results: Although DCS did not enhance overall treatment effects, the participants having received DCS did show a stronger treatment response. Exploratory session-by-session analyses revealed that DCS yielded higher symptom reduction in those participants that had more severe pretreatment PTSD and needed longer treatment., Conclusions: The present study found preliminary support for the augmentation of exposure therapy with DCS, specifically for patients with more severe PTSD needing longer treatment., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Cumulative evidence has suggested investigation of the efficacy of Replication-Competent Adenovirus-mediated Suicide Gene Therapy in newly-diagnosed Prostate Cancer (ReCAP). There is a challenge in designing an efficacy trial for newly-diagnosed prostate cancer given its long natural history. The regulatory agency recommended a Phase II trial for safety before conducting the efficacy trial., Experimental Design: The ReCAP trial is an adaptive seamless, multi-site open-label, randomized Phase II/III trial. Two hundred eighty men will be randomized to receive either replication-competent adenovirus-mediated suicide gene therapy followed by radiation (Arm 1) or radiation alone (Arm 2). Phase II trial component will include the first 21 patients in Arm 1 with complete toxicity through day 90 for safety evaluation. The primary efficacy endpoint is the time free from biochemical and/or clinical failure (FFF). The secondary efficacy endpoints are 2-year prostate biopsies and overall survival. Unequal spaced interim looks are proposed with the adaptive sample-size re-estimation., Results: This trial has been approved by the FDA for the study therapy investigation and is currently recruiting patients., Conclusions: Challenges remain in designing newly-diagnosed prostate cancer trials. Adaptive seamless design is time-saving and a cost-effective design in the development of novel medical therapies, but requires a specified statistical plan in the decision process involved., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In 1923, Friedrich Wohlwill described two patients with a "microscopic form of periarteritis nodosa," which was distinct from the classical form. This disease, now known as microscopic polyangiitis (MPA), is a primary systemic vasculitis characterized by inflammation of the small-caliber blood vessels and the presence of circulating antineutrophil cytoplasmic antibodies. Typically, microscopic polyangiitis presents with glomerulonephritis and pulmonary capillaritis, although involvement of the skin, nerves, and gastrointestinal tract is not uncommon. Treatment of MPA generally requires use of a cytotoxic agent (such as cyclophosphamide) in addition to high-dose glucocorticoids. Recent research has focused on identifying alternate treatment strategies that minimize or eliminate exposure to cytotoxic agents. This article reviews the history, pathogenesis, clinical manifestations, and treatment of MPA., (Copyright 2010 Elsevier Inc. All rights reserved.)

Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder that occurs when tumor cells undergo rapid decomposition spontaneously or in response to cytoreductive therapy. Delayed recognition of the metabolic imbalances caused by the massive release of tumor cell contents may result in clinical complications such as acute kidney injury, seizures, and cardiac arrhythmias. Prevention, the key principle in TLS management, relies on the identification of patients at risk for developing TLS during chemotherapy or because of disease progression. TLS-related risk factors pertain to tumor type (particularly hematologic malignancies), specific tumor characteristics (e.g. bulky tumor, high cellular proliferation rate, sensitivity to cytoreductive therapy), and other host-related factors. A comprehensive grading system proposed by Cairo and Bishop classifies TLS syndromes into laboratory or clinical TLS, thus facilitating TLS prevention and management. The mainstays of TLS management include monitoring of electrolyte abnormalities, vigorous hydration, prophylactic antihyperuricemic therapy with allopurinol, and rasburicase treatment of patients at high TLS risk or with established hyperuricemia. Urine alkalinization and use of diuretics remain controversial clinical practices. In this review, we describe the incidence of, risk factors for, and diagnostic characteristics of TLS and summarize strategies for the prevention and management of TLS-associated metabolic abnormalities, particularly hyperuricemia. We specifically highlight recently published TLS management guidelines, which focus on the prevention of TLS and hyperuricemia based on a patient's level of risk, and the important role of nephrologists in the prevention and treatment of one of the most serious complications of TLS, acute kidney injury., (Copyright (c) 2009. Published by Elsevier Ltd.)

Background: Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder., Method: This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity., Results: Results indicated large effect sizes for the additive benefit of d-cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received d-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration., Conclusions: This pilot study extends support for the role of d-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder., (2010. Published by Elsevier Inc.)

Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes.

Purpose: To compare the relative effectiveness and side effect profiles of antimetabolite drugs in the treatment of noninfectious ocular inflammation., Design: Retrospective cohort study., Participants: A total of 257 patients with inflammatory eye disease seen in a single-center, academic practice and treated with an antimetabolite as a first-line immunosuppressive agent from 1984 to 2006., Methods: Data recorded included demographics, antimetabolite and prednisone doses, use of other immunosuppressive drugs, response to therapy, and side effects associated with drug use., Main Outcome Measures: Ability to control ocular inflammation and to taper prednisone to

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.

Relapsing polychondritis is a rare disease most commonly presenting as inflammation of the cartilage of the ears and nose. Auricular chondritis, with red ears resembling infectious cellulitis, is the most common initial finding. Antibodies to type II collagen in cartilage are found, and the earlobes are classically spared. Chronic disease may result in a flabby, droopy ear, cauliflower ear, or saddle nose deformity. Acute involvement of the tracheal cartilage may cause collapse of the airway with obstruction and pulmonary infections. Arthritis may be oligoarticular or polyarticular, most often involving the costochondral junctions. Other manifestations include audiovestibular damage; heart valve disease; and neurologic, ocular, and renal disease. Corticosteroids remain the major treatment. Other therapies include nonsteroidal anti-inflammatory drugs, dapsone, colchicine, azathioprine, methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine, and infliximab.

Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

Purpose: To evaluate long-term tonometric outcomes of trabeculectomy with adjunctive mitomycin C (MMC) and its efficacy in achieving a range of intraocular pressures (IOP) in phakic patients with open-angle glaucoma., Design: Retrospective cohort study., Methods: Three levels of success were defined by these criteria: (A) IOP < or =18 mmHg and IOP reduction of 20%; (B) IOP < or =15 mmHg and IOP reduction of 25%; and (C) IOP < or =12 and IOP reduction of 30%. Kaplan-Meier survival analyses were used to assess outcomes. Cox's proportional hazard regression analysis was used to identify risk factors for failure., Participants: Two hundred twenty-five phakic patients (292 eyes) with open-angle glaucoma, > or =40 years of age at time of trabeculectomy., Main Outcome Measures: The primary outcome was qualified success rate (with or without medications) according to the defined criteria. Secondary outcomes include IOP level and number of medications at 1 and 3 years after surgery, postoperative complications, and need for further glaucoma surgery., Results: Mean IOP (+/-standard deviation) decreased from 18.8 mmHg (+/-6.1 mmHg) before surgery to 11.3 mmHg (+/-4.5 mmHg) at 1 year and 11.1 mmHg (+/-4.2 mmHg) at 3 years (P<0.001 for both). The mean number of medications decreased from 2.8 (+/-1.0) to 0.4 (+/-0.7) at 1 year and 0.7 (+/-1.0) at 3 years (P<0.001 for both). The success rates were 85%, 84%, and 79% at 1 year for criteria A, B, and C, respectively; and 62%, 56%, and 46% for these criteria, respectively, at 3 years. Postoperative laser suture lysis was associated with a higher rate of failure for criteria B and C (P<0.001 for both), the hazard ratio (HR) was 1.7 for criteria B and 2.0 for criteria C. Prior argon laser trabeculoplasty was associated with higher risk of failure for criteria C (HR = 1.6; P = 0.05)., Conclusions: Trabeculectomy with MMC effectively reduces IOP in phakic open-angle glaucoma, but long-term low IOPs are achieved in only half of the cases. Laser suture lysis after trabeculectomy and prior argon laser trabeculoplasty are associated with a higher risk of failure when low IOPs are required.

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine (S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine (S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine (S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.

Seven dogs with parasitologically proven clinical visceral leishmaniosis (Leishmania infantum infection) were treated with a combination of allopurinol and sodium stibogluconate. The dogs received first orally 15 mg/kg of allopurinol every 12 h until the clinical signs improved, in the following 1 month period allopurinol at same dose and subcutaneously 30 mg/kg of sodium stibogluconate combination were given daily and at the end of the combined treatment, allopurinol was continued alone at the same dose till the end of 8 months. During the treatment period, dogs were supported by additional proteins, vitamins, and minerals. A long acting insecticide (collar or drop) was also used in order to prevent further parasite transmission. Follow-up was maintained by clinical, clinicopathological evaluation, and parasitological examination of lymph node, serology using the indirect immunofluorescent antibody test (IFAT). Before treatment commenced, the most important clinical signs were exfoliative dermatitis, ulcerations, peripheral lymhadenopathy, pale mucous membranes, weight loss, and ocular lesions. Clinicopathological findings included commonly anaemia, hyperproteinaemia, hyperglobulinaemia and hypoalbuminaemia. Before the treatment, amastigotes were seen in six of the seven dogs by examination of lymph node aspiration, and IFAT-titers were positive in all dogs. At the end of 8 months treatment, remission of clinical signs, restoration to normal of clinicopathological abnormalities were noticed. Lymph node aspiration was performed on three out of the seven dogs at the end of the treatment because of the very small sizes of the lymph nodes, and no amastigotes were observed. Although the mean IFAT-titer of the dogs were significantly (P < 0.001) lower compared with pretreatment, IFAT-titers of dogs were still positive. No relapses occurred during treatment period and a 6-24-month duration after the end of therapy. Based on the above results, long-term use of allopurinol combined with sodium stibogluconate together with support treatment concluded to have enough therapeutic efficacies in the treatment of dogs with visceral leishmaniosis. Observations of the cases for possible relapses were still going on and insecticide application was carefully carrying on in order preventing a possible re-infection.

Background: Studies of hypothalamic secretion of corticotropin-releasing hormone (CRH) in patients with panic disorder in the nonpanic state (using CRH tests) are contradictory. No data about the hypothalamic-pituitary response to metyrapone are available., Methods: Study participants included 14 patients with panic disorder (DSM-IV criteria) and 14 healthy control subjects who underwent a standard overnight metyrapone test and a combined metyrapone/low-dose dexamethasone test., Results: Significant treatment effects of metyrapone and combined metyrapone/dexamethasone were found on plasma corticotropin, cortisol, and 11-deoxycortisol, but no differences between patients and control subjects emerged. Considering visual analogue scale ratings of anxiety, tension, restlessness, and Beck Depression Inventory scores as covariates, no group effects were detected., Conclusions: Standard overnight metyrapone tests do not support a hypersecretion of hypothalamic CRH in panic disorder. Furthermore, no evidence for increased glucocorticoid negative feedback in panic was found. Hypothalamic CRH secretion in the nonpanic state needs further research.

Objective: To determine the efficacy of a combination of 5-fluorouracil and low-molecular-weight heparin (LMWH) to improve the outcome of surgery for established proliferative vitreoretinopathy (PVR)., Design: Double-masked, prospective, randomized, placebo-controlled clinical trial., Setting: Three tertiary-referral teaching hospital vitreoretinal surgical units., Patients: One hundred fifty-seven patients with established PVR (grade C, anterior or posterior) undergoing vitrectomy surgery., Intervention: All patients underwent vitreoretinal surgery and silicone oil exchange with or without membrane peeling and/or retinectomy. Patients were randomly allocated to perioperative infusion with or without 5-fluorouracil (200 microg/ml) and LMWH (5 IU/ml) in Hartmann's solution for 1 hour., Outcome Measures: The primary outcome measure was defined as posterior retinal reattachment after removal of silicone oil without any reoperations at 6 months. Secondary outcome measures recorded were posterior retinal reattachment, localized/tractional retinal detachment, visual acuity, macular pucker, hypotony, glaucoma, keratopathy, and cataract. Removal of silicone oil and reoperations were also recorded., Results: Overall, at 6 months 84% of patients had full retinal reattachment and 94% had stable posterior retinal reattachment. There was no significant difference in success in the primary outcome measure (56%, treatment group; 51%, placebo group; P = 0.59) or in secondary outcome measures or rates of complications. Secondary macular pucker occurred less often in the treatment group (6% vs. 17% at 6 months, P = 0.068)., Conclusions: A perioperative infusion of combined 5-fluorouracil and LMWH does not significantly increase the success rate of vitreoretinal surgery for established PVR.

Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored.

Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.

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.

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. Interactions between acetaldehyde, reactive oxygen and nitrogen species, inflammatory mediators and genetic factors appear to play prominent roles in the development of ALD. The cornerstone of therapy for ALD is lifestyle modification, including drinking and smoking cessation and losing weight, if appropriate. Nutrition intervention has been shown to play a positive role on both an inpatient and outpatient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis and pentoxifylline appears to be a promising anti-inflammatory therapy. Some complementary and alternative medicine agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve quality of life and, in some cases, decrease short-term mortality.

Either ribavirin (RBV) or cyclophosphamide (CY) can shift an immune response from Th2 toward a Th1 cytokine profile. CY is used in this role in various current cancer immunotherapy attempts but with mixed success. More potent and reliable immunoadjuvants and Th1 response biasing methods are needed. RBV is used today mainly to augment interferon-alpha treatment of hepatitis C. RBV shifts an immune response from Th2 toward Th1 more effectively than CY and may be a safe and useful adjuvant for current cancer immunotherapeutic efforts. RBV is thought to act by inhibition of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is an essential cofactor for all known isoforms of nitric oxide synthase. Lowered nitric oxide favors Th1 development as high levels favor Th2 weighting.

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.

Background: Patients receiving home parenteral nutrition (HPN) because of intestinal failure are at high risk of developing osteoporosis., Objective: We studied the effect of the bisphosphonate clodronate on bone mineral density (BMD) and markers of bone turnover in HPN patients., Design: A 12-mo, double-blind, randomized, placebo-controlled trial was conducted to study the effect of 1500 mg clodronate, given intravenously every 3 mo for 1 y, in 20 HPN patients with a bone mass T score of the hip or lumbar spine of less than -1. The main outcome measure was the difference in the mean percentage change in the BMD of the lumbar spine measured by dual-energy X-ray absorptiometry. Secondary outcome measures included changes in the BMD of the hip, forearm, and total body and biochemical markers of bone turnover, ie, serum osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline., Results: The mean (+/-SEM) BMD of the lumbar spine increased by 0.8 +/- 2.0% in the clodronate group and decreased by 1.6 +/- 2.0% in the placebo group (P = 0.43). At all secondary skeletal sites (ie, hip, total body, and distal forearm), we observed no changes or small increases in the BMD of the clodronate group and decreases in the BMD of the placebo group. In the clodronate group, biochemical markers of bone resorption decreased significantly (P < 0.05)., Conclusions: Clodronate significantly inhibits bone resorption as assessed by changes in biochemical markers of bone turnover. Although the mean BMD increased in the clodronate group, cyclic clodronate therapy failed to increase spinal BMD significantly at 12 mo.

Background/aims: This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC)., Methods: Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months., Results: All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC., Conclusions: Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found.