Search

Suicide gene therapy mediated by mesenchymal stem cells with their ability to engraft into tumors makes these therapeutic stem cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we evaluated the therapeutic efficacy of human mesenchymal stem cells derived from bone marrow and from adipose tissue, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracerebral rat C6 glioblastoma in a simulated clinical therapeutic scenario. Intracerebrally grown glioblastoma was treated by resection and subsequently with single or repeated intracerebral inoculations of therapeutic stem cells followed by a continuous intracerebroventricular delivery of 5-fluorocytosine using an osmotic pump. Kaplan-Meier survival curves revealed that surgical resection of the tumor increased the survival time of the resected animals depending on the extent of surgical intervention. However, direct injections of therapeutic stem cells into the brain tissue surrounding the postoperative resection cavity led to a curative outcome in a significant number of treated animals. Moreover, the continuous supply of therapeutic stem cells into the brain with growing glioblastoma by osmotic pumps together with continuous prodrug delivery also proved to be therapeutically efficient. We assume that observed curative therapy of glioblastoma by stem cell-mediated prodrug gene therapy might be caused by the destruction of both tumor cells and the niche where glioblastoma initiating cells reside., (© 2013 UICC.)

Background: Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up., Design: Fecal samples from 10 Crohn's disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing., Results: After quality control, 6,194-11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025). Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001) and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01)., Conclusion: Shifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course.

To determine the effect of hyperuricemia and allopurinol therapy on renal functions in chronic kidney disease (CKD) stage 3-4, we studied 96 patients in stage 3-4 CKD (57% male, age 65.3 ± 12.4 years). The mean estimated glomerular filtration rate (GFR) was 44.62 ± 14.38 iriL/ min/1.73 m 2 . The study patients were divided into non-allopurinol users (n = 47) and those using allopurinol (n = 49) in the last 12 months. Serum uric acid (UA) and C-reactive protein levels decreased after allopurinol therapy (P = 0.00 and P = 0.04, respectively), but no change was observed in the control group during the study period. In the allopurinol group, the mean GFR increased 3.3 ±1.2 mL/min/1.73 m 2 /year, while it decreased 1.3 ± 0.6 mL/min/1.73 m 2 in the control group during the follow-up period (P = 0.04); the patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and renal resistance index (RRI) (P-values were <0.05). The patients with stable renal functions or GFR change <10% (n = 25) at the end of 12 months had significantly lower LDL and RRI values and more allopurinol users than the group with decreasing GFR (74% vs. 48%, P <0.05). In the regression analysis, UA and RRI were found as independent variables (r 2 = 0.68, P <0.01; r 2 = 0.25, P <0.01) that affected loss of renal function. We conclude that our study suggests a role for allopurinol, an effective agent in lowering serum UA levels, as a reliable therapeutic option in controlling renal progression in pre-dialysis CKD patients.

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 x 10(6)/L, an absolute neutrophil count >1,000 x 10(6)/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM.

Background: To identify the determinants of recurrence following primary pterygium excision combined with conjunctival autograft (CAG) and intraoperative use of Mitomycin C (MMC) or 5-Fluorouracil (5-FU)., Methods: A randomized controlled clinical trial comparing 5-FU (50 mg/ml) plus CAG versus MMC (0.01%) plus CAG in preventing recurrence of primary pterygium following excision., Results: A total of 80 eyes of 80 subjects were studied, with 46 eyes in the 5-FU group and 34 eyes in the MMC group. The mean age was 50.7 +/- 13.1 years with a male: female ratio of 0.95:1. Mean follow up period was 35.2 +/- 29.1 weeks. The overall recurrence rate was 10%, with a rate of 8.7% in the 5-FU group and 11.8% in the MMC group. The mean age of the patients who had a recurrence was 38.1 +/- 13.3 years compared to 52.1 +/- 12.4 years in those without a recurrence (p = 0.003). The median size of the pterygium in patients who had a recurrence was 3.2mm, while the median size in patients who did not have a recurrence was 3.0mm (p = 0.8). Five (12.8%) males had a recurrence compared to three (7.3%) females (p = 0.48); while 10.5% of fleshy pterygia recurred compared to none (0%) of the non-fleshy pterygia (p = 1.00)., Conclusion: Younger age remains a risk factor for recurrence when both CAG and antimetabolites are combined in the treatment of pterygium, while the effect of gender, size and morphology of the pterygium may be diminished by such combination.

d-Cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3-5 times per week for 8weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions=26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score ≥20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Overcoming specific fears and subsequent anxiety can be greatly enhanced by the presence of familiar social partners, but the neural circuitry that controls this phenomenon remains unclear. To overcome this, the social interaction (SI) habituation test was developed in this lab to systematically investigate the effects of social familiarity on anxiety-like behavior in rats. Here, we show that social familiarity selectively reduced anxiety-like behaviors induced by an ethological anxiogenic stimulus. The anxiolytic effect of social familiarity could be elicited over multiple training sessions and was specific to both the presence of the anxiogenic stimulus and the familiar social partner. In addition, socially familiar conspecifics served as a safety signal, as anxiety-like responses returned in the absence of the familiar partner. The expression of the social familiarity-induced anxiolysis (SFiA) appears dependent on the prefrontal cortex (PFC), an area associated with cortical regulation of fear and anxiety behaviors. Inhibition of the PFC, with bilateral injections of the GABAA agonist muscimol, selectively blocked the expression of SFiA while having no effect on SI with a novel partner. Finally, the effect of D-cycloserine, a cognitive enhancer that clinically enhances behavioral treatments for anxiety, was investigated with SFiA. D-cycloserine, when paired with familiarity training sessions, selectively enhanced the rate at which SFiA was acquired. Collectively, these outcomes suggest that the PFC has a pivotal role in SFiA, a complex behavior involving the integration of social cues of familiarity with contextual and emotional information to regulate anxiety-like behavior.

Background: Trabeculectomy is performed as a treatment for many types of glaucoma in an attempt to lower the intraocular pressure. The surgery involves creating a channel through the sclera, through which intraocular fluid can leave the eye. If scar tissue blocks the exit of the surgically created channel, intraocular pressure rises and the operation fails. Antimetabolites such as 5-Fluorouracil (5-FU) are used to inhibit wound healing to prevent the conjunctiva scarring down on to the sclera. This is an update of a Cochrane review first published in 2000, and previously updated in 2009., Objectives: To assess the effects of both intraoperative application and postoperative injections of 5-FU in eyes of people undergoing surgery for glaucoma at one year., Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2013), EMBASE (January 1980 to July 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 25 July 2013. We also searched the reference lists of relevant articles and the Science Citation Index and contacted investigators and experts for details of additional relevant trials., Selection Criteria: We included randomised trials of intraoperative application and postoperative 5-FU injections compared with placebo or no treatment in trabeculectomy for glaucoma., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. We used standard methodological procedures expected by The Cochrane Collaboration. We contacted trial investigators for missing information. Data were summarised using risk ratio (RR), Peto odds ratio and mean difference, as appropriate.The participants were divided into three separate subgroup populations (high risk of failure, combined surgery and primary trabeculectomy) and the interventions were divided into three subgroups of 5-FU injections (intraoperative, regular dose postoperative and low dose postoperative). The low dose was defined as a total dose less than 19 mg., Main Results: Twelve trials, which randomised 1319 participants, were included in the review. As far as can be determined from the trial reports, the methodological quality of the trials was not high, including a high risk of detection bias in many. Of note, only one study reported low-dose postoperative 5-FU and this paper was at high risk of reporting bias.Not all studies reported population characteristics, of those that did mean age ranged from 61 to 75 years. 83% of participants were white and 40% were male. All studies were a minimum of one year long.A significant reduction in surgical failure in the first year after trabeculectomy was detected in eyes at high risk of failure and those undergoing surgery for the first time receiving regular-dose 5-FU postoperative injections (RR 0.44, 95% confidence interval (CI) 0.29 to 0.68 and 0.21, 0.06 to 0.68, respectively). No surgical failures were detected in studies assessing combined surgery. No difference was detected in the low-dose postoperative 5-FU injection group in patients undergoing primary trabeculectomy (RR 0.93, 95% CI 0.70 to 1.24). Peroperative 5-FU in patients undergoing primary trabeculectomy significantly reduced risk of failure (RR 0.67, 95% CI 0.51 to 0.88). This translates to a number needed to treat for an additional beneficial outcome of 4.1 for the high risk of failure patients, and 5.0 for primary trabeculectomy patients receiving postoperative 5-FU.Intraocular pressure was also reduced in the primary trabeculectomy group receiving intraoperative 5-FU (mean difference (MD) -1.04, 95% CI -1.65 to -0.43) and regular-dose postoperative 5-FU (MD -4.67, 95% CI -6.60 to -2.73). No significant change occurred in the primary trabeculectomy group receiving low-dose postoperative 5-FU (MD -0.50, 95% CI -2.96 to 1.96). Intraocular pressure was particularly reduced in the high risk of failure population receiving regular-dose postoperative 5-FU (MD -16.30, 95% CI -18.63 to -13.97). No difference was detected in the combined surgery population receiving regular-dose postoperative 5-FU (MD -1.02, 95% CI -2.40 to 0.37).Whilst no evidence was found of an increased risk of serious sight-threatening complications, other complications are more common after 5-FU injections. None of the trials reported on the participants' perspective of care.The quality of evidence varied between subgroups and outcomes, most notably the evidence for combined surgery and low-dose postoperative 5-FU was found to be very low using GRADE. The combined surgery postoperative 5-FU subgroup because no surgical failures have been reported and the sample size is small (n = 118), and the low-dose postoperative 5-FU group because of the small sample size (n = 76) and high risk of bias of the only contributing study., Authors' Conclusions: Postoperative injections of 5-FU are now rarely used as part of routine packages of postoperative care but are increasingly used on an ad hoc basis. This presumably reflects an aspect of the treatment that is unacceptable to both patients and doctors. None of the trials reported on the participants' perspective of care, which constitutes a serious omission for an invasive treatment such as this.The small but statistically significant reduction in surgical failures and intraocular pressure at one year in the primary trabeculectomy group and high-risk group must be weighed against the increased risk of complications and patient preference.

Purpose: We aimed to evaluate the intraoperative application of antimetabolites compared with anti-vascular endothelial growth factor (VEGF) agents with or without antimetabolites in trabeculectomy (Trab) for glaucoma., Methods: Relevant studies were selected through extensive search using PubMed, EMBASE, the Cochrane Library, and Web of Science databases in August 2013. The primary efficacy estimate was measured using weighted mean difference of the percentage of intraocular pressure reduction (IOPR%) from baseline to end-point, and the secondary efficacy estimates were odds ratio (OR) and 95% confidence interval (CI) for complete success rate and qualified success rate. ORs were also used to measure the tolerability estimate for adverse events. Meta-analyses of fixed or random effects models were conducted using RevMan software 5.2 to pool the results of the studies included. Heterogeneity was assessed using Chi(2) test and the I(2) measure., Results: Nine studies enrolling a total of 349 patients were included. The weighted mean difference of IOPR% from baseline was 7.23 (95% CI: 2.57-11.89) for antimetabolites vs. anti-VEGF agents and 3.96 (95% CI: -4.18-12.10) for antimetabolites vs. anti-VEGF agents plus antimetabolites. The pooled ORs comparing antimetabolites with anti-VEGF agents were 2.37 (95% CI: 0.78, 7.21) for the complete success rate and 1.93 (95% CI: 0.52, 7.16) for qualified success rate. The pooled ORs comparing antimetabolites with anti-VEGF agents plus antimetabolites were 1.43 (95% CI: 0.48, 4.29) for the complete success rate and 2.11 (95% CI: 0.12, 37.72) for qualified success rate. The rates of adverse events did not significantly differ between antimetabolites and anti-VEGF agents, with pooled ORs of 0.86 (0.28-2.69) for bleb leakage, 3.01 (0.45-20.10) for choroidal effusion, 0.96 (0.23-3.98) for flat anterior chamber, and 0.90 (0.12-6.60) for hypotony. Further, the rates of adverse events were similar between antimetabolites and anti-VEGF agents plus antimetabolites, with pooled ORs of 0.40 (0.08-2.00) and 8.00 (0.93-68.59) for bleb leakage and hypotony, respectively., Conclusions: In comparison with anti-VEGF agents, antimetabolites were more effective in lowering IOP in Trab, while the intraoperative application of these two types of agents did not indicate statistically significant differences in the complete success rate, qualified success rate, or incidence of adverse events.

The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.

Background: Essential hypertension is frequently associated with hyperuricemia in both adult and pediatric patients. Lowering serum uric acid level may provide greater benefit than simply treating hypertension., Patients and Methods: Forty-four adolescents, aged 12-19 years, newly diagnosed as essential hypertension (secondary hypertension was excluded) and previously untreated were randomized (open label trial) to receive either enalapril or enalapril plus allopurinol in combination. All participants had baseline serum uric acid level ≥5.5 mg/dl., Results: Baseline mean blood pressure (BP), age and body mass index were similar between the two groups. After 8 weeks' treatment, BP reduction was greater, percent of treatment group achieving target BP level was greater, and serum uric acid level was lower in the combination treatment group. There were no adverse effects during the course of therapy., Conclusion: Results suggest that uric acid reduction may be used as adjunctive antihypertensive therapy in hypertensive adolescents with hyperuricemia while closely monitoring for any adverse effect.

Antimetabolites are the most widely used and most efficacious group of anticancer drugs. Antimetabolites are also the oldest rationally designed anticancer drugs, targeted against RNA and DNA, and can, therefore, be considered as the first generation of targeted drugs. Unfortunately, resistance often develops, leading to the design of new antimetabolites, which either have a novel mechanism of action, bypass resistance or in combination enhance the effect of other drugs, such as another antimetabolite, other DNA, or protein kinase targeted anticancer drugs. Several novel antimetabolites are in clinical development. The cytidine-analog fluorocyclopentenylcytosine (RX-3117) is active in gemcitabine-resistant tumors and is activated by uridine-cytidine-kinase, can be incorporated into RNA and DNA and can downregulate DNA-methyltransferase-1. TAS-114 is a new generation dUTPase inhibitor. dUTPase normally prevents incorporation of dUTP and of the 5FU-nucleotide FdUTP into DNA. However, inhibition of dUTPase will enhance their incorporation, thereby increasing thymine-less cell-death. The formulation TAS-102 (trifluorothymidine and thymidine-phosphorylase-inhibitor) acts by incorporation into DNA and has shown efficacy in tumors progressing on 5FU therapy. Gemcitabine and cytarabine prodrugs were tested in model systems and have entered clinical evaluation. The elaidic-acid prodrugs of gemcitabine (CP-4126, CO101) and cytarabine (elacytarabine) failed in randomized Phase III studies. Two other gemcitabine prodrugs LY2334737 (gemcitabine with a valproic acid at the 5'-position) and NUC1031 (a 5'-arylphosphoamidate prodrug, with a side-chain at the 5'-phosphate) are in early clinical development. In summary, several novel antimetabolites show promise in clinical development, either because of a novel mechanism of action, or clever combination or by innovative prodrug design.

In recent years, several studies have demonstrated efficacy of d-cycloserine (DCS) enhanced exposure therapy across anxiety disorders. In this study we examined person-level variables that predicted response to DCS enhanced exposure therapy in a chronic, mixed trauma PTSD sample. The sample consisted of 67 treatment-seeking individuals, randomly allocated to receive exposure therapy augmented with DCS (50 mg) or identical looking placebo. We examined the following baseline predictors of treatment response: (1) demographic characteristics (age, gender, marital status, and education); (2) clinical characteristics (initial PTSD symptom severity, Axis I comorbidity, depression symptom severity, and antidepressants use); (3) personality characteristics (openness, conscientiousness, extraversion, agreeableness, and neuroticism). Outcome was measured with the PTSD Symptom Scale, Self-Report, which was assessed weekly during treatment. Two prescriptive variables were identified: conscientiousness and extraversion. For high conscientious participants, those who received DCS showed better outcome than those who received placebo. And for low extraversion, DCS showed superior outcome relative to placebo. Education was identified as a prognostic variable, it predicted response across both groups: higher education was related to worse outcome. Our results provide support for the influence of personality traits on DCS augmented exposure outcome and give more insight into possible working mechanisms of this novel treatment strategy. Ultimately, this may contribute to treatment matching strategies in order to improve treatment efficacy of exposure therapy for PTSD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.)

Immunosuppression after heart transplantation has significantly reduced the incidence of cellular rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes, particularly with respect to the reduced burden of cardiac allograft vasculopathy. Patients with antibody sensitization are potentially at higher risk of postoperative complications. Sensitized patients are undergoing heart transplantation with increased frequency, in part due to the emergence of ventricular assist device use as a bridge to heart transplantation. Despite improvements in immunosuppressive therapies, many challenges face physicians and patients, which will further refine and improve care of the post-heart transplant patient.

Objective: The aim of this study was to investigate the influence of the antiproliferative agent 5-Fluorouracil (5FU) over inhibition of spinal bone formation in an experimental rat model., Methods: The study included 30 6-month-old Sprague-Dawley rats divided into 3 groups. Aggressive periosteal denuding was performed by scalpel to induce punctuate bleeding in the posterior elements of the L4-L5 vertebrae in the spontaneous fusion model. Spinous processes were fixated by wires and no graft substitute was applied. Adcon-L was applied in Group 1, single-touch technique 5FU in Group 2. Group 3 was the control group. Rats were sacrificed at 4 weeks and specimens acquired for histological examination., Results: 5FU substantially inhibited fibroblast and inflammatory cell densities as well as bone formation compared to the control group. 5FU was considerably superior to Adcon-L with regard to inhibition of bone formation and inflammatory cells (p=0.0001)., Conclusion: 5FU can inhibit fusion, fibrosis and unwanted scar tissue in spinal surgery. We believe that after further studies on its local delivery dose, it can be used in humans for inhibition of unintended fusion.

Purpose: To report the use of intracameral 5-fluorouracil (5-FU) to treat epithelial downgrowth after performing a Descemet-stripping automated endothelial keratoplasty (DSAEK)., Methods: We describe the case of a 79-year-old woman who underwent a DSAEK for pseudophakic Fuchs endothelial corneal dystrophy. The patient required 2 repeat DSAEKs for graft failure and persistent, visually significant interface haze. Six months after the third and most recent DSAEK, the patient was followed up and found to have a visual acuity of 20/100. On examination, the patient continued to have a persistent interface haze. However, the patient also had a cellular anterior chamber reaction despite the administration of frequent topical corticosteroids, and subtle findings of a translucent, membranous growth over the iris. Argon laser photocoagulation of the area resulted in a whitening response, characteristic of epithelial growth., Results: Epithelial downgrowth was diagnosed, and intracameral 5-FU was administered. One month after the injection was given, the patient's examination results and vision improved to 20/60. Six months after the single injection, the patient had a clear DSAEK graft without interface haze, a quiet chamber, and 20/30 visual acuity., Conclusions: Epithelial downgrowth that occurs after performing a DSAEK can be treated successfully using intracameral 5-FU.

Introduction: Uveitis is a potentially visually debilitating disease when untreated or poorly controlled. Chronic intermediate, posterior, or panuveitis often requires systemic immunosuppressive therapy to prevent such visual loss., Areas Covered: This review discusses existing treatments for ocular inflammation including corticosteroids, antimetabolites, alkylating agents, T-cell inhibitors, and biologic agents. Potential drugs being studied in clinical trials are introducing new routes for local corticosteroid delivery, and novel immunomodulators are exploring new targets of the inflammatory cascade., Expert Opinion: Treatment options for uveitis have expanded from even a decade ago. However, more clinical trials and research are needed to further our understanding of the mechanisms of ocular inflammation and the safety and efficacy of novel therapies.

Background: Although differing in clinical presentation and prognosis, keloids and hypertrophic scars are generally characterized by abnormally proliferative scar tissue and are extremely debilitating. Several intralesional therapies have been studied in attempts to find a universally safe and effective modality, of which there are currently none., Objective: To provide a comprehensive review of current intralesional treatment modalities for keloids and hypertrophic scars., Methods and Materials: A PubMed search was performed for literature pertaining to intralesional treatment modalities for keloids and hypertrophic scars. References from retrieved articles were also considered for review., Results and Conclusion: Many intralesional therapies for keloids and hypertrophic scars are currently available to physicians and patients. Mechanisms of action and side effect profiles vary between these agents, and new approaches to keloids and hypertrophic scars are frequently being explored. Randomized controlled trials are needed to assess these new and promising modalities fully., (© 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.)

Purpose: The aim of this systematic review was to analyze the available literature and define clinical practice guidelines for the use of the following agents for the prevention and treatment of oral mucositis (OM): allopurinol, midline mucosa-sparing radiation blocks, payayor, pentoxifylline, timing of radiation therapy (RT) (morning versus late afternoon), pilocarpine, bethanechol, chewing gum, propantheline, and tetrachlorodecaoxide., Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, no guideline possible., Results: A total of 32 papers across 10 interventions were examined. New suggestions were developed against the use of systemic pilocarpine administered orally for prevention of OM during RT in head and neck cancer patients and in patients receiving high-dose chemotherapy, with or without total body irradiation, prior to hematopoietic stem cell transplantation. A suggestion was also made against the use of systemic pentoxifylline administered orally for the prevention of OM in patients undergoing bone marrow transplantation. No guideline was possible for any other agent reviewed due to inadequate and/or conflicting evidence., Conclusions: None of the agents reviewed was determined to be effective for the prevention or treatment of OM. Two agents, pilocarpine and pentoxifylline, were determined to be ineffective, in the populations listed above. Additional well-designed research is needed on other interventions.

Mitomycin C (MMC) and 5-fluorouracil (5-FU) are the most frequently utilized adjuvant therapies in trabeculectomy (TRAB), but there is no general consensus as to the direct comparative efficacy and safety of these two adjuvants. In this study, the authors conducted a meta-analysis to compare the efficacy and safety of augmenting TRAB with MMC or 5-FU. A systematic review with meta-analysis was conducted and five randomized controlled clinical trials comparing MMC versus 5-FU as adjunctive therapies were identified, totaling 416 participants. A lower pooled mean IOP and higher complete and qualified success rates were observed in the MMC arm than in the 5-FU arm. Epithelial corneal defects were the unique complication reported more frequently with 5-FU compared to MMC treatment. Compared to TRAB with 5-FU, TRAB with MMC was associated with higher rates of complete and qualified surgical success and was not associated with increased incidences of postoperative complications.

Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus (SLE) in childhood affecting more than 80% of patients. Treatment of this complication has undergone significant evolution in recent years. A series of randomized controlled trials has clarified the role of a variety of immunomodulating regimens including some novel biologic medications. This review touches on the major trials that have influenced practice and shaped current thinking about the treatment of proliferative lupus glomerulonephritis.

Ocular mucous membrane pemphigoid (MMP), as a potentially blinding disease, is an indication for systemic immunosuppressive treatment. Immunosuppressive agents are chosen with a "stepladder" approach, beginning with drugs having the fewest side effects. Dapsone, sulfapyridine/sulfasalazine and azathioprine are less successful in controlling inflammation than mycophenolate mofetil (MMF) and methotrexate (MTX). Moreover, compared to other immunosuppressive agents, MMF, followed by MTX, has the lowest rate of discontinuation due to side effects. Cyclophosphamide is the most potent immunosuppressive agent used for ocular MMP, but it should be used with caution because of life-threatening adverse effects. Intravenous immunoglobulin therapy (IVIg) should be considered for patients who are resistant to conventional immunosuppressive therapy, have significant adverse effects or contraindications to conventional therapy, or have uncontrolled rapidly progressive disease. If IVIg monotherapy is not successful after a period of ≥ 1 year, therapy with biological agents, such as rituximab or anti-TNF-α drugs, is suggested., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To analyze the long-term clinical outcomes of 5-fluorouracil (5FU)-enhanced trabeculectomy in patients with glaucoma secondary to uveitis (UG), to compare outcomes with those achieved elsewhere by primary mitomycin C-enhanced trabeculectomy and primary glaucoma drainage implant (GDI) surgery and to consider the optimal surgical approach in this group of patients., Methods: A retrospective analysis of a single-surgeon series of 31 eyes of 25 patients with UG attending the Manchester Uveitis Clinic who had undergone 5FU-enhanced trabeculectomy between October 2002 and August 2010. Main outcome measures were an intraocular pressure (IOP)<21 mm Hg with medications (unqualified success) and with medications (qualified success). Secondary outcome measures were IOP≤66% of initial IOP. Other risk factors and postoperative complications were also examined., Results: The mean follow-up was 5.1 years. Qualified success for postoperative IOP control of <21 was achieved in 90.3% at 1 year and 76.5% at 5 years. IOP<66% of initial IOP was achieved in 93.5% at 1 year and 82.3% at 5 years. No patients developed long-term hypotony. Patients under 30 years of age at surgery were at a higher risk for bleb failure and 50% in this age group went on to require GDI surgery., Conclusions: This study demonstrates good long-term survival rates of 5FU-enhanced trabeculectomy in patients with UG, comparable with results for primary open-angle glaucoma. The results also compare favorably with those of mitomycin C-enhanced trabeculectomy and GDIs in patients with UG, with a lower risk of complications. We conclude that for patients over 30 years, 5FU-enhanced trabeculectomy is appropriate first-line surgery, whereas GDI surgery should be used as the primary procedure for those under 30 years.

Canine leishmaniosis (CL) has become one of the most frequently diagnosed travel associated infection in dogs in Switzerland and Germany. The aim of the study was to define recommendations for treatment with allopurinol and follow-up examinations of dogs with CL in a non endemic area. 31 dogs infected with Leishmania were treated with allopurinol (10 - 15 mg/kg twice daily, per os) and the effectiveness was examined. The diagnosis had been confirmed by the detection of specific anti-Leishmania antibodies and/or Leihmania-DNA. 22 dogs had clinical signs (skin lesions, lameness or lack of fitness) and 9 dogs were asymptomatic but showed abnormal laboratory parameters. Under treatment with allopurinol the symptoms disappeared within 1 - 5 months in 20 dogs.

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.

Objectives: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that causes changes in cortical excitability. Recent double-blind placebo-controlled clinical trials suggest that tDCS may be efficacious in the treatment of depression. Pharmacological agents that prolong the effects of tDCS could lead to greater cumulative changes in cortical excitability, producing greater and more prolonged efficacy. One agent shown to prolong the excitability-enhancing effects of tDCS in healthy subjects is D-Cycloserine, a partial agonist at the glycine-binding site of N-methyl-D-aspartate receptors. We investigated whether combining prefrontal tDCS with D-Cycloserine could enhance and/or prolong the antidepressant effect of tDCS., Methods: Five depressed subjects who had relapsed or failed to achieve remission after receiving a previous course of prefrontal tDCS were recruited. In this open-label pilot study, subjects ingested 100-mg D-Cycloserine 2 hours before tDCS sessions. Subjects received 20 minutes of tDCS at 2 mA on consecutive weekdays for a total of 20 sessions. The anode was placed at pF3 and the cathode at F8 (10/20 system). Clinical response was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS)., Results: The change in Montgomery-Åsberg Depression Rating Scale scores was not greater with the combination of D-Cycloserine and tDCS than had previously been produced by tDCS alone. No significant additional adverse effects were reported., Conclusions: This pilot open-label study found that pretreatment with 100-mg D-Cycloserine 2 hours before tDCS was well tolerated but did not enhance the antidepressant efficacy of anodal prefrontal tDCS.

Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase., (© The Author(s) 2013.)

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.)

A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks.

Purpose: It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments., Methods: In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively., Results: Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003)., Conclusions: Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.

Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.

Background: This study examined the feasibility and preliminary effectiveness of d-cycloserine (DCS)-augmented cognitive behavioral therapy (CBT) for children and adolescents with difficult-to-treat Obsessive Compulsive Disorder, in a double-blind randomized controlled pilot trial (RCT)., Methods: Seventeen children and adolescents (aged 8-18 years) with a primary diagnosis of OCD, which was deemed difficult-to-treat, were randomly assigned to either nine sessions of CBT including five sessions of DCS-augmented exposure and response prevention (ERP) [ERP + DCS] or nine sessions of CBT including five sessions of placebo-augmented ERP [ERP + PBO]. Weight-dependent DCS or placebo doses (25 or 50 mg) were taken 1 hour before ERP sessions., Results: At posttreatment, both groups showed significant improvements with 94% of the entire sample classified as responders. However, a greater improvement in the ERP + DCS relative to the ERP + PBO condition was observed at 1-month follow-up on clinician-rated obsessional severity and diagnostic severity, and parent ratings of OCD severity. There were no changes across time or condition from 1- to 3-month follow-up., Conclusions: In this preliminary study, DCS-augmented ERP produced significant improvements in OCD severity from posttreatment to 1-month follow-up, relative to a placebo control condition, in severe and difficult-to-treat pediatric OCD. The significant effect on obsessional severity suggests that DCS augmentation might be associated with enhanced modification of obsessional thoughts during ERP, and warrants further investigation., (© 2013 Wiley Periodicals, Inc.)

Background: To identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn's disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn's disease., Methods: We identified cases of HSTCL in Crohn's disease in studies included in a comparative effectiveness review of Crohn's disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL., Results: We found 37 unique cases of HSTCL in patients with Crohn's disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn's disease based on the data contained in the case reports., Conclusion: Systematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than 'possible' between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.

Background-Aim: Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. PLA2G2A is also an important regulator of proliferation, invasion and metastasis in GC. However, no relation about PLA2G2A and chemosensitivity in GC cells was reported. 5-Fluorouracil (5-FU) is widely used for treatment of advanced gastric cancer. However, it is common for such patients to develop resistance to 5-FU, and this drug resistance becomes a critical problem for chemotherapy. The mechanisms underlying this resistance are largely unknown. In the present study, we investigated whether PLA2G2A could confer 5-FU resistance or sensitise in GC cells in vitro., Materials and Methods: The 5-FU sensitivity of GC cell lines SGC-7901, MKN-45, RF-48, N87, AGS, MKN-28, RF-1, MGC-803 were determined by MTT assays. PLA2G2A levels were determined by western blot assays. The effects of 5-FU on PLA2G2A expression were determined in vitro. PLA2G2A was inhibited by silencing of the PLA2G2A using small interfering RNA in vitro. PLA2G2A was overexpressed by transfection of full-long PLA2G2A cDNA in vitro, and the effects were evaluated on 5-FU sensitivity., Results: The cell lines SGC-7901, MKN-45, RF-48 and N87 were sensitive, whereas AGS, MKN-28, RF-1 and MGC-803 were resistant to 5-FU. Significant correlation was observed between basal PLA2G2A and 5-FU sensitivity. Silencing of PLA2G2A increased 5-FU killing in 5-FU-treated cells, and overexpression of PLA2G2A decreased 5-FU killing in 5-FU-treated cells., Conclusions: PLA2G2A was correlated with sensitivity to 5-FU. Silencing of PLA2G2A was sensitive to 5-FU treatment. Thus, PLA2G2A may be a useful therapeutic target for a subset of gastric cancers.

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: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. In several tumour entities, the tyrosine kinase receptor c-KIT is associated with tumour transformation in the epithelial tissue in cases of aberrant expression. Furthermore, tumour development and dissemination are a result of dysregulated cellular pathways such as the WNT/β-catenin pathway. β-Catenin is a multifunctional protein within the canonical WNT signalling pathway and a pivotal factor for the stabilization of cell-cell interactions. In malignant tissues, β-catenin triggers tumour proliferation and progression. The aim of this study is to investigate the expression patterns of c-KIT and β-catenin in human papillomavirus-negative and p16-positive SCC and to evaluate the chemosensitivity of the tumour cells to the chemotherapeutical agents docetaxel and 5-fluorouracil (5-FU)., Materials and Methods: We incubated the tumour cell lines with docetaxel (5 μmol/ml) and 5-FU (1 μmol/ml) and detected β-catenin and c-KIT by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) after 48, 72, 120, 192 and 240 h., Results: We found a reliable trend towards decreased β-catenin expression levels in p16-positive and p16-negative tumour cell lines when incubated with docetaxel, in addition to induced apoptotic effect. At best, 5-FU had a slight influence on the alteration of the expression of β-catenin. Dose escalation of docetaxel and 5-FU had no statistically significant effect on the expression of β-catenin or c-KIT. In HPV-negative HNSCC, a reduced expression level of β-catenin and c-KIT was detected in an incubation period-dependent manner. p16-transformed SCC (CERV196) cells were characterized by a reduced susceptibility to docetaxel induced alteration of β-catenin expression., Conclusion: We were unable to confirm the clinically-substantiated increased chemosensitivity of p16-positive tumour cells in vitro. Extended studies and clinical trials are needed to investigate these findings further in HPV-associated HNSCC.

The present study aimed to directly compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS). We compared the overall response rate (ORR) (complete responses, partial responses, marrow complete responses, and haematological improvements), overall survival (OS), event-free survival (EFS), time to leukaemic transformation, and adverse outcomes between azacitidine and decitabine. To minimize the effects of treatment selection bias in this observational study, adjustments were made using the propensity-score matching method. Among 300 patients, 203 were treated with azacitidine and 97 with decitabine. Propensity-score matching yielded 97 patient pairs. In the propensity-matched cohort, there were no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 22.9 months), EFS (7.7 vs. 7.0 months), and rate of leukaemic transformation (16% vs. 22% at 1 year). In patients ≥ 65 years of age, survival was significantly better in the azacitidine group (P = 0.017). Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes. We found that azacitidine and decitabine showed comparable efficacy. Among patients ≥ 65 years of age, survival was significantly better in the azacitidine group (ClinicalTrials.gov Identifier: NCT01409070)., (© 2013 Blackwell Publishing Ltd.)

In the current study, the partial NMDA receptor agonist D-cycloserine (DCS) rescued memory consolidation following systemic bacterial endotoxin exposure. DCS failed, however, to restore hippocampal BDNF mRNA levels that were diminished following a systemic administration of LPS, and did not alter NR1 or NR2C NMDA receptor subunit expression. These results extend prior research into the role of DCS in neural-immune interactions, and indicate that the detrimental effects of peripheral LPS administration on consolidation of contextual fear memory may be ameliorated with DCS treatment, though the mechanisms underlying these effects are currently unclear., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Optimum management to prevent recurrent kidney stones is uncertain., Purpose: To evaluate the benefits and harms of interventions to prevent recurrent kidney stones., Data Sources: MEDLINE, Cochrane, and other databases through September 2012 and reference lists of systematic reviews and randomized, controlled trials (RCTs)., Study Selection: 28 English-language RCTs that studied treatments to prevent recurrent kidney stones and reported stone outcomes., Data Extraction: One reviewer extracted data, a second checked accuracy, and 2 independently rated quality and graded strength of evidence., Data Synthesis: In patients with 1 past calcium stone, low-strength evidence showed that increased fluid intake halved recurrent composite stone risk compared with no treatment (relative risk [RR], 0.45 [95% CI, 0.24 to 0.84]). Low-strength evidence showed that reducing soft-drink consumption decreased recurrent symptomatic stone risk (RR, 0.83 [CI, 0.71 to 0.98]). In patients with multiple past calcium stones, most of whom were receiving increased fluid intake, moderate-strength evidence showed that thiazides (RR, 0.52 [CI, 0.39 to 0.69]), citrates (RR, 0.25 [CI, 0.14 to 0.44]), and allopurinol (RR, 0.59 [CI, 0.42 to 0.84]) each further reduced composite stone recurrence risk compared with placebo or control, although the benefit from allopurinol seemed limited to patients with baseline hyperuricemia or hyperuricosuria. Other baseline biochemistry measures did not allow prediction of treatment efficacy. Low-strength evidence showed that neither citrate nor allopurinol combined with thiazide was superior to thiazide alone. There were few withdrawals among patients with increased fluid intake, many among those with other dietary interventions and more among those who received thiazide and citrate than among control patients. Reporting of adverse events was poor., Limitations: Most trial participants had idiopathic calcium stones. Nearly all studies reported a composite (including asymptomatic) stone recurrence outcome., Conclusion: In patients with 1 past calcium stone, increased fluid intake reduced recurrence risk. In patients with multiple past calcium stones, addition of thiazide, citrate, or allopurinol further reduced risk., Primary Funding Source: Agency for Healthcare Research and Quality.

We report a case of Langerhans cell histiocytosis with a restricted presentation (eosinophilic granuloma of the mandible) complicated by multiple reactivations., (Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease., Aim: To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism., Methods: We describe the clinical efficacy and tolerability of allopurinol-thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25-33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment., Results: All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol-thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 10(8) red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 × 10(8) RBC (P = 0.01)., Conclusion: Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism., (© 2013 Blackwell Publishing Ltd.)

This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9.4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0.001) and it retained significance in multivariable model (Hazard Ratio 3.8, 95%CI 2.3-6.3,P < 0.001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in non-responders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein., (© 2013 Crown copyright. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)