Search

Purpose: The aim of this study was to report clinical observations suggesting the efficacy of topical 1% 5-fluorouracil (5-FU) in treating Demodex -associated blepharitis., Methods: An observational retrospective review of 13 eyes from 13 individuals with conjunctival neoplastic lesions and concomitant Demodex lash infestation that received topical 1% 5-FU eye drops. Patients underwent slit-lamp examination at each follow-up visit. Clinical photographs of the lash line were obtained after treatment initiation. In a subset of patients, lashes were epilated bilaterally and microscopically analyzed for presence of Demodex mites before and after treatment initiation., Results: The mean age of the population was 68 ± 14 years (range: 30-84 years) and 92% were male. In all 13 patients, a marked reduction in cylindrical dandruff was noted in the treated eye by slit-lamp examination after 2 cycles of 5-FU. There was complete resolution of cylindrical dandruff in 10 of 13 treated eyes compared with 0 resolution of cylindrical dandruff in untreated eyes ( P = 0.0001). In the 6 patients who received epilation, the lashes from the treated eye showed no Demodex , whereas lashes from the fellow untreated eye revealed persistent Demodex ., Conclusions: Topical 1% 5-FU shows efficacy in treating Demodex -associated blepharitis. Further studies are indicated to reproduce our findings and evaluate the potential use of 5-FU as a treatment ingredient., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity., Aims: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival., Methods: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient., Results: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase., Conclusions: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities., (© 2021. The Author(s).)

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 μM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G 2 /M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 μM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: The benefit of loco-regional treatments such as hepatic arterial infusion (HAI) in terms of survival and response rate is unclear. The aim of this work is to quantitatively summarize the results of both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing fluoropyrimidine-HAI (F-HAI) to systemic chemotherapy (SCT) for the treatment of colorectal liver metastases (CRLMs)., Methods: We searched the Cochrane Library, PubMed, EMBASE, and Web of Science up to July 1, 2021. The outcome measures were tumor response rate and overall survival (OS). Both RCTs and NRSIs comparing HAI to SCT for patients with unresectable CRLMs were included. The outcome measures were tumor response rate and OS. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2., Results: A total of 16 studies including 11 RCTs and 5 NRSIs were identified for the present meta-analysis. Nine RCTs compared F-HAI to SCT for patients with unresectable CRLMs and the pooled result indicated that patients who received F-HAI experienced more than twofold response rate than SCT, with a pooled risk ratio of 2.10 (95%CI 1.59-2.79; P < .00001). In addition, the pooled result based on RCTs showed that F-HAI had a significant benefit regarding OS, with a pooled HR of 0.83 (95% CI 0.70-0.99; P = .04). Similarly, the benefit of F-HAI in terms of OS was also observed in the results of NRSIs., Conclusions: Our results indicated that the F-HAI regimen had a greater tumor response rate and survival advantage than SCT for patients with unresectable CRLMs. Future propensity score-matched analyses with a large sample size should be conducted to support the evidence of our results based on RCTs and NRSIs., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX., Methods: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups., Results: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001)., Conclusion: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy., (© 2021 Wiley Periodicals LLC.)

Introduction: Delayed methotrexate clearance in several patients admitted to the oncology unit at a regional medical center necessitated the development of a pharmacist-driven protocol for supportive therapy with high-dose methotrexate. This performance improvement project evaluated the impact of the protocol on inpatient length of stay, patient safety, and clinical outcomes., Methods: Retrospective data were collected over 14 months pre-implementation and prospective data were collected over 19 months post-implementation. Primary outcomes included mean length of stay and incidence of kidney injury. Secondary outcomes included myelosuppression, treatment delays, mucositis, protocol adherence, and pharmacist interventions. Chi-squared and unpaired two sample t -test were used for data analysis., Intervention: A literature review of consensus recommendations for supportive care post high-dose methotrexate administration was conducted to develop the protocol. Education on implementation was provided to involved disciplines., Results: One-hundred ten high-dose methotrexate admissions for 23 patients were analyzed: 24 pre-protocol and 86 post-protocol. Mean length of stay was 5.17 nights pre-protocol and 3.91 nights post-protocol ( p  = 0.026). Incidence of kidney injury significantly decreased (16.7% pre-protocol versus 3.5% post-protocol; p  = 0.0394). Lower incidences of all-grade anemia (83.3% versus 58.1%), neutropenia (62.5% versus 29.1%), and thrombocytopenia (58.3% versus 33.7%) as well as treatment delays (29.2% versus 11.6%; p  = 0.036) were reported post protocol. No statistically significant difference in mucositis was detected. Pharmacist adherence to protocol was ≥80% resulting in 348 interventions with 99.4% provider acceptance., Conclusion: The implementation of a pharmacist-driven high-dose methotrexate management protocol resulted in a statistically significant decrease in inpatient length of stay and kidney injury. Further studies are needed to assess the impact on additional outcomes.

Purpose: To describe a patient with epithelial downgrowth after Descemet membrane endothelial keratoplasty., Methods: Case report., Results: A 73-year-old woman underwent triple Descemet stripping automated endothelial keratoplasty for cataract and corneal edema secondary to Fuchs endothelial dystrophy in the left eye elsewhere. Three years later, Descemet membrane endothelial keratoplasty was performed at our department due to graft failure. One month after the operation, her vision improved to 20/32 and maintained stable. At the 14-month visit, her visual acuity decreased, and a routine examination revealed epithelial downgrowth at the posterior surface of the cornea and partly beneath the graft, accompanied by presumed graft rejection. Therefore, repeat Descemet membrane endothelial keratoplasty with epithelial scraping and intracameral injection of 5-fluorouracil was indicated. She recovered 20/25 vision by 1 month after the surgery. However, small sheet-like epithelial downgrowth recurred 1 month later. The epithelial downgrowth was limited to the peripheral margin of the Descemet membrane endothelial keratoplasty graft and did not affect the visual axis. Epithelial downgrowth showed "islands" with connection between epithelial downgrowth and clear corneal incision on anterior segment optical coherence tomography images. Histopathologic evaluation of the removed Descemet membrane endothelial keratoplasty graft confirmed conjunctival epithelium as the source. Under close observation at the current 4-year follow-up, the epithelial downgrowth remained stable and localized and her vision increased to 20/20., Conclusion: Epithelial downgrowth can occur after Descemet membrane endothelial keratoplasty. The limited progression of epithelial downgrowth in this patient suggests that this condition after Descemet membrane endothelial keratoplasty even in the recurrence stage may cause less damage than expected and may only need to be observed closely if no progression occurs.

Background and Aims: The microbial ecosystem seems to be an important player for therapeutic intervenption in inflammatory bowel disease [IBD]. We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine [AZA] or anti-tumour necrosis factor [anti-TNF] antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome., Methods: Faecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as Crohn's Disease Activity Index [CDAI] < 150 in Crohn´s disease [CD], partial Mayo score <2 in ulcerative colitis [UC], and faecal calprotectin values <150 µg/g and C-reactive protein <5 mg/dl. 16S rRNA amplicon sequencing was performed. To predict microbial community metabolic processes, we constructed multispecies genome-scale metabolic network models., Results: Paired Bray-Curtis distance between baseline and follow-up time points was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared with patients without remission [p = 0.041]. In this model, the difference in butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA [p = 0.008]., Conclusions: In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: COVID-19 has been spreading worldwide with a significant death toll. Solid-organ transplantation (SOT) recipients are at higher risk due to their suppressed immune system. In this study, we aimed to conduct a systematic review on COVID-19 clinical manifestations and treatment strategies in SOT recipients., Methods: We searched three databases for relevant terms related to COVID-19 and transplantation. 50 studies, including 337 patients, were reviewed., Results: Two hundred thirty six patients were male, with a mean age of 49.9 years. The most prevalent group was the kidney 57.0%, followed by 17.2% heart and 13.6% liver. Fever and cough were the most reported clinical presentations. Infiltration (55.4%) in chest x-ray and ground-glass opacity (67.1%) in CT scans were the most radiological findings. It was found that 96.8% and 72.4% of patients present with CRP level and lymphocytopenia, respectively, and 70.6% of kidney recipients patients presented with high creatinine levels. The most common baseline immunosuppressants were calcineurin inhibitors (88.9%) and antimetabolites (73.2%). Antimetabolites (84.3%) and calcineurin inhibitors (54.3%) were discontinued/decreased 84.3% whereas glucocorticoids dosage almost has no change (77.9%) or even increased. 18.4% of cases had died, and 65.9% were discharged., Conclusions: Patients' demographics, signs, symptoms, and radiographic findings in SOT recipients are almost similar to the general population. However, gastrointestinal symptoms appear to be more common. There are different treatment strategies, but in most of them, antimetabolite and calcineurin inhibitors were decreased or discontinued, while corticosteroids were increased. Finally, COVID-19 seems to be more severe and has higher mortality in SOT recipients compared to the general population., (© 2020 Wiley Periodicals LLC.)

Microencapsulation of polysaccharidic nanoparticles is met with nanoscale and biological performance changes. This study designs soft agglomerates as nanoparticle vehicle without nanoparticles undergoing physical processes that alter their geometry. The nanoparticles were made of high molecular weight chitosan/pectin with covalent 5-fluorouracil/folate. Nanoparticle aggregation vehicle was prepared from low molecular weight chitosan. The nanoparticles and aggregation vehicle were blended in specific weight ratios to produce soft agglomerates. Nanoparticles alone are unable to agglomerate. Adding aggregation vehicle (< 2 μm) promoted soft agglomeration with nanoparticles deposited onto its surfaces with minimal binary coalescence. The large and rough-surfaced aggregation vehicle promoted nanoparticles deposition and agglomeration. A rounder vehicle allowed assembly of nanoparticles-on-aggregation vehicle into agglomerates through interspersing smaller between larger populations. Soft agglomeration reduced early drug release, and was responsive to intracapsular sodium alginate coat to further sustain drug release. The soft agglomerates can serve as a primary oral colon-specific vehicle., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Acacetin is a di-hydroxy and mono-methoxy flavone present in various plants, including black locust, Damiana, Silver birch. Literature information revealed that acacetin exhibits an array of pharmacological potential including chemopreventive and cytotoxic properties in cancer cell lines, prevents ischemia/reperfusion/myocardial infarction-induced cardiac injury, lipopolysaccharide (LPS), 1-methyl-4-phenyl pyridinium ion (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced neuroinflammation, LPS and sepsis-induced lung injury, rheumatoid and collagen-induced arthritis, inhibit the microbial growth, obesity, viral-mediated infections as well as hepatic protection., Purpose: This review highlights the therapeutic potential of acacetin, with updated and comprehensive information on the biological sources, chemistry, and pharmacological properties along with the possible mechanism of action, safety aspects, and future research opportunities., Study Design: The information was retrieved from various search engines, including Pubmed, SciFinder, Science direct, Inxight:drugs, Google scholar, and Meta cyc., Result: The first section of this review focuses on the detailed biological source of acacetin, chromatographic techniques used for isolation, chemical characteristics, the method for the synthesis of acacetin, and the available natural and synthetic derivatives. Subsequently, the pharmacological activities, including anti-cancer, anti-inflammatory, anti-viral, anti-microbial, anti-obesity, have been discussed. The pharmacokinetics data and toxicity profile of acacetin are also discussed., Conclusion: Acacetin is a potent molecule reported for its strong anti-inflammatory and anti-cancer activity, however further scientific evidence is essential to validate its potency in disease models associated with inflammation and cancer. There is limited information available for toxicity profiling of acacetin; therefore, further studies would aid in establishing this natural flavone as a potent candidate for research studies at clinical setup., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15 -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization., Competing Interests: The authors declare no competing interest.

Purpose: To evaluate the efficacy and safety of needle revision and examine factors predictive of failure., Methods: In total, 157 eyes of 131 patients that underwent needle revision augmented with either 5-fluorouracil or betamethasone for trabeculectomy failure were included in this retrospective study. Complete failure was defined as additional glaucoma surgery, ciliodestructive procedures, loss of light perception, sight-threatening complications, hypotony maculopathy, and surgical bleb revision. Success was defined as intraocular pressure ⩽ 18 (criterion A), ⩽15 (criterion B), and ⩽12 mmHg (criterion C) reached with (qualified) or without (complete) medications, and absence of any criteria of complete failure., Results: The median (interquartile range) follow-up was 25.0 (41.0) months. Complete failure rates were 19%, 26%, and 31% at 1, 2, and 3 years, respectively. For criterion A, qualified and complete success rates were, respectively, 77% and 69% at 1 year, 66% and 51% at 2 years, and 60% and 47% at 3 years. For criterion B, qualified and complete success rates were, respectively, 67% and 61% at 1 year, 48% and 42% at 2 years, and 44% and 39% at 3 years. For criterion C, qualified and complete success rates were, respectively, 43% and 41% at 1 year, 27% and 25% at 2 years, and 24% and 23% at 3 years. High baseline intraocular pressure and primary surgery were associated with higher and lower risks of complete failure, respectively., Conclusion: Needle revision is an effective and safe procedure to rescue failing trabeculectomy postponing or avoiding further glaucoma surgery. Eyes with low target intraocular pressure may have poor long-term outcomes.

Aims: Drug-induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs., Methods: Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed., Results: In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45-55% of neutrophils +45-55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms., Conclusion: The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM., (© 2019 The British Pharmacological Society.)

Caloric restriction mimetics (CRMs) provide an exciting antiaging intervention strategy. 2-Deoxy-D-glucose (2-DG), a glycolytic inhibitor, is known to work as a CRM at high doses; however, at chronic high dose it has been linked to increased mortality in rats. We have investigated chronic low-dose dietary administration of 2-DG on age-related stress protection in young and old male Wistar rats by evaluating age-dependent biomarkers in plasma and erythrocytes. Significant increase was observed in reactive oxygen species levels in 2-DG-treated rats (both young and old), concomitant with increase in activities of erythrocyte plasma membrane redox system (PMRS), catalase (CAT), and superoxide dismutase (SOD). 2-DG treatment also decreased plasma sialic acid and advanced glycation end products. We propose that 2-DG induces a mitohormetic response resulting in augmentation of defense mechanism(s) manifested by higher activity of PMRS, CAT, and SOD. Our findings provide evidence that at chronic low dose 2-DG could be a potential CRM.

Objective: Hyperuricemia has been epidemiologically associated with multiple comorbidities including chronic renal failure and cardiovascular disease. Cause and effect are difficult to address, given comorbidities associated with and prevalence of metabolic syndrome. One impediment to achieving serum uric acid (sUa) levels less than or equal to 6.0 mg/DL is the concept that allopurinol might be nephrotoxic. We examined the relation of sUa less than or equal to 6.0 mg/dL to renal function over time., Methods: This is a medical records review study of 348 hyperuricemia patients identified in 2015, as having been followed with serial uric acid measurements. After 1 year of serial urate levels, to allow for treatment, patient cohorts were defined: sUa less than or equal to 6.0 mg/dL and sUa greater than 6.0 mg/dL. A repeated measure model was used to test for an association between uric acid level and serum creatinine, while adjusting for covariates., Results: There was a significant difference in the least square means of serum creatinine comparing those who achieved an sUa less than or equal to 6.0 mg/dL versus sUa greater than 6.0 mg/dL (1.39 mg/dL [95% confidence interval, 1.30-1.48] vs 1.57 mg/dL [95% confidence interval, 1.46-1.69]; p = 0.0015). This is a between-group difference in creatinine of 0.18 mg/dL. If a change in serum creatinine of 0.2 is considered significant, this short-term between-group progression of renal failure approaches clinical significance., Conclusions: Given that most serial measures were within the first few years of follow-up, and change in renal function occurs slowly over time, the between group difference of sUa of 0.18 mg/dL is close to a clinically significant creatinine difference of 0.2 mg/dL.

Purpose: Evaluate the intraocular pressure (IOP) control in combined Ahmed Glaucoma Valve (AGV) implantation and trabeculectomy revision with adjunctive antimetabolite compared with AGV alone in patients who failed prior trabeculectomy., Methods: Consecutive cases of combined AGV implantation and trabeculectomy revision with adjunctive antimetabolite (combined group) after January 3, 2014 were case-matched to cases of AGV implantation alone (AGV-alone group) before January 3, 2014. Primary outcome measures were qualified success with stratified IOP targets based on criteria: (A) IOP≤18 mm Hg and 20% IOP reduction; (B) IOP≤15 mm Hg and 25% IOP reduction; (C) IOP≤12 mm Hg and 30% IOP reduction, and hypertensive phase (HP) rate. Secondary outcome measures were 1-year postoperative IOP and number of glaucoma medications and complications., Results: Twenty eyes (20 patients) in each group were included. Cumulative success for combined group and AGV-alone group at 1-year were: 74.0% versus 59.2% (criterion A, P=0.221), 61.9% versus 49.5% (B, P=0.183), and 54.2% versus 30.0% (C, P=0.033), respectively. In total, 50% (10 eyes) in the AGV-alone group developed HP compared with 15% (3 eyes) in the combined group (P=0.041). At 1-year follow-up, combined group had statistically significantly lower IOP than AGV-alone group (10.1±4.4, 13.3±2.9 mm Hg, respectively; P=0.028). There were no cases of bleb-related infections, choroidal effusion or hemorrhage, persistent hypotony, or hypotony maculopathy in either group., Conclusions: Combining AGV implantation with trabeculectomy revision with antimetabolite was associated with better tonometric success compared with AGV implantation alone in patients with previously failed trabeculectomy, particularly when a low IOP target (≤12 mm Hg) is required. Revised trabeculectomy may provide complimentary outflow facility to AGV.

Background: Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications., Aim: To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial., Methods: We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged <60 vs ≥60 years randomised to early combined immunosuppression or conventional management, using Cox proportional hazard analysis or modified Poisson model. In the early combined immunosuppression arm, patients with failure to achieve clinical remission within 4-12 weeks of corticosteroids were treated with a combination of tumour necrosis factor-α antagonist plus anti-metabolite and sequentially escalated in a stepwise algorithm., Results: Of 1981 patients, 311 were ≥60 years (15.7%; 173 randomised to early combined immunosuppression and 138 to conventional management). Over 24 months, 10% of older patients developed Crohn's disease-related complications (early combined immunosuppression vs conventional management: 6.4% vs 14.5%) and 14 patients died (3.5% vs 5.8%). There was no difference between younger and older patients in risk of achieving corticosteroid-free clinical remission (<60 years, early combined immunosuppression (72.6%) vs conventional management (64.4%): relative risk [RR], 1.06 [95% CI, 0.98-1.15] vs ≥60 years, early combined immunosuppression (74.8%) vs conventional management (63.0%): RR, 1.09 [0.90-1.33], P-interaction = 0.78) or time to major adverse outcome (<60 years: hazard ratio [HR], 0.71 [0.53-0.96] vs ≥60 years: HR, 0.69 [0.31-1.51], P-interaction = 0.92) with early combined immunosuppression vs conventional management., Conclusions: We observed no difference in efficacy and safety of early combined immunosuppression compared to conventional management in older and younger patients. Early combined immunosuppression may be considered as a treatment option in selected older patients with Crohn's disease with suboptimal disease control. Clinical Trial Identifier: NCT01030809., (© 2019 John Wiley & Sons Ltd.)

Background: Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined., Methods: Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test., Results: A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%)., Conclusions: Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.

Background: Current guideline recommendations for immunosuppression reduction after diagnosis of posttransplant lymphoproliferative disorder (PTLD) include stopping antimetabolites, reducing calcineurin inhibitors, and maintaining corticosteroids. However, the effect of immunosuppression on PTLD relapse risk after up-to-date therapy is unclear., Methods: This is a retrospective analysis of immunosuppression, patient baseline characteristics, and relapse risk measured as landmark time to progression (TTP) starting 1 year after start of therapy in 159 patients with B cell PTLD after solid organ transplantation treated in the prospective, international, multicenter PTLD-1 trials with either sequential treatment (rituximab followed by cyclophosphamide (CHOP-21 chemotherapy) 750 mg/m intravenously [IV] day (d) 1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (maximum, 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days) or risk-stratified sequential treatment (rituximab followed by rituximab or rituximab (R-CHOP-21 immunochemotherapy) 375 mg/m IV day (d) 1, cyclophosphamide 750 mg/m IV d1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (max. 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days)., Results: Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared with immunosuppression before diagnosis, significantly fewer patients received an antimetabolite or a calcineurin inhibitor (CNI) after diagnosis of PTLD. Relapse risk measured as landmark TTP was significantly higher for patients on corticosteroids compared to all others (P = 0.010) as well as for patients on ciclosporin compared with those on tacrolimus (P = 0.002), but similar for those on antimetabolites compared with all others (P = 0.912). In a Cox regression analysis of landmark TTP, corticosteroid-containing immunosuppression after diagnosis of PTLD (P = 0.002; hazard ratio, 11.195) and age (P = 0.001; hazard ratio, 1.076/year) were identified as independent, significant risk factors for PTLD relapse., Conclusions: In the prospective PTLD-1 trials, corticosteroid use after diagnosis of PTLD is associated with an increased risk of relapse, whereas the use of antimetabolites is not. These findings require prospective validation.

Objective: : To determine the efficacy of high-dose allopurinol in reducing left ventricular mass in patients with left ventricular hypertrophy by comparing its efficacy with febuxostat.., Methods: The randomised controlled interventional study was conducted at Mayo Hospital, Lahore, Pakistan, from April to December 2015, comprising patients with left ventricular hypertrophy on echocardiography. They were randomly divided into two equal groups, with Group A receiving allopurinol and Group B receiving febuxostat. Primary endpoint was reduction in left ventricular mass and left ventricular mass index as calculated by echocardiography. Patients were followed at third and sixth month of enrolment to detect regression. Patients were investigated for eosinophil's count, urine for micro albuminuria and renal function tests to monitor side effects of allopurinol. SPSS 20 was used for data analysis., Results: There were 76 patients divided into two groups of 38(50%) each. Mean reduction in left ventricular mass between baseline and at six months in Group A and Group B was 35.474±13.54 and 21.921±3.33 respectively (p=0.0001) while mean reduction in left ventricular mass index between baseline and at six months was 17.26±4.36 and 17.63±21.07 respectively (p=0.0001). Greater improvement was observed in Group A.., Conclusions: Allopurinol was found to be more effective than febuxostatin reducing the left ventricular mass and left ventricular hypertrophy independent of blood pressure.

Objectives: Uric acid (UA) control may be insufficient in chronic kidney disease (CKD) patients in the current era. It is unclear, however, whether this is the result of environmental effects, patient anthropometrics or insufficient dosing of medical therapy (allopurinol)., Methods: We have collected data on multiple clinical and laboratory parameters of 114 CKD clinic patients attending the nephrology clinic of the University of Mississippi Medical Center with an estimated glomerular filtration rate <45 mL · min -1 · 1.73 m 2 . We assessed the correlates of UA levels and the allopurinol doses along with achieved serum UA and urine pH., Results: The cohort consisted of middle-aged to elderly patients with a mean (± standard deviation) age of 62.1 (11.6) years; 45.6% were female, 68.4% were African American and 47.4% had a history of gout. The mean UA level was 7.7 (2.49) mg/dL (range 3.1-16), allopurinol dose was 192 (99) mg/day (range 50-450) and estimated glomerular filtration rate was 23.8 (11.3) mL · min -1 · 1.73 m 2 . While the overall serum bicarbonate level was 25 (3.2) mEq/L, urine pH was <6 in 60.5% of the cohort. Significant univariate correlates of the administered doses of allopurinol were weight ( r 0.317, P = 0.001), body mass index (BMI; r 0.313, P = 0.001), and female sex ( r - 0.198; P = 0.035). Achieved UA levels correlated directly with BMI ( r 0.201, r = 0.036) but inversely with the allopurinol dose ( r -0.196; P = 0.036). During logistic regression analysis with stepwise selection, only weight (β 0.313, P = 0.001) and sex (β -0.190, P = 0.039) proved to be predictive of the allopurinol dose; as for the achieved UA level, only BMI (β 0.271, P = 0.006) and the allopurinol dose (β -0.258; P = 0.009) had a significant effect., Conclusions: In patients with advanced CKD, conventional dosing recommendations for allopurinol are unlikely to suffice in reaching target serum UA goals. In our cohort, larger-than-usual allopurinol doses were well tolerated.

Aims: To evaluate, describe and quantify the diversity in postoperative antimetabolite administration and bleb needling practices among glaucoma specialists performing trabeculectomy surgery within the UK and Ireland., Methods: A cross-sectional online survey was distributed to all consultant glaucoma specialists who are on the United Kingdom and Eire Glaucoma Society (UKEGS) contact list. Participants were asked specific questions about their current practices for post-trabeculectomy antimetabolite administration followed by questions directly related to bleb needling procedures., Results: 60 (83%) of UKEGS glaucoma subspecialty consultants completed the survey. 70% of respondents administered 5-fluorouracil (5-FU) in their clinic room while 30% used a separate treatment room. Doses of 5-FU varied considerably but 70% used 5 mg as standard. Techniques used to reduce corneal toxicity included precipitation with amethocaine (44%) or benoxinate (14%), saline wash (14%) and modified injection technique (8%). Topical antibiotics and/or betadine were used to prevent infection following 5-FU injection in just over 50%. Bleb needling was exclusively performed in operating theatre by 56% of respondents and solely at the slit lamp in the clinic room by 12%. A further 30% used a combination of both theatre and outpatient clinic rooms. Anti-metabolites used were 5-FU (72%) and mitomycin C (22%) with 12% using either of the two substances., Conclusions: There is a significantly wide variety of current practices for antimetabolite administration and bleb needling within the UK and Ireland. This may be influenced by a glaucoma surgeon's specific experience and audit results as well as particular clinical set-up, availability of antimetabolite and clinic room space., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG ( p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group ( p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.

Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs) and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qβ bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD) and to simultaneously display multiple IgG-binding ZZ domains. After labeling with antibodies against the hPSC-specific surface glycan SSEA-5, EGFP-containing particles were shown to specifically bind undifferentiated cells in culture, and CD-containing particles were able to eliminate undifferentiated hPSCs with virtually no cytotoxicity to differentiated cells upon treatment with the prodrug 5-fluorocytosine.

Asymmetric flow field-flow fractionation (AF4) coupled with UV-Vis spectroscopy, multi-angle light scattering (MALS) and refractive index (RI) detection has been applied for the characterization of MIL-100(Fe) nanoMOFs (metal-organic frameworks) loaded with nucleoside reverse transcriptase inhibitor (NRTI) drugs for the first time. Empty nanoMOFs and nanoMOFs loaded with azidothymidine derivatives with three different degrees of phosphorylation were examined: azidothymidine (AZT, native drug), azidothymidine monophosphate (AZT-MP), and azidothymidine triphosphate (AZT-TP). The particle size distribution and the stability of the nanoparticles when interacting with drugs have been determined in a time frame of 24 h. Main achievements include detection of aggregate formation in an early stage and monitoring nanoMOF morphological changes as indicators of their interaction with guest molecules. AF4-MALS proved to be a useful methodology to analyze nanoparticles engineered for drug delivery applications and gave fundamental data on their size distribution and stability. Graphical abstract ᅟ.

Background: The few studies that evaluated taste function in Parkinson's disease (PD) showed inconsistent results. The inherited ability to taste the bitter compound of 6-n-propylthiouracil has been considered to be a paradigm of general taste perception. 6-n-propylthiouracil taste perception is mediated by the TAS2R38 receptor, and reduced 6-n-propylthiouracil sensitivity has been associated with several diseases not typically related to taste function., Objectives: We evaluated the 6-n-propylthiouracil taste perception and the TAS2R38 gene as genetic risk factors for the development of idiopathic PD in PD patients and healthy controls (HC)., Methods: The 6-n-propylthiouracil taste perception was assessed by testing the responsiveness, and the ability to recognize, 6-n-propylthiouracil and sodium chloride. The participants were classified for 6-n-propylthiouracil taster status and genotyped for the TAS2R38 gene., Results: A significant increase in the frequency of participants classified as 6-n-propylthiouracil nontasters and a reduced ability to recognize bitter taste quality of 6-n-propylthiouracil were found in PD patients when compared with healthy controls. The results also showed that only 5% of PD patients had the homozygous genotype for the dominant tasting variant of TAS2R38, whereas most of them carried the recessive nontaster form and a high number had a rare variant., Conclusions: Our results show that 6-n-propylthiouracil taster status and TAS2R38 locus are associated with PD. The 6-n-propylthiouracil test may therefore represent a novel, simple way to identify increased vulnerability to PD. Moreover, the presence of the nontasting form of TAS2R38 in PD may further substantiate that disease-associated taste disruption may represent a risk factor associated with the disease. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at least in part. Recent studies suggest that dual restriction of glycolysis and mitochondrial function may overcome this issue. Sonodynamic therapy (SDT), a prospective therapeutic modality for cancers, has been reported to induce mitochondria-dependent cell damage. Here, we investigated the combined effect of SDT and 2-deoxyglucose (2DG), an anti-glycolytic agent, on breast cancer both in vitro and in vivo. In vitro, we found that, compared with a single treatment, SDT + 2DG co-treatment significantly decreased cell viability and increased cell apoptosis. Moreover, the generation of reactive oxygen species was enhanced and mitochondrial membrane potential (MMP) was reduced after SDT + 2DG co-treatment. Furthermore, the oxidative phosphorylation was also restrained after SDT + 2DG co-treatment, further to cause the blockage of ATP provision. In vivo, SDT + 2DG markedly reduced tumor volume and weight, consistent with the in vitro findings. Furthermore, toxicology tests concurrently indicated that the dosages of sinoporphyrin sodium and 2DG were comparatively tolerable. Generally, these results indicated that SDT + 2DG combination therapy may be an available, promising therapy for highly metastatic breast cancer., (Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.)

Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.

Objective: To compare mean endothelial cell loss in patients of primary open angle glaucoma undergoing trabeculectomy with and without mitomycin C., Study Design: Randomised control study., Place and Duration of Study: Institute of Ophthalmology, Mayo Hospital, Lahore, from May 2016 to April 2017., Methodology: Patients with primary open angle glaucoma, not controlled with medication, were selected from the outpatient department. Patients with secondary glaucomas and concomitant ocular disease were excluded. Selected patients were divided into two groups of 30 each. Group A patients underwent trabeculectomy with adjunctive mitomycin C while group B patients underwent trabeculectomy alone. Pre- and post-trabeculectomy endothelial cell counts were recorded with the help of specular microsope and entered on proforma., Results: Median cell loss was 283 (66.50) when trabeculectomy was done with the use of adjunctive mitomycin C in group A while median endothelial cell loss was 72.50 (19.25) when the trabeculectomy was done without the use of adjunctive mitomycin C in group B., Conclusion: Use of mitomycin C causes more endothelial cell loss during trabeculectomy as compared to when done without it.

Introduction: Trabeculectomy is considered the standard for glaucoma surgery. Postoperative scarring is one the factors associated with surgery failure. Different antimetabolites have been used in order to reduce this risk, particularly 5-fluorouracil and mitomycin C. Although both are considered effective, it is not clear if they are different in terms of success of trabeculectomy and adverse effects., Methods: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach., Results and Conclusions: We identified four systematic reviews including 17 studies overall, of which 12 were randomized trials. We concluded mitomycin C might be more effective in reducing intraocular pressure and increasing qualified success compared to 5-fluorouracil. However, its use might be associated to a higher risk of complications.

D-cycloserine (DCS), a partial agonist at N-methyl-D-aspartate (NMDA) receptors, is used as an enhancer of exposure therapy for anxiety disorders. The purpose of the present study was to investigate the feasibility of using polymeric gels to increase the viscosity of the formulation and thereby increase the nasal residence time and sustained release of DCS in vitro. Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and methyl cellulose (MC) were prepared at concentrations of 0.5 to 5% w/v. Pluronic F-127 (PF-127) was prepared at concentrations of 15 to 35% w/v. pH, viscosity and in vitro DCS release behavior of the formulated gels were analyzed. All four gels that were tested, demonstrated sustained DCS release behavior over a 24-hour period, but with different rates. Based on the results of this study, HPMC, HPC, MC, and PF-127 are capable of increasing the viscosity of nasal gel formulations and of releasing DCS in sustained manner. Therefore, these polymeric gels can be suitable carriers for DCS nasal gel formulation.

Background: Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive., Methods: Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16-17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes., Results: We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6-24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2)., Conclusions: Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors.

Background and aim  The advent of direct-acting antivirals has revolutionized treatment of chronic hepatitis C with very high cure rates and excellent tolerability compared to interferon-based hepatitis C virus (HCV) treatment. However, long-term effects of interferon-free cure of HCV infection on the metabolic condition of patients have not been investigated so far. Methods  We investigated weight development during and after antiviral treatment of hepatitis C. In a prospective single-center cohort study, interferon-free antiviral treatment was initiated in 284 patients. Each patient's weight was monitored 1 year before the start of treatment, at baseline (BL), end of treatment (EOT), follow-up week 24 (FU24), and follow-up week 48 (FU48). Results  Weight gain after HCV cure was observed in 20 %, 33 %, and 44 % of patients at EOT, FU24, and FU48, respectively. The mean overall weight change at FU48 compared to baseline was 1.45 kg (95 % CI 0.44; 2.46, p = 0.02, compared to the pretreatment period). Multivariate regression revealed age as the only factor predicting weight change at FU48 (B - 0.107, 95 % CI, - 0.202 to - 0.011, p = 0.03), while gender, cirrhosis, diabetes mellitus, ribavirin, and body mass index had no influence. In the subgroup of patients younger than 60 years, mean weight gain at FU48 compared to baseline was 2.8 kg (95 % CI, 1.23 - 4.4). In contrast, patients 60 years and older had a mean weight change of - 0.04 kg (95 % CI, - 1.12 to 1.03, p = 0.005). Conclusions  Cure of HCV by interferon-free antiviral treatment was associated with weight gain in up to 44 % of patients during long-term follow-up. Weight gain occurred predominantly in patients younger than 60 years. The precise mechanism of weight gain remains to be elucidated., Competing Interests: Conflict of interest: BS received travel grants from Abbvie, MSD, Shionogi and Gilead. CHZS received a travel grand from Gilead and speaker fees from Gilead, MSD and Roche. MPM received consulting fees from Roche, BMS, Gilead, Boehringer Ingelheim, Novartis Tibotec, Vertex, GSK, MSD, grant/research support from Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Merck/MSD and lecture fees from Merck/MSD, Roche, BMS, Gilead. MC received research support from Merck, Roche, Gilead and speaking and/or consulting fees from Abbvie, BMS, Gilead, Merck, Novartis, Roche. HW received research support from Roche, BMS, Novartis, Abbott and speaking and/or consulting fees from Abbvie, Abbott, Achillon, BMS, Boehringer, Gilead, GSK, Merck, Novartis, Roche, Siemens, Transgene. All remaining authors declare that they have no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To investigate the therapeutic effect of allopurinol treatment on acute coronary syndrome and to elucidate its possible mechanism., Methods: Patients with acute coronary syndrome (n = 100) were recruited as research subjects in our hospital. The patients were randomly divided into two groups, an allopurinol group (n = 50) and a control group (n = 50). These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy; allopurinol therapy was added to the allopurinol group based on conventional treatment indications. Biochemical markers such as serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups. Indicators of oxidative stress and inflammatory response (MDA, OX-LDL, NO, hs-CRP and TNF-α), as well as cardiovascular events during 2-years follow-up, were recorded., Results: On admission, there was no difference in serum creatinine, uric acid, BNP, blood glucose or lipid levels between the two groups (P > 0.05). However, after 1 month of treatment, these levels were improved in patients in the allopurinol group compared to the control group (P < 0.05). MDA, OX-LDL, hs-CRP and TNF-α decreased after treatment periods of 14 days and 1 month. They were also decreased at 3 month, 6 month, 1 year, and 2 year follow-up visits. However, data from the allopurinol group demonstrated significantly lower levels than in the control group (P < 0.05). Additionally, compared with the control group, allopurinol treatment significantly elevated the level of NO (P < 0.05). The total effective rates of the allopurinol group are much higher than in the control group for both angina pectoris (93.2% and 76%, respectively) and ECG (96% and 82%, respectively). Most patients in the allopurinol group (n = 40) and the control group (n = 41) received stent implantation with no significant difference shown between them. The incidence of cardiovascular events during 2 years of follow-up in the allopurinol group was 10%; it was 30% in the control group., Conclusion: Allopurinol has a remarkable effect in the treatment of ACS and can improve the oxidative stress and inflammatory reaction indicators of patients. The protective mechanism of allopurinol might be achieved by suppressing the secretion and release of inflammatory mediators such as TNF-α, hs-CRP, OX-LDL and MDA while increasing levels of NO., (Copyright © 2017 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the changes in quality of life in noninfectious uveitis patients treated with 2 of the most commonly prescribed antimetabolite treatments., Design: Secondary analysis of a multicenter, block-randomized clinical trial., Methods: Eighty patients at Aravind Eye Hospitals in Madurai and Coimbatore, India, with noninfectious intermediate, posterior, or panuveitis were randomized to receive oral methotrexate, 25 mg weekly, or oral mycophenolate mofetil, 1 g twice daily, and were followed up monthly for 6 months. Best-corrected visual acuity, Indian Vision Function Questionnaire (IND-VFQ), and Medical Outcomes Study 36-item Short Form Survey (SF-36) were obtained at enrollment and at 6 months (or prior, in the event of early treatment failure)., Results: IND-VFQ scores, on average, increased by 9.2 points from trial enrollment to 6 months (95% confidence interval [CI]: 4.9, 13.5, P = .0001). Although the SF-36 physical component summary score did not significantly differ over the course of the trial, the mental component summary score decreased by 2.3 points (95% CI: -4.4, -0.1, P = .04) and the vitality subscale decreased by 3.5 points (95% CI: -5.6, -1.4, P = .001). Quality-of-life scores did not differ between treatment arms. Linear regression modeling showed a 3.2-point improvement in IND-VFQ score for every 5-letter improvement in visual acuity (95% CI: 1.9, 4.3; P < .001)., Conclusions: Although uveitis treatment was associated with increased vision and vision-related quality of life, patient-reported physical health did not change after 6 months of treatment, and mental health decreased. Despite improved visual outcomes, uveitis patients receiving systemic immunosuppressive therapy may experience a deterioration in mental health-related quality of life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Historically, mammary gland growth has been considered isometric the first 2 mo of life and then allometric until peripuberty. However, recent work indicated that the mammary gland might be responsive to nutrient intake preweaning. The objectives of this study were to describe the effects of nutrient intake preweaning on mammary gland development and to investigate cell specific proliferation during this phase of development. Twelve dairy heifer calves were fed either a fixed amount of milk replacer (MR; control, n = 6) or an amount of MR adjusted for BW (enhanced, n = 6). Control calves received a constant amount of a 28% crude protein, 15% fat milk MR per day that was equivalent to 2.8 Mcal of metabolizable energy intake per day; enhanced calves received 0.3 Mcal of metabolizable energy intake per kilogram of metabolic body weight (from 4.2 to 8.4 Mcal of metabolizable energy intake per day). All calves had constant access to water and a 22% crude protein commercial calf starter. Calves were killed at 54 ± 2 d. Control calves consumed 32.6 ± 2.4 kg of MR and 6.7 ± 0.5 kg of calf starter per calf, whereas the enhanced calves consumed 69.5 ± 2.4 kg of MR and 1.9 ± 0.5 kg of calf starter per calf over the 54-d period. Further, to evaluate putative stem cell proliferation, BrdU (5-bromo-2'-deoxyuridine; 5 mg/kg) was injected intramuscularly once per day between 12 to 15 d and again once per day between 24 to 27 d of life. Initial and final body weight for the control and enhanced treatments were 39.2, 61.0, 39.7, and 83.2 kg, respectively. At euthanasia, weights of liver, kidneys, pancreas, whole skinned mammary gland, and mammary parenchyma were measured. The growth rate of each organ was calculated using the concept of allometry as the difference in the change in organ weight as a percentage of body weight. The mammary glands of calves fed the enhanced diet were significantly heavier at euthanasia; when mammary parenchymal weight was analyzed, enhanced calves had 5.9 times greater mammary parenchymal mass, indicating the mammary gland was responsive to nutrient intake before weaning. Allometric growth of the mammary gland was initiated preweaning in the calves fed the enhanced treatment. Further characterization of mammary cells that retained BrdU label revealed no significant differences among the tissue slices analyzed between treatments; however, as calves fed the enhanced diet had more mammary parenchymal mass, if the number of label-retaining cells per counted slide were similar between treatments then the enhanced calves had a larger total population of putative mammary stem cells present in the mammary gland., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objective: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2 -/- ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy., Methods: To test these hypotheses, we assessed two therapies in Tk2 -/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP., Results: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2 -/- animals compared to dCMP+dTMP., Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652., (© 2017 American Neurological Association.)

The active tumor targeting ligands, hyaluronic acid (HA) and human serum albumin (HSA), are considered promising targeting moieties of drug carriers for cancer therapy. The chitosan nanoparticles loaded with methotrexate (MTX-CsNPs) were employed as the core for subsequent coating process. HA and HSA coating solutions were used at different concentrations. The effect of different HA Mw (1000, 360, 10kDa) was also investigated. The coated MTX-CsNPs was characterized proving the success of surface functionalization. The antitumor activity of the prepared MTX-CsNPs was evaluated on MCF-7 breast cancer cell lines. Results showed that both 360 and 10kDa HA allowed for successful HA adsorption, while its Mw and concentration determined negative charge density. HSA coating was accompanied by a slight increase in nanoparticles (NPs) size and a final positive surface charge. The in vitro cytotoxicity proved that HA and HSA coated MTX-CsNPs improved the antitumor activity compared to uncoated NPs and free drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study is to evaluate the efficacy of ethosomes encapsulated with 5-fluorouracil (5-FU) in treatment of laryngotracheal stenosis in rabbit models. The 5-FU ethosome was prepared by the thin film hydration method, and the amorphous, size distribution and the encapsulation efficiency was investigated. The tracheal mucosa were scraped about 0.5 cm with a nylon brush to induce the scar in airway grow, then models were divided into three groups: 5-FU ethosome group, 5-FU group and saline group, drug were injected into scar of every group by paracentesis guided under endoscope, respectively. The stenosis states were observed under laryngo fiberscope immediate, 7, 14 and 21 days after administrated. Airway stenosis of 5-FU ethosome group has no significant difference when compared with 5-FU group at 7 days after administration, but 5-FU ethosome significantly reduced the airway stenosis after 21-day administration when compared with 5-FU group again and has no restenosis during the period under observation. The fact that ethosomes encapsulated with 5-FU were effective for laryngotracheal stenosis suggests that it has potential as a new method for ameliorating airway stenosis originating from granulation tissue.

Rationale and Objectives: Adhesions are the most common complication after nasal surgery and revision. 5-Fluorouracil (5-FU) reduces various adhesions and epithelial growth related complications. The aim of this study was to evaluate the effects of 5-flurouracil application in the nasal cavity after a multi-procedure nasal surgery in term of complications frequency., Materials and Methodology: Institutional ethical approval was granted and a double-blinded prospective clinical trial was conducted to study the effect of 5-fu on post-operative complications. At the end of a combined endoscopic inferior turbinoplasty with one or more other nasal surgeries, 5-flurouracil-soaked cottonoid with 1mL of 5-flurouracil (5mg/mL) was applied in one side of nasal cavity and saline-soaked cottonoid was applied contralaterally and left for 5min. Patients were assessed over 2months postoperatively by a blinded observer in terms of adhesions, crustation, discharge, pain, discharge, loss of smell and other complications and nasal symptoms., Results: On the 1st follow up week postoperatively, adhesions were observed in (24 patients) 35%, bilateral in (6 patients) 9% and unilateral in (18 patients) 26%. Unilateral Adhesions were statistically significantly higher in control sides than those in 5-FU sides (22% vs 4% respectively) (p=0.025). Crustation, continued to statistically significantly diminish over time (p=0.035). On the 8th follow up week, adhesions reduction was still statistical significant at the 5-FU treated side (p=0.01)., Conclusion: 5-FU is safe and effective in preventing adhesions formation when applied during combined endoscopic inferior turbinoplasty procedure with other nasal procedure surgery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination., Methods: An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist., Results: Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670)., Conclusions: The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.

Background: The objective of this study was to evaluate and compare the evolution of the profile currently recommended by the International Renal Interest Society (IRIS) (sCr, UPC and sSDMA) with a panel of other different kidney biomarkers during treatment for canine leishmaniosis. This panel included three urinary glomerular biomarkers (uIgG, uCRP and uferritin) and three urinary tubular biomarkers (uGGT, uNAG and uRBP). These biomarkers were measured in two groups of dogs with canine leishmaniosis at IRIS stage I. Group 1: dogs showing proteinuria (UPC > 0.5) before treatment which did not decrease after treatment; Group 2: dogs showing proteinuria before treatment which decreased after treatment., Results: Group 1 showed no significant changes in any biomarker after treatment. In group 2, among the biomarkers recommended by the IRIS, only UPC showed a significant decrease after treatment. However all biomarkers of glomerular damage showed a significant decrease after treatment, with uIgG/Cr and uCRP/Cr showing the greater decreases. In addition uRBP/Cr and uNAG/Cr showed significant decreases after treatment., Conclusions: In dogs with leishmaniosis at IRIS stage I that reduced UPC after treatment, there were no significant changes in serum creatinine and sSDMA. However, all the urine biomarkers evaluated with exception of uGGT showed a significant decrease. These decreases were more evident in those markers related with glomerular function, being uIgG/Cr the biomarker more associated with UPC. Further studies involving a larger number of animals and histological analysis of the kidney would be recommended to confirm these findings and evaluate the routine practical use of these urine biomarkers in canine leishmaniosis.

Background: Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at higher risk of hypersensitivity reaction., Objectives: The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans., Methods: This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a change in the laboratory analyzer, making further comparisons inappropriate., Results: On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR (95% confidence interval, 4.8-11.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.003-0.20 mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4 years. There were 5 mild adverse events in the treated cases., Conclusions: Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should consider this potential benefit of allopurinol in the treatment of patients with hyperuricemia, those with overall maintained renal function.

The pharmacological blockade of memory reconsolidation has been suggested as a potential treatment to the attenuation of maladaptive memories associated to psychiatric disorders and drug addiction. To interfere with the process of fear memory reconsolidation using a manipulation safer than pharmacological interventions, here we examined whether a positive reinforcing stimulus (non-alcoholic beer, NB) post-memory retrieval can decrease the fear response in ethanol withdrawn (ETOH) animals. We first evaluated the potential interfering effect of NB on memory reconsolidation in non-ethanol dependent (control, CON) rats. Non-alcoholic beer intake shortly after memory retrieval attenuated the fear response in CON rats. A resistance to destabilization/reconsolidation process was previously observed in ETOH rats, which was reversed by the activation of NMDA receptor induced by pre-retrieval d-cycloserine (DCS) administration. Therefore, the influence of DCS (5mg/kg; i.p.) to facilitate the disruptive effect of NB on fear memory was examined in ETOH animals. As expected, NB was ineffective to attenuate the fear response in ETOH rats, with DCS being necessary to promote the disruptive effect of NB on the reconsolidation in these animals. Hence, DCS/reinforcing stimulus in combination with memory reactivation can be considered as an alternative approach for disrupting resistant fear memories., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50 % response, lasting 2 years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75 mg/m(2)/day, days 1-5, Len 10 mg/day, days 6-21, every 28 days), 6-month consolidation (Aza 75 mg/m(2)/day, days 1-5, every 28 days), and 12-month maintenance (Len 10 mg/day, days 1-21, every 28 days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76.3 years old (60-87), and 88 % with major comorbidities. Thirteen patients completed induction, 7 proceeded for consolidation, and 2 for maintenance. The overall response rate (ORR) was 72 % (18/25), with 6 (24 %) for CR, 3 (12 %) for marrow CR, and 9 (36 %) for hematologic improvement (HI). The 7 non-responding patients were on the study 3 days to 4.1 months. At 6 months, 4 of 6 evaluable patients achieved complete cytogenetic response and 2 with del (5q) at diagnosis. Adverse events (AEs) were as expected in these patients: grades III-IV, mainly hematologic-thrombocytopenia (20 patients) and neutropenia (13 patients). The common non-hematologic AEs were infections (14 patients), nausea (7), vomiting (7), diarrhea (7), and skin reactions (5). The median progression-free survival (PFS) was 12 ± 1.36 months, with median overall survival (OS) of 12 ± 1.7 months. Quality of life (FACT questionnaire) data were available for 12 patients with a tendency towards improved QoL. This trial with elderly HR-MDS patients with an expected poor prognosis demonstrates a high (72 %) response rate and a reasonable expected safety profile but a relatively short PFS and OS.