Neoadjuvant Interdigitated Chemoradiotherapy Using Mesna, Doxorubicin, and Ifosfamide for Large, High-grade, Soft Tissue Sarcomas of the Extremity: Improved Efficacy and Reduced Toxicity

Objectives: Patients with large, high-grade extremity soft tissue sarcoma (STS) are at high risk for both local and distant recurrence. RTOG 95-14, using a regimen of neoadjuvant interdigitated chemoradiotherapy with mesna, doxorubicin, ifosfamide, and dacarbazine followed by surgery and 3 cycles of adjuvant mesna, doxorubicin, ifosfamide, and dacarbazine, demonstrated high rates of disease control at the cost of significant toxicity (83% grade 4, 5% grade 5). As such, this regimen has not been widely adopted. Herein, we report our institutional outcomes utilizing a modified interdigitated chemoradiotherapy regimen, without dacarbazine, and current radiotherapy planning and delivery techniques for high-risk STS. Materials and Methods: Adults with large (≥5 cm; median, 12.9 cm), grade 3 extremity STS who were prospectively treated as part of our institutional standard of care from 2008 to 2016 are included. Neoadjuvant chemoradiotherapy consisted of 3 cycles of mesna, doxorubicin, and ifosfamide (MAI) and 44 Gy (22 Gy in 11 fractions between cycles of MAI) after which patients underwent surgical resection and received 3 additional cycles of MAI. Results: Twenty-six patients received the MAI treatment protocol. At a median follow-up of 47.3 months, 23 (88.5%) patients are still alive. Three year locoregional recurrence-free survival, disease-free survival, and overall survival are 95.0%, 64.0%, and 95.0%, respectively. There have been no therapy-related deaths or secondary malignancies. The nonhematologic grade 4 toxicity rate was 7.7%. Conclusions: Neoadjuvant interdigitated MAI radiotherapy followed by resection and 3 cycles of adjuvant MAI has resulted in acceptable and manageable toxicity and highly favorable survival in patients at greatest risk for treatment failure.

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The University of Florida Department of Radiation Oncology Guidelines for Treatment of Differentiated Thyroid Cancer With I-131 or External-beam Radiotherapy

The purpose of this paper is to summarize the University of Florida Department of Radiation Oncology guidelines for treatment of differentiated thyroid cancer with I-131 or external-beam radiotherapy. This article is not meant to compete with the many excellent book chapters and consensus guidelines that present comprehensive discussions of treatment options. This is a streamlined, "How we do it?" reference without substantial discussion of background or supporting data. To serve as a treatment reference, the great majority of the information is presented in topic-specific tables.

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Survival Outcome and Prognostic Factors After Pulmonary Metastasectomy in Sarcoma Patients: A 18-Year Experience at a Single High-volume Referral Center

Background: Metastatic sarcoma patients have a poor prognosis with 3-year survival rate of 25%. About 30% of them present isolated lung metastases. We aimed to analyze the clinical outcome of sarcoma patients undergoing pulmonary metastasectomy (PM) and prognostic factors associated with local control, disease-free, and overall survival (OS). Patients and Methods: All sarcoma patients undergoing PM at Humanitas Cancer Center were retrospectively reviewed. Analyzed variables included clinicopathologic, surgical, and survival data. Exclusion criterion comprised a follow-up period inferior to 1 year. A univariable and multivariable Cox regression analysis was performed (P

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Patterns of Care and Outcomes of Elderly Esophageal Cancer Patients Not Meeting Age-based Criteria of the CROSS Trial

Objectives: The CROSS trial established neoadjuvant chemoradiation followed by surgery (nCRT-S) as superior to surgery alone (S) for locally advanced esophageal cancer (EC). However, because patients above 75 years of age were excluded, this comparison cannot be extrapolated to older patients. This study of a large, contemporary national database evaluated practice patterns in elderly patients ineligible for CROSS, and analyzed overall survival (OS) between nCRT+S, S, and definitive CRT (dCRT). Materials and Methods: The National Cancer Data Base was queried for EC patients with cT1N1M0/T2-3N0-1M0 EC (per the CROSS trial) but 76 years and above of age. Multivariable logistic regression ascertained factors associated with nCRT+S (vs. S). Kaplan-Meier analysis evaluated OS; Cox multivariate analysis determined variables associated with OS. Propensity matching aimed to address group imbalances and indication biases. Results: Of 4099 total patients, 594 (14%) underwent nCRT+S, 494 (12%) underwent S, and 3011 (73%) underwent dCRT. Since 2010, trimodality management has risen, corresponding to declines in S and dCRT. Median OS in the respective groups were 26.7, 20.3, and 17.8 months (P0.05), with lower 30-day readmission and postoperative hospital stay (P

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Utilization of an Alternative Docetaxel-based Intraperitoneal Chemotherapy Regimen in Patients With Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma: A Continued Need for Ovarian Cancer Patients

Objective: The objective of this study was to report the tolerability and toxicity of a regimen consisting of intravenous (IV) docetaxel and intraperitoneal (IP) cisplatin and paclitaxel with granulocyte colony-stimulating factor support. Materials and Methods: We conducted a retrospective cohort study of patients with surgical stage II-IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated with an outpatient IP chemotherapy regimen consisting of docetaxel 75 mg/m2 IV and cisplatin 75 mg/m2 IP day 1 followed by paclitaxel 60 mg/m2 IP day 8 every 21 days. Grade 3 and 4 toxicity, dose delays and reductions, port complications, and tolerability are reported. Outcomes, including response rate, progression-free survival (PFS), overall survival (OS) are also reported. Results: A total of 60 patients received this IP regimen. Most common toxicities included neutropenia (47%), gastrointestinal (28%), and anemia (25%). Most patients (85%) experienced no IP port complications. Dose delay or reduction was required in 30% of patients. Two-thirds completed all prescribed cycles, with 80% of total planned cycles completed. Complete response was achieved for 88%, and 43% are currently without evidence of disease. Median PFS for all patients was 25.5 months (95% confidence interval [CI], 20.4-30.5 mo) while OS for all patients was 56.8 months (95% CI, 47.7-65.9 mo). For the 44 patients with stage III disease, median PFS was 22.1 months (95% CI, 16.3-28.0 mo), while median OS was 56.8 months (95% CI, 47.3-66.3 mo). Conclusions: This docetaxel-based IP chemotherapy regimen demonstrates an improved tolerability profile compared with GOG172. Additional evaluations on alternative IP regimens remain warranted. Short follow-up time limits survival assessment, but results are encouraging.

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Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer

Background: Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. Patients and Methods: Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. Results: A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P

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Neoadjuvant Chemotherapy Treatment Modifications in Ovarian Carcinoma: The Impact on Surgical Outcome and Progression-free Survival

Objective: Little is known on the impact of neoadjuvant chemotherapy (NACT) treatment modifications on surgical outcome and progression-free survival (PFS) in patients with ovarian carcinoma. We aimed to report the changes we made during NACT and to evaluate its impact on patient outcome. Methods: A retrospective cohort study of all women with advanced stage ovarian carcinoma treated with NACT followed by interval cytoreduction in one university-affiliated medical center (January 2005 to June 2017). We excluded those who were treated with NACT without any surgical intervention. NACT modifications included delay in treatment, change in chemotherapy, and dose reduction. Demographics, tumor characteristics, surgical outcome, and PFS were compared between patients exposed to NACT treatment modifications and those who received standard treatment. Results: Seventy-nine patients met inclusion criteria of whom, 59 patients received standard, nonmodified treatment and 20 patients modified NACT. There were no intergroup differences with respect to age at diagnosis (59.5±11.6 vs. 64.70±8.09, P=0.09) and stage of disease (P=0.13). Radiologic complete response rates (25.0% vs. 32.2%, P=0.545) and optimal cytoreduction rates (75.0% vs. 86.4%, P=0.23) were similar in both treatment groups. Mean PFS (in months) was comparable between patients receiving standard treatment and those who required NACT modifications (18.5 vs. 12.2, P=0.125). Conclusions: NACT treatment modifications did not affect surgical outcome and PFS. We conclude that when clinically indicated, dose alteration and scheduling can be implemented without apparent detriment to outcome.

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Differential Outcomes Among Immunosuppressed Patients With Merkel Cell Carcinoma: Impact of Immunosuppression Type on Cancer-specific and Overall Survival

Objectives: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with higher incidence among whites, elderly, and immunosuppressed patients. Although immunosuppressed MCC patients are at higher risk of recurrence and MCC-related death, it is unknown whether immunosuppression type is associated with differential outcomes. Materials and Methods: We retrospectively evaluated 89 nonmetastatic MCC patients with a diagnosis of chronic immunosuppression. Immunosuppression was categorized as chronic lymphocytic leukemia (31% of cohort), other hematologic malignancies (18%), solid organ transplant (21%), autoimmune disease (21%), and human immunodeficiency virus acquired deficiency syndrome (8%). Progression-free survival (PFS) and MCC-specific survival (MSS) were estimated with the cumulative incidence function. Overall survival (OS) was estimated by the Kaplan-Meier method. Results: With a median follow-up of 52 months, 53 deaths occurred (42 from MCC, 7 unknown, and 4 non-MCC). Two-year PFS, MSS, and OS were 30%, 55%, and 52%, respectively. Human immunodeficiency virus/acquired deficiency syndrome and solid organ transplant patients were diagnosed with MCC at a younger age (median 55 and 59 y, respectively) and with more advanced stage disease compared with other immunosuppressed subgroups. PFS did not significantly differ among the 5 immunosuppression subgroups (P=0.30), but significant differences were observed in MSS and OS (both P=0.01). Controlling for potential confounders for OS, including age and stage, immunosuppression type was still significantly associated with risk of death (P=0.01). Conclusions: Among immunosuppressed MCC patients, recurrent MCC is the major cause of mortality. The risk of death from MCC differs among immunosuppression types, suggesting important biological differences in host-tumor immune interactions.

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Disparities Predict for Higher Rates of Cut-through Hysterectomies in Locally Advanced Cervical Cancer

Objectives: The treatment of choice for locally advanced cervical cancer is definitive chemoradiation (CRT). Hysterectomy is not indicated due to higher-rates of cut-through resections leaving gross disease behind, requiring additional therapy with increasing morbidity and no benefit in overall survival (OS). The objectives of this study were to determine factors associated with cut-through hysterectomies and evaluate OS outcomes. Materials and Methods: The National Cancer Database (NCDB) was queried for patients 18 years and older with clinical Federation of Gynecology and Obstetrics stage IB2 to IVA. All patients underwent upfront hysterectomy and had known margin status. Cut-through hysterectomy was classified as presence of microscopic or macroscopic disease at the margin. Results: A total of 11,638 patients were included; 993 (8.5%) had positive margins. In patients with positive margins, 560 (56.4%) received postoperative CRT and 148 (14.9%) underwent postoperative radiation. Five-year OS was worse for those with cut-through resections when compared with those with negative margins, 66.0% versus 86.7%, respectively (hazard ratios, 3.08; P

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Clinical and Molecular Recursive Partitioning Analysis of High-grade Glioma Treated With IMRT

Introduction: Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables. Methods: Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. Results: We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (P

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Treatment Patterns and Survival of Elderly Patients With Breast Cancer Brain Metastases

Objectives: The main objective of this study was to analyze treatment patterns of elderly patients with breast cancer brain metastases (BCBM), evaluate characteristics associated with treatment selection, and to analyze trends in overall survival (OS) over time. Materials and Methods: We included women with BCBM reported to the Surveillance, Epidemiology, and End Results Medicare Program from 1992 to 2012. Treatments were recorded from Medicare claims from the date of brain metastases diagnosis until 60 days after. Treatments included resection, radiation, and chemotherapy. Cochran-Armitage tests were used for analysis of treatment patterns. Multinomial logistic regression was applied to determine factors associated with treatment selection. Cox regression modelled OS trends within each treatment modality across time. Results: Among 5969 patients included, treatment rates increased from 50% in 1992 to 64.1% in 2012 (P

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Comparison of Outcomes in Patients With Muscle-invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder Preservation

Purpose: Radical cystectomy currently remains the standard of care for muscle-invasive bladder cancer. However, surgery can be associated with considerable morbidity and mortality, including the removal of the bladder. An alternative strategy is to preserve the bladder through concurrent chemoradiation following a maximal transurethral resection of the tumor. National protocols using a bladder-preservation approach have demonstrated disease-specific outcomes comparable to radical cystectomy in selected patients, but these results have not been replicated in previously reported population-based series. Here, we describe an outcomes analysis of patients with muscle-invasive bladder cancer treated with either radical surgery or bladder-preserving chemoradiation (BPCRT) for those patients meeting BPCRT criterion using the National Cancer Database (NCDB). Materials and Methods: Using the NCDB, patients with American Joint Commission on Cancer clinical T2-3, N0, M0 urothelial carcinoma diagnosed between 2004 and 2013 were included for analysis. Only patients treated with definitive intent with either radical cystectomy or concurrent chemotherapy and radiation after a maximal transurethral tumor resection were included. Propensity-score matching was used. Results: Among 8454 eligible patients, 7276 (86%) underwent radical cystectomy, and 1178 (14%) underwent BPCRT. Patients undergoing BPCRT were significantly older (median age, 77 vs. 68 y; P

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Comparison of Clinical Characteristics and Outcomes in Relapsed Versus De Novo Metastatic Non–Small Cell Lung Cancer

Objectives: To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non–small cell lung cancer (NSCLC). Materials and Methods: We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed. Results: A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, P

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Safety and Efficacy of Cabozantinib for Metastatic Nonclear Renal Cell Carcinoma: Real-world Data From an Italian Managed Access Program

Objective: The activity of cabozantinib in nonclear cell histologies has not been evaluated. Materials and Methods: Data were collected across 24 Italian hospitals. Patients were aged 18 years and older with advanced nonclear cell renal cell carcinoma (RCC), with an Eastern Cooperative Oncology Group Performance Status 0 to 2, who had relapsed after previous systemic treatments for metastatic disease. Cabozantinib was administered orally at 60 mg once a day in 28 days cycles. Dose reductions to 40 or 20 mg were made due to toxicity. Adverse events (AEs) were monitored using CTCAE version 4.0. Results: Seventeen patients were enrolled. Three (18%) patients were diagnosed type I papillary RCC, 9 (53%) type II papillary, 3 (18%) chromophobe, and 2 (11%) with Bellini duct carcinoma. In total, 11 patients started with 60 mg. Six patients started a lower dose of 40 mg. Median progression-free survival was 7.83 months (0.4 to 13.4 mo), while median overall survival was not reached but 1-year overall survival was about 60%. Six patients (35%) experienced a partial response to treatment and 6 patients (35%) showed a stable disease. In the remaining 5 (30%), we observed a progressive disease. Grade 3 and 4 AEs were observed in 41% of patients. Among 20 patients, only 1 (6%) discontinued treatment due to AEs. Asthenia (41%), diarrhea (35%), aminotransferase increasing (35%), mucosal inflammation (35%), hand and foot syndrome (24%), and hypothyroidism (24%) were the most frequently AEs. Conclusions: Our data showed that, cabozantinib is a active and feasible treatment in patient with nonclear cell RCC.

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Challenging the Requirement to Treat the Contralateral Neck in Cases With >4 mm Tumor Thickness in Patients Receiving Postoperative Radiation Therapy for Squamous Cell Carcinoma of the Oral Tongue or Floor of Mouth

Hypothesis: While treating patients with postoperative radiotherapy (RT) for squamous cell carcinoma of the oral tongue or floor of mouth, we hypothesized a low risk of tumor recurrence in the contralateral neck in the absence of contralateral neck RT when the primary tumor is >1 cm from the midline regardless of tumor thickness (TT) or depth of invasion (DOI)>4 mm. Objective: The policy at our institution for many years has been to limit postoperative RT to the ipsilateral side when the primary tumor does not cross the midline, regardless of TT or DOI. We report the rate of isolated contralateral neck failure in this group. Materials and Methods: We retrospectively reviewed all patients treated with postoperative RT at our institution between 1998 and 2014 for pathologic stage T1-T4 N1-N2b squamous cell carcinoma of the oral tongue or floor of mouth that did not cross the midline and thus were treated with RT limited to the primary site +/− ipsilateral neck. Results: Our study population included 32 patients: 75% with close (5 mm in 68% of patients. There were no isolated contralateral neck recurrences with a median follow-up of 5 years. Conclusion: While delivering postoperative RT for oral tongue or floor of mouth cancer with pathologic neck stage N0-2b, the risk of not irradiating the contralateral neck is very low when the primary tumor does not cross the midline, regardless of other factors at the primary site, such as TT and DOI.

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Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Meta-Analysis

Objective: To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer. Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED. Results: There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10200 Gy. Conclusions: SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity of

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Nuclear Medicine Therapy With 223Radium-dichloride for Osseous Metastases in Prostate Carcinoma

Painful osseous metastasis resulting from castration-resistant prostate carcinoma is a common clinical problem. Historically, nuclear medicine offered several palliative beta-emitting radiopharmaceuticals targeting the skeleton with the goal of decreasing pain. However, these have largely been replaced by the alpha-emitting agent 223radium (Ra). 223Ra received Food and Drug Administration approval in 2013 for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases without visceral metastases. 223Ra offers an improved therapeutic profile due to its alpha-particle emissions resulting in a relatively higher linear energy transfer and lower particle range compared with beta-emitters. 223Ra also has demonstrated to increase overall survival in patients and to delay adverse skeletal events. Running a successful clinical nuclear therapy program with 223Ra requires a multidisciplinary team approach and this article suggests an implementation strategy from the authors' institution. Potential new nuclear radiopharmaceuticals still under investigation offering the future possibility of radioligand therapy are also discussed briefly.

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Metabolic relation of cyanobacteria to aromatic compounds

Abstract

Cyanobacteria, also known as blue-green (micro)algae, are able to sustain many types of chemical stress because of metabolic adaptations that allow them to survive and successfully compete in a variety of ecosystems, including polluted ones. As photoautotrophic bacteria, these microorganisms synthesize aromatic amino acids, which are precursors for a large variety of substances that contain aromatic ring(s) and that are naturally formed in the cells of these organisms. Hence, the transformation of aromatic secondary metabolites by cyanobacteria is the result of the possession of a suitable "enzymatic apparatus" to carry out the biosynthesis of these compounds according to cellular requirements. Another crucial aspect that should be evaluated using varied criteria is the response of cyanobacteria to the presence of extracellular aromatic compounds. Some aspects of the relationship between aromatic compounds and cyanobacteria such as the biosynthesis of aromatic compounds, the influence of aromatic compounds on these organisms and the fate of aromatic substances inside microalgal cells are presented in this paper. The search for this information has suggested that there is a lack of knowledge about the regulation of the biosynthesis of aromatic substances and about the transport of these compounds into cyanobacterial cells. These aspects are of pivotal importance with regard to the biotransformation of aromatic compounds and understanding them may be the goals of future research.

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Kinetically selective and potent inhibitors of HDAC8

Journal Name: Biological Chemistry
Issue: Ahead of print


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An engineered lipocalin that tightly complexes the plant poison colchicine for use as antidote and in bioanalytical applications

Journal Name: Biological Chemistry
Issue: Ahead of print


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Directed evolution of the 3C protease from coxsackievirus using a novel fluorescence-assisted intracellular method

Journal Name: Biological Chemistry
Issue: Ahead of print


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An Evaluation of Healthcare Use and Child Morbidity 4 Years After User Fee Removal in Rural Burkina Faso

Abstract

Objectives Increasing financial access to healthcare is proposed to being essential for improving child health outcomes, but the available evidence on the relationship between increased access and health remains scarce. Four years after its launch, we evaluated the contextual effect of user fee removal intervention on the probability of an illness occurring and the likelihood of using health services among children under 5. We also explored the potential effect on the inequality in healthcare access. Methods We used a comparative cross-sectional design based upon household survey data collected years after the intervention onset in one intervention and one comparison district. Propensity scores weighting was used to achieve balance on covariates between the two districts, which was followed by logistic multilevel modelling to estimate average marginal effects (AME). Results We estimated that there was not a significant difference in the reduced probability of an illness occurring in the intervention district compared to the non-intervention district [AME 4.4; 95% CI  1.0–9.8)]. However, the probability of using health services was 17.2% (95% CI 15.0–26.6) higher among children living in the intervention district relative to the comparison district, which rose to 20.7% (95% CI 9.9–31.5) for severe illness episodes. We detected no significant differences in the probability of health services use according to socio-economic status [χ² (5) = 12.90, p = 0.61]. Conclusions for Practice In our study, we found that user fee removal led to a significant increase in the use of health services in the longer term, but it is not adequate by itself to reduce the risk of illness occurrence and socioeconomic inequities in the use of health services.

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Differences in the imaging of Crohn’s disease patients between North America and Europe: are we ready to bridge the divide?

Abstract

The emphasis of treatment in Crohn's disease has evolved from a reactive model to "treat-to-target" approaches. Cross-sectional imaging has rapidly evolved in parallel, with a growing evidence base supporting its abilities for diagnosis, monitoring and prognostication. Whilst there are differences in emphasis between Europe and North America, particularly around the type of imaging modalities and patterns of multidisciplinary care, there is increasing convergence. This perspective piece provides an overview of the evolving role of cross-sectional imaging in Crohn's disease, discusses practice differences between North America and Europe and provides suggestions on areas for future collaboration and research priorities.

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Latanoprostene bunod ophthalmic solution 0.024% in the treatment of open-angle glaucoma: design, development, and place in therapy

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Visuospatial short-term memory and dorsal visual gray matter volume

Publication date: Available online 21 December 2018

Source: Cortex

Author(s): Dennis Dimond, Rebecca Perry, Giuseppe Iaria, Signe Bray

Abstract

Visual short-term memory (VSTM) is an important cognitive capacity that varies across the healthy adult population and is affected in several neurodevelopmental disorders. It has been suggested that neuroanatomy places limits on this capacity through a map architecture that creates competition for cortical space. This suggestion has been supported by the finding that primary visual (V1) gray matter volume (GMV) is positively associated with VSTM capacity. However, evidence from neurodevelopmental disorders suggests that the dorsal visual stream more broadly is vulnerable and atypical volumes of other map-containing regions may therefore play a role. For example, Turner syndrome is associated with concomitantly reduced volume of the right intraparietal sulcus (IPS) and deficits in VSTM. As posterior IPS regions (IPS0-2) contains topographic maps, together this suggests that posterior IPS volumes may also associate with VSTM. In this study, we assessed VSTM using two tasks, as well as a composite score, and used voxel-based morphometry of T1-weighted magnetic resonance images to assess GMV in V1 and right IPS0-2 in 32 healthy young adults (16 female). For comparison with previous work, we also assessed associations between VSTM and voxel-wise GMV on a whole-brain basis. We found that total brain volume (TBV) significantly correlated with VSTM, and that correlations between VSTM and regional GMV were substantially reduced in strength when controlling for TBV. In our whole-brain analysis, we found that VSTM was associated with GMV of clusters centered around the right putamen and left Rolandic operculum, though only when TBV was not controlled for. Our results suggest that VSTM ability is unlikely to be accounted for by the volume of an individual cortical region, and may instead rely on distributed structural properties.

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Atypical neural processing of rise time by adults with dyslexia

Publication date: Available online 21 December 2018

Source: Cortex

Author(s): Tilde Van Hirtum, Pol Ghesquière, Jan Wouters

Abstract

In recent studies phonological deficits in dyslexia are related to a deficit in the synchronization of neural oscillations to the dynamics of the speech envelope. The temporal features of both amplitude modulations and rise times characterize the speech envelope. Previous studies uncovered the inefficiency of the dyslexic brain to follow different amplitude modulations in speech. However, it remains to be investigated how the envelope's rise time mediates this neural processing. In this study we examined neural synchronization in students with and without dyslexia using auditory steady-state responses at theta, alpha, beta and low-gamma range oscillations (i.e. 4, 10, 20 and 40 Hz) to stimuli with different envelope rise times. Our results revealed reduced neural synchronization in the alpha, beta and low-gamma frequency ranges in dyslexia. Moreover, atypical neural synchronization was modulated by rise time for alpha and beta oscillations, showing that deficits found at 10 and 20 Hz were only evident when the envelope's rise time was significantly shortened. This impaired tracking of rise time cues may very well lead to the speech and phonological processing difficulties observed in dyslexia.

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Dopamine guides competition for cognitive control: Common effects of haloperidol on working memory and response conflict

Publication date: Available online 21 December 2018

Source: Cortex

Author(s): Sean James Fallon, Kinan Muhammed, Daniel S. Drew, Yuen-Siang Ang, Sanjay G. Manohar, Masud Husain

Abstract

Several lines of evidence suggest that dopamine modulates working memory (the ability to faithfully maintain and efficiently manipulate information over time) but its specific role has not been fully defined. Nor is it clear whether any effects of dopamine are specific to memory processes or whether they reflect more general cognitive mechanisms that extend beyond the working memory domain. Here, we examine the effect of haloperidol, principally a dopamine D₂ receptor antagonist, on the ability of humans to ignore distracting information or update working memory contents. We compare these effects to performance on an independent measure of cognitive control (response conflict) which has minimal memory requirements. Haloperidol did not selectively affect the ability to ignore or update, but instead reduced the overall quality of recall. In addition, it impaired the ability to overcome response conflict. The deleterious effect of haloperidol on response conflict was selectively associated with the negative effect of the drug on ignoring – but not updating – suggesting that dopamine affects protection of working memory contents and inhibition in response conflict through a common mechanism. These findings provide new insights into the role of dopamine D₂ receptors on human cognition. They suggest that D₂ receptor effects on protecting the memory contents from distraction might be related to a more general process that supports inhibitory control in contexts that do not require working memory.

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Increased Inhibition Following Negative Cues: A Possible Role for Enhanced Processing

Publication date: Available online 21 December 2018

Source: Cortex

Author(s): Hadas Okon-Singer, Avishai Henik, Shai Gabay

Abstract

Based on findings showing that attention is captured by aversive stimuli, previous studies have hypothesized that inhibition of return (IOR) is reduced at spatial locations previously occupied by threat cues. Yet evidence for this view is limited: Only a few studies have demonstrated a reduced degree of IOR following threat cues, while most have not found differences in IOR between aversive and neutral cues. In contrast to previous studies that used the spatial cuing paradigm and for the most part employed mild negative stimuli as cues, we examined the influence of highly aversive, colored and complex pictures of real life situations. As opposed to the stimuli used in previous studies, these pictures are thought to result in enhanced processing as well as in specific enhancement for threat pictures in comparison to neutral ones. Based on evidence indicating that enhanced processing of spatial cues results in increased IOR, we hypothesized that the negative picture cues employed in the present study would yield increased IOR. This hypothesis was confirmed in two experiments. We suggest that the enhancement of IOR following highly threatening cues may be related to efficient spatial orienting of attention in response to stimuli that are important from an evolutionary point of view. The results are discussed in the context of neurocognitive mechanisms that may underlie the modulation of IOR by emotional information.

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Water mobility spectral imaging of the spinal cord: parametrization of model-free Laplace MRI

Publication date: Available online 22 December 2018

Source: Magnetic Resonance Imaging

Author(s): Dan Benjamini, Peter J. Basser

Abstract

Diffusion magnetic resonance imaging (dMRI) of biological systems most often results in non-monoexponential signal, due to their complexity and heterogeneity. One approach to interpreting dMRI data without imposing tissue microstructural models is to fit the signal to a multiexponential function, which is sometimes referred to as an inverse Laplace transformation, and to display the coefficients as a distribution of the diffusivities, or water mobility spectra. Until recently, this method has not been used in a voxelwise manner, mainly because of heavy data requirements. With recent advancements in processing and experimental design, voxelwise Laplace MRI approaches are becoming feasible and attractive. The rich spectral information, combined with a three-dimensional image, presents a challenge because it tremendously increases the dimensionality of the data and requires a robust method for interpretation and analysis. In this work, we suggest parameterizing the empirically measured water mobility spectra using a bimodal lognormal function. This approach allows for a compact representation of the spectrum, and it also resolves overlapping spectral peaks, which allows for a robust extraction of their signal fraction. We apply the method on a fixed spinal cord sample and use it to generate robust intensity images of slow- and fast-diffusion components. Using the parametric variables, we create novel image contrasts, among them the information entropy of the water mobility spectrum, which pack unique features of the individual diffusion regimes in the investigated system.

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SMR Congress 2018 Abstracts

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The 28th Annual Meeting of the Japanese Society for Pigment Cell Research

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Issue Information

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The Joint Montagna Symposium on the Biology of Skin/Pan American Society for Pigment Cell Research Annual Meeting “Melanoma to Vitiligo: The Melanocyte in Biology and Medicine” October 17–22, 2018, Salishan Resort, Oregon

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BRN2, a POUerful driver of melanoma phenotype switching and metastasis

Abstract

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.

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List of Reviewers for PCMR (01.11.2017–31.10.2018)

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An accessory right hepatic artery derived from the superior mesenteric artery for anterior right liver lobe supply: a case report

Abstract

Purpose

During the last decades, it has been established that there are numerous individual anatomical variations of the arterial blood supply in human liver. In the present study, we examined the liver vascularization of an intrahepatic cholangiocarcinoma patient.

Methods

For surgical planning, an enhanced CT scan was performed and a three-dimensional model of liver vascularization constructed.

Results

The patient was diagnosed as a Michel's type VII hepatic artery variation. An accessory right hepatic artery arose from the superior mesenteric artery and had distributed into the right anterior liver to provide the blood supply of segments V and VIII, which was more medial than the territory of the right hepatic artery coming from the proper hepatic artery. At the same time, an accessory left hepatic artery originated from the left gastric artery.

Conclusion

We present a case in which an accessory right hepatic artery provided a territory more medial than a right hepatic artery coming from the proper right artery.

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Modification of the existing maximum residue level for captan in cranberries

Abstract

In accordance with Article 6 of Regulation (EC) No 396/2005, the Belgian Federal Public Service (FPS) for Health, Food chain safety and Environment, submitted an application as the competent national authority in Belgium to modify the existing maximum residue level (MRL) for the active substance captan in cranberries. The data submitted in support of the request were found to be sufficient to derive MRL proposal for cranberries. Adequate analytical methods for enforcement are available to control the residues of captan in plant matrices at the validated limit of quantification (LOQ) of 0.01 mg/kg for each analyte in the crops assessed. Based on the exposure calculation, EFSA concluded that the short‐term and long‐term intake of residues resulting from the use of captan according to the reported agricultural practice will not result in a consumer exposure exceeding the existing toxicological reference values.

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Modification of the existing maximum residue level for captan in hops

Abstract

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant ADAMA Agriculture BV on behalf of ADAMA Makhteshim Ltd. submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue level for the active substance captan in hops. The data submitted in support of the request were found to be insufficient to conclude whether the existing residue definitions are appropriate for hops. Although the number of residue trials is sufficient to derive a tentative maximum residue level (MRL) for hops according to the residue definitions derived for fruits and fruiting vegetables, EFSA did not recommend this MRL for being implemented in the MRL legislation because due to the lack of a reliable residue definition for risk assessment. Adequate analytical methods for enforcement are available to control the residues of captan in hops.

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Lies Matter

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Tonsillectomy using the BiZact: A pilot study in 186 children and adults

Abstract

1.The BiZact tonsillectomy device, produced by Medtronic (Minneapolis, MN, USA), was approved for market use in Australia by the Therapeutics Good Administration (TGA) in 2016 and is a new device for tonsillectomy

2.Results from this pilot study of 186 patients demonstrate a post‐operative hemorrhage rate of 4.3% similar to rates described by other studies.

3.BiZact tonsillectomy allows for a shortened operative time in the hands of both experienced and training surgeons with a median time of 5.1 minutes (range 1.5 – 26.5 minutes).

4.BiZact tonsillectomy is associated with reduced intraoperative blood loss with less than 1mL of blood loss observed in 71 (38.2%) cases and between 1‐10mL loss observed in 81 (43.5%) cases in this report.

5.This study demonstrates safety and feasibility of this device as a pilot study towards undertaking a prospective randomized trial comparing it to other tonsillectomy techniques.

This article is protected by copyright. All rights reserved.

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Basophil activation testing in occupational respiratory allergy to low molecular weight compounds

Purpose of review There is an unmet need for better immunological tests in cases of suspected occupational asthma to many workplace chemicals; here we consider the basophil activation test (BAT), a potential alternative to the detection of specific IgE antibodies. Recent findings BAT is fairly widely used in general allergy services; and there is increasing experience of its use in the diagnosis of occupational allergy to low molecular weight agents and chemicals including wood dusts, persulphates, antibiotics and latex. Summary There is potential for BAT to become a useful tool in the clinical consideration of occupational asthma and of its mechanisms, and even to take a place in a Bayesian-based diagnostic algorithm. Further development will only occur if specialist centres with appropriate facilities, and preferably in collaboration, contemplate its use. Correspondence to Johanna Feary, Department of Occupational Lung Disease, Royal Brompton Hospital, London SW3 6LR. Tel: +44 20 7594 7968; e-mail: j.feary@imperial.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A long-wavelength-emitting fluorescent probe for simultaneous discrimination of H2S/Cys/GSH and its bio-imaging applications

Publication date: 1 May 2019

Source: Talanta, Volume 196

Author(s): Huawei Niu, Bowen Ni, Keke Chen, Xiaopeng Yang, Wenbo Cao, Yong Ye, Yufen Zhao

Abstract

A long-wavelength fluorescent probe NR-CY was developed for simultaneous identification of cysteine/glutathione and sulphide by combining the derivative of Nile red with 7-nitrobenzofurazan. The response of NR-CY to thiols is regulated by intramolecular charge transfer and photoinduced electron transfer mechanisms. For sulphide at 560 nm, cysteine at 475 nm and glutathione at 425 nm, different absorbance increases can be observed. NR-CY can detect cysteine at fluorescence emission 543 nm and distinguish sulphide from other analytes by kinetic experiments at 636 nm. The probe showed a rapid response to these thiols (cysteine was 90 s and sulphide was 30 s). In addition, NR-CY has been successfully applied to live MCF-7 cell imaging.

Graphical abstract

A long-wavelength fluorescent probe NR-CY was developed for simultaneous identification of cysteine/glutathione and sulphide by combining the derivative of Nile red with 7-nitrobenzofurazan. The response of NR-CY to thiols is regulated by intramolecular charge transfer and photoinduced electron transfer mechanisms. For sulphide at 560 nm, cysteine at 475 nm and glutathione at 425 nm, different absorbance increases can be observed. NR-CY can detect cysteine at fluorescence emission 543 nm and distinguish sulphide from other analytes by kinetic experiments at 636 nm. The probe showed a rapid response to these thiols (cysteine was 90 s and sulphide was 30 s). In addition, NR-CY has been successfully applied to live MCF-7 cell imaging.

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Screen printed potentiometric sensor for therapeutic monitoring of rocuronium at the point of care

Publication date: 1 May 2019

Source: Talanta, Volume 196

Author(s): Diana K. Fahem, Ola M. El Houssini, Mohamed K. Abd El-Rahman, Hala E. Zaazaa

Abstract

Rocuronium bromide (ROC) is currently regarded as the 'gold-standard' in emergency medicine and anesthesia. Globally, millions of human beings are daily administered ROC at emergency settings where it is favored among all the neuromuscular blockers, particularly succinylcholine, for both its fast onset of action and short duration. However, it has been reported that 45% of patients in the post-anesthesia care unit are susceptible to residual postoperative paralysis, undesired ventilator effects and incomplete recovery after ROC administration. From an analytical chemistry perspective, direct determination of ROC is a difficult approach due to the complexity in isolation from biological specimens as well as the lack of a sensitive detection techniques and detectable chromophore. This contribution describes the development of a calix[6]arene-based screen-printed electrode (SPE) that is capable of ROC detection in biological samples at the point of care. This fabricated SPE (sensor 1) exhibited superior performance characteristics (slope, LOD and life time) with respect to an ionophore-free liquid-contact electrode, LCE, (sensor 2). The proposed SPE showed a linear response over a concentration from 1 µM to 10 mM, with a Nernstian slope of 57.9 mV/decade and a detection limit of 0.39 µM. Moreover, this sensor showed a considerable selectivity towards ROC in presence of the anticipated interfering ions. To investigate the ability of the SPE to detect ROC in real biological specimens, ROC has been spiked at a concentration comparable to its anticipated level in human plasma (C_max~ 40 µM) and the proposed SPE displayed an excellent platform for therapeutic drug monitoring (TDM) of ROC with respect to UV-spectrophotometry and LC/MS. Finally, the developed SPE was used for the determination of ROC in its commercial pharmaceutical formulation.

Graphical abstract

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A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

Light it up: A chemiluminescent 1,2‐dioxetane molecule functionalized with a triarylphosphine trigger can be used to quantify picomolar levels of azanone (HNO) through an azaylide‐mediated reaction using a kinetics‐based approach. This probe can be used for quantitative measurement of HNO concentration generated from the reaction of hydrogen sulfide (H₂S) and nitric oxide (NO) and can be loaded into living cells and animals to monitor HNO delivery in real‐time.

Abstract

Azanone (HNO) is a reactive nitrogen species with pronounced biological activity and high therapeutic potential for cardiovascular dysfunction. A critical barrier to understanding the biology of HNO and furthering clinical development is the quantification and real‐time monitoring of its delivery in living systems. Herein, we describe the design and synthesis of the first chemiluminescent probe for HNO, HNOCL‐1, which can detect HNO generated from concentrations of Angeli's salt as low as 138 nm with high selectivity based on the reaction with a phosphine group to form a self‐cleavable azaylide intermediate. We have capitalized on this high sensitivity to develop a generalizable kinetics‐based approach, which provides real‐time quantitative measurements of HNO concentration at the picomolar level. HNOCL‐1 can monitor dynamics of HNO delivery in living cells and tissues, demonstrating the versatility of this method for tracking HNO in living systems.

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High Throughput Strategies for the Discovery and Optimization of Catalytic Reactions

Homogeneous catalysis has provided chemists with numerous transformations to enable rapid construction of organic molecules. However, these reactions are complex, requiring multiple substrate‐dependent mechanistic steps to operate in harmony under a single set of experimental conditions. As a consequence, synthetic chemists often carry out laborious, empirical screening to identify suitable catalysts, solvents, and additives to achieve high yields and selectivity. In this Minireview, recently developed tools, technologies, and strategies will be described that improve this development process. In particular, the application of high throughput techniques to run more experiments, experimental design principles to access better data, and statistical tools to provide predictive models will be discussed.

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Bidentate Boron‐Lewis Acids – Selectivity in Host‐Guest Complex Formation

Bidentate boron‐Lewis acids based on 1,8‐diethynylanthracene were synthesised in two steps by initial stannylation of the terminal alkynes and subsequent tin‐boron exchange with different chloroboranes. The reactions are very selective and the target com¬pounds were obtained in high purity and good to excellent yields. Complexation experiments of 1,8‐bis[(diphenylboraneyl)ethynyl]anthracene with nitrogen bases (pyridine, pyrimidine, TMEDA) afforded stable adducts. Three adducts were structurally characterised by X‐ray diffraction. Competition experiments demonstrated the exchange of guests and quantum‐chemical calculations provided infor‐mation on their energetics. NMR experiments at low temperatures gave insight into the dynamic behaviour of the TMEDA adduct.

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Reductive Molybdenum‐Catalyzed Direct Amination of Boronic Acids with Nitro Compounds

The synthesis of aromatic amines is of utmost importance in a wide range of chemical contexts. We report a direct amination of boronic acids with nitro compounds to yield (hetero)aryl amines. The novel combination of a dioxomolybdenum(VI) catalyst and triphenylphosphine as inexpensive reductant has revealed to be decisive to achieve this new C‐N coupling. Our methodology has proven to be scalable, air and moisture tolerant, highly chemoselective and engages both aliphatic and aromatic nitro compounds. Moreover, this general and step‐economical synthesis of aromatic secondary amines showcases orthogonality to other aromatic amine syntheses as it tolerates aryl halides and carbonyl compounds.

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Colloidal Synthesis and Charge‐Carrier Dynamics of Cs2AgSb1‐yBiyX6 (X: Br, Cl; 0 ≤y ≤ 1) Double Perovskite Nanocrystals

A series of lead‐free double perovskite NCs: Cs2AgSb1‐yBiyX6 (X: Br, Cl; 0≤y≤1) NCs are synthesized. In particular, Cs2AgSbBr6 NCs is a new double perovskite material that has not been reported for the bulk form. Mixed Ag‐Sb/Bi NCs exhibit enhanced stability in colloidal solution compared to Ag‐Bi or Ag‐Sb NCs. Femtosecond transient absorption studies indicate the presence of two prominent fast trapping processes in the charge carrier relaxation. The two fast trapping processes are dominated by intrinsic self‐trapping (1~2 ps) due to giant exciton‐phonon coupling and surface defects trapping (50~100 ps), respectively. In addition, hot‐carrier relaxation is obviously slowed down at high pump fluence.

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A Water‐Soluble Perylene Bisimide Cyclophane as a Molecular Probe for the Recognition of Aromatic Alkaloids

Here we report a water‐soluble macrocyclic host based on perylene bisimide (PBI) chromophores which recognizes natural aromatic alkaloids in aqueous media by intercalating them into its hydrophobic cavity. The host‐guest binding properties of our newly designed receptor with several alkaloids were studied by UV‐vis and fluorescence titration experiments as the optical properties of the chromophoric host change significantly upon complexation of guests. Structural information on the host‐guest complexes was obtained by 1D and 2D NMR spectroscopy and molecular modelling. Our studies reveal a structure binding‐property relationship for a series of structurally diverse aromatic alkaloids with the new receptor and higher binding affinity for the class of harmala alkaloids. To our knowledge, this is the first example of a chromophoric macrocyclic host employed as a molecular probe for the recognition of aromatic alkaloids.

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Remarkable Oxygen‐Evolution Activity of Ca2‐xSrxFe2O6‐δ

The unprecedented catalytic activity of an iron‐based oxygen‐deficient perovskite for oxygen‐evolution reaction (OER) is reported, given the need for catalysts based on earth‐abundant elements. In addition, systematic trends in oxygen‐evolution activity as a function of composition, defect‐order and electrical conductivity have been demonstrated, leading to a methodical increase in OER catalytic activity: Ca2Fe2O6‐δ < CaSrFe2O6‐δ < Sr2Fe2O6‐δ. The latter material, which has the highest electrical conductivity and a unique type of defect‐order, exhibits the best OER activity. In conventional experiments using glassy carbon electrode, this compound shows superior OER activity compared to the current state of the art catalysts, Ba0.5Sr0.5Co0.8Fe0.2O3−δ and RuO2. It also offers an additional advantage, namely high intrinsic electrical conductivity, which allows Sr2Fe2O6‐δ to act as a catalyst without the need for glassy carbon electrode or carbon powder, that are frequently used for enhancing the charge transport in OER catalysts. Indeed, pure disks of this material exhibit an outstanding activity for OER, without any additives or need for electrode preparation.

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Base‐Mediated Defluorosilylation of sp2 & sp3 C–F Bonds Xiang‐Wei Liu, Cayetana Zarate and Ruben Martin*

The ability to selectively forge C–heteroatom bonds via C–F scission is typically accomplished by metal catalysts, specialized ligands and/or harsh conditions. Herein, we describe a base‐mediated defluorosilylation of unactivated sp2 and sp3 C–F bonds that obviates the need for metal catalysts. This protocol is characterized by its simplicity, mild conditions and wide scope, even within the context of late‐stage functionalization, constituting a complementary approach to existing C–Si bond‐forming protocols.

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Total Synthesis of (–)‐Merochlorin A

The first asymmetric total synthesis of the meroterpenoid (–) merochlorin A is described. The route features enantiospecific gold‐catalyzed tandem 1,3‐acyloxy migration/Nazarov/aldol reaction sequence to furnish the bicyclo[3.3.0]octane core in a single step from a linear propargylic 1,3‐enyne aldehyde. After completion of the central skeleton by reductive enol lactone rearrangement, late stage Diels–Alder cycloaddition/aromatization sequence installed the resorcinol. An additional salient feature of the synthesis is the assignment of the absolute configuration, which had not been determined previously.

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Stabilizing lithium into cross‐stacked nanotube sheets with ultra‐high specific capacity for lithium oxygen battery

Although lithium‐oxygen batteries possess high theoretical energy density and are considered as promising candidates for the next‐generation power systems, how to enhance the safety and cycling efficiency of the lithium anodes while maintaining the high energy storage capability remains difficult. Here, we overcome this challenge by cross‐stacking aligned carbon nanotubes into porous networks for ultrahigh‐capacity lithium anodes to afford high‐performance lithium‐oxygen batteries. The novel anode shows a reversible specific capacity of 3656 mAh/g, approaching the theoretical capacity of 3861 mAh/g of pure lithium. When this anode is employed for lithium‐oxygen full batteries, the cycling stability is significantly enhanced owing to the dendrite‐free morphology and stabilized solid electrolyte interface. This work presents a new pathway to high performance lithium‐oxygen batteries towards practical applications by designing cross‐stacked and aligned structures for one‐dimensional conducting nanomaterials.

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Directed evolution of a designer enzyme featuring an unnatural catalytic amino acid

The impressive rate accelerations that enzymes display in nature often result from boosting the inherent catalytic activities of side chains by their precise positioning inside a protein binding pocket. Here we show that such fine‐tuning is also possible for catalytic unnatural amino acids. Specifically, we report the directed evolution of a recently described designer enzyme, which utilizes an aniline side chain to promote a model hydrazone formation reaction. Consecutive rounds of directed evolution identified a number of mutations in the promiscuous binding pocket, in which the unnatural amino acid is embedded in the starting catalyst. When combined, these mutations boost the turnover frequency (kcat) of the designer enzyme by almost 100‐fold. Crucially, these gains result from strengthening the catalytic contribution of the unnatural amino acid, as the engineered designer enzymes outperform variants, in which the aniline side chain is replaced with a catalytically inactive tyrosine residue, by >200‐fold.

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Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers

Taming the CF₃ radical: A unique single‐electron transfer (SET) induced S_N2‐type reaction enables the construction of enantioenriched trifluoromethylated oxindoles using a hypervalent iodine‐based trifluoromethyl transfer reagent. A combination of magnesium Lewis acid catalysis and PyBOX‐type ligands successfully tames the highly reactive CF₃ radical to achieve excellent enantioselectivities.

Abstract

Demonstrated herein is the construction of trifluoromethylated quaternary carbon centers by an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed using a hypervalent iodine‐based trifluoromethyl transfer reagent in combination with a magnesium Lewis acid catalyst and PyBOX‐type ligands to achieve up to 99 % ee and excellent chemical yields. Mechanistic studies were performed by experimental and computational methods and suggest a single‐electron transfer induced S_N2‐type mechanism. This example is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine‐based reagents proceeding through such a reaction pathway.

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Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3‐Arylpyrroles

De novo construction of pyrrole: In the presence of a catalytic amount of Ag₂O and chiral phosphine ligand, the heteroannulation between isocyanoacetates and alkynyl ketones afforded the axially chiral 3‐arylpyrroles in good yields with excellent enantioselectivities.

Abstract

We report herein the first examples of catalytic enantioselective synthesis of axially chiral 3‐arylpyrroles. Reaction of α‐isocyanoacetates with β‐aryl‐α,β‐alkynic ketones in the presence of silver oxide and a phosphine ligand derived from Cinchona alkaloid occurred chemoselectively to afford enantioenriched 3‐arylpyrroles in high yields with excellent enantiomeric excesses. The pyrrole ring was constructed de novo in this process.

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Enantiospecific Synthesis of ortho‐Substituted 1,1‐Diarylalkanes by a 1,2‐Metalate Rearrangement/anti‐SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

The coupling of benzylamines, boronic esters, and aryl iodides gives 1,1‐diarylalkanes with high stereospecificity through a one‐pot sequential 1,2‐metalate rearrangement/anti‐S_N 2′ elimination/rearomatizing allylic Suzuki–Miyaura cross‐coupling reaction.

Abstract

The one‐pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N‐activator, the boronate complex formed from an ortho‐lithiated benzylamine and a boronic ester undergoes stereospecific 1,2‐metalate rearrangement/anti‐S_N2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ‐selective allylic Suzuki–Miyaura cross‐coupling to generate 1,1‐diarylalkanes. When enantioenriched α‐substituted benzylamines are employed, the corresponding 1,1‐diarylalkanes are formed with high stereospecificity.

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Assembling a Hybrid Pd Catalyst from a Chiral Anionic CoIII Complex and Ligand for Asymmetric C(sp3)–H Functionalization

An unusual hybrid palladium catalyst containing an anionic chiral Co^III complex and a chiral phosphoramidite ligand shows a high capacity for catalyzing asymmetric thioamide‐directed C(sp³)−H arylation and delivers excellent yields and enantioselectivity (up to 99 % yield, 99 % ee). Significant synergy between the chiral ligand and the anion in terms of stereochemical control was observed.

Abstract

An unusual hybrid palladium catalyst containing an anionic chiral Co^III complex and a chiral phosphoramidite ligand shows a high capacity for catalyzing asymmetric thioamide‐directed C(sp³)−H arylation and delivers excellent yield and enantioselectivity (up to 99 % yield, 99 % ee). Significant synergy between the chiral ligand and the anion in terms of stereochemical control was observed. Mechanistic investigations have revealed both the nature of the C−H activation and the origin of the enantioselectivity.

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Orientation of an Amphiphilic Copolymer to a Lamellar Structure on a Hydrophobic Surface and Implications for CO2 Capture Membranes

The structural orientation of an amphiphilic polymer to a highly ordered lamellar structure is observed on a hydrophobic surface. Upon using this material, a high CO₂ permeability of 501 Barrer and a CO₂/N₂ ideal selectivity of 77.2 are obtained, which exceed the Robeson upper bound limit.

Abstract

The structural orientation of an amphiphilic crystalline polymer to a highly ordered microphase‐separated lamellar structure on a hydrophobic surface is presented. It is formed by the surface graft polymerization of poly(ethylene glycol)behenyl ether methacrylate onto poly(trimethylsilyl) propyne in the presence of allylamine. In particular, allylamine plays a pivotal role in controlling the crystalline phase, configuration, and permeation properties. The resulting materials are effectively used to improve the CO₂ capture property of membranes. Upon the optimization of the reaction conditions, a high CO₂ permeability of 501 Barrer and a CO₂/N₂ ideal selectivity of 77.2 are obtained, which exceed the Robeson upper bound limit. It is inspiring to surpass the upper bound limit via a simple surface modification method.

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Active Edge‐Site‐Rich Carbon Nanocatalysts with Enhanced Electron Transfer for Efficient Electrochemical Hydrogen Peroxide Production

A carbon nanocatalyst that is rich in active edge sites is developed, which shows high activity and selectivity for electrochemical H₂O₂ production. The H₂O₂ production activity surpasses previously reported catalysts in alkaline media, and can sustainably produce H₂O₂ for 16 h with Faradaic efficiency reaching 99 %. The superior activity can be correlated to the enhanced electron transfer capabilities of the (oxygenated) edge‐rich carbon.

Abstract

A highly efficient, metal‐free carbon nanocatalyst is presented that possesses abundant active, oxygenated graphitic edge sites. The edge site‐rich nanocarbon catalyst exhibits about 28 times higher activity for H₂O₂ production than a basal plane‐rich carbon nanotube with a H₂O₂ selectivity over 90 %. The oxidative treatment further promotes the H₂O₂ generation activity to reach close to the thermodynamic limit. The optimized nanocarbon catalyst shows a very high H₂O₂ production activity, surpassing previously reported catalysts in alkaline media. Moreover, it can stably produce H₂O₂ for 16 h with Faradaic efficiency reaching 99 % and accumulated H₂O₂ concentration of 24±2 mm. Importantly, we find that the heterogeneous electron transfer kinetics of the carbon‐based catalyst is closely related to the electrocatalytic activity, suggesting that first outer‐sphere electron transfer to O₂ is an important step governing the H₂O₂ production rate.

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Hydrogen‐Bonding‐Regulated Supramolecular Nanostructures and Impact on Multivalent Binding

Bonded with a purpose: Two bolaamphiphiles consisting of a hydrophobic naphthalene diimide unit connected at one end to a hydrophilic wedge by a H‐bonding group (hydrazide or amide) and at the other to a glucose moiety showed distinct H‐bonding‐regulated behavior with the formation of vesicles or cylindrical micelles (see picture). The adaptive cylindrical micelles formed by amide H‐bonding exhibited superior multivalent binding with concanavalin A.

Abstract

Herein we describe the H‐bonding‐regulated nanostructure, thermodynamics, and multivalent binding of two bolaamphiphiles NDI‐1 and NDI‐2 consisting of a hydrophobic naphthalene diimide connected to a hydrophilic wedge by a H‐bonding group and a glucose moiety on its two arms. NDI‐1 and NDI‐2 differ by the single H‐bonding group, namely, hydrazide or amide, which triggers the formation of vesicles and cylindrical micelles, respectively. Although the extended H‐bonding ensures stacking with head‐to‐head orientation and the formation of an array of the appended glucose moieties in both systems, the adaptive cylindrical structure exhibited superior multivalent binding with concanavalin A (ConA) to that of the vesicle. A control amphiphile lacking a H‐bonding group assembled with a random lateral orientation to produce spherical micelles without any notable multivalent binding.

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Copper‐Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates with Phosphaalkynes to Prepare 1,3‐Azaphospholes

Building bridges: A copper‐catalyzed synthesis of phosphorus‐ and nitrogen‐containing heterocycles is described. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, bis(diphenylphosphino)methane, and potassium carbonate afford the corresponding 1,3‐azaphospholes in high yields with complete selectivity. Dicopper complexes were identified as active species.

Abstract

A novel copper‐catalyzed synthetic method is described for phosphorous‐ and nitrogen‐containing heterocycles such as 1,3‐azaphospholes. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, bis(diphenylphosphino)methane (dppm), and potassium carbonate afford the corresponding 1,3‐azaphospholes in high yields with complete selectivity. Some dppm‐bridged dicopper complexes were identified as active species for the formation of 1,3‐azaphospholes.

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Hydrogenation of Borylated Arenes

No longer flat: A cis‐selective hydrogenation of abundant aryl boronic acids and their derivatives catalyzed by Rh–CAAC is reported. The reaction tolerates a variety of boron‐protecting groups and provides direct access to a broad range of saturated borylated carbo‐ and heterocycles with various functional groups. The utility of these saturated cyclic building blocks was demonstrated by post‐functionalization of the boron group.

Abstract

A cis‐selective hydrogenation of abundant aryl boronic acids and their derivatives catalyzed by rhodium cyclic (alkyl)(amino)carbene (Rh–CAAC) is reported. The reaction tolerates a variety of boron‐protecting groups and provides direct access to a broad scope of saturated, borylated carbo‐ and heterocycles with various functional groups. The transformation is strategically important because the versatile saturated boronate products are difficult to prepare by other methods. The utility of the saturated cyclic building blocks was demonstrated by post‐functionalization of the boron group.

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Effect of Audibility and Suprathreshold Deficits on Speech Recognition for Listeners With Unilateral Hearing Loss

Objectives: We examined the influence of impaired processing (audibility and suprathreshold processes) on speech recognition in cases of sensorineural hearing loss. The influence of differences in central, or top-down, processing was reduced by comparing the performance of both ears in participants with a unilateral hearing loss (UHL). We examined the influence of reduced audibility and suprathreshold deficits on speech recognition in quiet and in noise. Design: We measured speech recognition in quiet and stationary speech-shaped noise with consonant–vowel–consonant words and digital triplets in groups of adults with UHL (n = 19), normal hearing (n = 15), and bilateral hearing loss (n = 9). By comparing the scores of the unaffected ear (UHL+) and the affected ear (UHL−) in the UHL group, we were able to isolate the influence of peripheral hearing loss from individual top-down factors such as cognition, linguistic skills, age, and sex. Results: Audibility is a very strong predictor for speech recognition in quiet. Audibility has a less pronounced influence on speech recognition in noise. We found that, for the current sample of listeners, more speech information is required for UHL− than for UHL+ to achieve the same performance. For digit triplets at 80 dBA, the speech recognition threshold in noise (SRT) for UHL− is on average 5.2 dB signal to noise ratio (SNR) poorer than UHL+. Analysis using the speech intelligibility index (SII) indicates that on average 2.1 dB SNR of this decrease can be attributed to suprathreshold deficits and 3.1 dB SNR to audibility. Furthermore, scores for speech recognition in quiet and in noise for UHL+ are comparable to those of normal-hearing listeners. Conclusions: Our data showed that suprathreshold deficits in addition to audibility play a considerable role in speech recognition in noise even at intensities well above hearing threshold. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. ACKNOWLEDGMENTS: The authors thank all the people who participated in the study, Hans van Beek for technical assistance and software development, and Sabine Engels for proofreading. The authors have no conflicts of interest to disclose. Address for correspondence: S. Theo Goverts, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Otolarynghology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: st.goverts@vumc.nl Received January 10, 2018; accepted October 21, 2018. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Microbial keratitis: Significant increase in Gram-positive bacterial infection

Types of organisms and in-vitro susceptibility of bacterial isolates from patients with microbial keratitis: A trend analysis of 8 years p. 49
Sujata Das, Ruchipriya Samantaray, Aparajita Mallick, Srikant K Sahu, Savitri Sharma
DOI:10.4103/ijo.IJO_500_18  
Purpose: To report the distribution and trends of types of organisms and antibiotic susceptibility of the bacterial isolates obtained from patients with microbial keratitis. Methods: Microbiology records of culture-positive microbial keratitis that underwent a diagnostic corneal scraping and cultures were reviewed. Fungal, bacterial, and parasitic culture results and antibiotic susceptibility profile of bacteria were analyzed and comparisons were made between two halves of the study period (2007–2010 vs. 2011–2014). Results: A total of 3981 corneal scrapings were processed during the 8-year study period. Pathogen was recovered in culture in 1914 (48.1%) samples. Fungi, bacteria, and parasites constituted 38.7%, 60%, and 1.3% of the total isolates, respectively. The common fungal isolates were Aspergillus spp. (224/868, 25.8%) and Fusarium spp. (200/868, 23.0%), while common Gram-positive bacteria were Streptococcus pneumoniae (217/1125, 19.3%) and Staphylococcus aureus (185/1125, 16.4%), and common Gram-negative bacteria was Pseudomonas spp. (99/219, 45.2%). There was no significant difference in proportion of bacterial (P = 0.225) and fungal (P = 0.421) keratitis between the first half and second half of the study period. There was a significant increase in proportion of Gram-positive isolates (P = 0.015) [353/758 (46.6%) vs. 772/1482 (52.1%)] and decrease in proportion of Gram-negative organisms (P = 0.044) [88/758 (11.6%) vs. 131/1482 (8.8%)] in the recent years. In-vitro antibiotic susceptibility testing showed decrease in susceptibility to moxifloxacin for Pseudomonas spp. (P = 0.016) in recent years. Conclusion: Prevalence of fungal and bacterial keratitis has remained unchanged over the years. This study shows a significant increase in Gram-positive bacterial infection and decrease in Gram-negative bacterial infection of the cornea in the recent years.
http://www.ijo.in/currentissue.asp?sabs=y

Giant cell arteritis related arteritic anterior ischemic optic neuropathy

http://www.ijo.in/viewimage.asp?img=IndianJOphthalmol_2019_67_1_142_248176_f1.jpg

: Clinico-pathological correlation

Mohit Dogra, Ramandeep Singh, Mangat R Dogra
Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:

Dr. Mohit Dogra
Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012 
India

DOI: 10.4103/ijo.IJO_881_18

A 63-year-old male presented with sudden painless vision loss in his right eye of 2 day duration. He had no perception of light, Relative afferent pupillary defect (RAPD), pale disc edema along with an inferotemporal branch retinal artery occlusion [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Clinical diagnosis of arteritic anterior ischemic optic neuropathy was made, and systemic examination revealed repeated bouts of fever and right sided scalp tenderness.^[1],[2] Right side temporal artery biopsy revealed giant cell arteritis. The patient was treated with intravenous pulse steroids and immunosuppressive therapy.^[2],[3] In cases of severe vision loss with pale disc edema, giant cell arteritis should be kept in mind.^[4],[5]

Figure 1: (a) showing pale disc edema (blue arrows) with an inferotemporal branch retinal artery occlusion, (b and c) showing "wedge shaped" equatorial choroidal infarcts on fluorescein angiogram, and (d) right side temporal artery biopsy at 200× magnification showing intimal proliferation with breaks in the internal elastic lamina (yellow arrows) with extravasation of red blood cells in the tunica media (black arrow) with minimal inflammatory cells, suggestive of vasculitis Click here to view

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 

References

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2.	Wayand CM, Bartley GB. Giant cell arteritis: New concepts inpathogenesis and implications of management. Am J Ophthalmol1997;123:392-5.
3.	Guevara M, Kollipara CS. Recent advances ingiant cell arteritis. CurrRheumatol Rep 2018;20:25.
4.	HayrehSS. Management of ischaemic optic neuropathy. Indian J Ophthalmol 2011;59:123-36.
5.	Attaseth T, Vanikieti K, Poonyathalang A, Preechawat P, Jindahra P, Wattanatranon D. Anterior ischemic optic neuropathydue tobiopsy-provengiant cell arteritisin Thai patients. ClinOphthalmol 2015;9:1071-5.