Cyclic peptide marine metabolites and CuII

Cyclic pseudo-peptides derived from marine metabolites of the genus Lissoclinum bistratum and Lissoclinum patella have attracted scientific interest in the last two decades. Their structural properties and solution dynamics have been analyzed in detail, elaborate synthetic procedures for the natural products and synthetic derivatives developed, the biosynthetic pathways studied and it now is possible to produce them biosynthetically. Initially, these macrocyclic ligands were studied due to their medicinal and pharmaceutical potential-some of the isolated cyclic pseudo-peptides show high cytotoxic and antiviral activity. A major focus in the last decade has been on their Cu coordination chemistry, as a number of studies have indicated that dinuclear Cu complexes of cyclic peptides may be involved in the ascidians' metabolism, and this is the focus of the present review

Infectious disease outbreaks among forcibly displaced persons: an analysis of ProMED reports 1996-2016

Background: The United Nations Refugee Agency (UNHCR) estimates the number of forcibly displaced people increased from 22.7 million people in 1996 to 67.7 million people in 2016. Human mobility is associated with the introduction of infectious disease pathogens. The aim of this study was to describe the range of pathogens in forcibly displaced populations over time using an informal event monitoring system. Methods: We conducted a retrospective analysis of ProMED, a digital disease monitoring system, to identify reports of outbreak events involving forcibly displaced populations between 1996 and 2016. Number of outbreak events per year was tabulated. Each record was assessed to determine outbreak location, pathogen, origin of persons implicated in the outbreak, and suspected versus confirmed case counts. Results: One hundred twenty-eight independent outbreak events involving forcibly displaced populations were identified. Over 840,000 confirmed or suspected cases of infectious diseases such as measles, cholera, cutaneous leishmaniasis, dengue, and others were reported in 48 destination countries/territories. The average rate of outbreak events concerning forcibly displaced persons per total number of reports published on ProMED per year increased over time. The majority of outbreak events (63%) were due to acquisition of disease in the destination country. Conclusion: This study found that reports of outbreak events involving forcibly displaced populations have increased in ProMED. The events and outbreaks detected in this retrospective review underscore the importance of capturing displaced populations in surveillance systems for rapid detection and response

The Economic Cost of Community-Based Interventions to Improve Breast Cancer Control among African-American Women

A number of intervention strategies to improve the rate of early stage breast cancer detection have been proposed and evaluated. Though good effectiveness data exist, policymakers and medical administrators may be reluctant to implement such interventions because of cost considerations. Few cost-effectiveness analyses have been conducted on culturally-sensitive interventions that increase mammography screening rates or reduce barriers to receiving timely diagnostic testing and treatment for African-American women. This paper discusses an innovative cost effectiveness model, funded by the National Cancer Institute, and presents microeconomic estimates the cost of twelve community-based intervention strategies designed to improve early stage breast cancer detection rates and appropriate follow-up after an abnormal mammogram among African-American women. An innovation in the estimates is to include the value of women’s time. Community-based program costs range from $47 to$161 per patient on an ongoing basis. Same day scheduling of a mammogram with or without patient transportation, public service announcements, physician education, physician audit with feedback, and same day scheduling of a biopsy cost $47-$53 per patient per year on an ongoing basis. Interventions that require fulltime personnel to maintain the program, such as patient reminder letters, theory-based education, physician reminders, and telephone counseling, are more expensive and cost approximately $54-$57 per patient on an ongoing basis. The three most expensive interventions are the mobile mammography van, lay health workers, and church based navigators, costing approximately $67-$161 per patient In conclusion, the added costs of community-based cancer control programs for vulnerable African-American women are small and have the potential to be offset by the gains in quality-adjusted life years saved as a result of detection at an earlier stage of diagnosis and improved follow-up and treatment, particularly among high-risk communities

Idiopathic sclerosing orbital inflammation mimicking a malignant spindle cell tumor in a dog

A dog presented with a retrobulbar mass, diagnosed histopathologically as malignant spindle cell neoplasia. Emergence of analogous findings in the contralateral orbit prompted extended immunohistochemistry of the original mass and reassignment to idiopathic sclerosing orbital inflammation. Early incisional biopsy with extended immunohistochemical analysis should be considered for canine orbital tumors

Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model

BACKGROUND: Even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model. METHODS: In vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10mg/kg using oral gavage and IV at 5 and 1mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n=5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry.In vivo PK: NP046 solutions in water were administered orally (50 and 10mg/kg) and IV (5mg/kg) to male C57BL/6 mice (n=5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046. RESULTS: NP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50mg/kg and 10mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4hours. CONCLUSION: Even though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted

Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair

Carcinogenesis and neoplastic progression are mediated by the accumulation of somatic mutations. Here we report that the local density of somatic mutations in cancer genomes is highly reduced specifically in accessible regulatory DNA defined by DNase I hypersensitive sites. This reduction is independent of any known factors influencing somatic mutation density and is observed in diverse cancer types, suggesting a general mechanism. By analyzing individual cancer genomes1, we show that the reduced local mutation density within regulatory DNA is linked to intact global genome repair machinery, with nearly complete abrogation of the hypomutation phenomenon in individual cancers that possess mutations in multiple nucleotide excision repair components. Together, our results connect chromatin structure, gene regulation and cancer-associated somatic mutation

The TeleStroke Mimic (TM)‐Score: A Prediction Rule for Identifying Stroke Mimics Evaluated in a Telestroke Network

Background: Up to 30% of acute stroke evaluations are deemed stroke mimics (SM). As telestroke consultation expands across the world, increasing numbers of SM patients are likely being evaluated via Telestroke. We developed a model to prospectively identify ischemic SMs during Telestroke evaluation. Methods and Results: We analyzed 829 consecutive patients from January 2004 to April 2013 in our internal New England–based Partners TeleStroke Network for a derivation cohort, and 332 cases for internal validation. External validation was performed on 226 cases from January 2008 to August 2012 in the Partners National TeleStroke Network. A predictive score was developed using stepwise logistic regression, and its performance was assessed using receiver‐operating characteristic (ROC) curve analysis. There were 23% SM in the derivation, 24% in the internal, and 22% in external validation cohorts based on final clinical diagnosis. Compared to those with ischemic cerebrovascular disease (iCVD), SM had lower mean age, fewer vascular risk factors, more frequent prior seizure, and a different profile of presenting symptoms. The TeleStroke Mimic Score (TM‐Score) was based on factors independently associated with SM status including age, medical history (atrial fibrillation, hypertension, seizures), facial weakness, and National Institutes of Health Stroke Scale >14. The TM‐Score performed well on ROC curve analysis (derivation cohort AUC=0.75, internal validation AUC=0.71, external validation AUC=0.77). Conclusions: SMs differ substantially from their iCVD counterparts in their vascular risk profiles and other characteristics. Decision‐support tools based on predictive models, such as our TM Score, may help clinicians consider alternate diagnosis and potentially detect SMs during complex, time‐critical telestroke evaluations

Trauma, Bereavement and Loss : Key Learning and Messages from Research and Practice

Professionals, and wider society, are becoming increasingly aware of the prevalence of traumatic and adverse childhood experiences, and of the potentially enduring and detrimental impact of such experiences on emotional, psychological and physical health and wellbeing. As a result, there is increased policy and practice attention paid to identifying, understanding and addressing trauma and adversity among individuals. Importantly, this attention is not solely focused on trauma-specialist provision for individuals who are known to have experienced trauma, but also on ensuring that the entire workforce is trauma-informed, as outlined in the Transforming Psychological Trauma framework (NHS Education for Scotland, 2017)

The Lantern Vol. 64, No. 1, Fall 1996

• Sleepwalk • Icky • Hauling the Load • Between Days • First Day • Slipping • College Roommates • Full Moon in Scorpio • Summer Madness • Learning French • nEverglades • The Way Around • Rain • Solacehttps://digitalcommons.ursinus.edu/lantern/1149/thumbnail.jp

Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans

Although the process of drug development requires efficacy and toxicity testing in animals prior to human testing, animal models have limited ability to accurately predict human responses to xenobiotics and other insults. Societal pressures are also focusing on reduction of and, ultimately, replacement of animal testing. However, a variety of in vitro models, explored over the last decade, have not been powerful enough to replace animal models. New initiatives sponsored by several US federal agencies seek to address this problem by funding the development of physiologically relevant human organ models on microscopic chips. The eventual goal is to simulate a human-on-a-chip, by interconnecting the organ models, thereby replacing animal testing in drug discovery and development. As part of this initiative, we aim to build a three-dimensional human liver chip that mimics the acinus, the smallest functional unit of the liver, including its oxygen gradient. Our liver-on-a-chip platform will deliver a microfluidic three-dimensional co-culture environment with stable synthetic and enzymatic function for at least 4 weeks. Sentinel cells that contain fluorescent biosensors will be integrated into the chip to provide multiplexed, real-time readouts of key liver functions and pathology. We are also developing a database to manage experimental data and harness external information to interpret the multimodal data and create a predictive platform