bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Mycobacterium tuberculosis lipoarabinomannan antigen assay and rapid serology blood test for the diagnosis of bovine tuberculosis in Ethiopia
Authors: Zewude Aboma , Mohammed Temesgen , Terfassa Lemma , Hunt W. Garrett , Pan Xueliang , Balada-Llasat Joan Miquel , Gebreyes Wondwossen , Torrelles Jordi B. , Wang Shu-Hua , Ameni Gobena
Published: October 2019

Background

Bovine tuberculosis (bTB) is prevalent in dairy cattle in Ethiopia. Currently used diagnostic tools such as the single intradermal comparative tuberculin test (SICTT) are time consuming and labor intensive. A rapid, easy-to-use and cost-effective diagnostic test would greatly contribute to the control of bTB in developing countries like Ethiopia. In the present study, two point-of-care diagnostic tests were evaluated for the detection of bTB: LIONEX® Animal TB Rapid test, a membrane-based test for the detection of antibodies to Mycobacterium bovis in blood and ALERE® Determine TB Lipoarabinomannan (LAM) Ag, an immunoassay for the detection of lipoarabinomannan (LAM) antigen (Ag) of mycobacteria in urine. A combination of the SICTT and gamma interferon (IFN-γ) test was used as the gold standard for the validation of these point-of-care tests, as it was not feasible to slaughter the study animals to carry out the historical gold standard of mycobacterial culture. A total of 175 heads of cattle having three different bTB infection categories (positive SICTT, negative SICTT, and unknown SICTT status) were used for this study.

Result

The sensitivity and specificity of TB LAM Ag were 72.2% (95% CI = 62.2, 80.4) and 98.8% (95% CI = 93.6, 99.7), respectively, while the sensitivity and specificity of the LIONEX Animal TB rapid test assay were 54% (95% CI = 44.1 64.3) and 98.8% (95% CI = 93.6, 99.7) respectively. The agreement between TB LAM Ag and SICTT was higher (κ = 0.85; 95% CI = 0.65–0.94) than between TB LAM Ag and IFN-γ (κ = 0.67; 95% CI = 0.52–0.81). The agreement between LIONEX Animals TB Rapid blood test and SICTT was substantial, (κ = 0.63; 95% CI = 0.49–0.77) while the agreement between LIONEX Animal TB rapid blood test and IFN-γ test was moderate (κ = 0.53; 95% CI = 0.40–0.67). Analysis of receiver operating curve (ROC) indicated that the area under the ROC curve (AUC) for TB LAM Ag was 0.85 (95% CI = 0.79–0.91) while it was 0.76 (95% CI; =0.69–0.83) for LIONEX Animal TB rapid test assay.

Conclusion

This study showed that TB LAM Ag had a better diagnostic performance and could potentially be used as ancillary either to SICTT or IFN-γ test for diagnosis of bTB.
Effect of temperature and time after collection on buck sperm quality
Authors: Hahn Kirsten , Failing Klaus , Wehrend Axel
Published: October 2019

Background

Different parameters are assessed as part of the semen analysis but a standard protocol for evaluation of goat semen is still missing. The aim of this study was to analyse two different factors affecting buck sperm quality in the post-collection period prior to adding the extender. Here we examined the effects of two handling temperatures (20 °C, 37 °C) and various examination time points (3–30 min) after semen collection.

Results

Examination time point had a significant influence on raw sperm viability (p < 0.05), motility (p < 0.05) and on semen pH (p < 0.05). The two different handling temperatures had no significant effect on sperm viability (p > 0.05), motility (p > 0.05), with the exception of fast moving sperm (p = 0.04), or on semen pH (p > 0.05).

Conclusion

Examination time point was identified as factor strongly influencing raw peacock buck semen after collection. Raw goat semen can tolerate room temperatures for at least 10 min without impacting overall semen quality. In order to obtain comparable results, semen samples should always be examined within 10 min after collection.
Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans
Authors: Smith Jennifer A. , Raisky Jeremy , Ratliff Scott M. , Liu Jiaxuan , Kardia Sharon L. R. , Turner Stephen T. , Mosley Thomas H. , Zhao Wei
Published: October 2019

Background

Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries.

Methods

We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996–2000), and measures of target organ damage were assessed in a follow-up visit (2000–2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated.

Results

After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR,p = 0.004), relative wall thickness (RWT,p = 0.022), and left ventricular mass index (LVMI,p = 0.007), and with lower ankle-brachial index (ABI,p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed.

Conclusions

Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.
Development of effective anti-influenza drugs: congeners and conjugates – a review
Authors: Shie Jiun-Jie , Fang Jim-Min
Published: October 2019

Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial
Authors: Clegg Lindsay E. , Penland Robert C. , Bachina Srinivas , Boulton David W. , Thuresson Marcus , Heerspink Hiddo J. L. , Gustavson Stephanie , Sjöström C. David , Ruggles James A. , Hernandez Adrian F. , Buse John B. , Mentz Robert J. , Holman Rury R.
Published: October 2019

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes.

Methods

In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses.

Results

In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m2/year).

Conclusions

This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality.

Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.
Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease
Authors: Kim Mee Kyoung , Han Kyungdo , Joung Han Na , Baek Ki-Hyun , Song Ki-Ho , Kwon Hyuk-Sang
Published: October 2019

Background

The aim of the present study was to identify a threshold for the cholesterol level at which the risk of cardiovascular disease (CVD) begins to increase in people with type 2 diabetes mellitus (DM).

Methods

Using the Korean National Health Insurance Service database, 2,077,135 people aged ≥ 40 years with type 2 DM who underwent regular health checks between 2009 and 2012 were included. Subjects with previous CVD were excluded. Cox regression analyses were performed to estimate the risk of CVD for each low-density lipoprotein cholesterol (LDL-C) group using the < 70 mg/dL as the reference group.

Results

There were 78,560 cases of stroke (3.91%), and 50,791 myocardial infarction (MI, 2.53%) during a median follow-up of 7.1 years. Among participants not taking statins, LDL-C levels of 130–159 mg/dL and ≥ 160 mg/dL were significantly associated with the risk of MI: the hazard ratios (HRs) (95% confidence interval) were 1.19 (1.14–1.25) and 1.53 (1.46–1.62), respectively. Among participants taking statins, all categories of LDL-C level ≥ 70 mg/dL were significantly associated with increased risk of stroke and MI.

Conclusions

We identified an increased risk of CVD in people with an LDL-C level ≥ 130 mg/dL among individuals with type 2 DM not taking statins. The risk of CVD was significantly higher in those taking statins with an LDL-C level ≥ 70 mg/dL.
Upregulation of FNDC5 gene expression in C2C12 cells after single and combined treatments of resveratrol and ATRA
Authors: Abedi-Taleb Elahe , Vahabi Zahra , Sekhavati-Moghadam Ehsan , Khedmat Leila , Jazayeri Shima , Saboor-Yaraghi Ali Akbar
Published: October 2019

Background

Irisin is a newly discovered myokine that secreted from skeletal muscle cells. Several studies showed that irisin involves in thermogenesis and increases the expression of browning markers such as uncoupling protein-1 that in turns induces the conversion of white adipose tissue to brown fat. Resveratrol (Res) and all-trans retinoic acid (ATRA) can also upregulate the expression of thermogenesis genes. In the present study, the effects of single and combined treatments of Res and ATRA on fibronectin type III domain containing 5 (FNDC5) gene expression was explored.

Methods

The mouse myoblasts, C2C12 cells, were seeded in 6-well plastic plates and cultured in DMEM media. After differentiation, in a pilot study, C2C12 myotubes were treated with different concentrations of Res and ATRA for 12 h. The best result was obtained by treatment of 1and 25 μM of Res and 1 μM of ATRA. Then the main study was continued by single and combined treatment of these compounds at chosen concentration. After treatments, total RNA was extracted from C2C12 cells. Complementary DNA (cDNA) was generated by the cDNA synthesis kit and FNDC5 mRNA expression was evaluated by the real-time PCR method.

Results

The FNDC5 gene expression in C2C12 myotubes of alone-treated with 1 μM, 25 μM Res and 10 μM ATRA did not change compared to vehicle group. However, in combination-treated the expression of FNDC5 gene was significantly increased compared to vehicle group.

Conclusion

This is the first evidence that Res and ATRA can regulate FNDC5 gene expression in C2C12 myotubes. More investigations are necessary to explore the therapeutic effects of these nutrients in obesity, diabetes, cardiac and neurovascular disease.
Potential molecular mechanism of ACE gene at different time points in STEMI patients based on genome-wide microarray dataset
Authors: Guan Yao-Zong , Yin Rui-Xing , Zheng Peng-Fei , Deng Guo-Xiong , Liu Chun-Xiao , Wei Bi-Liu
Published: October 2019

Background

This study aimed to investigate the angiotensin converting enzyme (ACE) co-expression genes and their pathways involved in ST-segment elevation myocardial infarction (STEMI) at different time points.

Methods

The array data set of GSE59867 was examined for the ACE co-expression genes in peripheral blood samples from 111 patients with STEMI at four time points (admission, discharge, and 1 and 6 months after MI). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene Ontology (GO) annotation and protein-protein interaction (PPI) of the co-expression genes were determined using online analytical tools. The Cytoscape software was used to create modules and hub genes.

Results

The number of biological processes (BP), cellular components (CC) and molecular functions (MF) was 43, 22 and 24 at admission; 18, 19 and 11 at discharge; 30, 37 and 21 at 1 month after MI; and 12, 19 and 14 at 6 months after MI; respectively. There were 6 BP, 8 CC and 4 MF enriched at every time point. The co-expression genes were substantially enriched in 12, 5, 6 and 14 KEGG pathways at the four time points, respectively, but no KEGG pathway was found to be common in all time points. We identified 132 intersectional co-expression genes (90 positive and 42 negative) from the four time points and 17 BP, 13 CC, 11 MF and 7 KEGG pathways were enriched. In addition, the PPI network contained 129 nodes and 570 edges, and only 1 module was identified to be significantly enriched in just 1 BP (chromatin-mediated maintenance of transcription).

Conclusions

The results of the present study showed that the ACE co-expression genes and their pathways involved in STEMI were significantly different at four different time points. These findings may be helpful for further understanding the functions and roles of ACE in different stages of STEMI, and providing reference for the treatment of STEMI.
Associations between dietary micronutrient intake and molecular-Bacterial Vaginosis
Authors: Tuddenham Susan , Ghanem Khalil G. , Caulfield Laura E. , Rovner Alisha J. , Robinson Courtney , Shivakoti Rupak , Miller Ryan , Burke Anne , Murphy Catherine , Ravel Jacques , Brotman Rebecca M.
Published: October 2019

Objectives

Bacterial vaginosis (BV), a clinical condition characterized by decreased vaginal Lactobacillus spp., is difficult to treat. We examined associations between micronutrient intake and a low-Lactobacillus vaginal microbiota as assessed by molecular methods (termed “molecular-BV”).

Methods

This cross-sectional analysis utilized data collected at the baseline visit of the Hormonal Contraception Longitudinal Study, a cohort of reproductive-aged women followed over 2 years while initiating or ceasing hormonal contraception (HC). The Block Brief 2000 Food Frequency Questionnaire was administered and micronutrient intakes were ranked. Vaginal microbiota composition was assessed using 16S rRNA gene amplicon sequencing and clustered into community state types (CSTs) based on the types and relative abundance of bacteria detected. Associations between the lowest estimated quartile intake of nutrients and having a low-Lactobacillus CST (molecular-BV) were evaluated by logistic regression. Separate models were built for each nutrient controlling for age, body mass index, behavioral factors, HC use and total energy intake. We also conducted a literature review of existing data on associations between micronutrient intakes and BV.

Results

Samples from 104 women were included in this analysis. Their mean age was 25.8 years (SD 4.3), 29.8% were African American, 48.1% were using HC, and 25% had molecular-BV. In adjusted multivariable analyses, the lowest quartile of betaine intake was associated with an increased odds of molecular-BV (aOR 9.2, p value < 0.01, [CI 2.4–35.0]).

Conclusions

This is the first study to assess the association between estimated micronutrient intake and molecular-BV. Lower energy-adjusted intake of betaine was associated with an increased risk of molecular-BV. Betaine might have direct effects on the vaginal microenvironment or may be mediated through the gut microbiota. Additional research is needed to determine reproducibility of this finding and whether improved intake of select micronutrients such as betaine decreases the risk of BV and its sequelae.
Phenotyping viral infection in sweetpotato using a high-throughput chlorophyll fluorescence and thermal imaging platform
Authors: Wang Linping , Poque Sylvain , Valkonen Jari P. T.
Published: October 2019

Background

Virus diseases caused by co-infection with Sweet potato feathery mottle virus (SPFMV) and Sweetpotato chlorotic stunt virus (SPCSV) are a severe problem in the production of sweetpotato (Ipomoea batatas L.). Traditional molecular virus detection methods include nucleic acid-based and serological tests. In this study, we aimed to validate the use of a non-destructive imaging-based plant phenotype platform to study plant-virus synergism in sweetpotato by comparing four virus treatments with two healthy controls.

Results

By monitoring physiological and morphological effects of viral infection in sweetpotato over 29 days, we quantified photosynthetic performance from chlorophyll fluorescence (ChlF) imaging and leaf thermography from thermal infrared (TIR) imaging among sweetpotatoes. Moreover, the differences among different treatments observed from ChlF and TIR imaging were related to virus accumulation and distribution in sweetpotato. These findings were further validated at the molecular level by related gene expression in both photosynthesis and carbon fixation pathways.

Conclusion

Our study validated for the first time the use of ChlF- and TIR-based imaging systems to distinguish the severity of virus diseases related to SPFMV and SPCSV in sweetpotato. In addition, we demonstrated that the operating efficiency of PSII and photochemical quenching were the most sensitive parameters for the quantification of virus effects compared with maximum quantum efficiency, non-photochemical quenching, and leaf temperature.
Analysis of economic burden and its associated factors of twenty-three rare diseases in Shanghai
Authors: Cai Xiaoshu , Yang Hui , Genchev Georgi Z. , Lu Hui , Yu Guangjun
Published: October 2019

Background

It is estimated that at present there are over 10 million rare disease patients in China. Recently an increased focus from policy perspective has been placed on rare diseases management. Improved disease definitions and the releases of local and national rare disease lists are some of the steps taken already. Despite these developments, few Chinese rare disease-related epidemiology and economic studies exist, thus hindering assessment of the true burden of rare diseases. For a rare disease with an effective treatment, this is a particularly important aspect due to the often-high cost associated.

Objective

The goal of this study is to address the data scarcity on the subject of rare diseases economic impact in China. We aim to address an existing knowledge gap and to provide a timely analysis of the economic burden of 23 rare diseases in Shanghai, China.

Methods

We utilized the data from the Health Information Exchange system of Shanghai and employed statistical modeling to analyze the economic burden of rare diseases with an effective treatment in Shanghai.

Results

First, we described the actual direct medical expenditure and analyzed its associated factors. Second, we found age, disease type, number of complications, and payment type were significantly associated with rare disease medical direct costs. Third, a generalized linear model was employed to estimate the annual direct cost. The mean direct medical cost was estimated as ¥9588 (US$1521) for inpatients and ¥1060 (US$168) for outpatients, and was over ¥15 million (~US$2.4 million) per year overall.

Conclusion

Our study is one of the first quantifying the economic burden of an extensive set of rare diseases in Shanghai and China. Our results can serve to inform healthcare-focused policy making, contribute to the increase of public awareness, and incentivize development of rare-disease strategies and treatments specific to the Chinese context.
Unsuccessful intravenous D-mannose treatment in PMM2-CDG
Authors: Grünert Sarah C. , Marquardt Thorsten , Lausch Ekkehart , Fuchs Hans , Thiel Christian , Sutter Martin , Schumann Anke , Hannibal Luciana , Spiekerkoetter Ute
Published: October 2019

Background

PMM2-CDG (Phosphomannomutase 2 - Congenital disorder of glycosylation-Ia; CDG-Ia) is the most common glycosylation defect, often presenting as a severe multisystem disorder that can be fatal within the first years of life. While mannose treatment has been shown to correct glycosylation in vitro and in vivo in mice, no convincing effects have been observed in short-term treatment trials in single patients so far.

Results

We report on a boy with a severe PMM2-CDG who received a continuous intravenous mannose infusion over a period of 5 months during the first year of life in a dose of 0.8 g/kg/day. N-glycosylation of serum glycoproteins and mannose concentrations in serum were studied regularly. Unfortunately, no biochemical or clinical improvement was observed, and the therapy was terminated at age 9 months.

Conclusion

Postnatal intravenous D-mannose treatment seems to be ineffective in PMM2-CDG.
Current concepts of perioperative monitoring in high-risk surgical patients: a review
Authors: Aseni Paolo , Orsenigo Stefano , Storti Enrico , Pulici Marco , Arlati Sergio
Published: October 2019

A substantial number of patients are at high-risk of intra- or post-operative complications or both. Most perioperative deaths are represented by patients who present insufficient physiological reserve to meet the demands of major surgery. Recognition and management of critical high-risk surgical patients require dedicated and effective teams, capable of preventing, recognize, start treatment with adequate support in time to refer patients to the satisfactory ICU level provision. The main task for health-care planners and managers is to identify and reduce this severe risk and to encourage patient’s safety practices. Inadequate tissue perfusion and decreased cellular oxygenation due to hypovolemia, heart dysfunction, reduced cardiovascular reserve, and concomitant diseases are the most common causes of perioperative complications. Hemodynamic, respiratory and careful sequential monitoring have become essential aspects of the clinical practice both for surgeons and intensivists. New monitoring techniques have changed significantly over the past few years and are now able to rapidly identify shock states earlier, define the etiology, and monitor the response to different therapies. Many of these techniques are now minimally invasive or non-invasive. Advanced hemodynamic and respiratory monitoring combines invasive, non-invasive monitoring skills. Non-invasive ultrasound has emerged during the last years as an essential operative and perioperative evaluation tool, and its use is now rapidly growing. Perioperative management guided by appropriate sequential clinical evaluation combined with respiratory and hemodynamic monitoring is an established tool to help clinicians to identify those patients at higher risk in the attempt to reduce the complications rate and potentially improve patient outcomes. This review aims to provide an update of currently available standard concepts and evolving technologies of the various respiratory and hemodynamic monitoring systems for the high-risk surgical patients, highlighting their potential usefulness when integrated with careful clinical evaluation.
Myeloid-derived suppressor cells in hematological malignancies: friends or foes
Authors: Lv Meng , Wang Ke , Huang Xiao-jun
Published: October 2019

Myeloid-derived suppressor cells (MDSCs) are newly identified immature myeloid cells that are characterized by the ability to suppress immune responses and expand during cancer, infection, and inflammatory diseases. Although MDSCs have attracted a lot of attention in the field of tumor immunology in recent years, little is known about their multiple roles in hematological malignancies as opposed to their roles in solid tumors. This review will help researchers better understand the various characteristics and functions of MDSCs, as well as the potential therapeutic applications of MDSCs in hematological malignancies, including lymphoma, multiple myeloma, leukemia, and hematopoietic stem cell transplantation.
A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer
Authors: Wang Jinhua , Xing Yajing , Wang Yingying , He Yundong , Wang Liting , Peng Shihong , Yang Lianfang , Xie Jiuqing , Li Xiaotao , Qiu Wenwei , Yi Zhengfang , Liu Mingyao
Published: October 2019

Background

Cancer-initiating cell (CIC), a functionally homogeneous stem-like cell population, is resonsible for driving the tumor maintenance and metastasis, and is a source of chemotherapy and radiation-therapy resistance within tumors. Targeting CICs self-renewal has been proposed as a therapeutic goal and an effective approach to control tumor growth. BMI-1, a critical regulator of self-renewal in the maintenance of CICs, is identified as a potential target for colorectal cancer therapy.

Methods

Colorectal cancer stem-like cell lines HCT116 and HT29 were used for screening more than 500 synthetic compounds by sulforhodamine B (SRB) cell proliferation assay. The candidate compound was studied in vitro by SRB cell proliferation assay, western blotting, cell colony formation assay, quantitative real-time PCR, flow cytometry analysis, and transwell migration assay. Sphere formation assay and limiting dilution analysis (LDA) were performed for measuring the effect of compound on stemness properties. In vivo subcutaneous tumor growth xenograft model and liver metastasis model were performed to test the efficacy of the compound treatment. Student’s t test was applied for statistical analysis.

Results

We report the development and characterization of a small molecule inhibitor QW24 against BMI-1. QW24 potently down-regulates BMI-1 protein level through autophagy-lysosome degradation pathway without affecting the BMI-1 mRNA level. Moreover, QW24 significantly inhibits the self-renewal of colorectal CICs in stem-like colorectal cancer cell lines, resulting in the abrogation of their proliferation and metastasis. Notably, QW24 significantly suppresses the colorectal tumor growth without obvious toxicity in the subcutaneous xenograft model, as well as decreases the tumor metastasis and increases mice survival in the liver metastasis model. Moreover, QW24 exerts a better efficiency than the previously reported BMI-1 inhibitor PTC-209.

Conclusions

Our preclinical data show that QW24 exerts potent anti-tumor activity by down-regulating BMI-1 and abrogating colorectal CICs self-renewal without obvious toxicity in vivo, suggesting that QW24 could potentially be used as an effective therapeutic agent for clinical colorectal cancer treatment.
Robust taxonomic classification of uncharted microbial sequences and bins with CAT and BAT
Authors: von Meijenfeldt F. A. Bastiaan , Arkhipova Ksenia , Cambuy Diego D. , Coutinho Felipe H. , Dutilh Bas E.
Published: October 2019

Current-day metagenomics analyses increasingly involve de novo taxonomic classification of long DNA sequences and metagenome-assembled genomes. Here, we show that the conventional best-hit approach often leads to classifications that are too specific, especially when the sequences represent novel deep lineages. We present a classification method that integrates multiple signals to classify sequences (Contig Annotation Tool, CAT) and metagenome-assembled genomes (Bin Annotation Tool, BAT). Classifications are automatically made at low taxonomic ranks if closely related organisms are present in the reference database and at higher ranks otherwise. The result is a high classification precision even for sequences from considerably unknown organisms.
Comparison of cytosine base editors and development of the BEable-GPS database for targeting pathogenic SNVs
Authors: Wang Ying , Gao Runze , Wu Jing , Xiong Yi-Chun , Wei Jia , Zhang Sipin , Yang Bei , Chen Jia , Yang Li
Published: October 2019

A variety of base editors have been developed to achieve C-to-T editing in different genomic contexts. Here, we compare a panel of five base editors on their C-to-T editing efficiencies and product purity at commonly editable sites, including some human pathogenic C-to-T mutations. We further profile the accessibilities of 20 base editors to all possible pathogenic mutations in silico. Finally, we build the BEable-GPS (Base Editable prediction of Global Pathogenic SNVs) database for users to select proper base editors to model or correct disease-related mutations. The in vivo comparison and in silico profiling catalog the availability of base editors and their broad applications in biomedical studies.
Susceptibility to insecticides and resistance mechanisms in three populations of Aedes aegypti from Peru
Authors: Pinto Jesus , Palomino Miriam , Mendoza-Uribe Leonardo , Sinti Carmen , Liebman Kelly A. , Lenhart Audrey
Published: October 2019

Background

Epidemics of dengue, chikungunya and Zika are a growing threat to areas whereAedes aegyptiare present. The efficacy of chemical control ofAe. aegyptiis threatened by the increasing frequency of insecticide resistance. The objective of this study was to determine the susceptibility status as well as the biochemical and molecular mechanisms underlying insecticide resistance in three populations ofAe. aegyptiin high risk areas of dengue, chikungunya, and Zika in Peru.

Methods

Bioassays were conducted on adultAe. aegyptito evaluate their susceptibility to insecticides used currently or historically for mosquito control in Peru, including six pyrethroids, three organophosphates and one organochlorine, in populations ofAe. aegyptifrom the districts of Chosica (Department of Lima), Punchana (Department of Loreto) and Piura (Department of Piura). Resistance mechanisms were determined by biochemical assays to assess activity levels of key detoxification enzyme groups (nonspecific esterases, multi-function oxidases, glutathione S-transferases and insensitive acetylcholinesterase). Real-time PCR assays were used to detect twokdrmutations (V1016I and F1534C) on the voltage-gated sodium channel gene.

Results

Resistance to DDT was detected in all three populations, and resistance to pyrethroids was detected in all populations except the population from Chosica, which still exhibited susceptibility to deltamethrin. Resistance to organophosphates was also detected, with the exception of populations from Punchana and Piura, which still demonstrated susceptibility to malathion. In general, no increase or alteration of activity of any enzyme group was detected. Both 1016I and 1534C alleles were detected in Punchana and Piura, while only the 1534C allele was detected in Chosica.

Conclusions

The results suggest that resistance to multiple classes of insecticides exist in areas important toAe. aegypti-borne disease transmission in Peru. The F1534C mutation was present in all 3 populations and the V1016I mutation was present in 2 populations. To our knowledge, this is the first report of the presence of 1016I and 1534C inAe. aegyptiin Peru. The absence of highly elevated enzymatic activity suggests that target site resistance is a key mechanism underlying insecticide resistance in these populations, although further research is needed to fully understand the role of metabolic resistance mechanisms in these populations.
Impact of a single round of mass drug administration with azithromycin on active trachoma and ocular Chlamydia trachomatis prevalence and circulating strains in The Gambia and Senegal
Authors: Harding-Esch Emma M. , Holland Martin J. , Schémann Jean-François , Sillah Ansumana , Sarr Boubacar , Christerson Linus , Pickering Harry , Molina-Gonzalez Sandra , Sarr Isatou , Andreasen Aura A. , Jeffries David , Grundy Chris , Mabey David C. W. , Herrmann Bjorn , Bailey Robin L.
Published: October 2019

Background

Mass drug administration (MDA) with azithromycin is a cornerstone of the trachoma elimination strategy. Although the global prevalence of active trachoma has declined considerably, prevalence persists or even increases in some communities and districts. To increase understanding of MDA impact, we investigated the prevalence of active trachoma and ocular C. trachomatis prevalence, organism load, and circulating strains at baseline and one-year post-MDA in The Gambia and Senegal.

Methods

Pre- and one-year post-MDA, children aged 0–9 years were examined for clinical signs of trachoma in six Gambian and 12 Senegalese villages. Ocular swabs from each child’s right conjunctiva were tested for evidence of ocular C. trachomatis infection and organism load (ompA copy number), and ompA and multi-locus sequence typing (MLST) was performed.

Results

A total of 1171 children were examined at baseline and follow-up in The Gambia. Active trachoma prevalence decreased from 23.9% to 17.7%, whereas ocular C. trachomatis prevalence increased from 3.0% to 3.8%. In Senegal, 1613 and 1771 children were examined at baseline and follow-up, respectively. Active trachoma prevalence decreased from 14.9% to 8.0%, whereas ocular C. trachomatis prevalence increased from 1.8% to 3.6%. Higher organism load was associated with having active trachoma and severe inflammation. Sequence typing demonstrated that all Senegalese samples were genovar A, whereas Gambian samples were a mix of genovars A and B. MLST provided evidence of clustering at village and household levels and demonstrated differences of strain variant frequencies in Senegal, indicative of an “outbreak”. MLST, including partial ompA typing, provided greater discriminatory power than complete ompA typing.

Conclusions

We found that one round of MDA led to an overall decline in active trachoma prevalence but no impact on ocular C. trachomatis infection, with heterogeneity observed between villages studied. This could not be explained by MDA coverage or number of different circulating strains pre- and post-MDA. The poor correlation between active trachoma and infection prevalence supports the need for further work on alternative indicators to clinical signs for diagnosing ocular C. trachomatis infection. MLST typing has potential molecular epidemiology utility, including better understanding of transmission dynamics, although relationship to whole-genome sequence variability requires further exploration.
Freshwater snails of biomedical importance in the Niger River Valley: evidence of temporal and spatial patterns in abundance, distribution and infection with Schistosoma spp.
Authors: Rabone Muriel , Wiethase Joris Hendrik , Allan Fiona , Gouvras Anouk Nathalie , Pennance Tom , Hamidou Amina Amadou , Webster Bonnie Lee , Labbo Rabiou , Emery Aidan Mark , Garba Amadou Djirmay , Rollinson David
Published: October 2019

Background

Sound knowledge of the abundance and distribution of intermediate host snails is key to understanding schistosomiasis transmission and to inform effective interventions in endemic areas.

Methods

A longitudinal field survey of freshwater snails of biomedical importance was undertaken in the Niger River Valley (NRV) between July 2011 and January 2016, targeting Bulinus spp. and Biomphalaria pfeifferi (intermediate hosts of Schistosoma spp.), and Radix natalensis (intermediate host of Fasciola spp.). Monthly snail collections were carried out in 92 sites, near 20 localities endemic for S. haematobium. All bulinids and Bi. pfeifferi were inspected for infection with Schistosoma spp., and R. natalensis for infection with Fasciola spp.

Results

Bulinus truncatus was the most abundant species found, followed by Bulinus forskalii, R. natalensis and Bi. pfeifferi. High abundance was associated with irrigation canals for all species with highest numbers of Bulinus spp. and R. natalensis. Seasonality in abundance was statistically significant in all species, with greater numbers associated with dry season months in the first half of the year. Both B. truncatus and R. natalensis showed a negative association with some wet season months, particularly August. Prevalences of Schistosoma spp. within snails across the entire study were as follows: Bi. pfeifferi: 3.45% (79/2290); B. truncatus: 0.8% (342/42,500); and B. forskalii: 0.2% (24/11,989). No R. natalensis (n = 2530) were infected. Seasonality of infection was evident for B. truncatus, with highest proportions shedding in the middle of the dry season and lowest in the rainy season, and month being a significant predictor of infection. Bulinus spp. and Bi. pfeifferi showed a significant correlation of snail abundance with the number of snails shedding. In B. truncatus, both prevalence of Schistosoma spp. infection, and abundance of shedding snails were significantly higher in pond habitats than in irrigation canals.

Conclusions

Evidence of seasonality in both overall snail abundance and infection with Schistosoma spp. in B. truncatus, the main intermediate host in the region, has significant implications for monitoring and interrupting transmission of Schistosoma spp. in the NRV. Monthly longitudinal surveys, representing intensive sampling effort have provided the resolution needed to ascertain both temporal and spatial trends in this study. These data can inform planning of interventions and treatment within the region.
Bacillus pumilus probiotic feed supplementation mitigates Lawsonia intracellularis shedding and lesions
Authors: Opriessnig Tanja , Karuppannan Anbu K. , Beckler Dana , Ait-Ali Tahar , Cubas-Atienzar Ana , Halbur Patrick G.
Published: October 2019

The causative agent of ileitis, Lawsonia intracellularis, is commonly associated with diarrhea and reduced weight gain in growing pigs. The effect of in-feed probiotics on L. intracellularis infection dynamics was evaluated. In brief, 70 2.5-week-old-pigs were randomly divided into six groups with 10–20 pigs each. All pigs were fed an age appropriate base ration for the duration of the study, which was supplemented with one of three Bacillus strains including B. amyloliquefaciens (T01), B. licheniformis (T02) and B. pumilus (T03). Another group was orally vaccinated with a commercial live L. intracellularis vaccine (VAC) at 3 weeks of age. At 7 weeks of age, T01-LAW, T02-LAW, T03-LAW, VAC-LAW and the POS-CONTROL groups were challenged with L. intracellularis while the NEG-CONTROL pigs were not challenged. All pigs were necropsied 16 days later. By the time of inoculation, all VAC-LAW pigs had seroconverted and at necropsy 10–65% of the pigs in all other challenged groups were also seropositive. The results indicate a successful L. intracellularis challenge with highest bacterial DNA levels in POS-CONTROL pigs, VAC-LAW pigs and T01-LAW pigs. There was a delay in onset of shedding in T02-LAW and T03-LAW groups, which was reflected in less severe macroscopic and microscopic lesions, reduced intralesional L. intracellularis antigen levels and a lower area under the curve for bacterial shedding. Under the study conditions, two of the probiotics tested suppressed L. intracellularis infection. The obtained findings show the potential of probiotics in achieving antibiotic-free control of L. intracellularis.
A case report of severe nasal ischemia from cold agglutinin disease and a novel treatment protocol including HBOT
Authors: Kohlert Scott , McLean Laurie , Scarvelis Dimitrios , Thompson Calvin
Published: October 2019

Cold agglutinin disease (CAD) is a rare condition leading to blood agglutination and autoimmune hemolytic anemia. Cutaneous ischemia resulting from CAD in the head and neck is uncommon. Treatment regimens and outcomes vary widely in the literature and no clear protocol exists. This manuscript describes a patient with CAD who developed severe ischemia of the nose that resolved completely without sequellae following a medical regimen of aspirin, low molecular weight heparin, nitroglycerin ointment and hyperbaric oxygen therapy (HBOT). To our knowledge, this is the first reported case where nitroglycerin ointment or HBOT was successfully employed in the treatment of this complication.
Differences in patients derived from otolaryngology and other specialties with sleep apnea
Authors: Salas Constanza , Dreyse Jorge , Contreras Andrea , Nazar Gonzalo , Astorquiza Constanza , Cabezon Rodrigo , Labarca Gonzalo , Jorquera Jorge
Published: October 2019

Background

Snoring is a main concern in patients who consult an otolaryngologist (ENT physicians) and patients who have cardiovascular comorbidities or excessive daytime sleepiness who usually consult with other specialists. The aim of this study was to describe the clinical differences in patients with obstructive sleep apnea (OSA) referred from ENT or other specialists.

Methods

A prospective study was carried out between June 2015 and July 2018 in a tertiary center. We included patients with suspected OSA referred by the Home Sleep Apnea Test (HSAT) from different specialties such as ENT or other specialties. The main outcome measures of our study were demographic characteristics, clinical characteristics, sleep questionnaire results and HSAT results between OSA patients referred from ENT or other specialists. We used a t-test and chi-squared test for analysis. The diagnostic accuracy of the sleep questionnaires was achieved using receiver operating characteristic (ROC) curve and the area under the curve (AUC).

Results

A total of 481 patients were included. OSA was occurred in 82.4% of the subjects (90 in ENT and 306 in other specialties). Patients with OSA referred from other specialists were older than ENT patients (55 ± 13 vs 44 ± 12; p < 0.001), there was more obesity (IMC 31 ± 5.0 vs 28.7 ± 3.8; p < 0,001), a larger neck circumference (42.2 cm ± 3.7 vs 40.6 cm ± 3.0; p < 0.001) and more reported comorbidities (p < 0.001). ENT patients reported mild OSA (46% vs 31%, p = 0.015) and more positional apnea (62% vs 39%, p = 0.002). In this group, the STOP-BANG questionnaire showed an AUC 0.695 vs AUC 0.804, and for sensitivity, the best cutoff was 4 points. Patients referred from otorhinolaryngology are different from those referred from other specialties. Clinical evaluation and screening of OSA should be patient-centered according to these clinical findings.
Laparoscopic transhiatal suture closure for spontaneous esophageal rupture: a case report
Authors: Hayakawa Shunsuke , Mitsui Akira , Kato Yuko , Morimoto Shota , Watanabe Kaori , Shamoto Tomonari , Wakasugi Takehiro , Kuwabara Yoshiyuki
Published: October 2019

Background

Spontaneous esophageal rupture is a rare but serious disease with high mortality. Conservative treatment and endoscopic therapy have been reported, but surgical treatment is still a basic modality of therapy. In addition to thoracotomy, recent studies have reported treatment with thoracoscopic surgery and laparoscopic transhiatal repair. In this study, we report a patient who underwent laparoscopic transhiatal suture closure for spontaneous esophageal rupture with favorable postoperative course. We also discuss indication for laparoscopic surgery for spontaneous esophageal rupture.

Case presentation

A 70-year-old man visited our hospital with chief complaints of epigastric pain and vomitus niger. He was diagnosed with spontaneous esophageal rupture in the left wall of the lower esophagus by computed tomography and upper gastrointestinal (GI) series. At 11 h after the onset of symptoms, we performed laparoscopic transhiatal suture closure and lavage drainage. We performed transhiatal esophageal replacement using the 5-hole approach. We observed a perforation of 2 cm in diameter at the site of the rostral portion approximately 4 cm from the esophageal hiatus. All layers were closed with three stitches using 3–0 absorbable sutures. No perforation was observed in the thoracic cavity. The total operative time was 178 min, and total bleeding was 2 ml. He had no postoperative complications and was discharged on day 15 after the procedure. He received continuous proton pump inhibitor therapy as an outpatient. Healing cicatrization was found at the site of rupture by esophagogastroscopy. The patient was advised to improve his lifestyle and has shown no signs of recurrence over 2 years from the date of surgery.

Conclusions

Simple closure of all the layers using laparoscopic transhiatal simple closure was useful in the treatment of esophageal rupture as a less invasive approach for patients who meet the following conditions: stable general condition, intrathoracic perforation, and the perforation site is identified as the lower esophagus by pre-operative examination.