bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear magnetic resonance‐based metabolomics reveals similar metabolomics profiles in undifferentiated peripheral spondyloarthritis and reactive arthritis
Authors: Ahmed Sakir , Dubey Durgesh , Chowdhury Abhra , Chaurasia Smriti , Guleria Anupam , Kumar Sandeep , Singh Rajeev , Kumar Dinesh , Misra Ramnath
Published: February 2019

Introduction

After exclusion of reactive, psoriatic and enteritis‐associated arthritis, a group of “undifferentiated” peripheral spondyloarthritis (pSpA) remains. This group shares genetics, T‐cell repertoire, and cytokines with reactive arthritis (ReA). ReA is preceded by gut or urogenital infection. Otherwise the two may be similar. We know little of the metabolic pathways driving undifferentiated pSpA or ReA. Nuclear magnetic resonance (NMR)‐based metabolomics presents a hypothesis‐free approach to study and compare metabolic pathways driving undifferentiated pSpA and ReA.

Methods

Serum and synovial fluid metabolomes of 19 ReA and 13 undifferentiated pSpA, and serum metabolome of 18 controls were profiled using 1H‐based NMR. Partial least square‐discriminant analysis (PLS‐DA) identified metabolites different in patients as compared to controls. Multivariate analysis confirmed these. Altered metabolic pathways were identified using metabolites set enrichment analysis (MSEA). The serum and synovial fluid metabolomes of ReA and undifferentiated pSpA were compared.

Results

Ten serum metabolites of ReA/undifferentiated pSpA were different from those of controls. Six metabolites were different between serum and synovial fluid of these patients. MSEA identified five pathways different between patients and controls, and five pathways different between serum and synovial fluid of patients. PLS‐DA showed no difference between the metabolomes of serum or of synovial fluid between ReA and undifferentiated pSpA.

Discussion

Identified metabolic pathways may be explored further to understand the pathogenesis and to target therapeutics. The similar immuno‐metabolic pathways suggest similar pathogenesis of ReA and undifferentiated pSpA. Thus, they should be studied as a single disease entity.
Cyanophage MazG is a pyrophosphohydrolase but unable to hydrolyse magic spot nucleotides
Authors: Rihtman Branko , Bowman‐Grahl Sabine , Millard Andrew , Corrigan Rebecca M. , Clokie Martha R. J. , Scanlan David J.
Published: February 2019

Bacteriophage possess a variety of auxiliary metabolic genes of bacterial origin. These proteins enable them to maximize infection efficiency, subverting bacterial metabolic processes for the purpose of viral genome replication and synthesis of the next generation of virion progeny. Here, we examined the enzymatic activity of a cyanophage MazG protein – a putative pyrophosphohydrolase previously implicated in regulation of the stringent response via reducing levels of the central alarmone molecule (p)ppGpp. We demonstrate, however, that the purified viral MazG shows no binding or hydrolysis activity against (p)ppGpp. Instead, dGTP and dCTP appear to be the preferred substrates of this protein, consistent with a role preferentially hydrolysing deoxyribonucleotides from the high GC content host Synechococcus genome. This showcases a new example of the fine‐tuned nature of viral metabolic processes.
Clinical and computed tomography characteristics of non‐small cell lung cancer with ALK gene rearrangement: Comparison with EGFR mutation and ALK/EGFR‐negative lung cancer
Authors: Mori Mio , Hayashi Hideyuki , Fukuda Minoru , Honda Sumihisa , Kitazaki Takeshi , Shigematsu Kazuto , Matsuyama Naohiro , Otsubo Mayumi , Nagayasu Takeshi , Hashisako Mikiko , Tabata Kazuhiro , Uetani Masataka , Ashizawa Kazuto
Published: February 2019

Background

The study was conducted to evaluate the clinical and computed tomography (CT) findings of non‐small cell lung cancer (NSCLC) patients to distinguish between ALK gene rearrangement, EGFR mutation, and non‐ALK/EGFR (no genetic abnormalities).

Methods

We enrolled 201 patients with primary NSCLC who had undergone molecular testing for both ALK gene rearrangement and EGFR mutation. The clinical features and CT findings of the main lesion and associated pulmonary abnormalities were investigated.

Results

Female gender (P = 0.0043 vs. non‐ALK/EGFR), young age (P = 0.0156 vs. EGFR), and a light or never smoking history (P = 0.0039 vs. non‐ALK/EGFR) were significant clinical characteristics of NSCLC with ALK gene rearrangement. The significant CT characteristics compared to NSCLC with EGFR mutation were a large mass (P = 0.0155), solid mass (P = 0.0048), and no air bronchogram (P = 0.0148). A central location (P = 0.0322) and lymphadenopathy (P = 0.0353) were also more frequently observed. Coexisting emphysema was significantly less frequent in NSCLC patients with ALK gene rearrangement (P = 0.0135) than non‐ALK/EGFR.

Conclusions

NSCLC with ALK gene rearrangement was more likely to develop in younger women with a light or never smoking history. The characteristic CT findings of NSCLC with ALK gene rearrangement were a large solid mass, less air bronchogram, a central location, and lymphadenopathy.
Activity of fungicide mixtures againstBotrytis cinereaisolates resistant to benzimidazoles, strobilurins and dicarboximides
Authors: Ebrahimzadeh Fatemeh , Abrinbana Masoud
Published: February 2019

Botrytis cinerea, the causal agent of grey mould in a broad range of crops, is considered a high‐risk plant pathogen for fungicide resistance development. The use of fungicide mixtures, particularly combinations with synergistic activity, can be a useful tactic to counteract resistance build‐up in pathogen populations. The present study aimed to investigate the effects of different ratios of two‐way mixtures of carbendazim, iprodione, kresoxim‐methyl, tebuconazole and penconazole on fourB. cinereaisolates that were sensitive or resistant to benzimidazoles, dicarboximides and strobilurins. The isolates that were resistant to benzimidazoles and strobilurins had E198A and G143A mutations in β‐tubulin andcytochrome bgenes, respectively. The mixtures had different effects on each of the isolates in vitro but, in 13 combinations, the synergistic effect was observed against all or three isolates. In greenhouse experiments, 11 fungicide combinations used in decreased (EC75) concentrations showed the maximum control efficiency. The two follow‐up greenhouse experiments using six selected combinations revealed they were highly effective against additional isolates with various fungicide resistance profiles. The identified mixtures‐ratios have potential for use in grey mould management programs in the greenhouse.
JNK modifies neuronal metabolism to promote proteostasis and longevity
Authors: Wang Lifen , Davis Sonnet S. , Borch Jensen Martin , Rodriguez‐Fernandez Imilce A. , Apaydin Cagsar , Juhasz Gabor , Gibson Bradford W. , Schilling Birgit , Ramanathan Arvind , Ghaemmaghami Sina , Jasper Heinrich
Published: February 2019

Aging is associated with a progressive loss of tissue and metabolic homeostasis. This loss can be delayed by single‐gene perturbations, increasing lifespan. How such perturbations affect metabolic and proteostatic networks to extend lifespan remains unclear. Here, we address this question by comprehensively characterizing age‐related changes in protein turnover rates in the Drosophila brain, as well as changes in the neuronal metabolome, transcriptome, and carbon flux in long‐lived animals with elevated Jun‐N‐terminal Kinase signaling. We find that these animals exhibit a delayed age‐related decline in protein turnover rates, as well as decreased steady‐state neuronal glucose‐6‐phosphate levels and elevated carbon flux into the pentose phosphate pathway due to the induction of glucose‐6‐phosphate dehydrogenase (G6PD). Over‐expressing G6PD in neurons is sufficient to phenocopy these metabolic and proteostatic changes, as well as extend lifespan. Our study identifies a link between metabolic changes and improved proteostasis in neurons that contributes to the lifespan extension in long‐lived mutants.
Cerebellar alterations in cannabis users: A systematic review
Authors: Blithikioti Chrysanthi , Miquel Laia , Batalla Albert , Rubio Belen , Maffei Giovanni , Herreros Ivan , Gual Antoni , Verschure Paul , Balcells‐Oliveró Mercedes
Published: February 2019

Cannabis is the most used illicit substance in the world. As many countries are moving towards decriminalization, it is crucial to determine whether and how cannabis use affects human brain and behavior. The role of the cerebellum in cognition, emotion, learning, and addiction is increasingly recognized. Because of its high density in CB1 receptors, it is expected to be highly affected by cannabis use. The aim of this systematic review is to investigate how cannabis use affects cerebellar structure and function, as well as cerebellar‐dependent behavioral tasks. Three databases were searched for peer‐reviewed literature published until March 2018. We included studies that focused on cannabis effects on cerebellar structure, function, or cerebellar‐dependent behavioral tasks. A total of 348 unique records were screened, and 40 studies were included in the qualitative synthesis. The most consistent findings include (1) increases in cerebellar gray matter volume after chronic cannabis use, (2) alteration of cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision making, and associative learning. Age of onset and higher exposure to cannabis use were frequently associated with increased cannabis‐induced alterations. Chronic cannabis use is associated with alterations in cerebellar structure and function, as well as with deficits in behavioral paradigms that involve the cerebellum (eg, eyeblink conditioning, memory, and decision making). Future studies should consider tobacco as confounding factor and use standardized methods for assessing cannabis use. Paradigms exploring the functional activity of the cerebellum may prove useful as monitoring tools of cannabis‐induced impairment.
Fetus morphology changes by second‐trimester ultrasound in pregnant women drinking alcohol
Authors: Ferraguti Giampiero , Merlino Lucia , Battagliese Gemma , Piccioni Maria Grazia , Barbaro Greta , Carito Valentina , Messina Marisa Patrizia , Scalese Bruna , Coriale Giovanna , Fiore Marco , Ceccanti Mauro
Published: February 2019

Fetal alcohol spectrum disorders (FASDs) are a group of negative conditions occurring in children exposed to alcohol during gestation. The early discovery of FASD is crucial for mother and infant follow‐ups. In this study, we investigated in pregnant women the association between urine ethylglucuronide (EtG—a biomarker of alcohol drinking) and indicators of the physical characteristics of FASD by prenatal ultrasound in the second trimester of gestation. We also correlated these data with the AUDIT‐C, T‐ACE/TACER‐3, TWEAK, and food habit diary, screening questionnaires used to disclose alcohol drinking during pregnancy. Forty‐four pregnant women were randomly enrolled and examined for ultrasound investigation during the second trimester of gestation. Urine samples were provided by pregnant women immediately after the routine interviews. EtG determinations were performed with a cutoff established at 100 ng/mL, a value indicating occasional alcohol drinking. Fifteen of the enrolled pregnant women overcame the EtG cutoff (34.09%). Analysis of variance (ANOVA) revealed that the fetuses of the positive EtG pregnant women had significantly longer interorbital distance and also significantly increased frontothalamic distance (P's < 0.02). Quite interestingly, no direct correlation was found between EtG data and both food diary and AUDIT‐C. However, a significant correlation was observed between urinary EtG and T‐ACE (r = 0.375; P = 0.012) and between urinary EtG and TWEAK (r = 0.512; P < 0.001) and a concordance with all questionnaire for EtG values higher than 500 ng/mL. This study provides clinical evidence that the diagnosis of maternal alcohol consumption during pregnancy by urine EtG may disclose FASD‐related damage in the fetus.
Longitudinal study of factors associated with informal care provision: Evidence from older Australians
Authors: Peng Rong , Anstey Kaarin J.
Published: February 2019

Objective

To explore the factors associated with informal care provision by older Australians.

Methods

Longitudinal cohorts of the Personality and Total Health Through Life project (PATH) were used to build a generalised estimating equation model.

Results

Older adults who are engaged in volunteer and religious activities are 27.6% and 33.8%, respectively, more likely to provide informal care than their counterparts who are not engaged in these activities. Older adults who formerly provided care are four times more likely to have a continued caregiving role than their counterparts who did not formerly provide care. Those in marriage‐type relationships are 50.9% more likely, and those with primary responsibility for household and income tasks are respectively 28.0% and 31.0% more likely, to provide care than their counterparts.

Conclusion

Personal values for social responsibility and role responsibility are significant predictors of informal care provision by older Australians.
Combined immune therapy grade IV dermatitis in metastatic melanoma
Authors: Randhawa Manreet , Archer Christine , Gaughran Gregory , Miller Andrew , Morey Adrienne , Dua Divyanshu , Yip Desmond
Published: February 2019

Checkpoint inhibition is the mainstay of treatment in metastatic melanoma. More recently combined cytotoxic T‐lymphocyte antigen‐4 and programmed‐death‐1 blockade has resulted in improved response rates and overall survival in treatment naïve patients compared to monotherapy albeit with increased rates of adverse events. Dermatologic toxicities are an emerging consequence of the use of checkpoint inhibitors and have reportedly been more prevalent with the use of combined therapy. However, grade 3 and 4 adverse event rates are still less than 5%. Here, we report a case of a 63‐year‐old Caucasian male with metastatic melanoma treated with first line combined ipilimumab and nivolumab who then developed a steroid refractory, biopsy confirmed pityriasis lichenoides‐like, drug related rash that resolved with cyclosporine. Time of onset was 24 days and presenting symptoms demonstrated a maculopapular rash presenting over the back and chest with pruritus. Unfortunately, the patient subsequently had multi‐organ failure with acute kidney injury requiring dialysis, hypotension requiring vasopressor support, hepatic dysfunction, and bilateral lung infiltrates resulting in a fatal outcome. This case report highlights the effective use of cyclosporine as an immunomodulatory agent in the management of severe dermatological toxicity due to combination immunotherapy.
Glutathione‐S‐transferase M1 polymorphism and pro‐inflammatory cytokines tumour necrosis factor‐α and interleukin‐1β are associated with preeclampsia in Serbian women
Authors: Sljivancanin Jakovljevic Tamara , Kontic‐Vucinic Olivera , Nikolic Nadja , Carkic Jelena , Soldatovic Ivan , Milasin Jelena
Published: February 2019

Problem

Preeclampsia has a multifactorial origin with genetic, immunological, and environmental factors described as main contributors to its onset. This study aimed to investigate glutathione‐S‐transferase M1 (GSTM1) and glutathione‐S‐transferase T1 (GSTT1) gene polymorphisms, the expression of pro‐inflammatory cytokines (TNF‐α, IL‐1β, IL‐6), and the potential relationship between GST polymorphisms and cytokine expression levels in preeclampsia and uncomplicated pregnancy.

Method of Study

This prospective case‐control study included 50 women with preeclampsia and 50 healthy pregnant women. DNA and RNA were extracted from women leukocytes. Deletion polymorphisms were analyzed by PCR, while cytokine mRNA expression was analyzed by real‐time PCR.

Results

GSTM1 null genotype with present GSTT1 increased the risk for preeclampsia development. Deletion of GSTT1 without deletion of GSTM1 increased the risk for early preeclampsia. Relative mRNA expression of TNF‐α was significantly higher in preeclampsia compared to healthy pregnant women (P = 0.006). Expression of IL‐1β was significantly higher in severe and late preeclampsia compared to the control group (P = 0.005, P = 0.007, respectively). A significant positive correlation between TNF‐α and IL‐1β was observed (Spearman's ρ = 0.312, P = 0.028) and between IL‐1β and IL‐6, in preeclampsia group (Spearman's ρ = 0.296, P = 0.037). IL‐1β was significantly increased in patients with GSTT1 null genotype (P = 0.015) while IL‐6 was increased in patients with GSTM1 null genotype (P = 0.015).

Conclusions

GSTM1 null genotype represents a risk factor for preeclampsia development, while GSTT1 null genotype favors early preeclampsia. Preeclampsia is also associated with increased expression of pro‐inflammatory cytokines, predominantly TNF‐α and IL‐1β.
Lipoxin A4 interferes with embryo implantation via suppression of epithelial‐mesenchymal transition
Authors: Xu Zhangye , Zhao Shenzhi , Zhou Tong , Liao Tingting , Huang Xianping , Xiang Huiqiu , Zhang Qiong , Huang Yanjun , Lin Feng , Ye Duyun , Huang Yinping
Published: February 2019

Problem

To test whether lipoxin A4 (LXA4) interferes with embryo implantation via suppression of epithelial‐mesenchymal transition (EMT).

Method of study

We developed a mouse model of LXA4 blocking embryo implantation and detected the indicators of EMT to confirm that LXA4 inhibits EMT might be a mechanism of interfering with the embryo implantation. We detected integrin‐linked kinase (ILK), N‐formylpeptide receptor 2 (FPR2), vascular endothelial growth factor, matrix metalloproteinases (MMPs), Akt, GSK3β, NF‐ĸB, twist, vimentin, fibronectin, and β‐catenin mRNA expression using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and real‐time RT‐PCR; localized protein expression using immunohistochemistry and Western blotting assay; MMPs activity assay by gelatin zymography; and the status of implantation in pregnant animals assessed by pontamine blue reaction test.

Results

Preimplantation administration of LXA4 resulted in implantation failure. LXA4 has a time‐ and dose‐dependent effect on embryo implantation. Day 0.5 after fertilization is the most effective time to use LXA4 to block embryo implantation. (a) LXA4 reduced endometrial stroma edema; (b) LXA4 inhibited the activity of MMP9 and significantly upregulated the expression of β‐catenin, and downregulated the expression of vimentin, fibronectin, twist, NF‐κB, Akt, and Gsk‐3β in the endometrium and TEV‐1 cells; (c) LXA4 upregulated the expression of FPR2, and downregulated the expression of ILK; FPR2‐overexpressing had an inhibitory effect on ILK in TEV‐1 cells.

Conclusion

LXA4 inhibits EMT which attenuates ILK action by enhancing FPR2; therefore, this might be a mechanism of interfering with embryo implantation.
Preimplantation genetic testing for aneuploidy (PGT‐A): The biology, the technology and the clinical outcomes
Authors: Homer Hayden Anthony
Published: February 2019

Preimplantation genetic testing for aneuploidy (PGT‐A) seeks to identify preimplantation embryos with a normal chromosome complement (euploid) during in vitro fertilisation (IVF). By sifting out embryos with abnormal chromosome numbers (aneuploid), PGT‐A should theoretically improve pregnancy success. However, earlier versions of PGT‐A were ineffective, and in some cases, detrimental, due to biopsy‐induced trauma and because the technology at the time could analyse only a fraction of all chromosomes. More recently, the emergence of technologies enabling all chromosomes to be analysed and a switch to less traumatic blastocyst‐stage biopsy have seen widespread uptake of PGT‐A. Assessing the full impact of blastocyst biopsy PGT‐A requires consideration of multiple factors, including embryonic mosaicism, sensitivity of the technological platform used, embryo loss during long‐term in vitro culture, embryo cryopreservation and inter‐clinic variability in expertise. Significantly, there hasnt yet been an appropriately designed randomised controlled trial (RCT) of blastocyst biopsy PGT‐A analysed by intention‐to‐treat that accounts for all these parameters on a per‐cycle basis. The three RCTs reporting benefits studied outcomes on a per‐embryo transfer basis were small and underpowered and demonstrated benefits for a very select sub‐group of good prognosis patients. The liberal use of this very expensive IVF add‐on for other patient populations has not yet been shown to be effective, or indeed, without harm.
Neutrophil‐to‐lymphocyte ratio in age‐related macular degeneration: a systematic review and meta‐analysis
Authors: Niazi Siar , Krogh Nielsen Marie , Sørensen Torben Lykke , Subhi Yousif
Published: February 2019

Age‐related macular degeneration (AMD) is aetiologically linked to immunological ageing and dysfunction. One aspect of this is the altered neutrophil‐to‐lymphocyte ratio (NLR), which in other domains have been associated with inflammation and angiogenesis, and therefore investigated in patients with AMD in several papers. In this systematic review and meta‐analysis, we summarize findings in patients with AMD in relation to NLR, both qualitatively and quantitatively. We searched PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central and identified six studies from where we extracted data on 1178 individuals (777 patients with AMD and 401 healthy controls). Patients with AMD had a higher NLR (weighted mean difference: 0.37, CI 95% 0.08 to 0.66, p = 0.013) when compared to healthy controls. In subgroup analyses, we did not find a significant difference between patients with dry AMD and healthy controls (weighted mean difference: 0.34, CI 95% −0.03 to 0.69, p = 0.068), but did find a strong significant difference between patients with neovascular AMD and healthy controls (weighted mean difference: 0.54, CI 95% 0.23 to 0.86, p = 0.00068). Hence, we find that the association between AMD and elevated NLR may have stronger relevance to the neovascular subtype of AMD. However, the clinical value of measuring the NLR remains unclear.
INFRASTRUCTURE PROVISION, POLITICS AND RELIGION: INSIGHTS FROM TUNISIA'S NEW DEMOCRACY
Authors: FOURATI Maleke , ESTACHE Antonio
Published: February 2019

This paper analyzes the relationship between access to infrastructure services and support for religious parties based on the evidence produced by a recent democratic experience in Tunisia in which a religious political party, Ennahdha, governed from 2011 to 2014. The experience points to a complex relationship. In the 2011 election, areas with higher access are associated with higher support for Ennahdha than areas with lower access. In the 2014 election, however, infrastructure access is positively correlated with support for the party in areas where access had improved but negatively correlated with support for the party in areas that already had high access. A possible pragmatic general implication is that, to be politically competitive, religious parties, cannot bet solely on their religious commitment to provide basic services, including infrastructure, to the poor. They need to recognize the multiplicity of voter's concerns and their evolving agenda.
EVALUATING THE COSTS, QUALITY, AND VALUE FOR MONEY OF INFRASTRUCTURE PUBLIC‐PRIVATE PARTNERSHIPS: A SYSTEMATIC LITERATURE REVIEW
Authors: HELBY PETERSEN Ole
Published: February 2019

Public‒private partnerships (PPPs) are often promoted as a means to lower the costs and increase the quality and value for money (VfM) of public construction and infrastructure projects. While the increasing capital stock of PPPs warrants evaluation of their performance there has until now been limited systematic assessment of PPP versus conventional public procurement. This article contributes to the literature by presenting the findings of a systematic review of empirical peer‐reviewed studies comparing the costs, quality, and/or VfM of infrastructure PPP projects with conventional public procurement. The international literature suggests that PPPs are on average more costly and provide approximately similar VfM as conventional procurement. The number of empirical evaluations is limited, however, and evidence on the quality of infrastructure facilities is particularly scarce. While infrastructure PPPs continue to proliferate, systematic assessment of their performance is warranted to assist policy‐makers in choosing the procurement method that offers best value for taxpayers, users and society.
WHAT DO CITIZENS THINK ABOUT PUBLIC ENTERPRISES? SUBJECTIVE SURVEY DATA ON THE LEGITIMACY OF THE ECONOMIC ACTIVITIES OF THE GERMAN PUBLIC SECTOR
Authors: SIDKI Marcus , BOLL David
Published: February 2019

We analyse the legitimacy of public enterprises that perform economic activities by focusing on the citizens’ subjective preferences, i.e. determining their political legitimacy. Using data from a representative survey conducted among 318 citizens of the German state of Rhineland‐Palatine, we explore determinants for the support of either privatisation efforts or the instrumental thesis, a widespread principle in German‐speaking countries, which considers public enterprises solely as instruments to fulfil economic policy objectives. Our results indicate that the respondents’ perception of the efficiency of public enterprises as well as their personal economic situation are important factors for the support of privatisation. The influential factors for the use of public enterprises as policy instruments are political ideology, the perception of a higher security of supplying goods and services as well as opinions regarding corporate social responsibility. The subjective preferences of a (democratic) country's citizens are thus an important reason why the public sector should or should not play an active part in providing goods and services. This can play an important role when decision makers from the public sector are keen to take into account the citizens’ approval or disapproval of privatisation measures.
Resilience in the Workplace: A Multilevel Review and Synthesis
Authors: Hartmann Silja , Weiss Matthias , Newman Alexander , Hoegl Martin
Published: February 2019

In an increasingly dynamic business environment, the concept of resilience is fundamental to understanding how employees successfully handle adversity. Yet, the operationalisation of the concept, the factors which lead to its development, and how and why it influences outcomes of interest to organisations are issues still under debate in the literature. In this article, we address these debates by undertaking a critical review of research on resilience in the workplace at both the individual and team levels. We pinpoint different conceptualisations of resilience and highlight how resilience has been measured in extant quantitative work. Further, we provide a systematic literature review of empirical work on the antecedents and outcomes of resilience at the individual and team levels, as well as conduct a review of work that has introduced resilience as a moderator or mediator. In doing so, we highlight theoretical approaches that have been adopted to study resilience in the workplace. Based on our review of the extant empirical work on resilience, we develop a roadmap for future research. In particular, we pinpoint relevant theoretical approaches that help us understand the mechanisms underlying the development and outcomes of resilience and highlight opportunities for empirical advancement of the literature.
In vitro binding of cefovecin to plasma proteins in Australian marsupials and plasma concentrations of cefovecin following single subcutaneous administration to koalas (Phascolarctos cinereus)
Authors: Gharibi S , Vogelnest L , Govendir M
Published: February 2019

Background

Cefovecin has a long duration of antibiotic activity in cats and dogs, somewhat attributable to its high plasma protein binding.

Aims

To determine the cefovecin binding to plasma proteins in vitro in selected Australian marsupials and to quantify the change in cetovecin concentration over time following subcutaneous injection in koalas.

Methods and results

Various cefovecin concentrations were incubated with plasma and quantified using HPLC. The median (range) bound percentages when 10 μg/mL of cefovecin was incubated with plasma were 11.1 (4.1–20.4) in the plasma of the Tasmanian devil, 12.7 (5.8–17.3) in the koala, 18.9 (14.6–38.0) in the eastern grey kangaroo, 16.9 (15.7–30.2) in the common brush‐tailed possum, 37.6 (25.3–42.3) in the eastern ring‐tailed possum and 36.4 (35.0–38.3) in the red kangaroo, suggesting that cefovecin may have a shorter duration of action in these species than in cats and dogs. Cefovecin binding to plasma proteins in thawed, frozen equine plasma was also undertaken for assay quality control and the median (range) plasma protein binding (at 10 μg/mL) was 95.6% (94.9–96.6%). Cefovecin was also administered to six koalas at 8 mg/kg subcutaneously and serial blood samples were collected at 3, 6, 24, 48, 72, 96 h thereafter. Cefovecin plasma concentrations were not quantifiable in four koalas and in the other two, the mean plasma concentration at t = 3 h was 1.04 ± 0.01 μg/mL.

Conclusion

Because of the limited pharmacokinetic data generated, no further pharmacokinetic analysis was performed; however, a single injected bolus of cefovecin is likely to have a short duration of action in koalas (hours, rather than days).
Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities
Authors: Burkhardt Birgit , Hermiston Michelle L.
Published: February 2019

Lymphoblastic lymphoma (LBL) is the second most common type of Non‐Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25–35% of all cases. The majority, 70–80%, is of T‐lymphoblastic origin while 20–25% arise from B lymphoblasts. With current therapy, the event‐free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T‐LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.
A deep‐learning model using automated performance metrics and clinical features to predict urinary continence recovery after robot‐assisted radical prostatectomy
Authors: Hung Andrew J. , Chen Jian , Ghodoussipour Saum , Oh Paul J. , Liu Zequn , Nguyen Jessica , Purushotham Sanjay , Gill Inderbir S. , Liu Yan
Published: February 2019

Objectives

To predict urinary continence recovery after robot‐assisted radical prostatectomy (RARP) using a deep learning (DL) model, which was then used to evaluate surgeon's historical patient outcomes.

Subjects and Methods

Robotic surgical automated performance metrics (APMs) during RARP, and patient clinicopathological and continence data were captured prospectively from 100 contemporary RARPs. We used a DL model (DeepSurv) to predict postoperative urinary continence. Model features were ranked based on their importance in prediction. We stratified eight surgeons based on the five top‐ranked features. The top four surgeons were categorized in ‘Group 1/APMs’, while the remaining four were categorized in ‘Group 2/APMs’. A separate historical cohort of RARPs (January 2015 to August 2016) performed by these two surgeon groups was then used for comparison. Concordance index (C‐index) and mean absolute error (MAE) were used to measure the model's prediction performance. Outcomes of historical cases were compared using the Kruskal–Wallis, chi‐squared and Fisher's exact tests.

Results

Continence was attained in 79 patients (79%) after a median of 126 days. The DL model achieved a C‐index of 0.6 and an MAE of 85.9 in predicting continence. APMs were ranked higher by the model than clinicopathological features. In the historical cohort, patients in Group 1/APMs had superior rates of urinary continence at 3 and 6 months postoperatively (47.5 vs 36.7%, P = 0.034, and 68.3 vs 59.2%, P = 0.047, respectively).

Conclusion

Using APMs and clinicopathological data, the DeepSurv DL model was able to predict continence after RARP. In this feasibility study, surgeons with more efficient APMs achieved higher continence rates at 3 and 6 months after RARP.
Selective tetramodal bladder‐preservation therapy, incorporating induction chemoradiotherapy and consolidative partial cystectomy with pelvic lymph node dissection for muscle‐invasive bladder cancer: oncological and functional outcomes of 107 patients
Authors: Kijima Toshiki , Tanaka Hajime , Koga Fumitaka , Masuda Hitoshi , Yoshida Soichiro , Yokoyama Minato , Ishioka Junichiro , Matsuoka Yoh , Saito Kazutaka , Kihara Kazunori , Fujii Yasuhisa
Published: February 2019

Objectives

To evaluate the oncological and functional outcomes associated with selective tetramodal bladder‐sparing therapy, comprising maximal transurethral resection of bladder tumour (TURBT), induction chemoradiotherapy (CRT), and consolidative partial cystectomy (PC) with pelvic lymph node dissection (PLND).

Materials and Methods

In the present study, 154 patients with non‐metastatic muscle‐invasive bladder cancer (MIBC), prospectively enrolled in the tetramodal bladder‐preservation protocol, were analysed. After TURBT and induction CRT, patients showing complete remission were offered consolidative PC with PLND for the achievement of bladder preservation. Pathological response to induction CRT was evaluated using PC specimens. Oncological and functional outcomes after bladder preservation were evaluated using the following endpoints: MIBC‐recurrence‐free survival (RFS); cancer‐specific survival (CSS); overall survival (OS), and cross‐sectional assessments of preserved bladder function and quality of life (QoL) including uroflowmetry, bladder diary, International Prostate Symptom Score, Overactive Bladder Symptom Score and the 36‐item Short‐Form Health Survey (SF‐36) score.

Results

The median follow‐up period was 48 months. Complete MIBC remission was achieved in 121 patients (79%) after CRT, and 107 patients (69%) completed the tetramodal bladder‐preservation protocol comprising consolidative PC with PLND. Pathological examination in these 107 patients revealed residual invasive cancer (≥pT1) that was surgically removed in 11 patients (10%) and lymph node metastases in two patients (2%). The 5‐year MIBC‐RFS, CSS and OS rates in the 107 patients who completed the protocol were 97%, 93% and 91%, respectively. As for preserved bladder function, the median maximum voided volume, post‐void residual urine volume, and nighttime frequency were 350 mL, 25 mL, and two voids, respectively. In the SF‐36, patients had favourable scores, equivalent to the age‐matched references in all the QoL scales.

Conclusion

Selective tetramodal bladder‐preservation therapy, incorporating consolidative PC with PLND, yielded favourable oncological and functional outcomes in patients with MIBC. Consolidative PC may have contributed to the low rate of MIBC recurrence in patients treated according to this protocol.
Ultrasound guidance can be used safely for renal tract dilatation during percutaneous nephrolithotomy
Authors: Armas‐Phan Manuel , Tzou David T. , Bayne David B. , Wiener Scott V. , Stoller Marshall L. , Chi Thomas
Published: February 2019

Objectives

To compare clinical outcomes in patients who underwent percutaneous nephrolithotomy (PCNL) with renal tract dilatation performed under fluoroscopic guidance vs renal tract dilatation with ultrasound guidance.

Patients and Methods

We conducted a prospective observational cohort study, enrolling successive patients undergoing PCNL between July 2015 and March 2018. Included in this retrospective analysis were cases where the renal puncture was successfully obtained with ultrasound guidance. Cases were then grouped according to whether fluoroscopy was used to guide renal tract dilatation or not. All statistical analyses were performed using Stata version 15.1 including univariate (Fisher's exact test, Welch's t‐test) and multivariate analyses (binomial logistic regression, ordinal logistic regression, and linear regression).

Results

A total of 176 patients underwent PCNL with successful ultrasonography‐guided renal puncture, of whom 38 and 138 underwent renal tract dilatation with fluoroscopic vs ultrasound guidance, respectively. There were no statistically significant differences in patient age, gender, body mass index (BMI), preoperative hydronephrosis, stone burden, procedure laterality, number of dilated tracts, and calyceal puncture location between the two groups. Among ultrasound tract dilatations, a higher proportion of patients were placed in the modified dorsal lithotomy position as opposed to prone, and a significantly shorter operating time was observed. Only modified dorsal lithotomy position remained statistically significant after multivariate regression. There were no statistically significant differences in postoperative stone clearance, complication rate, or intra‐operative estimated blood loss. A 5‐unit increase in a patient's BMI was associated with 30% greater odds of increasingly severe Clavien–Dindo complications. A 5‐mm decrease in the preoperative stone burden was associated with 20% greater odds of stone‐free status. No variables predicted estimated blood loss with statistical significance.

Conclusions

Renal tract dilatation can be safely performed in the absence of fluoroscopic guidance. Compared to using fluoroscopy, the present study demonstrated that ultrasonography‐guided dilatations can be safely performed without higher complication or bleeding rates. This can be done using a variety of surgical positions, and future studies centred on improving dilatation techniques could be of impactful clinical value.
Agonist‐induced desensitisation of β3‐adrenoceptors: Where, when, and how?
Authors: Okeke Katerina , Angers Stephane , Bouvier Michel , Michel Martin C.
Published: February 2019

β3‐Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration may be limited by receptor‐induced desensitisation. Whereas the β2‐adrenoceptor has phosphorylation sites that are important for desensitisation, the β3‐adrenoceptor lacks these; therefore, it had been assumed that β3‐adrenoceptors are largely resistant to agonist‐induced desensitisation. While all direct comparative studies demonstrate that β3‐adrenoceptors are less susceptible to desensitisation than β2‐adrenoceptors, desensitisation of β3‐adrenoceptors has been observed in many models and treatment settings. Chimeric β2‐ and β3‐adrenoceptors have demonstrated that the C‐terminal tail of the receptor plays an important role in the relative resistance to desensitisation but is not the only relevant factor. While the evidence from some models, such as transfected CHO cells, is inconsistent, it appears that desensitisation is observed more often after long‐term (hours to days) than short‐term (minutes to hours) agonist exposure. When it occurs, desensitisation of β3‐adrenoceptors can involve multiple levels including down‐regulation of its mRNA and the receptor protein and alterations in post‐receptor signalling events. The relative contributions of these mechanistic factors apparently depend on the cell type under investigation. Which if any of these factors is applicable to the human urinary bladder remains to be determined.

Linked Articles

This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc
The MC4 receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage
Authors: Chen Shengpan , Zuo Yuchun , Huang Lei , Sherchan Prativa , Zhang Jian , Yu Zhengtao , Peng Jianhua , Zhang Junyi , Zhao Lianhua , Doycheva Desislava , Liu Fei , Zhang John H. , Xia Ying , Tang Jiping
Published: February 2019

Background and Purpose

Inflammasome‐mediated pyroptosis is an important neuronal cell death mechanism. Previous studies reported that activation of melanocortin MC4 receptor exerted neuroprotection in several neurological diseases. Here, we have investigated the role of MC4 receptor activation with RO27‐3225 in suppressing neuronal pyroptosis after experimental intracerebral haemorrhage (ICH) and the underlying mechanism.

Experimental Approach

One hundred and sixty‐nine male CD1 mice were used. ICH was induced by injection of bacterial collagenase into the right‐side basal ganglia. RO27‐3225, a selective agonist of MC4 receptor, was injected intraperitoneally at 1 hr after ICH. To elucidate the underlying mechanism, we used the specific MC4 receptor antagonist HS024 and NQDI‐1, a specific inhibitor of the apoptosis signalling‐regulating kinase 1 (ASK1). Neurological tests, Western blot, Fluoro‐Jade C, TUNEL, and immunofluorescence staining were conducted.

Key Results

Expression of MC4 receptor and the NOD‐like receptor family, pyrin domain containing 1 (NLRP1) inflammasome in brain were increased after ICH. RO27‐3225 treatment decreased neuronal pyroptosis and neurobehavioural deficits at 24 and 72 hr after ICH. RO27‐3225 reduced the expression of p‐ASK1, p‐JNK, p‐p38 MAPK, NLRP1 inflammasome, cleaved caspase‐1, and IL‐1β after ICH. HS024 pretreatment prevented the effects of RO27‐3225. Similar to RO27‐3225, NQDI‐1 alone improved neurological functions and down‐regulated ASK1/JNK/p38MAPK expression after ICH.

Conclusions and Implications

RO27‐3225 suppressed NLRP1‐dependent neuronal pyroptosis and improved neurological function, possibly mediated by activation of MC4 receptor and inhibition of ASK1/JNK/p38 MAPK signalling pathways, after experimental ICH in mice. The MC4 receptor may be a promising therapeutic target for the management of ICH.
Pollen analogues are transported across greater distances in bee‐pollinated than in hummingbird‐pollinated species of Justicia (Acanthaceae)
Authors: Schmidt‐Lebuhn Alexander N. , Müller Matthias , Pozo Inofuentes Paola , Encinas Viso Francisco , Kessler Michael
Published: February 2019

Several hummingbird‐pollinated plant lineages have been demonstrated to show increased rates of diversification compared to related insect‐pollinated lineages. It has been argued that this pattern is produced by a higher degree of specialization on part of both hummingbirds and plants. We here test an alternative hypothesis: The often highly territorial hummingbirds may on average carry pollen over shorter distances than other pollinators and drive diversification by reducing gene flow distances. We present experimental data from pollen analogue tracking showing shorter dispersal distances in hummingbird‐pollinated than in bee‐pollinated species among ten Neotropical species of Justicia (Acanthaceae).

Abstract in Spanish is available with online material.
QSAR of clinically important EGFR mutant L858R/T790M pyridinylimidazole inhibitors
Authors: Fatima Shehnaz , Pal Divyani , Agarwal Subhash Mohan
Published: February 2019

EGFR is a well‐established therapeutic target of clinical relevance in cancer. However, acquisition of secondary mutation (T790M) makes first‐generation inhibitors ineffective. Therefore, to circumvent the problem of resistance, new T790M/L858R (TMLR) double mutant inhibitors are required. In this study, fragment‐based QSAR models (GQSAR) were generated for pyridinylimidazole derivatives having biological activity against TMLR mutants. The GQSAR model developed using partial least squares regression via stepwise forward–backward variable selection technique showed best results as judged using statistical parameters (r2, q2, and pred_r2). Additionally, applicability domain of the model was verified using Williams plot, which indicated that the predicted data are reliable. The GQSAR provided site‐specific clues wherein modifications related to decreasing lipophilic character and rotatable bonds and increasing SaaCHE‐index are required for improving inhibitory activity. Overall, the study indicated that the presence of acrylamide at R5 is essential for covalent bond formation with Cys797 and occurrence of aromatic residue at R2 is required for occupying hydrophobic region next to Met790 gatekeeper residue. Based on this information, new derivatives were designed that show better inhibitory activity than the experimentally reported most active molecules. Thus, the model developed can be used to design new pyridinylimidazole derivatives with improved TMLR bioactivity.
Screening of the FANCA gene mutational hotspots in the Pakistani fanconi anemia patients revealed 19 sequence variations
Authors: Shahid Muhammad , Firasat Sabika , Satti Humayoon Shafique , Satti Tariq Mahmood , Ghafoor Tariq , Sharif Imtenan , Afshan Kiran
Published: February 2019

Fanconi anemia (FA) is a recessive disorder that predispose to bone marrow failure and multiple congenital anomalies in affected individuals worldwide. To date, 22 FA genes are known to harbor sequence variations in disease phenotype. Among these, mutations in the FANCA gene are associated with 60% to 70% of FA cases. The aim of the present study was to screen FA cases belonging to consanguineous Pakistani families for selected exons of FANCA gene which are known mutational hotspots for Asian populations. Blood samples were collected from 20 FA cases and 20 controls. RNA was extracted and cDNA was synthesized from blood samples of cases. DNA was extracted from blood samples of cases and ethnically matched healthy controls. Sanger's sequencing of the nine selected exons of FANCA gene in FA cases revealed 19 genetic alterations of which 15 were single nucleotide variants, three were insertions and one was microdeletion. Of the total 19 sequence changes, 13 were novel and six were previously reported. All identified variants were evaluated by computational programs including SIFT, PolyPhen‐2 and Mutation taster. Seven out of 20 analyzed patients were carrying homozygous novel sequence variations, predicted to be associated with FA. These disease associated novel variants were not detected in ethnically matched controls and depict genetic heterogeneity of disease.
DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella
Authors: Li Yang , Sha Yanwei , Wang Xiong , Ding Lu , Liu Wensheng , Ji Zhiyong , Mei Libin , Huang Xianjing , Lin Shaobin , Kong Shuangbo , Lu Jinhua , Qin Weibing , Zhang Xinzhong , Zhuang Jianmin , Tang Yunge , Lu Zhongxian
Published: February 2019

Multiple morphological abnormalities of flagella (MMAF) is one kind of severe teratozoospermia. Gene mutations reported in previous works only revealed the pathogenesis of approximately half of the MMAF cases, and more genetic defects in MMAF need to be explored. In the present study, we performed a genetic analysis on Han Chinese men with MMAF using whole‐exome sequencing. After filtering out the cases with known gene mutations, we identified five novel mutation sites in the DNAH2 gene in three cases from three families. These mutations were validated through Sanger sequencing and absent in all control individuals. In silico analysis revealed that these DNAH2 variations are deleterious. The spermatozoa with DNAH2 mutations showed severely disarranged axonemal structures with mitochondrial sheath defection. The DNAH2 protein level was significantly decreased and inner dynein arms were absent in the spermatozoa of patients. ICSI treatment was performed for two MMAF patients with DNAH2 mutations and the associated couples successfully achieved pregnancy, indicating good nuclear quality of the sperm from the DNAH2 mutant patients. Together, these data suggest that the DNAH2 mutation can cause severe sperm flagella defects that damage sperm motility. These results provide a novel genetic pathogeny for the human MMAF phenotype.