bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient and caregiver perspectives on burden of disease manifestations in late-onset Tay-Sachs and Sandhoff diseases
Authors: Lyn Nicole , Pulikottil-Jacob Ruth , Rochmann Camille , Krupnick Robert , Gwaltney Chad , Stephens Nick , Kissell Julie , Cox Gerald F. , Fischer Tanya , Hamed Alaa
Published: April 2020

Background

The GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme β-hexosaminidase A (HEXA) or β-hexosaminidase B (HEXB) genes, respectively. A minority of patients have a late-onset form of disease that presents from late-childhood to adulthood and has a slowly progressive course with prolonged survival.

Little research has been published documenting patient experiences with late-onset Tay-Sachs and Sandhoff diseases and how the disease impacts their daily lives and functioning. This study explored the most frequent symptoms and functional impacts experienced by patients with late-onset GM2 gangliosidosis through interviews with patients and caregivers.

Methods

A qualitative research study design was employed, using three focus groups and 18 one-on-one interviews with patients who were recruited at the National Tay-Sachs and Allied Diseases Annual Family Conference. Transcripts were generated from the discussions, and patient quotes were analyzed using a content analysis approach. Concepts were aggregated into symptom and functional impacts, and the frequency of mention in the focus groups and individual interviews was calculated.

Key findings

Many of the frequently described symptoms [muscle weakness (n = 19, 95%), “clumsy” gait (n = 12, 60%), fatigue (n = 10, 50%)] and impacts [difficulty walking (n = 19, 95%), falling (n = 17, 85%), and climbing stairs (n = 16, 80%)] disclosed by patients and caregivers were similar to those previously reported in the literature. However, less frequently described symptoms such as gastrointestinal issues (n = 4, 20%) and coughing fits (n = 5, 25%) have been expanded upon. This study evaluated the immediate impact of these symptoms on the patients’ lives to highlight the burden of these symptoms and the functional limitations on daily living activities, independence, and emotional well-being. The findings were used to develop a conceptual disease model that could serve as a foundation for patient-centered outcomes in clinical trials and provide insights to the medical community that may benefit patient care.

Conclusions

This study contributes to the current understanding of symptoms associated with late-onset GM2 gangliosidosis, and further identifies the many consequences and impacts of the disease. These symptoms and impacts could be measured in clinical trials to examine the effects of novel treatments from the patient perspective.
PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells
Authors: Jang Ji Eun , Eom Ju-In , Jeung Hoi-Kyung , Chung Haerim , Kim Yu Ri , Kim Jin Seok , Cheong June-Won , Min Yoo Hong
Published: April 2020

Background

The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition.

Methods

We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34+CD38− leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay.

Results

The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition.

Conclusions

PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.
Long non-coding RNA NCK1-AS1 promotes the tumorigenesis of glioma through sponging microRNA-138-2-3p and activating the TRIM24/Wnt/β-catenin axis
Authors: Huang Lifa , Li Xu , Ye Hui , Liu Yajun , Liang Xiaolong , Yang Chao , Hua Lin , Yan Zhaoxian , Zhang Xin
Published: April 2020

Background

Glioma is a common brain malignancy with high mortality. The competing endogenous RNA (ceRNA) networks may play key roles in cancer progression. This study was conducted to probe the role of long noncoding RNA (lncRNA) NCK1-AS1 in glioma progression and the involved mechanisms.

Methods

Microarray analyses were performed to explore the lncRNAs/miRNAs/genes with differential expression in glioma. NCK1-AS1 levels in glioma tissues and normal brain tissues, and in glioma cell lines and normal human glial cells were identified. The interactions among NCK1-AS1, miR-138-2-3p and TRIM24 were validated through luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Gain- and loss-of functions of NCK1-AS1, miR-138-2-3p and TRIM24 were performed to identify their roles in the behaviors of glioma cells. The activity of the Wnt/β-catenin pathway was measured. In vivo experiments were performed as well.

Results

High expression of NCK1-AS1 was found in glioma tissues and cells, especially in U251 cells. Online predictions and the integrated experiments identified that NCK1-AS1 elevated the TRIM24 expression through sponging miR-138-2-3p, and further activated the Wnt/β-catenin pathway. Artificial silencing of NCK1-AS1 or up-regulation of miR-138-2-3p led to inhibited proliferation, invasion and migration but promoted cell apoptosis of U251 cells, while up-regulation of TRIM24 reversed these changes, and it activated the Wnt/β-catenin pathway. The in vitro results were reproduced in in vivo experiments.

Conclusions

Our study suggested that NCK1-AS1 might elevate TRIM24 expression and further activate the Wnt/β-catenin pathway via acting as a ceRNA for miR-138-2-3p. Silencing of NCK1-AS1 might inhibit the progression of glioma.
Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/β-catenin positive feedback loop
Authors: Lin Xia-Hui , Liu Hua-Hua , Hsu Shu-Jung , Zhang Rui , Chen Jie , Chen Jun , Gao Dong-Mei , Cui Jie-Feng , Ren Zheng-Gang , Chen Rong-Xin
Published: April 2020

Background

Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.

Methods

HCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.

Results

CM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.

Conclusions

We identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.
RETRACTED ARTICLE: LncRNA CTBP1-AS2 sponges miR-216a to upregulate PTEN and suppress endometrial cancer cell invasion and migration
Authors: Wang Qing-an-zi , Yang Yongxiu , Liang Xiaolei
Published: April 2020

Background

Although lncRNA CTBP1-AS2 has been functionally analyzed only in cardiomyocyte hypertrophy and diabetes, analysis of TCGA dataset revealed its downregulation in endometrial carcinoma (EC), indicating its involvement in EC.

Results

In this study we found that CTBP1-AS2 was downregulated in EC and correlated with poor survival. MiR-216a might form base pairs with CTBP1-AS2 based on RNA-RNA interaction, which was confirmed by luciferase activity assay. Interestingly, upregulation of PTEN was observed after CTBP1-AS2 overexpression. Transwell assay showed that CTBP1-AS2 and PTEN overexpression led to decreased cancer cell invasion and migration and reduced enhancing effects of miR-216a on cell invasion and migration. It was known that miR-216a targeted PTEN.

Conclusion

Therefore, CTBP1-AS2 may sponge miR-216a to upregulate PTEN, thereby suppressing endometrial cancer cell invasion and migration.
Bronchiectasis Information and Education: a randomised, controlled feasibility trial
Authors: Hester Katy L. M. , Ryan Vicky , Newton Julia , Rapley Tim , De Soyza Anthony
Published: April 2020

Background

There has been comparatively little patient information about bronchiectasis, a chronic lung disease with rising prevalence. Patients want more information, which could improve their understanding and self-management. A novel information resource meeting identified needs has been co-developed in prior work. We sought to establish the feasibility of conducting a multi-centre randomised controlled trial to determine effect of the information resource on understanding, self-management and health outcomes.

Methods/design

We conducted an unblinded, single-centre, randomised controlled feasibility trial with two parallel groups (1:1 ratio), comparing a novel patient information resource with usual care in adults with bronchiectasis. Integrated qualitative methods allowed further evaluation of the intervention and trial process. The setting was two teaching hospitals in North East England. Participants randomised to the intervention group received the information resource (website and booklet) and instructions on its use. Feasibility outcome measures included willingness to enter the trial, in addition to recruitment and retention rates. Secondary outcome measures (resource use and satisfaction, quality of life, unscheduled healthcare presentations, exacerbation frequency, bronchiectasis knowledge and lung function) were recorded at baseline, 2 weeks and 12 weeks.

Results

Sixty-two participants were randomised (control group = 30; intervention group = 32). Thirty-eight (61%) were female, and the participants’ median age was 65 years (range 15–81). Median forced expiratory volume in 1 s percent predicted was 68% (range 10–120). Sixty-two of 124 (50%; 95% CI, 41–59%) of potentially eligible participants approached were recruited. Sixty (97%) of 62 participants completed the study (control group, 29 of 30 [97%]; 95% CI, 83–99%; 1 unrelated death; intervention group, 31 [97%] of 32; 95% CI, 84–99%; 1 withdrawal). In the intervention group, 27 (84%) of 32 reported using the information provided, and 25 (93%) of 27 of users found it useful, particularly the video content. Qualitative data analysis revealed acceptability of the trial and intervention. Web analytics recorded over 20,000 page views during the 16-month study period.

Conclusion

The successful recruitment process, high retention rate and study form completion rates indicate that it appears feasible to conduct a full trial based on this study design. Worldwide demand for online access to the information resource was high.

Trial registration

ISRCTN Registry, ISRCTN84229105. Registered on 25 July 2014.
An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial
Authors:   for the NeoVanc Consortium, Hill Louise F. , Turner Mark A. , Lutsar Irja , Heath Paul T. , Hardy Pollyanna , Linsell Louise , Jacqz-Aigrain Evelyne , Roilides Emmanuel , Sharland Mike
Published: April 2020

Background

Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin’s continued efficacy.

Methods

NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excludingStaphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation.

The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA.

The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h.

Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.

Discussion

Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.

Trial registration

ClinicalTrials.gov,NCT02790996. Registered on 7 April 2016.

EudraCT, 2015–000203-89. Entered on 18 July 2016.
Distribution and diversity of olefins and olefin-biosynthesis genes in Gram-positive bacteria
Authors: Surger Maximilian , Angelov Angel , Liebl Wolfgang
Published: April 2020

Background

The natural production of olefins (unsaturated aliphatic hydrocarbons) by certain bacterial genera represents an alternative and sustainable source of biofuels and lubricant components. The biochemical steps of olefin biosynthesis via the ole pathway encoded by oleABCD have been unraveled recently, and the occurrence of olefins has been reported for several Gram-negative and Gram-positive bacteria. However, the distribution and diversity of olefins among the Gram-positive bacteria has not been studied in detail.

Results

We report the distribution of olefin synthesis gene clusters in the bacterial domain and focus on the olefin composition and the determinants of olefin production within the phylum of Actinobacteria. The olefin profiles of numerous genera of the Micrococcales order were analyzed by GC/MS. We describe for the first time olefin synthesis in representatives of the genera Pseudarthrobacter, Paenarthrobacter, Glutamicibacter, Clavibacter, Rothia, Dermacoccus, Kytococcus, Curtobacterium, and Microbacterium. By exchange of the native ole genes of Micrococcus luteus with the corresponding genes of actinobacteria producing different olefins, we demonstrate that the olefin composition can be manipulated with respect to chain length and isomer composition.

Conclusions

This study provides a catalogue of the diversity of olefin structures found in the Actinobacteria. Our ole gene swapping data indicate that the olefin structures are fundamentally determined by the substrate specificity of OleA, and at the same time by the availability of a sufficient supply of suitable fatty acyl-CoA substrates from cellular fatty acid metabolism. This makes OleA of Gram-positive bacteria a promising target for structural analysis and protein engineering aiming to generate olefin chain lengths and isomer profiles which are designed to match the requirements of various industrial applications.
Strategies for the production of biochemicals in bioenergy crops
Authors: Lin Chien-Yuan , Eudes Aymerick
Published: April 2020

Industrial crops are grown to produce goods for manufacturing. Rather than food and feed, they supply raw materials for making biofuels, pharmaceuticals, and specialty chemicals, as well as feedstocks for fabricating fiber, biopolymer, and construction materials. Therefore, such crops offer the potential to reduce our dependency on petrochemicals that currently serve as building blocks for manufacturing the majority of our industrial and consumer products. In this review, we are providing examples of metabolites synthesized in plants that can be used as bio-based platform chemicals for partial replacement of their petroleum-derived counterparts. Plant metabolic engineering approaches aiming at increasing the content of these metabolites in biomass are presented. In particular, we emphasize on recent advances in the manipulation of the shikimate and isoprenoid biosynthetic pathways, both of which being the source of multiple valuable compounds. Implementing and optimizing engineered metabolic pathways for accumulation of coproducts in bioenergy crops may represent a valuable option for enhancing the commercial value of biomass and attaining sustainable lignocellulosic biorefineries.
Differential regulation and correlation between galectin-9 and anti-CCP antibody (ACPA) in rheumatoid arthritis patients
Authors: Fujita Yuya , Asano Tomoyuki , Matsuoka Naoki , Temmoku Jumpei , Sato Shuzo , Matsumoto Haruki , Furuya Makiko Yashiro , Suzuki Eiji , Watanabe Hiroshi , Kawakami Atsushi , Migita Kiyoshi
Published: April 2020

Background

Galectin-9 (Gal-9) is involved in the regulatory process of immune responses or inflammation. The aim of the present study is to characterize circulating Gal-9 in patients with rheumatoid arthritis (RA) and its relationship with RA disease activity and phenotype.

Methods

A total of 116 RA patients and 31 age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joint scoring system (DAS28-ESR). Levels of Gal-9 in serum were determined by enzyme-linked immunosorbent assay (ELISA).

Results

Serum levels of Gal-9 were significantly higher in patients with RA compared to those in controls (median 7577 pg/ml [interquartile range (IQR) 5570–10,201] versus 4738 pg/ml [IQR 4267–5630], p = 0.001). There were significant differences in serum Gal-9 between RA patients with and without RA-ILD (9606 pg/ml [IQR 8522–12,167] versus 7078 pg/ml [IQR 5225–9447], p < 0.001) or those with and without advanced joint damage (stage II–IV, 9606 pg/ml [IQR 8522–12,167] versus 7078 pg/ml [IQR 5225–9447], p < 0.001). Although serum levels of Gal-9 correlated with the titers of ACPA (r = 0.275, p = 0.002), levels of ACPA titers conferred the different relationship, between serum Gal-9 and inflammatory mediators or RA disease activity. Although Gal-9 was correlated with ACPA titers (r = 0.508, p = 0.002), there was no correlation between Gal-9 levels and erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3 (MMP-3), or DAS28-ESR in RA patients with high titers of ACPA (> 200 U/ml). Conversely, Gal-9 was correlated with MMP-3 (r = 0.300, p = 0.007) or DAS28-ESR (r = 0.331, p = 0.004) but not with ACPA titer in RA patients with low titers of ACPA titers (< 200 U/ml).

Conclusions

Serum levels of Gal-9 were increased in RA patients and associated with RA disease activity in RA patients without high titers of ACPA. The levels of ACPA titers may influence the values of circulating Gal-9 in RA patients with various clinical phenotypes. These data suggest that Gal-9 possessed the properties of pro-inflammatory or arthropathic biomarker under the status of ACPA titers.
Retrospective analysis of infliximab and adalimumab treatment in a large cohort of juvenile dermatomyositis patients
Authors:   for the Juvenile Dermatomyositis Research Group (JDRG), Campanilho-Marques Raquel , Deakin Claire T. , Simou Stefania , Papadopoulou Charalampia , Wedderburn Lucy R. , Pilkington Clarissa A.
Published: April 2020

Background

Anti-TNF treatment may be useful for the treatment of patients with refractory juvenile dermatomyositis (JDM). The aim of this study was to describe the use of infliximab and adalimumab therapy in juvenile dermatomyositis as an adjunctive treatment.

Methods

Sixty children recruited to the UK JDM Cohort and Biomarker Study that had received at least 3 months of anti-TNF treatment (infliximab or adalimumab) were studied. Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing (MMT8) and physician’s global assessment (PGA) were recorded. Skin disease was assessed using the modified skin disease activity score (DAS). Data were analysed using Friedman’s test for repeated measures analysis of variance.

Results

Compared to baseline, there were improvements at 6 and 12 months in skin disease (χ2(2) = 15.52, p = 0.00043), global disease (χ2(2) = 8.14, p = 0.017) and muscle disease (CMAS χ2(2) = 17.02, p = 0.0002 and MMT χ2(2) = 10.56, p = 0.005) in infliximab patients. For patients who switched from infliximab to adalimumab, there was improvement in global disease activity (χ2(2) = 6.73, p = 0.03), and trends towards improvement in CMAS, MMT8 and modified DAS. The median initial prednisolone dose was 6 [0–10] mg, and final was 2.5 [0–7.5] mg (p < 0.0001). Fifty-four per cent of patients had a reduction in the number and/or size of calcinosis lesions. Twenty-five per cent switched their anti-TNF treatment from infliximab to adalimumab. 66.7%of the switches were to improve disease control, 26.7% due to adverse events and 6.6% due to patient preference. A total of 13.9 adverse reactions occurred in 100 patient-years, of which 5.7 were considered serious.

Conclusion

Reductions in muscle and skin disease, including calcinosis, were seen following treatment with infliximab and adalimumab.
Transgenic conversion of ω-6 to ω-3 polyunsaturated fatty acids via fat-1 reduces the severity of post-traumatic osteoarthritis
Authors: Kimmerling Kelly A. , Oswald Sara J. , Huebner Janet L. , Little Dianne , Kraus Virginia B. , Kang Jing X. , Wu Chia-Lung , Guilak Farshid
Published: April 2020

Background

Dietary fatty acid (FA) content has been shown to influence the development of post-traumatic osteoarthritis (PTOA) in obesity. We used the fat-1 transgenic mouse to examine the hypothesis that endogenous reduction of ω-6 to ω-3 FA ratio, under the same dietary conditions, would mitigate metabolic inflammation and the pathogenesis of PTOA in obese male and female mice.

Methods

Male and female fat-1 and wild-type littermates were fed either a control diet or an ω-6 FA-rich high-fat diet and underwent destabilization of the medial meniscus (DMM) surgery to induce PTOA. OA severity, synovitis, and osteophyte formation were determined histologically, while biomarker and lipidomic analyses were performed to evaluate levels of adipokines, insulin, pro-/anti-inflammatory cytokines, and FAs in serum and joint synovial fluid. Multivariable models were performed to elucidate the associations of dietary, metabolic, and mechanical factors with PTOA.

Results

We found that elevated serum levels of ω-3 FAs in fat-1 mice as compared to wild-type controls fed the same diet resulted in reduced OA and synovitis in a sex- and diet-dependent manner, despite comparable body weights. The fat-1 mice showed trends toward decreased serum pro-inflammatory cytokines and increased anti-inflammatory cytokines. Multivariable analysis for variables predicting OA severity in mice resulted in correlations with serum FA levels, but not with body weight.

Conclusions

This study provides further evidence that circulating FA composition and systemic metabolic inflammation, rather than body weight, may be the major risk factor for obesity-associated OA. We also demonstrate the potential genetic use of ω-3 FA desaturase in mitigating PTOA in obese patients following injury.
Antibacterial activity of ethoxzolamide against Helicobacter pylori strains SS1 and 26695
Authors: Rahman Mohammad M. , Tikhomirova Alexandra , Modak Joyanta K. , Hutton Melanie L. , Supuran Claudiu T. , Roujeinikova Anna
Published: April 2020

With the rise of bacterial resistance to conventional antibiotics, re-purposing of Food and Drug Administration (FDA) approved drugs currently used to treat non-bacteria related diseases as new leads for antibacterial drug discovery has become an attractive alternative. Ethoxzolamide (EZA), an FDA-approved diuretic acting as a human carbonic anhydrase inhibitor, is known to kill the gastric pathogenic bacterium Helicobacter pylori in vitro via an, as yet, unknown mechanism. To date, EZA activity and resistance have been investigated for only one H. pylori strain, P12. We have now performed a susceptibility and resistance study with H. pylori strains SS1 and 26695. Mutants resistant to EZA were isolated, characterized and their genomes sequenced. Resistance-conferring mutations were confirmed by backcrossing the mutations into the parent strain. As with P12, resistance to EZA in strains SS1 and 26695 does not develop easily, since the rate of spontaneous resistance acquisition was less than 10−8. Acquisition of resistance was associated with mutations in 3 genes in strain SS1, and in 6 different genes in strain 26695, indicating that EZA targets multiple systems. All resistant isolates had mutations affecting cell wall synthesis and control of gene expression. EZA’s potential for treating duodenal ulcers has already been demonstrated. Our findings suggest that EZA may be developed into a novel anti-H. pylori drug.
Prevalence and antimicrobial susceptibility of Arcobacter species in human stool samples derived from out- and inpatients: the prospective German Arcobacter prevalence study Arcopath
Authors: Brückner Vanessa , Fiebiger Ulrike , Ignatius Ralf , Friesen Johannes , Eisenblätter Martin , Höck Marlies , Alter Thomas , Bereswill Stefan , Gölz Greta , Heimesaat Markus M.
Published: April 2020

Background

Arcobacter species, particularly A. butzleri, but also A. cryaerophilus constitute emerging pathogens causing gastroenteritis in humans. However, isolation of Arcobacter may often fail during routine diagnostic procedures due to the lack of standard protocols. Furthermore, defined breakpoints for the interpretation of antimicrobial susceptibilities of Arcobacter are missing. Hence, reliable epidemiological data of human Arcobacter infections are scarce and lacking for Germany. We therefore performed a 13-month prospective Arcobacter prevalence study in German patients.

Results

A total of 4636 human stool samples was included and Arcobacter spp. were identified from 0.85% of specimens in 3884 outpatients and from 0.40% of specimens in 752 hospitalized patients. Overall, A. butzleri was the most prevalent species (n = 24; 67%), followed by A. cryaerophilus (n = 10; 28%) and A. lanthieri (n = 2; 6%). Whereas A. butzleri, A. cryaerophilus and A. lanthieri were identified in outpatients, only A. butzleri could be isolated from samples of hospitalized patients. Antimicrobial susceptibility testing of Arcobacter isolates revealed high susceptibilities to ciprofloxacin, whereas bimodal distributions of MICs were observed for azithromycin and ampicillin.

Conclusions

In summary, Arcobacter including A. butzleri, A. cryaerophilus and A. lanthieri could be isolated in 0.85% of German outpatients and ciprofloxacin rather than other antibiotics might be appropriate for antibiotic treatment of infections. Further epidemiological studies are needed, however, to provide a sufficient risk assessment of Arcobacter infections in humans.
Effect of inspiratory muscle-loaded exercise training on peak oxygen uptake and ventilatory response during incremental exercise under normoxia and hypoxia
Authors: Ogawa Takeshi , Nagao Maiko , Fujii Naoto , Nishiyasu Takeshi
Published: April 2020

Background

Although numerous studies have reported the effect of inspiratory muscle training for improving exercise performance, the outcome of whether exercise performance is improved by inspiratory muscle training is controversial. Therefore, this study investigated the influence of inspiratory muscle-loaded exercise training (IMLET) on peak oxygen uptake (VO2peak), respiratory responses, and exercise performance under normoxic (N) and hypoxic (H) exercise conditions. We hypothesised that IMLET enhances respiratory muscle strength and improves respiratory response, thereby improvingVO2peakand work capacity under H condition.

Methods

Sixteen university track runners (13 men and 3 women) were randomly assigned to the IMLET (n = 8) or exercise training (ET) group (n = 8). All subjects underwent 4 weeks of 20-min 60%VO2peakcycling exercise training, thrice per week. IMLET loaded 50% of maximal inspiratory pressure during exercise. At pre- and post-training periods, subjects performed exhaustive incremental cycling under normoxic (N; 20.9 ± 0%) and hypoxic (H; 15.0 ± 0.1%) conditions.

Results

Although maximal inspiratory pressure (PImax) significantly increased after training in both groups, the extent of PImax increase was significantly higher in the IMLET group (from 102 ± 20 to 145 ± 26 cmH2O in IMLET; from 111 ± 23 to 127 ± 23 cmH2O in ET;P < 0.05). In both groups,VO2peakand maximal work load (Wmax) similarly increased both under N and H conditions after training (P < 0.05). Further, the extent of Wmaxdecrease under H condition was lower in the IMLET group at post-training test than at pre-training (from − 14.7 ± 2.2% to − 12.5 ± 1.7%;P < 0.05). Maximal minute ventilation in both N and H conditions increased after training than in the pre-training period.

Conclusions

Our IMLET enhanced the respiratory muscle strength, and the decrease in work capacity under hypoxia was reduced regardless of the increase inVO2peak.
Comparative evaluation of 68Ga-labelled TATEs: the impact of chelators on imaging
Authors: Xia Yuxiao , Zeng Chengrun , Zhao Yanhong , Zhang Xinyi , Li Zibo , Chen Yue
Published: April 2020

Background

68Ga-labelled peptides targeting somatostatin receptor 2 (SSTR2) have demonstrated encouraging results in managing patients with neuroendocrine tumours (NETs). In addition to metal chelation, bifunctional chelators have also been found to impact imaging outcomes due to their differences in stability, charge, hydrophilicity, etc. In the present work, a comparative pharmacokinetic evaluation and imaging characteristics were performed between 68Ga-labelled somatostatin analogues (TATE) using NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as bifunctional chelating agents (BFCAs).

Results

Both 68Ga-NOTA-TATE and 68Ga-DOTA-TATE were obtained with high radiochemical purity. 68Ga-NOTA-TATE demonstrated higher in vitro stability (≥ 99%) than 68Ga-DOTA-TATE (≥ 95%) after 3 h of incubation. The water solubilities (partition coefficients, − 1.76 ± 0.06 vs. − 2.72 ± 0.16) and plasma protein binding rates (12.12% vs. 30.6%) were lower for 68Ga-NOTA-TATE than for 68Ga-DOTA-TATE. Differential pharmacokinetics and comparable tumour affinities (within 1 h) were observed in AR42J tumour-bearing mice. Healthy volunteer imaging studies showed comparable distribution patterns of these two imaging agents. However, the maximum standardized uptake values (SUVmax) of the two tracers varied in each organ. The two PET agents demonstrated almost identical SUVmax values in the kidneys. 68Ga-NOTA-TATE did have a lower SUVmax in most other organs compared with 68Ga-DOTA-TATE, including the liver (4.2 vs. 10.1), potentially due to the lower protein binding rate.

Conclusion

68Ga-NOTA-TATE and 68Ga-DOTA-TATE demonstrated comparable tumour uptake in an AR42J mouse model. An initial clinical study revealed that 68Ga-NOTA-TATE may have reduced background uptake in the major organs such as the liver. Although the subject numbers were limited, further investigation of 68Ga-NOTA-TATE is warranted for detecting SSTR2-positive neuroendocrine tumours.
Generalizations of some classical theorems to D-normal operators on Hilbert spaces
Authors: Dana M. , Yousefi R.
Published: April 2020

We say that a Drazin invertible operatorTon Hilbert space is of class$[DN]$[DN]if$T^{D}T^{*} = T^{*}T^{D}$TDT∗=T∗TD. The authors in (Oper. Matrices 12(2):465–487, 2018) studied several properties of this class. We prove the Fuglede–Putnam commutativity theorem for D-normal operators. Also, we show thatThas the Bishop property$(\beta)$(β). Finally, we generalize a very famous result on products of normal operators due to I. Kaplansky to D-normal matrices.
Emerging coexistence of three PMQR genes on a multiple resistance plasmid with a new surrounding genetic structure of qnrS2 in E. coli in China
Authors: Tao Ying , Zhou Kaixin , Xie Lianyan , Xu Yanping , Han Lizhong , Ni Yuxing , Qu Jieming , Sun Jingyong
Published: April 2020

Background

Quinolones are commonly used for treatment of infections by bacteria of the Enterobacteriaceae family. However, the rising resistance to quinolones worldwide poses a major clinical and public health risk. This study aimed to characterise a novel multiple resistance plasmid carrying three plasmid-mediated quinolone resistance genes in Escherichia coli clinical stain RJ749.

Methods

MICs of ceftriaxone, cefepime, ceftazidime, ciprofloxacin, and levofloxacin for RJ749 and transconjugant c749 were determined by the Etest method. Conjugation was performed using sodium azide-resistant E. coli J53 strain as a recipient. The quinolone resistance-determining regions of gyrA, gyrB, parC, and parE were PCR-amplified.

Results

RJ749 was highly resistant to quinolones, while c749 showed low-level resistance. S1-nuclease pulsed-field gel electrophoresis revealed that RJ749 and c749 both harboured a plasmid. PCR presented chromosomal mutation sites of the quinolone resistance-determining region, which mediated quinolone resistance. The c749 genome comprised a single plasmid, pRJ749, with a multiple resistance region, including three plasmid-mediated quinolone resistance (PMQR) genes (aac (6′)-Ib-cr, qnrS2, and oqxAB) and ten acquired resistance genes. One of the genes, qnrS2, was shown for the first time to be flanked by two IS26s. Three IS26-mediated circular molecules carrying the PMQR genes were detected.

Conclusions

We revealed the coexistence of three PMQR genes on a multiple resistance plasmid and a new surrounding genetic structure of qnrS2 flanked by IS26 elements. IS26 plays an important role in horizontal spread of quinolone resistance.
Inferring residency and movement patterns of horse-eye jack Caranx latus in relation to a Caribbean marine protected area acoustic telemetry array
Authors: Novak Ashleigh J. , Becker Sarah L. , Finn John T. , Danylchuk Andy J. , Pollock Clayton G. , Hillis-Starr Zandy , Jordaan Adrian
Published: April 2020

Background

Information regarding the movement ecology of horse-eye jack Caranx latus throughout the Caribbean is limited despite their prevalence. Passive acoustic telemetry was used to infer movement patterns of seven adult C. latus within Buck Island Reef National Monument (BIRNM), a no-take marine protected area (MPA) northeast of St. Croix, U.S. Virgin Islands. In addition, a preliminary exploration of detections recorded outside of BIRNM was used to gain knowledge of the potential for larger scale movements. Ascertaining long-term movement patterns, including residency, mobility, and identifying core activity spaces can play a considerable role in how MPAs, like BIRNM, are adapted to meet the needs of mobile species.

Results

High residency index values were observed for individual C. latus within the BIRNM array (mean ± SE: 0.913 ± 0.04, range 0.75–1.0) across the 17 months monitored. Most fish were also detected on receivers located outside BIRNM. An observed to expected detection ratio revealed that despite high residency, only 9.6% of expected transmissions were detected based on the average tag transmission rate. Network analysis revealed high individual connectivity with many of the receivers inside BIRNM and a large number of core use receivers (mean: 10.7, range 6–14) within individual networks.

Conclusions

Most C. latus were present in BIRNM at least twice per day, but were overall detected below the expected rates, demonstrating mobility, large core activity spaces and wide use of the acoustic array inside BIRNM and greater St. Croix shelf. How residency is inferred from acoustic telemetry detections, and interpreted for species with variable mobility, has important considerations for spatial management planning and telemetry analyses. For MPA development to meet the spatial requirements of species with mixed resident–mobile spatial ecology, detailed long-term movement data are required. Assessing residency in MPAs using acoustic telemetry should be formalized and carefully interpreted based on specific species, environmental conditions, and array configuration.
Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes
Authors: Tsymala Irina , Nigritinou Magdalini , Zeka Bleranda , Schulz Rouven , Niederschick Felix , Matković Mia , Bauer Isabel J. , Szalay Michael , Schanda Kathrin , Lerch Magdalena , Misu Tatsuro , Fujihara Kazuo , Bennett Jeffrey L. , Dahle Charlotte , Pache Florence , Rommer Paulus , Leutmezer Fritz , Illes Zsolt , Leite Maria Isabel , Palace Jacqueline , Scholze Petra , Reindl Markus , Lassmann Hans , Bradl Monika
Published: April 2020

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
Further evidence of Ceratobasidium D.P. Rogers (Basidiomycota) serving as the ubiquitous fungal associate of Platanthera leucophaea (Orchidaceae) in the North American tallgrass prairie
Authors: Thixton Hana L. , Esselman Elizabeth J. , Corey Laura L. , Zettler Lawrence W.
Published: April 2020

Background

In the United States and Canada, ca. one-half of native orchid species are now threatened with extinction. A number of these species are restricted to tallgrass prairies of central North America, such as the Eastern Prairie Fringed Orchid, Platanthera leucophaea (Nutt.) Lindl.—a U.S. Federally threatened species.

Results

We provide new records of fungi recovered from roots of P. leucophaea and five other orchid species inhabiting prairie sites in Illinois and neighboring states during a 10-year period (2008–2017). A total of 39 fungal endophytes were isolated from Cypripedium candidum (1), Platanthera lacera (1), P. leucophaea (32), P. peramoena (3), Spiranthes lacera (1), and S. magnicamporum (1), 31 (79%) of which were assignable to Ceratobasidium and the remainder to Tulasnella. These fungi were acquired from 16 different sites, 13 of which are new records including two new state records (Iowa, Wisconsin). Molecular analysis revealed that some Ceratobasidium strains were virtually identical despite being geographically isolated by > 300 km.

Conclusions

This study, encompassing a decade of work, confirms that Platanthera leucophaea is a mycorrhizal specialist with heavy reliance on Ceratobasidium with the tallgrass prairie ecosystem of North America. Our isolation of Ceratobasidium from P. leucophaea spanning additional sites suggests that the association is widespread. Such information should provide conservationists and land managers with more confidence in developing protocols that facilitate the long-term conservation of this prairie orchid.
Spinal cord autoregulation using near-infrared spectroscopy under normal, hypovolemic, and post-fluid resuscitation conditions in a swine model: a comparison with cerebral autoregulation
Authors: Kurita Tadayoshi , Kawashima Shingo , Morita Koji , Nakajima Yoshiki
Published: April 2020

Background

Few studies have investigated spinal cord autoregulation using near-infrared spectroscopy (NIRS). Here, we assessed spinal cord autoregulation under normal, hypovolemic, and post-fluid resuscitation conditions compared with cerebral autoregulation.

Methods

Ten pigs (36.1 ± 1.1 kg) were anesthetized with 2.5% isoflurane, before phenylephrine administration at 0.5, 1, 2, and 5 μg kg−1 min−1in a stepwise fashion at 10-min intervals (baseline), followed by similar administration of sodium nitroprusside (SNP). Hypovolemia was induced by a 600-ml bleed (25% estimated total blood volume). Only phenylephrine was readministered (same protocol). Hypovolemia was reversed by infusing 600 ml hydroxyethyl starch, before readministering phenylephrine and SNP. The relationships between mean arterial pressure (MAP) and cerebral, thoracic, and lumbar spinal cord tissue oxygenation indices (TOIs) were evaluated.

Results

Thoracic and lumbar spinal cord TOIs were approximately 15% and 10% lower, respectively, than the cerebral TOI at similar MAPs. The average relationship between MAP and each TOI showed an autoregulatory pattern, but negative correlations were observed in the cerebral TOI during phenylephrine infusion. A 600-ml bleed lowered each relationship < 5% and subsequent fluid resuscitation did not change the relationship. Individual oxygenation responses to blood pressure indicated that the spinal cord is more pressure-passive than the cerebrum. Paradoxical responses (an inverse relationship of tissue oxygenation to MAP) were observed particularly in cerebrum during phenylephrine infusion and were rare in the spinal cord.

Conclusions

Spinal cord autoregulation is less robust than cerebral autoregulation and more pressure-dependent. Similar to cerebral oxygenation, spinal cord oxygenation is volume-tolerant but is more sensitive to hypotension.
Psychological therapy for mood instability within bipolar spectrum disorder: a single-arm feasibility study of a dialectical behaviour therapy-informed approach
Authors: Wright Kim , Palmer Gemma , Javaid Mahmood , Mostazir Mohammod , Lynch Tom
Published: April 2020

Background

We sought to evaluate the acceptability of a psychological therapy programme (Therapy for Inter-episode Mood Variability in Bipolar Disorder (ThrIVe-B)) for individuals with ongoing bipolar mood instability and the feasibility and acceptability of potential trial procedures. We also evaluated the performance of clinical and process outcome measures and the extent to which the programme potentially represents a safe and effective intervention.

Method

We conducted an open (uncontrolled) trial in which 12 individuals with a bipolar spectrum diagnosis commenced the ThrIVe-B programme after completing baseline assessments. The programme comprised 16 group skills training sessions plus individual sessions and a supporting smartphone application. Follow-up assessments were at therapy end-point and 6 months post-treatment.

Results

Nine participants completed treatment. Ten provided end-of-treatment data; of these, nine were satisfied with treatment. Interviews with participants and clinicians indicated that the treatment was broadly feasible and acceptable, with suggestions for improvements to content, delivery and study procedures. Exploration of change in symptoms was consistent with the potential for the intervention to represent a safe and effective intervention.

Conclusions

Conducting further evaluation of this approach in similar settings is likely to be feasible, whilst patient reports and the pattern of clinical change observed suggest this approach holds promise for this patient group. Future research should include more than one study site and a comparison arm to address additional uncertainties prior to a definitive trial.

Trial registration

Trial Registration: ClinicalTrials.gov NCT02637401; registered 22.12.15 (retrospectively registered).