bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of second-line therapy in IVIg-refractory Kawasaki disease: a systematic review
Authors: Crayne Courtney B. , Mitchell Chace , Beukelman Timothy
Published: November 2019

Background

Evidence remains contradictory regarding second-line therapy in patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIg). The objective of this study aims to evaluate the efficacy and safety of three treatments [i.e. a second IVIg infusion, methylprednisolone (IVMP), and infliximab (IFX)] in patients with refractory KD.

Methods

A systematic search of PubMed, Embase, Cochrane, and ClinicalTrials.gov using predefined MeSH terms was performed from 1990 through 2017. Relevance screening was performed by two independent reviewers. Inclusion criteria included English-only, original clinical data. Eight studies met the inclusion criteria. Fever resolution, coronary lesions, and adverse event outcomes were extracted and pooled for analysis.

Results

Of the 388 patients included from the 8 studies analyzed, a majority received a second IVIg dose (n = 263, 68%). Fever resolution was comparable between IVIg (72%) and IVMP (73%). IFX (88%) significantly increased fever resolution by approximately 20% compared to IVIg re-dose (RR 1.2; [95% CI: 1.1–1.4]; p = 0.03) and IVMP (RR 1.2; [95% CI: 1.0–1.5]; p = 0.04). Clinical significance of differences in coronary outcomes remains unclear.

Conclusions

This combined analysis was limited due to variability in design and data reporting methods between the studies and risk of bias. In the absence of a clinical trial, IFX monotherapy as second-line treatment should be considered in patients who fail to respond to initial IVIg. This conclusion is based on a systematic review of the literature with pooled outcome data analysis suggesting IFX is more effective in fever resolution compared to a second IVIg dose and IVMP.
Protein target identification and toxicological mechanism investigation of silver nanoparticles-induced hepatotoxicity by integrating proteomic and metallomic strategies
Authors: Xu Ming , Yang Qiuyuan , Xu Lining , Rao Ziyu , Cao Dong , Gao Ming , Liu Sijin
Published: November 2019

Background

Silver nanoparticles (AgNPs), as promising anti-microbials and anti-cancer therapeutics, the toxicological effect and killing efficiency towards cells need in-depth investigation for better applications in daily life and healthcare fields. Thus far, limited studies have yet elucidated the protein targets of AgNPs and silver ions (Ag+) released from intracellular AgNPs dissolution in hepatocytes, as well as potential interaction mechanism.

Results

Through integrating proteomic and metallomic methodologies, six intracellular protein targets (i.e. glutathione S-transferase (GST), peroxiredoxin, myosin, elongation factor 1, 60S ribosomal protein and 40S ribosomal protein) were ultimately identified and confirmed as AgNPs- and Ag+ −binding proteins. Toward a deep understanding the direct interaction mechanism between AgNPs and these protein targets, GST was chosen as a representative for toxicological investigation. The results revealed that AgNPs could remarkably deplete the enzyme activity of GST but did not depress the expressions, resulting in elevated intracellular oxidative stress and cell death. Finally, both “Ag+ effect” and “particle-specific effect” were demonstrated to concomitantly account for the overall cytotoxicity of AgNPs, and the former relatively contributed more via activity depletion of GST.

Conclusions

Collectively, our major contribution is the development of an efficient strategy to identify the intracellular AgNPs-targeted protein (e.g. GST) through integrating proteomic and metallomic methodologies, which is helpful to accelerate the interpretation of underlying toxicological mechanism of AgNPs.
Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines
Authors: Todorovic Vesna , Prevc Ajda , Zakelj Martina Niksic , Savarin Monika , Brozic Andreja , Groselj Blaz , Strojan Primoz , Cemazar Maja , Sersa Gregor
Published: November 2019

Background

Treatment options for recurrent head and neck tumours in the previously irradiated area are limited, including re-irradiation due to radioresistance of the recurrent tumour and previous dose received by surrounding normal tissues. As an in vitro model to study radioresistance mechanisms, isogenic cells with different radiosensitivity can be used. However, they are not readily available. Therefore, our objective was to establish and characterize radioresistant isogenic human pharyngeal squamous carcinoma cells and to evaluate early radiation response in isogenic parental, radioresistant and radiosensitive cells.

Methods

Radioresistant cells were derived from parental FaDu cells by repeated exposure to ionizing radiation. Radiosensitivity of the established isogenic radioresistant FaDu-RR cells was evaluated by clonogenic assay and compared to isogenic parental FaDu and radiosensitive 2A3 cells. Additional phenotypic characterization of these isogenic cells with different radiosensitivity included evaluation of chemosensitivity, cell proliferation, cell cycle, radiation-induced apoptosis, resolution of DNA double-strand breaks, and DNA damage and repair signalling gene expression before and after irradiation.

Results

In the newly established radioresistant cells in response to 5 Gy irradiation, we observed no alteration in cell cycle regulation, but delayed induction and enhanced resolution of DNA double-strand breaks, lower induction of apoptosis, and pronounced over-expression of DNA damage signalling genes in comparison to parental cells. On the other hand, radiosensitive 2A3 cells were arrested in G2/M-phase in response to 5 Gy irradiation, had a prominent accumulation of and slower resolution of DNA double-strand breaks, and no change in DNA damage signalling genes expression.

Conclusions

We concluded that the emergence of the radioresistance in the established radioresistant isogenic cells can be at least partially attributed to the enhanced DNA double-strand break repair, altered expression of DNA damage signalling and repair genes. On the other hand, in radiosensitive isogenic cells the reduced ability to repair a high number of induced DNA double-strand breaks and no transcriptional response in DNA damage signalling genes indicate on a lack of adaptive response to irradiation. Altogether, our results confirmed that these isogenic cells with different radiosensitivity are an appropriate model to study the mechanisms of radioresistance.
Intra-articular platelet-rich plasma injection for knee osteoarthritis: a summary of meta-analyses
Authors: Chen Pu , Huang Liuwei , Ma Yufeng , Zhang Dong , Zhang Xiaozhe , Zhou Jun , Ruan Anmin , Wang Qingfu
Published: November 2019

Objective

The purpose of this study was (1) to perform a summary of meta-analyses comparing platelet-rich plasma (PRP) injection with hyaluronic acid (HA) and placebo injection for KOA patients, (2) to determine which meta-analysis provides the best available evidence to making proposals for the use of PRP in the treatment of KOA patients, and (3) to highlight gaps in the literature that require future investigation.

Material and methods

PubMed, EMBASE, and Cochrane databases search were performed for meta-analyses which compared PRP injection with HA or placebo. Clinical outcomes and adverse events were extracted from these meta-analyses. Meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses (QUOROM) systems and the Oxman-Guyatt quality appraisal tool. The Jadad decision algorithm was also used to determine which meta-analysis provided the best available evidence.

Results

Four meta-analyses were included in our study, and all of these articles were Level I evidence. The QUOROM score of each included meta-analysis range from 14 to 17 points (mean score 15, maximum score 18), and the Oxman-Guyatt score range from 4 to 6 points (mean score 5, maximum score 7). Three meta-analyses indicated PRP showed more benefit in pain relief and functional improvement than the control group, and the other one suggested no difference between these groups. All included meta-analyses found no statistical difference in adverse events between these groups. In addition, a meta-analysis conducted by Shen et al. got the highest methodological quality score and suggested that PRP provided better pain relief and function improvement in the treatment of KOA.

Conclusions

For short-term follow-up (≤1 year), intra-articular PRP injection is more effective in terms of pain relief and function improvement in the treatment of KOA patients than HA and placebo, and there is no difference in the risk of an adverse event between PRP and HA or placebo.

Level of evidence

Level I evidence, a summary of meta-analyses

Trial registration

PROSPERO ID CRD42018116168
Three-dimensional-printed custom-made hemipelvic endoprosthesis for primary malignancies involving acetabulum: the design solution and surgical techniques
Authors: Wang Jie , Min Li , Lu Minxun , Zhang Yuqi , Wang Yitian , Luo Yi , Zhou Yong , Duan Hong , Tu Chongqi
Published: November 2019

Background

This study is to describe the detailed design and surgical techniques of three-dimensional (3D)-printed custom-made endoprosthesis for hemipelvic tumorous bone defect.

Methods

According to the pelvic tumor resection classification by Enneking and Dunham, the hemipelvis is divided into three zones including the ilium (P1), acetabulum (P2), and pubis and ischium (P3). Thirteen patients were included in this study. Of these, P1 and P2 were involved in three cases, while P1, P2, and P3 were involved in 10. Based on radiography data, 3D pelvic model was rebuilt, and virtual surgery was simulated. Different fixation methods were applied according to residual bone volume. Parameters of the first sacral (S1) vestibule, second sacral (S2) vestibule, the narrowest zone of superior pubic medullary cavity (NPSPMC), and the resected surface of superior pubic medullary cavity (RSSPMC) were selectively measured in various fixation methods. Model overlapping, feature simplifying, and size controlling were three basic steps during design procedure. Volume proportion of porous structure was determined according to estimated weight of resected specimen. Acetabular location, anteversion, and inclination were modulated. Screw diameter, direction, and combination were considered. The osteotomy guides and plastic models were used during surgery.

Results

Of 13 cases, after P1 resection, endoprostheses were fixed to sacra (8; 61.5%), ilia (3; 23.1%), and both (2; 15.4%). After P3 resection, endoprostheses were fixed to residual acetabulum (3; 23.1%), and residual pubis by stem (8; 61.5%) or “cap-like” structure (2; 15.4%). Mean area of the S1vestibule, S2vestibule, RSSPMC, and PSPMC were 327.9 (222.2 to 400), 131.7 (102.6 to 163.6), 200.5 (103.8 to 333.2), and 79.8 mm2(40.4 to 126.2), respectively. Porous structure with 600 μm pore size and 70% porosity accounted for 68.8% (53.0 to 86.0) of the whole endoprosthesis on average. Mean acetabular anteversion and inclination were designed as 23.2° (20 to 25) and 42.4° (40 to 45). Median numbers of screws designed in the S1vestibule was 5 (IQR, 4 to 6), in the S2 vestibule was 1 (IQR, 1 to 2), in the ilium was 5 (IQR, 2 to 6), and in the pubis was 1 (IQR, 1 to 1), while screws designed in the ischium was all 2. Median number of screws inserted in the S1vestibule was 4 (IQR, 3 to 4), in the S2vestibule was 1 (IQR, 1 to 1), in the ilium was 3 (IQR, 1 to 5), in the pubis was 1 (IQR, 0 to 1), and in the ischium was 1 (IQR, 1 to 1).

Conclusions

This study firstly presents detailed design and related surgical techniques of 3D-printed custom-made hemipelvic endoprosthesis reconstruction. Osseointegration is critical for long-term outcome and requires three design elements including interface connection, porous structure, and initial stability achieved by precise matching and proper fixation methods.
TAVI-in-homograft (TiH): open transcatheter aortic valve replacement in calcified aortic homograft case reports
Authors: Gennari Marco , Giambuzzi Ilaria , Polvani Gianluca , Agrifoglio Marco
Published: November 2019

Background

Redo surgery in patient who underwent aortic valve replacement with an aortic homograft can result technically challenging because of the massive calcification of the conduit.

Case presentation

We present a case of a patient who underwent open surgery on cardiopulmonary bypass assistance to implant a standard transcatheter aortic bioprosthesis through aortotomy in an off-label procedure and we discuss its safety and feasibility.

Conclusions

The combination of open cardiac surgery and open trans-aortic implant of a transcatheter prosthesis may reduce the surgical risk shrinking the technical difficulties that the implantation of a standard surgical prosthesis would have given.
Predictive value of transabdominal intestinal sonography in critically ill patients: a prospective observational study
Authors: Gao Tao , Cheng Min-Hua , Xi Feng-Chan , Chen Yan , Cao Chun , Su Ting , Li Wei-Qin , Yu Wen-Kui
Published: November 2019

Background

This study examined the feasibility of transabdominal intestinal ultrasonography in evaluating acute gastrointestinal injury (AGI).

Methods

A total of 116 patients were included. Intestinal ultrasonography was conducted daily within 1 week after admission to the intensive care unit. Ultrasonography indicators including intestinal diameter, changes in the intestinal folds, thickness of the intestinal wall, stratification of the intestinal wall, and intestinal peristalsis (movement of the intestinal contents) were observed to determine the acute gastrointestinal injury ultrasonography (AGIUS) score. The gastrointestinal and urinary tract sonography ultrasound (GUTS) protocol score was also calculated. During the first week of the study, the gastrointestinal failure (GIF) score was determined daily. The correlations between transabdominal intestinal scores (AGIUS and GUTS) and the GIF score were analyzed to clarify the feasibility of evaluating AGI through observation of the intestine. The utility of intestinal ultrasonography indicators in predicting feeding intolerance was investigated to improve the ability of clinicians to manage AGI.

Results

A total of 751 ultrasonic examinations were performed with 511 images (68%) considered to be of “good quality.” AGIUS and GUTS scores differed significantly between AGI patients (GIF score 0–2) and non-AGI patients (GIF score 3–4) (p < 0.001). Both scores correlated positively with GIF score (r = 0.54, p < 0.001; r = 0.66, p < 0.001). These ultrasonography indicators could predict feeding intolerance, with an area under the receiver operating characteristic curve of 0.60 (0.48–0.71; intestinal diameter), 0.76 (0.67–0.85; intestinal folds), 0.71 (0.62–0.80; wall thickness), 0.77 (0.69–0.86; wall stratification), and 0.78 (0.68–0.88; intestinal peristalsis). Compared to patients with a normal rate of peristalsis (5–10/min), patients with abnormal peristalsis rates (< 5/min or > 10/min) have increased risk for feeding intolerance (16/83 vs. 25/33, p < 0.001).

Conclusions

The transabdominal intestinal ultrasonography represents an effective means for assessing gastrointestinal injury in critically ill patients. Intestinal ultrasonography indicators, especially the degree of intestinal peristalsis, may be used to predict feeding intolerance.

Trial registration

ClinicalTrial.gov, NCT03589248. Registered 04 July 2018—retrospectively registered.
Efficacy of verum and sham acupoint catgut embedding for treatment of obesity: Study protocol for a randomized controlled trial
Authors: Zhou Yu-Mei , Yan Bing , Yuan Wei-Qu , Yu Hai-Bo , Yang Zhuo-Xin
Published: November 2019

Background

Obesity has become a major public health hazard with epidemic proportions, affecting adults, adolescents, and children of both genders. Previous studies have suggested that acupoint catgut embedding (ACE) might be a potential therapeutic approach for obesity. The purpose of this study is to conduct a rigorous and normative trial to determine the efficacy of ACE for obesity.

Methods/design

A total of 99 eligible patients diagnosed with obesity will be recruited in this study. They will be randomly allocated to either the verum ACE group, sham ACE group, or waiting list (WL) group, with 33 patients in each group. Each patient in the two ACE-based groups will receive eight sessions of treatment, lasting over 8 weeks. The primary outcome is the reduction of body mass index (BMI) after treatment. Secondary outcomes will include waist circumference (WC), hip circumference (HC), waist:hip ratio, body fat percentage, blood lipid level, subcutaneous fat area, visceral fat area, and World Health Organization Quality of Life (WHOQOL). All the outcomes will be evaluated at baseline, at the end of the 8 weeks of treatments, and at 3 months of follow-up. The evaluators and data analyzers will be blinded to group allocation.

Discussion

The findings of this randomized, sham-, and WL-controlled trial will help to investigate the influence of ACE on clinical variables as well as visceral fat area of obesity, which will provide high-quality evidence on the efficacy of ACE for obesity.

Trial registration

Chinese Clinical Trial Registry,ChiCTR1800020248. Registered on December 21, 2018.
Influence of volatile anesthesia versus total intravenous anesthesia on chronic postsurgical pain after cardiac surgery using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials criteria: study protocol for a prospective randomized controlled trial
Authors: Yu Hong , Zheng Jian-Qiao , Hua Yu-Si , Ren Shuo-Fang , Yu Hai
Published: November 2019

Background

Many patients develop chronic postsurgical pain (CPSP) after cardiac surgery, which interferes with their sleep, mood, and quality of life. Studies have suggested that propofol improves postoperative analgesia compared with volatile anesthetics, but its preventive effect on CPSP following cardiac surgery is still unknown. This study compares the incidence of CPSP following cardiac surgery for those receiving volatile anesthesia and those receiving propofol-based total intravenous anesthesia (TIVA) using criteria recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT).

Methods/design

This is a prospective randomized controlled trial. In total, 500 adults undergoing cardiac surgery will be randomly allocated to the volatile or the TIVA group. The volatile group will receive sevoflurane or desflurane during surgery as general anesthesia. The TIVA group will receive propofol-based intravenous agents and no volatile agents during surgery. The primary outcomes will be the frequency of CPSP at 3 months, 6 months, and 1 year after surgery. In this case, CPSP is sternal or thoracic pain. It is defined as either (1) numerical rating scale (NRS) > 0 or (2) meeting all six IMMPACT criteria for CPSP. The IMMPACT criteria are validated pain instruments.

Discussion

To our knowledge, this is the first prospective randomized controlled trial to investigate the prevention of CPSP following cardiac surgery for patients receiving volatile anesthesia compared to those receiving propofol-based TIVA using validated pain instruments in accordance with the IMMPACT recommendations. This study will provide important information on which of these two anesthetic regimens is better for preventing CPSP after cardiac surgery.

Trial registration

Chictr.org.cn,ChiCTR1900020747. Registered on 16 January 2019.
A manual-based family intervention for families living with the consequences of traumatic injury to the brain or spinal cord: a study protocol of a randomized controlled trial
Authors: Soendergaard Pernille Langer , Wolffbrandt Mia Moth , Biering-Sørensen Fin , Nordin Malin , Schow Trine , Arango-Lasprilla Juan Carlos , Norup Anne
Published: November 2019

Background

Acquiring a traumatic injury constitutes a severe life change for the survivor, but also for the surrounding family. The paradigm of helping the family has primarily been on psychosocial interventions targeting caregivers. However, interventions including both survivor and caregivers should be an essential part of treatment, as the whole family’s functional level and mental health can be affected. The current study protocol presents a manualized family intervention for families living with traumatic injury to the brain (TBI) or spinal cord (tSCI). The objectives are to investigate if the intervention improves quality of life (QoL) and decreases burden. It is hypothesized that the family intervention improves problem-solving strategies and family dynamics, which will reduce the burden. This may improve the caregivers’ mental health, which will improve the support to the survivor and QoL.

Methods

The study is an interventional, two-arm, randomized controlled trial. During a 2-year period, a total of 132 families will be included. Participants will be recruited from East-Denmark. Inclusion criteria are (1) TBI or tSCI, (2) ≥ 18 years of age, (3) ≥ 6 months to ≤ 2 years since discharge from hospital, (4) ability to understand and read Danish, (5) cognitive abilities that enable participation, and (6) a minimum of one family member actively involved in the survivor’s life. Exclusion criteria are (1) active substance abuse, (2) aphasia, (3) prior neurologic or psychiatric diagnose, and (4) history of violence. Within each disease group, families will be allocated randomly to participate in an intervention or a control group with a ratio 1:1. The intervention groups receive the family intervention consisting of eight sessions of 90 min duration. Families in the control groups receive 2 h of psychoeducation. All participants complete questionnaires on QoL, self-perceived burden, family dynamics, problem-solving strategies, mental health, and resilience at pre-intervention, post-intervention, and 6-month follow up.

Conclusion

If the intervention is found to have effect, the study will contribute with novel knowledge on the use of a manual-based intervention including the entire family. This would be of clinical interest and would help families living with the consequences of TBI or tSCI.

Trials registration

ClinicalTrials.gov, NCT03814876. Retrospectively registered on 24 January 2019.
Use of next-generation amplicon sequencing to study Blastocystis genetic diversity in a rural human population from Mexico
Authors: Rojas-Velázquez Liliana , Maloney Jenny G. , Molokin Aleksey , Morán Patricia , Serrano-Vázquez Angélica , González Enrique , Pérez-Juárez Horacio , Ximénez Cecilia , Santin Monica
Published: November 2019

Background

The intestinal parasite Blastocystis is found in humans and animals around the world. It is spread through the consumption of contaminated food and water and has been associated with a variety of intestinal symptoms. Blastocystis is one of the most common intestinal parasites in humans, yet its prevalence and distribution in humans in North America is not well characterized.

Methods

Next-generation amplicon sequencing of a region of the Blastocystis SSU rRNA gene was applied to DNA extracted from fecal specimens obtained from 182 inhabitants of a rural population in Mexico to characterize Blastocystis prevalence, subtype distribution, and intra-host subtype diversity in humans.

Results

Of the 182 samples tested in this study, 68.1% (124) contained one or more Blastocystis subtypes. Subtype 3 was the most common subtype observed and was found in 81.5% of the positive samples. Subtype 1, 16.9% of the positive samples, and subtype 2, 17.7% of the positive samples, were also found in this population. Mixed infections were observed in 13.7% of the positive samples. In this population, the odds of having Blastocystis increased in adulthood (> 15 years; OR: 1.72, P < 0.0001), and the odds of having subtype 1 increased in the presence of farm animals (OR: 1.51, P = 0.03). The odds of having subtype 1, subtype 2, or a mixed infection decreased in the presence of cement flooring (OR: − 1.61, P = 0.005; OR: − 1.14, P = 0.03; OR: − 1.48, P = 0.02) possibly indicating socioeconomic factors are involved in the risk of acquiring one of these subtypes.

Conclusions

These data contribute to our understanding of the epidemiology of Blastocystis infection in humans and can be used to shape future studies which aim to better characterize the transmission pathways and health outcomes of Blastocystis infections.
Further evaluation of recombinant Tsol-p27 by enzyme-linked immunoelectrotransfer blot for the serodiagnosis of cysticercosis in pigs from Mozambique
Authors: Nhancupe Noemia , Noormahomed Emilia V. , Afonso Sonia , Svard Staffan , Lindh Johan
Published: November 2019

Background

Porcine cysticercosis has a negative impact on human health and the meat industry, as it makes infected meat unaproprieted for consuption and it is the main etiology of epileptic seizures in developing countries. There are multiple serological assays that use crude antigens with high sensitivity and specificity for the diagnosis of both porcine and human cysticercosis. Nonetheless, antigen preparation is time-consuming, needs a well-equipped laboratory and trained personnel and places those manipulating the meat at great risk for infection. New serodiagnostic approaches to the diagnosis of porcine and human cysticercosis have been directed towards the development of recombinant deoxyribonucleic acid technology for the generation of synthetic proteins that can serve as simplified, low-cost and harmless substitutes for native antigens. The aim of the present study was to further evaluate the recombinant Tsol-p27 protein as a target molecule in immunoassays for the serodiagnosis of porcine cysticercosis. From these data, we hoped to develop recommendations regarding its use in the serodiagnosis of porcine cysticercosis.

Results

We studied a panel of 83 naturally infected pig sera from Angónia District, Mozambique, an endemic area for porcine and human cysticercosis. These sera were previously tested by antigen enzyme-linked immunosorbent assay (Ag-ELISA) to detect antigens of T. solium. The serum panel was processed by enzyme-linked immunoelectrotransfer blot (EITB) assay against the recombinant Tsol-p27 protein and the Ag-ELISA assay results were used to compare and evaluate the performance of Tsol-p27 for the diagnosis of cysticercosis. Out of 83 sera, 24 (29.0%) were positive for Tsol-p27 and 59 (71%) were negative in the same assay. From the 37 sera that tested positive to Ag-ELISA, 11 (13.3%) were positive to Tsol-p27, while from 46 sera that tested negative to Ag-ELISA, 33 (39.7%) also tested negative to Tsol-p27. The sensitivity and specificity of Tsol-p27 was 29.7% and 71.7%, respectively, while the positive predictive value and negative predictive value were 45.8% and 55.9%, respectively, as calculated using Medcalc® version 15.0 software (MedCalc Software, Ostend, Belgium).

Conclusion

While Tsol-p27 recombinant protein might be suitable for testing human sera, its performance in pigs is not acceptable, so other recombinant proteins should be evaluated alone or multiplexed.
Evidence for densovirus integrations into tapeworm genomes
Authors: Herz Michaela , Brehm Klaus
Published: November 2019

Background

Tapeworms lack a canonical piRNA-pathway, raising the question of how they can silence existing mobile genetic elements (MGE). Investigation towards the underlying mechanisms requires information on tapeworm transposons which is, however, presently scarce.

Methods

The presence of densovirus-related sequences in tapeworm genomes was studied by bioinformatic approaches. Available RNA-Seq datasets were mapped against the Echinococcus multilocularis genome to calculate expression levels of densovirus-related genes. Transcription of densovirus loci was further analyzed by sequencing and RT-qPCR.

Results

We herein provide evidence for the presence of densovirus-related elements in a variety of tapeworm genomes. In the high-quality genome of E. multilocularis we identified more than 20 individual densovirus integration loci which contain the information for non-structural and structural virus proteins. The majority of densovirus loci are present as head-to-tail concatemers in isolated repeat containing regions of the genome. In some cases, unique densovirus loci have integrated close to histone gene clusters. We show that some of the densovirus loci of E. multilocularis are actively transcribed, whereas the majority are transcriptionally silent. RT-qPCR data further indicate that densovirus expression mainly occurs in the E. multilocularis stem cell population, which probably forms the germline of this organism. Sequences similar to the non-structural densovirus genes present in E. multilocularis were also identified in the genomes of E. canadensis, E. granulosus, Hydatigera taeniaeformis, Hymenolepis diminuta, Hymenolepis microstoma, Hymenolepis nana, Taenia asiatica, Taenia multiceps, Taenia saginata and Taenia solium.

Conclusions

Our data indicate that densovirus integration has occurred in many tapeworm species. This is the first report on widespread integration of DNA viruses into cestode genomes. Since only few densovirus integration sites were transcriptionally active in E. multilocularis, our data are relevant for future studies into gene silencing mechanisms in tapeworms. Furthermore, they indicate that densovirus-based vectors might be suitable tools for genetic manipulation of cestodes.
A search to the target tissue in which RA-specific inflammation starts: a detailed MRI study to improve identification of RA-specific features in the phase of clinically suspect arthralgia
Authors: Matthijssen Xanthe M. E. , Wouters Fenne , Boeters Debbie M. , Boer Aleid C. , Dakkak Yousra J. , Niemantsverdriet Ellis , van der Helm-van Mil Annette H. M.
Published: November 2019

Objective

Based on a unique cohort of clinically suspect arthralgia (CSA) patients, we analysed which combinations of MRI features at onset were predictive for rheumatoid arthritis (RA) development. This was done to increase our comprehension of locations of RA onset and improve the predictive accuracy of MRI in CSA.

Methods

In the discovery cohort, 225 CSA patients were followed on clinical arthritis development. Contrast-enhanced 1.5 T MRIs were made of unilateral metacarpophalangeal (MCP) (2–5), wrist, and metatarsophalangeal (1–5) joints at baseline and scored for synovitis, tenosynovitis, and bone marrow edema. Severity, number, and combinations of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference. Cox regression was used for predictor selection. Predictive values were determined at 1 year follow-up. Results were validated in 209 CSA patients.

Results

In both cohorts, 15% developed arthritis < 1 year. The multivariable Cox model selected presence of MCP-extensor peritendinitis (HR 4.38 (2.07–9.25)) and the number of locations with subclinical inflammation (1–2 locations HR 2.54 (1.11–5.82); ≥ 3 locations HR 3.75 (1.49–9.48)) as predictors. Severity and combinations of inflammatory lesions were not selected. Based on these variables, five risk categories were defined: no subclinical inflammation, 1–2 locations, or ≥ 3 locations, with or without MCP-extensor peritendinitis. Positive predictive values (PPVs) ranged 5% (lowest category; NPV 95%) to 67% (highest category). Similar findings were obtained in the validation cohort; PPVs ranged 4% (lowest category; NPV 96%) to 63% (highest category).

Conclusion

Tenosynovitis, particularly MCP-extensor peritendinitis, is among the first tissues affected by RA. Incorporating this feature and number of locations with subclinical inflammation improved prediction making with PPVs up to 63–67%.
The effect of pilocarpine on dental caries in patients with primary Sjögren’s syndrome: a database prospective cohort study
Authors: Hsu Chung-Yuan , Hung Kuo-Chun , Lin Ming-Shyan , Ko Chi-Hua , Lin Yu-Sheng , Chen Tien-Hsing , Lin Chun-Yu , Chen Ying-Chou
Published: November 2019

Background

Primary Sjögren’s syndrome (pSS) is associated with dental caries. Pilocarpine, a salivary stimulant, can improve the amount and flow rate of saliva in patients with pSS. This study aimed to assess whether the risk of dental caries decreases with the use of pilocarpine in patients with pSS.

Methods

For this prospective cohort study, we identified pSS patients from the catastrophic illnesses registry of the National Health Insurance Research Database of Taiwan between 2009 and 2013. We divided participants into pilocarpine and non-user groups based on the pilocarpine prescriptions available during the first 3-month follow-up. The primary endpoint was dental caries. The secondary endpoints were periodontitis and oral candidiasis. We compared the risk of these oral manifestations using the Cox proportional hazard model.

Results

A total of 4973 patients with new-onset pSS were eligible for analysis. After propensity score matching, we included 1014 patients in the pilocarpine group and 2028 patients in the non-user group. During the mean follow-up of 2.6 years, the number of events was 487 in the pilocarpine group (48.0%) and 1047 in the non-user group (51.6%); however, the difference was not significant (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.82 to 1.06). Furthermore, there was no significant difference between groups regarding risk of periodontitis (HR 0.91, 95% CI 0.81 to 1.03) and oral candidiasis (HR 1.16, 95% CI 0.70 to 1.94).

Conclusion

Pilocarpine may have no protective effect on dental caries, periodontitis, or oral candidiasis in patients with pSS.
Hydroxychloroquine inhibits IL-1β production from amyloid-stimulated human neutrophils
Authors: Fujita Yuya , Matsuoka Naoki , Temmoku Jumpei , Furuya Makiko Yashiro , Asano Tomoyuki , Sato Shuzo , Kobayashi Hiroko , Watanabe Hiroshi , Suzuki Eiji , Urano Takeshi , Kozuru Hideko , Yatsuhashi Hiroshi , Koga Tomohiro , Kawakami Atsushi , Migita Kiyoshi
Published: November 2019

Background

Hydroxychloroquine (HCQ) is used for the treatment of patients with rheumatic diseases. We tested the hypothesis that HCQ affects the NLRP3 inflammasome, which is involved in autoinflammation.

Methods

Human neutrophils were stimulated with serum amyloid A (SAA) in vitro and measured for IL-1β and caspase-1 (p20) secretion by ELISA. Pro-IL-1β mRNA expression in human neutrophils was quantified by real-time RT-PCR.

Results

SAA stimulation induced significant production of IL-1β in human neutrophils. SAA stimulation also induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression in human neutrophils. HCQ pretreatment significantly inhibited the SAA-induced IL-1β production in human neutrophils, but did not affect the SAA-induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression. Furthermore, SAA stimulation induced cleaved caspase-1 (p20) secretion from human neutrophils, and this release was suppressed by HCQ pretreatment.

Conclusions

Treatment with HCQ was associated with impaired production of IL-1β in SAA-stimulated human neutrophils without affecting the priming process of the NLRP3 inflammasome such as pro-IL-1β or NLRP3 induction. These findings suggest that HCQ affects the NLRP3 activation process, resulting in the impaired IL-1β production in human neutrophils, as representative innate immune cells.
Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone
Authors: Xuan Fengjun , Yano Fumiko , Mori Daisuke , Chijimatsu Ryota , Maenohara Yuji , Nakamoto Hideki , Mori Yoshifumi , Makii Yuma , Oichi Takeshi , Taketo Makoto Mark , Hojo Hironori , Ohba Shinsuke , Chung Ung-il , Tanaka Sakae , Saito Taku
Published: November 2019

Background

Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage.

Methods

Wnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generatedPrg4-CreERT2;Ctnnb1fl/flandPrg4-CreERT2;Ctnnb1-ex3fl/wtmice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells.

Results

Wnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels ofCreb1, a potent transcription factor forPrg4.

Conclusions

We demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.
Contribution of adipocyte precursors in the phenotypic specificity of intra-articular adipose tissues in knee osteoarthritis patients
Authors: Eymard Florent , Pigenet Audrey , Rose Cindy , Bories Anouchka , Flouzat-Lachaniette Charles-Henri , Berenbaum Francis , Chevalier Xavier , Houard Xavier , Nourissat Geoffroy
Published: November 2019

Background

Intra-articular adipose tissues (IAATs) are involved in osteoarthritis (OA) pathophysiology. We hypothesize that mesenchymal cells residing in IAATs may account for the specific inflammatory and metabolic patterns in OA patients.

Methods

Adipocyte precursors (preadipocytes and dedifferentiated fat cells (DFATc)) from IAATs (infrapatellar and suprapatellar fat pads) and autologous subcutaneous adipose tissues (SCATs) were isolated from knee OA patients. The ability of these precursors to differentiate into adipocytes was assessed by oil red O staining after 14 days of culture in adipogenic medium. The gene expression of adipocyte-related transcription factors (C/EBP-α and PPAR-γ) and development-related factors (EN1 and SFRP2) were analyzed. The inflammatory pattern was assessed by RT-qPCR and ELISA (interleukin 6 (IL-6), IL-8, Cox2, and prostaglandin E2 (PGE2)) after a 24-h stimulation by IL-1β (1 ng/mL) and by conditioned medium from OA synovium.

Results

IAAT preadipocytes displayed a significantly higher ability to differentiate into adipocytes and expressed significantly more C/EBP-α mRNA than SCAT preadipocytes. IAAT preadipocytes expressed significantly less EN-1 and SFRP2 mRNA than SCAT preadipocytes. Unstimulated IAAT preadipocytes displayed a less inflammatory pattern (IL-6, IL-8, and Cox2/PGE2) than SCAT preadipocytes. In contrast, the response of IAAT preadipocytes to an inflammatory stimulus (IL-1β and conditioned media of OA synovium) was exacerbated compared to that of SCAT preadipocytes. Similar results were obtained with DFATc.

Conclusion

IAAT adipocyte precursors from OA patients have a specific phenotype, which may account for the unique phenotype of OA IAATs. The exacerbated response of IAAT preadipocytes to inflammatory stimulation may contribute to OA pathophysiology.
Dataset for file fragment classification of image file formats
Authors: Fakouri Reyhane , Teimouri Mehdi
Published: November 2019

Objectives

File fragment classification of image file formats is a topic of interest in network forensics. There are a few publicly available datasets of files with image formats. Therewith, there is no public dataset for file fragments of image file formats. So, a big research challenge in file fragment classification of image file formats is to compare the performance of the developed methods over the same datasets.

Data description

In this study, we present a dataset that contains file fragments of ten image file formats: Bitmap, Better Portable Graphics, Free Lossless Image Format, Graphics Interchange Format, Joint Photographic Experts Group, Joint Photographic Experts Group 2000, Joint Photographic Experts Group Extended Range, Portable Network Graphic, Tagged Image File Format, and Web Picture. Corresponding to each format, the dataset contains the file fragments of image files with different compression settings. For each pair of file format and compression setting, 800 file fragments are provided. Totally, the dataset contains 25,600 file fragments.
Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood
Authors: Lardenoije Roy , Roubroeks Janou A. Y. , Pishva Ehsan , Leber Markus , Wagner Holger , Iatrou Artemis , Smith Adam R. , Smith Rebecca G. , Eijssen Lars M. T. , Kleineidam Luca , Kawalia Amit , Hoffmann Per , Luck Tobias , Riedel-Heller Steffi , Jessen Frank , Maier Wolfgang , Wagner Michael , Hurlemann René , Kenis Gunter , Ali Muhammad , del Sol Antonio , Mastroeni Diego , Delvaux Elaine , Coleman Paul D. , Mill Jonathan , Rutten Bart P. F. , Lunnon Katie , Ramirez Alfredo , van den Hove Daniël L. A.
Published: November 2019

Background

Late-onset Alzheimer’s disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD.

Results

We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (− 3.76% 5mC, pŠidák = 1.07E−06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E−04), RHBDF2 (− 3.45% UC, pŠidák = 4.85E−06), and C3 (− 1.20% UC, pŠidák = 1.57E−03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E−04).

Conclusions

The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.
Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma
Authors: Watson Zachary L. , Yamamoto Tomomi M. , McMellen Alexandra , Kim Hyunmin , Hughes Connor J. , Wheeler Lindsay J. , Post Miriam D. , Behbakht Kian , Bitler Benjamin G.
Published: November 2019

Background

Euchromatic histone-lysine-N-methyltransferases 1 and 2 (EHMT1/2, aka GLP/G9A) catalyze dimethylation of histone H3 lysine 9 (H3K9me2) and have roles in epigenetic silencing of gene expression. EHMT1/2 also have direct roles in DNA repair and are implicated in chemoresistance in several cancers. Resistance to chemotherapy and PARP inhibitors (PARPi) is a major cause of mortality in high-grade serous ovarian carcinoma (HGSOC), but the contribution of the epigenetic landscape is unknown.

Results

To identify epigenetic mechanisms of PARPi resistance in HGSOC, we utilized unbiased exploratory techniques, including RNA-Seq and mass spectrometry profiling of histone modifications. Compared to sensitive cells, PARPi-resistant HGSOC cells display a global increase of H3K9me2 accompanied by overexpression of EHMT1/2. EHMT1/2 overexpression was also observed in a PARPi-resistant in vivo patient-derived xenograft (PDX) model. Genetic or pharmacologic disruption of EHMT1/2 sensitizes HGSOC cells to PARPi. Cell death assays demonstrate that EHMT1/2 disruption does not increase PARPi-induced apoptosis. Functional DNA repair assays show that disruption of EHMT1/2 ablates homologous recombination (HR) and non-homologous end joining (NHEJ), while immunofluorescent staining of phosphorylated histone H2AX shows large increases in DNA damage. Propidium iodide staining and flow cytometry analysis of cell cycle show that PARPi treatment increases the proportion of PARPi-resistant cells in S and G2 phases, while cells treated with an EHMT1/2 inhibitor remain in G1. Co-treatment with PARPi and EHMT1/2 inhibitor produces an intermediate phenotype. Immunoblot of cell cycle regulators shows that combined EHMT1/2 and PARP inhibition reduces expression of specific cyclins and phosphorylation of mitotic markers. These data suggest DNA damage and altered cell cycle regulation as mechanisms of sensitization. RNA-Seq of PARPi-resistant cells treated with EHMT1/2 inhibitor showed significant gene expression changes enriched in pro-survival pathways that remain unexplored in the context of PARPi resistance, including PI3K, AKT, and mTOR.

Conclusions

This study demonstrates that disrupting EHMT1/2 sensitizes HGSOC cells to PARPi, and suggests a potential mechanism through DNA damage and cell cycle dysregulation. RNA-Seq identifies several unexplored pathways that may alter PARPi resistance. Further study of EHMT1/2 and regulated genes will facilitate development of novel therapeutic strategies to successfully treat HGSOC.
Proteomic features characterization of Hymenoptera venom allergy
Authors: Matuszewska Eliza , Matysiak Joanna , Bręborowicz Anna , Olejniczak Katarzyna , Kycler Zdzisława , Kokot Zenon J. , Matysiak Jan
Published: November 2019

Background

Hymenoptera venom allergy is one of the most frequent causes of anaphylaxis. In its most severe form, the reaction to wasp and honey bee stings may be life-threatening. Therefore, immediate and proper diagnosis of venom allergy and implementation of suitable therapy are extremely important. Broadening the knowledge on the mechanism of the allergic reaction may contribute to the improvement of both diagnostic and treatment methods. Thus, this study aimed to discover changes in protein expression in serum of patients allergic to Hymenoptera (wasp and honeybee) venom and to point out proteins and peptides involved in the allergic inflammation.

Methods

Serum proteomic patterns typical to allergic patients and healthy volunteers were obtained with MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight) mass spectrometer. The spectra were processed, analyzed and compared using advanced bioinformatics tools. The discriminative peaks were subjected to identification with liquid chromatography coupled with tandem mass spectrometry.

Results

This methodology allowed for the identification of four features differentiating between allergy and control groups. They were: fibrinogen alpha chain, coagulation factor XIII chain A, complement C4-A, and inter-alpha-trypsin inhibitor heavy chain H4. All of these proteins are involved in allergic inflammatory response.

Conclusions

Extending the knowledge of the Hymenoptera venom sensitization will contribute to the development of novel, sensitive and specific methods for quick and unambiguous allergy diagnosis. Understanding the basis of the allergy at the proteomic level will support the improvement of preventive and therapeutic measures.