bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium
Authors: Poppenberg Kerry E. , Jiang Kaiyu , Tso Michael K. , Snyder Kenneth V. , Siddiqui Adnan H. , Kolega John , Jarvis James N. , Meng Hui , Tutino Vincent M.
Published: October 2019

Background

Genetics play an important role in intracranial aneurysm (IA) pathophysiology. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are linked to IA but how they affect disease pathobiology remains poorly understood. We used Encyclopedia of DNA Elements (ENCODE) data to investigate the epigenetic landscapes surrounding genetic risk loci to determine if IA-associated SNPs affect functional elements that regulate gene expression and if those SNPs are most likely to impact a specific type of cells.

Methods

We mapped 16 highly significant IA-associated SNPs to linkage disequilibrium (LD) blocks within the human genome. Within these regions, we examined the presence of H3K4me1 and H3K27ac histone marks and CCCTC-binding factor (CTCF) and transcription-factor binding sites using chromatin immunoprecipitation-sequencing (ChIP-Seq) data. This analysis was conducted in several cell types relevant to endothelial (human umbilical vein endothelial cells [HUVECs]) and inflammatory (monocytes, neutrophils, and peripheral blood mononuclear cells [PBMCs]) biology. Gene ontology analysis was performed on genes within extended IA-risk regions to understand which biological processes could be affected by IA-risk SNPs. We also evaluated recently published data that showed differential methylation and differential ribonucleic acid (RNA) expression in IA to investigate the correlation between differentially regulated elements and the IA-risk LD blocks.

Results

The IA-associated LD blocks were statistically significantly enriched for H3K4me1 and/or H3K27ac marks (markers of enhancer function) in endothelial cells but not in immune cells. The IA-associated LD blocks also contained more binding sites for CTCF in endothelial cells than monocytes, although not statistically significant. Differentially methylated regions of DNA identified in IA tissue were also present in several IA-risk LD blocks, suggesting SNPs could affect this epigenetic machinery. Gene ontology analysis supports that genes affected by IA-risk SNPs are associated with extracellular matrix reorganization and endopeptidase activity.

Conclusion

These findings suggest that known genetic alterations linked to IA risk act on endothelial cell function. These alterations do not correlate with IA-associated gene expression signatures of circulating blood cells, which suggests that such signatures are a secondary response reflecting the presence of IA rather than indicating risk for IA.
A comparison of machine learning classifiers for dementia with Lewy bodies using miRNA expression data
Authors: Shigemizu Daichi , Akiyama Shintaro , Asanomi Yuya , Boroevich Keith A. , Sharma Alok , Tsunoda Tatsuhiko , Sakurai Takashi , Ozaki Kouichi , Ochiya Takahiro , Niida Shumpei
Published: October 2019

Background

Dementia with Lewy bodies (DLB) is the second most common subtype of neurodegenerative dementia in humans following Alzheimer’s disease (AD). Present clinical diagnosis of DLB has high specificity and low sensitivity and finding potential biomarkers of prodromal DLB is still challenging. MicroRNAs (miRNAs) have recently received a lot of attention as a source of novel biomarkers.

Methods

In this study, using serum miRNA expression of 478 Japanese individuals, we investigated potential miRNA biomarkers and constructed an optimal risk prediction model based on several machine learning methods: penalized regression, random forest, support vector machine, and gradient boosting decision tree.

Results

The final risk prediction model, constructed via a gradient boosting decision tree using 180 miRNAs and two clinical features, achieved an accuracy of 0.829 on an independent test set. We further predicted candidate target genes from the miRNAs. Gene set enrichment analysis of the miRNA target genes revealed 6 functional genes included in the DHA signaling pathway associated with DLB pathology. Two of them were further supported by gene-based association studies using a large number of single nucleotide polymorphism markers (BCL2L1:P = 0.012, PIK3R2:P = 0.021).

Conclusions

Our proposed prediction model provides an effective tool for DLB classification. Also, a gene-based association test of rare variants revealed that BCL2L1 and PIK3R2 were statistically significantly associated with DLB.
Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo – a post-hoc analysis of the BACE randomized controlled trial
Authors:   On behalf of the BACE trial investigators, Vermeersch Kristina , Belmans Ann , Bogaerts Kris , Gyselinck Iwein , Cardinaels Nina , Gabrovska Maria , Aumann Joseph , Demedts Ingel K. , Corhay Jean-Louis , Marchand Eric , Slabbynck Hans , Haenebalcke Christel , Vermeersch Stefanie , Verleden Geert M. , Troosters Thierry , Ninane Vincent , Brusselle Guy G. , Janssens Wim
Published: October 2019

Background

In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality.

Objectives

(1) To investigate the intervention’s effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions.

Methods

Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time.

Results

Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97,p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81,p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80;p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60,p = 0.005), or low blood eosinophil count (<300cells/μL, RR = 0.33, 95%CI:0.17;0.64,p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses.

Conclusions

This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy.

Trial registration

ClinicalTrials.gov number.NCT02135354.
Isolation and characterization of extracellular vesicles from Broncho-alveolar lavage fluid: a review and comparison of different methods
Authors: Carnino Jonathan M. , Lee Heedoo , Jin Yang
Published: October 2019

Extracellular vesicles (EVs) are cell-derived membranous vesicles secreted by cells into the extracellular space, which play a role in cell to cell communication. EVs are categorized into 3 groups depending on their size, surface marker, and method of release from the host cell. Recently, EVs have become of interest in the study of multiple disease etiologies and are believed to be potential biomarkers for many diseases. Multiple different methods have been developed to isolate EVs from different samples such as cell culture medium, serum, blood, and urine. Once isolated, EVs can be characterized by technology such as nanotracking analysis, dynamic light scattering, and nanoscale flow cytometry. In this review, we summarize the current methods of EV isolation, provide details into the three methods of EV characterization, and provide insight into which isolation approaches are most suitable for EV isolation from bronchoalveolar lavage fluid (BALF).
Exploring the key communicator role of exosomes in cancer microenvironment through proteomics
Authors: Kim HuiSu , Kim Dong Wook , Cho Je-Yoel
Published: October 2019

There have been many attempts to fully understand the mechanism of cancer behavior. Yet, how cancers develop and metastasize still remain elusive. Emerging concepts of cancer biology in recent years have focused on the communication of cancer with its microenvironment, since cancer cannot grow and live alone. Cancer needs to communicate with other cells for survival, and thus they secrete various messengers, including exosomes that contain many proteins, miRNAs, mRNAs, etc., for construction of the tumor microenvironment. Moreover, these intercellular communications between cancer and its microenvironment, including stromal cells or distant cells, can promote tumor growth, metastasis, and escape from immune surveillance. In this review, we summarized the role of proteins in the exosome as communicators between cancer and its microenvironment. Consequently, we present cancer specific exosome proteins and their unique roles in the interaction between cancer and its microenvironment. Clinically, these exosomes might provide useful biomarkers for cancer diagnosis and therapeutic tools for cancer treatment.
Complementary biobank of rodent tissue samples to study the effect of World Trade Center exposure on cancer development
Authors: Lieberman-Cribbin Wil , Tuminello Stephanie , Gillezeau Christina , van Gerwen Maaike , Brody Rachel , Mulholland David J. , Horton Lori , Sisco Maureen , Prophete Colette , Zelikoff Judith , Lee Hyun-Wook , Park Sung-Hyun , Chen Lung-Chi , Cohen Mitchell D. , Taioli Emanuela
Published: October 2019

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.
Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants
Authors: Tsubota Maho , Fukuda Ryotaro , Hayashi Yusuke , Miyazaki Takaya , Ueda Shin , Yamashita Rika , Koike Nene , Sekiguchi Fumiko , Wake Hidenori , Wakatsuki Shuji , Ujiie Yuka , Araki Toshiyuki , Nishibori Masahiro , Kawabata Atsufumi
Published: October 2019

Background

Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system.

Methods

CIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay.

Results

Intraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin.

Conclusions

Our data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.
Evaluating the effectiveness of a combined approach to improve utilization of adolescent sexual reproductive health services in Kenya: a quasi-experimental design study protocol
Authors: Mutea Lilian , Ontiri Susan , Macharia Sheila , Tzobotaro Meital , Ajema Carolyne , Odiara Vincent , Kadiri Francis , Orero Solomon , Kabue Mark , Michielsen Kristien , Gichangi Peter
Published: October 2019

Background

Access to and utilization of adolescent sexual and reproductive health (ASRH) services remains poor. ASRH services in Kenya are primarily offered in health facilities and include counselling, information, and services on family planning, sexually transmitted infections, and HIV and basic life skills. The Ministry of Education also provides age-appropriate sexual and reproductive health information in schools. This paper presents a study protocol that will evaluate the effectiveness of a combined approach toward improving utilization of ASRH services.

Methods

This will be a quasi-experimental study utilizing qualitative and quantitative methods. During the formative phase, data will be collected through focus group discussions, in-depth interviews, and key informant interviews to explore the barriers and facilitators of provision and utilization of ASRH services. A quantitative design will be used to obtain baseline and endline data through household surveys and client exit interviews. Following the formative and baseline household and client exit assessments, an intervention focusing on provision of ASRH service package targeting boys and girls will be implemented for 18 months. The package will include contextualized ASRH services, including counselling and age-appropriate, comprehensive sexual education for behavior change with an aim to increase utilization of ASRH services. An analysis of the primary outcome (utilization of ASRH services) will be undertaken to establish the difference in difference between the control and intervention arm, before the intervention (using the baseline survey data) and after the intervention (using the endline survey data).

Discussion

Adolescents have now been included in the World Health Organization’s Global strategy for women’s, children’s and adolescents’ health (2016–2030), acknowledging the unique health challenges facing young people and their pivotal role as drivers of change in the post-2015 era. This study will generate evidence on whether a combined school, facility, and community approach works toward improving utilization of ASRH services. The information generated from the study will be beneficial for programming as it will identify underlying reasons for low utilization of ASRH services. Results will help to shape ASRH programs and reduce teenage pregnancy within Kenya and other similar low middle-income countries.

Trial registration

The study is registered at http://www.pactr.org/, registration number PACTR201906738029948.
Identifying novel biomarkers of the pediatric influenza infection by weighted co-expression network analysis
Authors: Zarei Ghobadi Mohadeseh , Mozhgani Sayed-Hamidreza , Farzanehpour Mahdieh , Behzadian Farida
Published: October 2019

Background

Despite the high yearly prevalence of Influenza, the pathogenesis mechanism and involved genes have not been fully known. Finding the patterns and mapping the complex interactions between different genes help us to find the possible biomarkers and treatment targets.

Methods

Herein, weighted gene co-expression network analysis (WGCNA) was employed to construct a co-expression network among genes identified by microarray analysis of the pediatric influenza-infected samples.

Results

Three of the 38 modules were found as the most related modules to influenza infection. At a functional level, we found that the genes in these modules regulate the immune responses, protein targeting, and defense to virus. Moreover, the analysis of differentially expressed genes disclosed 719 DEGs between the normal and infected subjects. The comprehensive investigation of genes in the module involved in immune system and viral defense (yellow module) revealed thatSP110,HERC5,SAMD9L,RTP4,C19orf66,HELZ2,EPSTI1, andPHF11which were also identified as DEGs (exceptC19orf66) have the potential to be as the biomarkers and also drug targeting for the treatment of pediatric influenza.

Conclusions

The WGCN analysis revealed co-expressed genes which were involved in the innate immune system and defense to virus. The differentially expressed genes in the identified modules can be considered for designing drug targets. Moreover, modules can help to find pathogenesis routes in the future.
Characteristics of human papillomaviruses distribution in Guizhou Province, China
Authors: Chen Zuyi , Li Qiongyao , Huang Qiong , Liu Huaqing , Jiang Hongwu , Chen Zehui , An Zhengyuan , Luo Qingfang
Published: October 2019

Background

Human papillomavirus (HPV) is one of the most common sexually transmitted viruses. Data about HPV infection in Guizhou is limited.

Methods

56,768 cervical samples were collected and genotyped for 15 main high risk and 6 main low risk HPV types.

Results

16.95% (9623/56768) of samples were HPV positive; 90.70% (8728/9623) of HPV positive women were infected by high risk HPV. High risk and high risk mix infection (1458; 70.85%) was the most common mix HPV infection type. The highest HPV detection rate was found in age group 41–45 years old (detection rate = 17.89%) (χ2 = 204.77; P < 0.001); the highest within-group HPV infection rates were found in the ≤20 (25.62%) and ≥ 61 (24.67%) years old age groups, the lowest within-group HPV infection rate was found in the 31–35 years old age group (15.02%). The highest mix infection proportions were found in the ≥61 (36.06%) and ≤ 20 (33.63%) years old age groups (χ2 = 111.21; P < 0.001), the lowest mix infection proportion was found in the 41–45 (17.42%) years old age group. The highest high risk infection proportions were found in the 26–30 (92.98%), ≥61 (92.68%), and 36–40 (92.16%) years old age groups (χ2 = 31.72; P < 0.001), the lowest high risk infection proportion was found in the ≤20 (84.96%) years old age group. HPV infection rates varied with seasons in Guizhou.

Conclusions

Characteristics of HPV distribution in Guizhou were identified. There were significant differences in HPV distribution among age groups, prevention strategies should be adjusted according to the characteristics.
The effects of zinc deficiency on homeostasis of twelve minerals and trace elements in the serum, feces, urine and liver of rats
Authors: Yu Qingli , Sun Xiaohan , Zhao Jiali , Zhao Lan , Chen Yanfeng , Fan Lina , Li Zixiang , Sun Yongzhi , Wang Maoqing , Wang Fan
Published: October 2019

Background

Zinc deficiency can change the concentrations of minerals and trace elements in the body. However, previous studies still had many limitations.

Objective

To reveal the effects of zinc deficiency on homeostasis of 16 minerals and trace elements.

Methods

Forty-five rats were divided randomly into three groups: normal zinc diet (30 mg/kg), low zinc diet (10 mg/kg), and pair-fed diet(30 mg/kg). The concentrations of 16 minerals and trace elements in serum, feces, urine, and liver were measured by inductively coupled plasma mass spectrometry. The excretion of 16 elements in urine and feces were calculated and compared.

Results

Zinc-deficient rats exhibited significant changes in up to 12 minerals and trace elements. The low zinc diet induced decreased excretion of zinc and concentrations of zinc in serum, feces, urine, and liver. Zinc deficiency increased feces concentrations of Mg, Cu, Se, K, Ag, Fe and Mn; decreased the concentrations of Mg, Cu, Se, K in liver and urine, and a diminished amount of Ag was observed in serum. Decreased urinary concentrations of Zn Ca, Mg, Cu, Se, K, Na, As and Cr, suggested that zinc-deficient rats increased the 9 elements’ renal reabsorption. Decreased concentrations of Ca in liver, urine, and feces, decreased excretion in urine and feces and increased serum total Ca suggested that zinc deficiency increased the redistribution of Ca in serum or other tissues. Zinc deficiency increased excretion of Cu, Se, Fe; and decreased the excretion of other 8 elements except for Ag.

Conclusions

Zinc deficiency changed the excretion, reabsorption and redistribution of 12 minerals and trace elements in rats. Our findings are the first to show that zinc deficiency alters the concentrations of Ag, Cr, and As.

Graphical abstract
A failed review of CCE site inspection standards and processes
Authors: Innes Stanley I. , Leboeuf-Yde Charlotte , Walker Bruce F.
Published: October 2019

Background

Accreditation of educational programs involves an independent agency assessing quality against a set of defined standards. Site inspection teams are appointed by an accrediting agency and compile a report with the intention of identifying deficiencies and making recommendations for their rectification and continued improvement. For chiropractic programs accreditation is carried out by Councils on Chiropractic Education (CCEs). However, the reliability of their site inspection teams remains unknown. Recent research has suggested that variability in chiropractic practice may be partially traced back to the education provider. This raises the possibility of deficient accreditation procedures that may include unsatisfactory site inspection standards or processes or the accreditation standards by which they work to.

We sought to compare the various CCEs documented standards and processes for site inspection teams for similarities and differences with the intent of making recommendations to create uniform and high quality standards. Further, we sought to compare a sample of CCEs site inspection team surveys / reports for commonly identified recommendations and quality improvements and determine if they are adequately described in their accreditation standards.

Method

In December of 2018 invitation emails were sent to 4 CCEs through their website portals outlining a proposed study investigating site inspection teams’ standards and processes. Access was requested to all appropriately redacted documentation relating to site inspection teams and their chiropractic program reports. Follow up emails were sent several weeks later.

Results

Only one of four of the CCEs responded by providing the requested information.

Conclusion and recommendations

Three CCEs did not cooperate with this educational research. The possible reasons for the non-engagement is discussed.
Estimating intrafraction tumor motion during fiducial-based liver stereotactic radiotherapy via an iterative closest point (ICP) algorithm
Authors: Li Wu-zhou , Liang Zhi-wen , Cao Yi , Cao Ting-ting , Quan Hong , Yang Zhi-yong , Li Qin , Dai Zhi-tao
Published: October 2019

Background

Tumor motion may compromise the accuracy of liver stereotactic radiotherapy. In order to carry out a precise planning, estimating liver tumor motion during radiotherapy has received a lot of attention. Previous approach may have difficult to deal with image data corrupted by noise. The iterative closest point (ICP) algorithm is widely used for estimating the rigid registration of three-dimensional point sets when these data were dense or corrupted. In the light of this, our study estimated the three-dimensional (3D) rigid motion of liver tumors during stereotactic liver radiotherapy using reconstructed 3D coordinates of fiducials based on the ICP algorithm.

Methods

Four hundred ninety-five pairs of orthogonal kilovoltage (KV) images from the CyberKnife stereo imaging system for 12 patients were used in this study. For each pair of images, the 3D coordinates of fiducial markers inside the liver were calculated via geometric derivations. The 3D coordinates were used to calculate the real-time translational and rotational motion of liver tumors around three axes via an ICP algorithm. The residual error was also investigated both with and without rotational correction.

Results

The translational shifts of liver tumors in left-right (LR), anterior-posterior (AP),and superior-inferior (SI) directions were 2.92 ± 1.98 mm, 5.54 ± 3.12 mm, and 16.22 ± 5.86 mm, respectively; the rotational angles in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were 3.95° ± 3.08°, 4.93° ± 2.90°, and 4.09° ± 1.99°, respectively. Rotational correction decreased 3D fiducial displacement from 1.19 ± 0.35 mm to 0.65 ± 0.24 mm (P<0.001).

Conclusions

The maximum translational movement occurred in the SI direction. Rotational correction decreased fiducial displacements and increased tumor tracking accuracy.
How to restore rotation center in total hip arthroplasty for developmental dysplasia of the hip by recognizing the pathomorphology of acetabulum and Harris fossa?
Authors: Zhang Heng , Zhou Jiansheng , Guan Jianzhong , Ding Hai , Wang Zhiyan , Dong Qirong
Published: October 2019

Purpose

To restore rotation center exactly in total hip arthroplasty (THA) is technically challenging for patients with end-stage osteoarthritis due to developmental dysplasia of the hip (DDH). The technical difficulty is attributable to the complex acetabular changes. In this study, we investigated the pathomorphology of acetabulum and Harris fossa of Crowe types I to IV and discussed the method of restoring rotation center of the hip.

Methods

This study retrospectively reviewed 56 patients (59 hips) who underwent cementless THA due to end-stage osteoarthritis of DDH. The pathomorphology of acetabulum and Harris fossa was observed during operations. Using the preoperative and postoperative pelvic radiographs, the vertical and the horizontal distances of hip rotation center were measured in order to evaluate the effects of restoring rotation center of the hip.

Results

Adult DDH acetabulum could be classified into four basic pathological types which include the shallow cup shape, the dish shape, the shell shape, and the triangular shape. Adult DDH Harris fossa could be classified into four pathological types, including the crack shape, the closed shape, the triangle shape, and the shallow shape, in accordance with the osteophyte coverage. The vertical and horizontal distances of hip rotation center on the pelvic radiographs before and after operations were as follows: the preoperative vertical distance of hip rotation center was (39.96 ± 5.65) mm, and the postoperative one was (13.83 ± 2.66) mm; the preoperative horizontal distance of hip rotation center was (42.15 ± 6.42) mm, and the postoperative one was (28.12 ± 4.56) mm.

Conclusions

The acetabulum and Harris fossa can display different pathological types on account of different degrees of dislocation and osteophyte hyperplasia in the end-stage osteoarthritis of adult DDH. The hip rotation center can be accurately restored by locating the acetabular center with Harris fossa and acetabular notch as the marks.
Identifying the role of ASPN and COMP genes in knee osteoarthritis development
Authors: Mishra Abhishek , Awasthi Sachin , Raj Saloni , Mishra Priya , Srivastava Rajeshwar Nath
Published: October 2019

Background

Osteoarthritis (OA) is a common cause of musculoskeletal disability among elders and is characterized by late-onset degeneration of articular cartilage. OA affects various joints, commonly hand, knee, and hip, with clinical features that are unique to each joint. This study was initiated to identify and evaluate the role of the ASPN and COMP genes in the development of knee OA.

Methods

A case–control study was carried out involving 500 cases with knee OA (diagnosed by the American College of Rheumatology) and an equal number of healthy controls. Blood was drawn for genomic DNA isolation. PCR-RFLP and TaqMan assay methods were used to identify the SNPs. mRNA and protein expression of genes were carried out in peripheral blood lymphocytes (PBLs) by RT-PCR and Western immunoblotting. The data obtained were analyzed for the statistical significance between control and case groups.

Results

The variant genotype of ASPN and COMP genes was found to be present at a relatively higher frequency in cases than controls. RT-PCR and immunochemical studies revealed increased mRNA and protein expression of such gene in PBLs isolated from cases of knee OA as compared to healthy control.

Conclusion

The allelic alteration in ASPN and COMP genes in knee OA cases points to the role of these genes in the development of knee OA. Further, increased mRNA and protein expression of ASPN and COMP in peripheral blood samples of patients with the disease suggest that expression profile of candidate gene could be used as a biomarker for predicting the development and progression of knee OA.
Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls
Authors: Catania Alessia , Iuso Arcangela , Bouchereau Juliette , Kremer Laura S. , Paviolo Marina , Terrile Caterina , Bénit Paule , Rasmusson Allan G. , Schwarzmayr Thomas , Tiranti Valeria , Rustin Pierre , Rak Malgorzata , Prokisch Holger , Schiff Manuel
Published: October 2019

Background

Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts.

Results

We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells.

Conclusions

In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.
Effect of armed conflict on vaccination: evidence from the Boko haram insurgency in northeastern Nigeria
Authors: Sato Ryoko
Published: October 2019

Background

Armed conflicts can have severe adverse effects on population health, both directly and indirectly, through the destruction of health care systems. This paper evaluates the causal effect of the Boko Haram insurgency in northeastern Nigeria on the vaccination rate.

Methods

By matching children’s birth months and the months of armed conflict, we evaluate the effect of armed conflict on the vaccination rate of children. We use two datasets: the Nigeria Demographic and Health Survey (DHS) for vaccinations and the Uppsala Conflict Data Program (UCDP) Georeferenced Event Dataset (UCDP GED) for armed-conflict events.

Results

We find a large negative effect of conflict events on the likelihood of vaccination; if an armed conflict occurs within 10 km from where a child resides, the odds that child receives any vaccination are 47.2% lower. Odds ratio for BCG and DPT1 is 0.55 and 0.52 respectively. We also find that armed conflicts have more impact among the non-educated population than among the educated.

Conclusion

Overall, armed conflicts had a devastating effect on the vaccination of young children who were born at the time of these conflicts in northeastern Nigeria. A reduced vaccination rate puts the vulnerable population in affected areas at risk of contracting vaccine-preventable diseases.
Role of mitochondria and cardiolipins in growth inhibition of breast cancer cells by retinoic acid
Authors: Terao Mineko , Goracci Laura , Celestini Valentina , Kurosaki Mami , Bolis Marco , Di Veroli Alessandra , Vallerga Arianna , Fratelli Maddalena , Lupi Monica , Corbelli Alessandro , Fiordaliso Fabio , Gianni Maurizio , Paroni Gabriela , Zanetti Adriana , Cruciani Gabriele , Garattini Enrico
Published: October 2019

Background

All-trans-retinoic-acid (ATRA) is a promising agent in the prevention/treatment of breast-cancer. There is growing evidence that reprogramming of cellular lipid metabolism contributes to malignant transformation and progression. Lipid metabolism is implicated in cell differentiation and metastatic colonization and it is involved in the mechanisms of sensitivity/resistance to different anti-tumor agents. The role played by lipids in the anti-tumor activity of ATRA has never been studied.

Methods

We used 16 breast cancer cell-lines whose degree of sensitivity to the anti-proliferative action of ATRA is known. We implemented a non-oriented mass-spectrometry based approach to define the lipidomic profiles of each cell-line grown under basal conditions and following treatment with ATRA. To complement the lipidomic data, untreated and retinoid treated cell-lines were also subjected to RNA-sequencing to define the perturbations afforded by ATRA on the whole-genome gene-expression profiles. The number and functional activity of mitochondria were determined in selected ATRA-sensitive and –resistant cell-lines. Bio-computing approaches were used to analyse the high-throughput lipidomic and transcriptomic data.

Results

ATRA perturbs the homeostasis of numerous lipids and the most relevant effects are observed on cardiolipins, which are located in the mitochondrial inner membranes and play a role in oxidative-phosphorylation. ATRA reduces the amounts of cardiolipins and the effect is associated with the growth-inhibitory activity of the retinoid. Down-regulation of cardiolipins is due to a reduction of mitochondria, which is caused by an ATRA-dependent decrease in the expression of nuclear genes encoding mitochondrial proteins. This demonstrates that ATRA anti-tumor activity is due to a decrease in the amounts of mitochondria causing deficits in the respiration/energy-balance of breast-cancer cells.

Conclusions

The observation that ATRA anti-proliferative activity is caused by a reduction in the respiration and energy balance of the tumor cells has important ramifications for the therapeutic action of ATRA in breast cancer. The study may open the way to the development of rational therapeutic combinations based on the use of ATRA and anti-tumor agents targeting the mitochondria.
Can we still do something-and what? - for a seemingly missing syndrome?: “Yes we can”
Authors: Piumelli Raffaele , Arzilli Cinzia , Nassi Niccolò , Peruzzi Marta , Ernst Carola-Maria , Salvatori Cristina
Published: October 2019

In this letter, the authors compare the incidence of SUDI and SIDS in the Tuscany Region to the incidence reported by Campi and Bonati in their paper “Can we still do something-and what?- for a seemingly missing syndrome?” that was recently published in this journal. The Tuscany data are directly gathered from the autopsies while the others from the death certificates that are often not reilable, thus causing an understimation of the phenomenon. The real picture of the extent of SIDS is crucial to evaluate the effectiveness of back to sleep campaigns.
Remotely controlled mandibular positioning of oral appliance therapy during polysomnography and drug-induced sleep endoscopy compared with conventional subjective titration in patients with obstructive sleep apnea: protocol for a randomized crossover trial
Authors: Dieltjens Marijke , Braem Marc J. , Op de Beeck Sara , Vroegop Anneclaire V. M. T. , Kazemeini Elahe , Van de Perck Eli , Beyers Jolien , Kastoer Chloé , Wouters Kristien , Willemen Marc , Verbraecken Johan A. , Vanderveken Olivier M.
Published: October 2019

Background

The amount of mandibular protrusion is a key factor in optimizing the efficacy of mandibular advancement device (MAD) therapy in an individual patient diagnosed with obstructive sleep apnea. This process is called titration and is generally based on resolution of subjective symptoms like snoring and/or daytime sleepiness as a function of protrusion. An objective approach uses a remotely controlled mandibular positioner (RCMP) during a full-night polysomnography (PSG), in analogy with continuous positive airway pressure (CPAP) titration. More recently, the feasibility of RCMP use during drug-induced sleep endoscopy (DISE) titration was reported.

Methods

This randomized crossover trial will compare DISE-assisted titration to PSG-guided titration, as well as with the conventional subjective titration method. The primary outcome is the actual mandibular protrusive position found to be the most optimal for each tested titration procedure. Furthermore, the therapeutic efficacy will be compared among the different titration modalities using level 1 sleep studies.

Discussion

Currently, the optimal titration of MAD therapy is most often based on ‘trial and error’. The conventional method relies on subjective improvement in symptoms, although this may not provide the most accurate indicator for efficient titration. Therefore, relying on objective criteria in the titration process should be advantageous. In analogy with CPAP, titration of the most optimal mandibular protrusion could be performed using RCMP during an overnight titration PSG. Recently, it was shown that titration under direct visualization of upper airway patency and collapsibility is feasible using the RCMP during DISE. However, no clinical results for such a procedure are as yet available. This study is the first to compare the most optimal mandibular protrusive position according to three titration procedures, as well as to compare the therapeutic efficacy of these titration methods.

Trial registration

ClinicalTrials.gov, NCT03716648. Registered on 23 October 2018.
Lignin degradation potential and draft genome sequence of Trametes trogii S0301
Authors: Liu Yuan , Wu Yuanyuan , Zhang Yu , Yang Xulei , Yang En , Xu Huini , Yang Qiliang , Chagan Irbis , Cui Xiuming , Chen Weimin , Yan Jinping
Published: October 2019

Background

Trametes trogii is a member of the white-rot fungi family, which has a unique ability to break down recalcitrant lignin polymers to CO2 and water, and they have enormous potential to biodegrade a wide range of toxic environmental pollutants. Because of its industrial potential, the identification of lignin-degrading enzyme systems in Trametes is an important area of research. Development and utilization of industrial value genes are suffering due to deficiency knowledge of genome available for their manipulation.

Results

In the present study, Homokaryotic strains of T. trogii S0301 were screened and sequencing by PacBio Sequel II platform. The final draft genome is ~ 39.88 Mb, with a contig N50 size of 2.4 Mb, this was the first genome sequencing and assembly of T. trogii species. Further analyses predicted 14,508 protein-coding genes. Results showed that T. trogii S0301 contains 602 genes encoding CAZymes, include 211 glycoside hydrolase and 117 lignin-degrading family genes, nine laccases related genes. Small subunit ribosomal RNA gene (18S rRNA) sequencing confirms its phylogenetic position. Moreover, T. trogii S0301 has the largest number of cytochromes P450 (CYPs) superfamily genes compare to other fungi. All these results are consistent with enzymatic assays and transcriptome analysis results. We also analyzed other genome characteristics in the T. trogii S0301genome.

Conclusion

Here, we present a nearly complete genome for T. trogii S0301, which will help elucidate the biosynthetic pathways of the lignin-degrading enzyme, advancing the discovery, characterization, and modification of novel enzymes from this genus. This genome sequence will provide a valuable reference for the investigation of lignin degradation in the Trametes genus.
First report of canine ocular thelaziosis in the Republic of Moldova
Authors: Dumitrache Mirabela Oana , Ionică Angela Monica , Voinițchi Eugeniu , Chavdar Nicolai , D’Amico Gianluca
Published: October 2019

Background

Countries of eastern Europe are considered, due to several risk factors, more vulnerable to infections with newly (re)emerging pathogens. During the last decade, in several European countries, reports of autochthonous cases of ocular thelaziosis due to Thelazia callipaeda have been published, posing a great concern from both veterinary and public health perspective. However, in the Republic of Moldova only limited epidemiological data are available regarding zoonotic vector-borne pathogens and, until now, no data exist on the zoonotic nematode T. callipaeda.

Methods

In September 2018, an 11-year-old dog, mixed-breed, intact male was referred to a private veterinary clinic from Chișinău, Republic of Moldova, with a history of 2 weeks of an ocular condition affecting the right eye. The ophthalmological exam revealed the presence of nematode parasites in the conjunctival sac and under the third eyelid. The collected parasites were identified by morphological techniques and molecular analysis.

Results

A total of 7 nematodes were collected, and 5 females and 2 males of T. callipaeda were identified morphologically. The BLAST analysis confirmed the low genetic variability of this parasite in Europe. The travel history of the patient allowed us to confirm the autochthonous character of the case.

Conclusions

To the best of our knowledge, this is the first report of thelaziosis in dogs from the Republic of Moldova, which confirms the spreading trend of T. callipaeda and the existence of an autochthonous transmission cycle of this zoonotic parasite in the country.
Trypanosoma cruzi infection associated with atypical clinical manifestation during the acute phase of the Chagas disease
Authors: Rangel-Gamboa Lucia , López-García Lirio , Moreno-Sánchez Francisco , Hoyo-Ulloa Irma , Vega-Mémije María Elisa , Mendoza-Bazán Nancy , Romero-Valdovinos Mirza , Olivo-Díaz Angélica , Villalobos Guiehdani , Martínez-Hernández Fernando
Published: October 2019

Background

Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi and is transmitted by triatomine insects. Clinical manifestations vary according to the phase of the disease. Cutaneous manifestations are usually observed in the acute phase (chagoma and Romaña’s sign) or after reactivation of the chronic phase by immunosuppression; however, a disseminated infection in the acute phase without immunosuppression has not been reported for CD. Here, we report an unusual case of disseminated cutaneous infection during the acute phase of CD in a Mexican woman.

Methods

Evaluation of the patient included a complete clinical history, a physical exam, and an exhaustive evaluation by laboratory tests, including ELISA, Western blot and PCR.

Results

Skin biopsies of a 50-year-old female revealed intracellular parasites affecting the lower extremities with lymphangitic spread in both legs. The PCR tests evaluated biopsy samples obtained from the lesions and blood samples, which showed a positive diagnosis for T. cruzi. Partial sequencing of the small subunit ribosomal DNA correlated with the genetic variant DTU II; however, serological tests were negative.

Conclusions

We present a case of CD with disseminated skin lesions that was detected by PCR and showed negative serological results. In Mexico, an endemic CD area, there are no records of this type of manifestation, which demonstrates the ability of the parasite to initiate and maintain infections in atypical tissues.