bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of single‐nucleotide polymorphism in pri‐microRNA‐124 on poststroke motor function recovery
Authors: Chen Shangjun , Chen Yuhong , Gao Yadong , Zuo Yi , Zhou Xiaowei
Published: December 2018

Background

Stroke is a leading cause of long‐term disability and further one of the main causes of motor impairment. The current study aimed to investigate whether miR‐124 polymorphism (rs531564) influences the motor function of patients after stroke.

Methods

In total, 56 patients with stroke‐induced motor dysfunction were enrolled. Box and block test (BBT) and Fugl‐Meyer assessment (FMA) were performed to evaluate the motor functions in all participants. Computation analysis, luciferase activity, PCR assays, and Western blot analysis were performed to reveal the molecular mechanism underlying the effect of miR‐124 polymorphism on motor functions.

Results

The 56 participants were genotyped as CC, CG, and GG, respectively. The serum miR‐124 was significantly upregulated in the CC group than that in the GC and GG groups. According to the result of FMA or BBT, there was no obvious difference in upper and lower limb motor functions between CC and CG/GG groups 1 week after the treatment. In addition, scores of BBT and FMA exhibited apparent improvement in both groups at 1 month and 3 months after the treatment. Furthermore, improvements in the CG/GG groups were more significant as compared with those in the CC group. CDK4 was a target of miR‐124, and the effect of miR‐124 on the motor function recovery might be mediated by CDK4.

Conclusion

The presence of a minor allele, G, of miR‐124 polymorphism (rs531564) reduced the expression of miRNA and upregulated the expression of CDK4, which may contribute to the effect of rs531564 on the motor function recovery in poststroke patients.
LncRNA‐MIAT regulates fibrosis in hypertrophic cardiomyopathy (HCM) by mediating the expression of miR‐29a‐3p
Authors: Zhou Jing , Zhou Yu , Wang Cong‐xia
Published: December 2018

Aim

This study aimed to investigate the molecular mechanism underlying the fibrosis in hypertrophic cardiomyopathy (HCM).

Method

Quantitative real‐time polymerase chain reaction (qRT‐PCR) was performed to measure the expression of potentially relevant microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in patients with HCM suffering from fibrosis and patients with HCM free of fibrosis. In addition, the regulatory relationship between lncRNAs and miR‐29a was studied using a luciferase assay. Subsequently, area under the receiver‐operating characteristics (ROC) curve (AUC) analysis was conducted to predict the diagnostic value of myocardial infarction‐associated transcript (MIAT), miR‐29a, H19, and MEG3 in patients with HCM. Finally, the predicted regulatory relationship betwe en miR‐29a and MIAT was validated by transfecting cells with different plasmids.

Result

miR‐29a and MIAT were differently expressed between the fibrosis (+) HCM group and the fibrosis (−) HCM group, thus establishing a negative relationship between the expression of these two genes. In addition, both MIAT and miR‐29a showed the ability to accurately predict the prognosis in patients with HCM. Furthermore, the luciferase activity of wild‐type MIAT was evidently suppressed in cells transfected with miR‐29a mimics, suggesting that the expression of miR‐29a was apparently downregulated in the presence of MIAT.

Conclusion

The results obtained in this study collectively indicated that the MIAT might be associated with the development of fibrosis (+) HCM via negatively regulating the expression of miR‐29a.
A long noncoding RNAs signature to improve survival prediction in endometrioid endometrial cancer
Authors: Xu Qinyang , Yang Qin , Zhou Yang , Yang Bikang , Jiang Rongzhen , Ai Zhihong , Teng Yincheng
Published: December 2018

Purpose

The dysregulation of long noncoding RNAs (lncRNAs) has been reported to be correlated to carcinogenesis and cancer progression. Endometrial cancer (EC), arising from the endometrium or the inner lining of the uterus, is one of the most common gynecological malignancies. We aim to explore the prognostic value of the lncRNAs in patients with endometrioid endometrial cancer (EEC) and to identify the potential lncRNA signature for predicting survival of patients with EEC.

Methods

We performed a genome‐wide analysis of the lncRNA expression profiling in The Cancer Genome Atlas (TCGA)‐Uterine Corpus Endometrial Carcinoma database (408 EEC) to identify the prognosis related lncRNAs for the EEC. The patients with EEC were randomly divided into a training set (204 for endometrioid) and a testing set (204 for endometrioid). The lncRNA signature was identified in the training set, and then independently validated in the testing set and the complete set (training set plus testing set).

Results

We developed a nine‐lncRNA signature‐based risk score in the patients with EEC. The risk score based on the novel lncRNAs signature was able to separate patients of training set into high‐and low‐risk groups with significantly different overall survival and progression‐free survival. These can also be successfully confirmed in the testing set and complete set.

Conclusion

A nine‐lncRNA expression signature was identified and validated which can predict EEC patient’s survival. These findings may have important implications in the understanding of the potential therapeutic methods for patients with EEC.
Electrospun poly‐l‐lactic acid/polyvinyl alcohol nanofibers improved insulin‐producing cell differentiation potential of human adipose‐derived mesenchymal stem cells
Authors: Ojaghi Mohammad , Soleimanifar Fatemeh , Kazemi Alireza , Ghollasi Marzieh , Soleimani Masoud , Nasoohi Nikoo , Enderami Seyed Ehsan
Published: December 2018

Combination of adipose‐derived mesenchymal stem cells (ADSCs) and synthetic materials in terms of pancreatic tissue engineering can be considered as a treatment of diabetes. This study aimed to evaluate the differentiation of human ADSCs to pancreatic cells on poly‐l‐lactic acid/polyvinyl alcohol (PLLA/PVA) nanofibers as a three‐dimensional (3D) scaffold. Mesenchymal stem cells (MSCs) were characterized for mesenchymal surface markers by flow cytometry. Then ADSCs were seeded on 3D scaffolds and treated with pancreatic differentiation medium. Immunostaining assay showed that ADSCs were very efficiently differentiated into a relatively homogeneous population of insulin‐producing cells. Moreover, real‐time RT‐PCR results revealed that pancreas‐specific markers were highly expressed in 3D scaffolds compared with their expression in tissue culture plates and this difference in expression level was significant. In addition, insulin and C‐peptide secreted in response to varying concentrations of glucose in the 3D scaffold group was significantly higher than that in 2D culture. The results of the present study confirmed that PLLA/PVA scaffold seeded with ADSCs could be a suitable option in pancreatic tissue engineering.
Effect of Tribulus terrestris saponins on proliferation of adipose‐derived mesenchymal stem cells
Authors: Patel Apurva , Soni Anjali , Sharma Preeti
Published: December 2018

Adipose‐derived mesenchymal stem cells (ASCs) transplantation has shown great promise for treating various diseases; however, poor viability of transplanted ASCs because of oxidative stress has limited its therapeutic efficiency. Plant saponins are recently been reported to have antioxidant activity tested in various cancer cell lines. This study was designed to investigate the protective effects of Tribulus terrestris saponins (TTS) on the proliferation of ASCs. The cytotoxic activity of hydrogen peroxide (H2O2) was determined by treating ASCs with 100, 200, 300, 400, and 500 µM H2O2 for 2 hours. ASCs were treated with 6.25, 12.5, 25, 50, and 100 µg/mL concentrations of TTS for the proliferative experiment. To check the protective effect of TTS, experiments were designed in two ways. In one set, ASCs were pretreated with different concentrations of TTS for 2 hours and then apoptosis was induced by treating them with 400 µM H2O2 for next 2 hours, while in other set, ASCs were first treated with 400 µM H2O2 for 2 hours and subsequently with different concentrations of TTS for 24 hours. The vitality and proliferation potential of cells were detected by 3‐(4,5‐Dimethylthiazol‐2‐Yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The result of the current study shows that in response to stress‐induced by H2O2 at concentration of 400 µM, ASCs underwent growth arrest and cell viability was reduced to half while treatment with TTS before and after H2O2 exposure significantly prevents premature apoptosis. The findings suggest that saponins may act as an effective protective agent against oxidative stress–induced ASCs apoptosis.
Overexpression of Hes1 is involved in sensitization of K562 cells to Imatinib
Authors: Eskandari Sedigheh , Yazdanparast Razieh
Published: December 2018

Tyrosine kinase inhibitor (TKI)‐based therapy has created promising results among much chronic myeloid leukemia (CML) patients. Imatinib as a relatively specific inhibitor of Bcr‐Abl is at present one of the undisputed therapeutic agent for newlydiagnosed patients with CML. However, the occurrence of imatinib‐resistance enlightens the urgent need to identify other therapeutic agents against CML. Juglone (5‐hydroxy‐2‐methyl‐1, 4‐naphthoquinone) exerts cytotoxic effects against various human cancer cell lines. However, the mechanisms through which Juglone induces anticancer effects in CML especially in comparison with imatinib treatment remain unknown. Our results revealed that Juglone‐inhibited K562 cells growth through inducing apoptosis. Based on our Western blot analyses, Juglone significantly reduced p‐Akt levels and increased the expression level of Forkhead box O1 (FoxO1) and FoxO3a proteins. Moreover, hairy/enhancer of split‐1 (Hes1) protein, overexpressed under the influence of Juglone, is apparently involved in Juglone‐induced apoptosis among K562 cells. Conversely, treatment with imatinib attenuated Hes1 protein expression. Considering the different functional mechanism of Juglone compared with imatinib, it seems that Juglone treatment could be a useful alternative strategy for the treatment of patients with imatinib‐resistance.
Wnt signaling reprograms metabolism in dental pulp stem cells
Authors: Uribe‐Etxebarria Véronica , Agliano Alice , Unda Fernando , Ibarretxe Gaskon
Published: December 2018

Human dental pulp stem cells (DPSCs) can differentiate to a wide range of different cell lineages, and share some gene expression and functional similarities with pluripotent stem cells. The stemness of DPSCs can also be pharmacologically enhanced by the activation of canonical Wnt signaling. Here, we examined the metabolic profile of DPSCs during reprogramming linked to Wnt activation, by a short (48 hr) exposure to either the GSK3‐β inhibitor BIO (6‐bromoindirubin‐3´‐oxine) or human recombinant protein WNT‐3A. Both treatments largely increased glucose consumption, and induced a gene overexpression of pyruvate and mitochondrial acetyl‐coA producing enzymes, thus activating mitochondrial tricarboxylic acid cycle (TCA) metabolism in DPSCs. This ultimately led to an accumulation of reducing power and a mitochondrial hyperpolarization in DPSCs. Interestingly, Nile Red staining showed that lipid fuel reserves were being stored in Wnt‐activated DPSCs. We associate this metabolic reprogramming with an energy‐priming state allowing DPSCs to better respond to subsequent high demands of energy and biosynthesis metabolites for cellular growth. These results show that enhancement of the stemness of DPSCs by Wnt activation comes along with a profound metabolic remodeling, which is distinctly characterized by a crucial participation of mitochondrial metabolism.
Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency‐mediated mitochondrial dysregulation
Authors: Whang Young Mi , Kim Myeong Joo , Cho Min Ji , Yoon Hoyub , Choi Young Wook , Kim Tae‐Hyoung , Chang In Ho
Published: December 2018

Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has significant potential for application in the treatment of urothelial carcinoma (URCa) of the bladder. Previous studies have shown that regulation of the AMP‐activated serine/threonine protein kinase (AMPK)–mTOR signaling pathway enhances apoptosis by inducing autophagy or mitophagy in bladder cancer. Alteration of liver kinase B1 (LKB1)‐AMPK signaling leads to mitochondrial dysfunction and the accumulation of autophagy‐related proteins as a result of mitophagy, resulting in enhanced cell sensitivity to drug treatments. Therefore, we hypothesized that LKB1 deficiency in URCa cells could lead to increased sensitivity to rapamycin by inducing mitochondrial defect‐mediated mitophagy. To test this, we established stable LKBI‐knockdown URCa cells and analyzed the effects of rapamycin on their growth. Rapamycin enhanced growth inhibition and apoptosis in stable LKB1‐knockdown URCa cells and in a xenograft mouse model. In spite of the stable downregulation of LKB1 expression, rapamycin induced AMPK activation in URCa cells, causing loss of the mitochondrial membrane potential, ATP depletion, and ROS accumulation, indicating an alteration of mitochondrial biogenesis. Our findings suggest that the absence of LKB1 can be targeted to induce dysregulated mitochondrial biogenesis by rapamycin treatment in the design of novel therapeutic strategies for bladder cancer.
Type I IFNs in the female reproductive tract: The first line of defense in an ever-changing battleground
Authors: Cumming Helen E , Bourke Nollaig M
Published: December 2018

The primary function of the female reproductive tract (FRT) is to enable successful reproduction, yet the biologic mechanisms required to accomplish this, which include fluctuating sex hormones and tolerance of semen and a semi-allogeneic fetus, can leave this unique mucosal environment susceptible to pathogenic challenge. Consequently, the FRT has evolved specialized innate and adaptive immune responses tailored to protecting itself from infection without compromising reproductive success. A family of innate immune cytokines that has emerged as important regulators of these immune responses is the type I IFNs. Type I IFNs are typically rapidly produced in response to pathogenic stimulation and are capable of sculpting pleotropic biologic effects, including immunomodulation, antiproliferative effects, and inducing antiviral and bactericidal molecules. Here, we review what is currently known about type I IFN-mediated immunity in the FRT in human, primate, and murine models and explore their importance with respect to three highly relevant FRT infections: HIV, Zika, and Chlamydia.

Type 1 IFNs in the epithelium in the female reproductive tract. Constitutively expressed IFNɛ provides a primary barrier to prevent initial infection, whereas IFNα and IFNβ are rapidly induced to respond once pathogens are detected.
Artificial Intelligence and the Role of Leadership
Authors: Smith Ashley M. , Green Mark
Published: December 2018

A future artificial intelligence (AI) leadership position will likely include a new follower, the AI machine. The continued rise in retired‐aged individuals illustrates the need to replace a traditional workforce with alternatives. Robots tend to be non‐functional without leaders. With this new position, AI leaders will engage in processes that focus on leading the programmers of the AI machine as well as influencing decisions made by AI machines post‐programming. Communication standards should be set for both the human and machine members. It is unclear if this new position will be referred to as leadership or management, but standards should be in place for proper supervision of these machines. Leadership research has found that behaviors such as charismatic influences and relationship building are important for leading humans. AI leadership may require adjustments to current influences used for humans. Building relationships with AI machines is expected to be altered with greater focus needed on ethical and moral mentoring. Such a focus may utilize top‐down and bottom‐up roboethics, with decreased focus on getting machine followers to feel part of an in‐group. The current paper provides ideas for leading teams of AI machines and their programmers.
Surrogate‐assisted design of microstrip corporate feeds integrated with linear microstrip array apertures for required sidelobe levels
Authors: Koziel Slawomir , Ogurtsov Stanislav
Published: December 2018

A systematic computer‐aided design of low‐sidelobe linear microstrip antenna arrays is proposed. It starts from identifying the corporate feed architecture which is optimal for a given excitation taper under constrains imposed on the power splits within the feed. The novelty of the approach includes utilization of a numerically efficient simulation‐based kriging model of unequal split microstrip junctions for implementation of the optimal microstrip feed, and simulation‐based tuning of the excitation taper. The tuning is carried out with surrogate‐assisted optimization which is based on the electromagnetic simulations of an integrated array circuit comprising the aperture and the feed. Additionally, in‐phase excitation of the array aperture radiators is ensured with a simulation‐based correction of the corporate feed microstrip branches. The approach is implemented iteratively to realize the nominal sidelobe level. The approach is demonstrated with design of a 12‐element H‐plane 25‐dB sidelobe level Tschebyscheff array. Experimental validation is provided.
Downregulation of tyrosine hydroxylase phenotype after AAV injection above substantia nigra: Caution in experimental models of Parkinson’s disease
Authors: Albert Katrina , Voutilainen Merja H. , Domanskyi Andrii , Piepponen T. Petteri , Ahola Sari , Tuominen Raimo K. , Richie Christopher , Harvey Brandon K. , Airavaara Mikko
Published: December 2018

Adeno‐associated virus (AAV) vector‐mediated delivery of human α‐synuclein (α‐syn) gene in rat substantia nigra (SN) results in increased expression of α‐syn protein in the SN and striatum which can progressively degenerate dopaminergic neurons. Therefore, this model is thought to recapitulate the neurodegeneration in Parkinson's disease. Here, using AAV to deliver α‐syn above the SN in male and female rats resulted in clear expression of human α‐syn in the SN and striatum. The protein was associated with moderate behavioral deficits and some loss of tyrosine hydroxylase (TH) in the nigrostriatal areas. However, the immunohistochemistry results were highly variable and showed little to no correlation with behavior and the amount of α‐syn present. Expression of green fluorescent protein (GFP) was used as a control to monitor gene delivery and expression efficacy. AAV‐GFP resulted in a similar or greater TH loss compared to AAV‐α‐syn and therefore an additional vector that does not express a protein was tested. Vectors with double‐floxed inverse open reading frame (DIO ORF) encoding fluorescent proteins that generate RNA that is not translated also resulted in TH downregulation in the SN but showed no significant behavioral deficits. These results demonstrate that although expression of wild‐type human α‐syn can cause neurodegeneration, the variability and lack of correlation with outcome measures are drawbacks with the model. Furthermore, design and control selection should be considered carefully because of conflicting conclusions due to AAV downregulation of TH, and we recommend caution with having highly regulated TH as the only marker for the dopamine system.
Ultrasound Assessment of Hepatobiliary and Splenic Changes in Patients With Dengue and Warning Signs During the Acute and Recovery Phases
Authors: Ferreira Bruno Doriguetto Couto , Correia Dalmo
Published: December 2018

Objectives

To evaluate whether abdominal ultrasound (US) with a gallbladder (GB) contractility study or motor function test can be used as a diagnostic tool in patients with dengue and warning signs in acute and recovery phases.

Methods

Fifty‐one individuals in the acute phase of dengue presenting with warning signs (dengue group) and 49 healthy individuals without a history of dengue or hepatobiliary disease (control group) were studied with abdominal US and a GB contractility study.

Results

Statistical differences in US measurements of the liver (right lobe, P = .012; left lobe, P = .001) and spleen (P = .008) dimensions, GB wall thickness (P < .001), and the GB emptying fraction (P < .001) were observed in dengue during the acute phase compared with the control group. After 60 days, abdominal US of the dengue group showed a statistical difference in liver (right lobe, P < .001; left lobe, P = .078) and spleen (P < .001) dimensions, GB wall thickness, and the GB emptying fraction (P < .001) compared with the results obtained during the acute phase. Furthermore, a statistical difference in the spleen volume and GB emptying fraction (P < .001) was observed when comparing dengue after clinical recovery and the control group. Abdominal pain in patients with dengue was positively associated with hepatomegaly (P = .031), splenomegaly (P = .008), increased GB wall thickness (P = .016), and a reduced GB emptying fraction (P = .038) during the acute phase and with splenomegaly (P = .001) and a reduced GB emptying fraction (P = .003) after clinical recovery.

Conclusions

Abdominal US with a GB motor function test can be used as a diagnostic tool in patients with dengue during acute and recovery phases.
The unique methodological challenges of winter limnology
Authors: Block Benjamin D. , Denfeld Blaize A. , Stockwell Jason D. , Flaim Giovanna , Grossart Hans‐Peter F. , Knoll Lesley B. , Maier Dominique B. , North Rebecca L. , Rautio Milla , Rusak James A. , Sadro Steve , Weyhenmeyer Gesa A. , Bramburger Andrew J. , Branstrator Donn K. , Salonen Kalevi , Hampton Stephanie E.
Published: December 2018

Winter is an important season for many limnological processes, which can range from biogeochemical transformations to ecological interactions. Interest in the structure and function of lake ecosystems under ice is on the rise. Although limnologists working at polar latitudes have a long history of winter work, the required knowledge to successfully sample under winter conditions is not widely available and relatively few limnologists receive formal training. In particular, the deployment and operation of equipment in below 0°C temperatures pose considerable logistical and methodological challenges, as do the safety risks of sampling during the ice‐covered period. Here, we consolidate information on winter lake sampling and describe effective methods to measure physical, chemical, and biological variables in and under ice. We describe variation in snow and ice conditions and discuss implications for sampling logistics and safety. We outline commonly encountered methodological challenges and make recommendations for best practices to maximize safety and efficiency when sampling through ice or deploying instruments in ice‐covered lakes. Application of such practices over a broad range of ice‐covered lakes will contribute to a better understanding of the factors that regulate lakes during winter and how winter conditions affect the subsequent ice‐free period.
Induction of fat apoptosis by a non‐thermal device: Mechanism of action of non‐invasive high‐intensity electromagnetic technology in a porcine model
Authors: Weiss Robert A. , Bernardy Jan
Published: December 2018

Objectives

While controlled thermal changes in subcutaneous tissue have been used to trigger apoptosis of fat cells and have been proven clinically efficacious, another mechanism of electromagnetic stress suggests that fat apoptosis could be achieved by a non‐thermal manner as well. This animal model study investigates the use of a non‐invasive high‐intensity magnetic field device to induce apoptosis in fat cells.

Methods

Yorkshire pigs (N = 2) received one treatment (30 minutes) in the abdominal area using a High‐Intensity Focused Electromagnetic (HIFEM) device. Punch biopsy samples of fat tissue and blood samples were collected at the baseline, 1 and 8 hours after the treatment. Biopsy samples were sectioned and evaluated for the levels of an apoptotic index (AI) by the TUNEL method. Statistical significance was examined using the rANOVA and Tukey's test (α 5%). Biopsy samples were also assessed for molecular biomarkers. Blood samples were evaluated to determine changes related to fat and muscle metabolism. Free fatty acids (FFA), triacylglycerol (TG), glycerol and glucose (Glu) were used as the main biomarkers of fat metabolism. Creatinine, creatinine kinase (CK), lactate dehydrogenase (LDH) and interleukin 6 (IL6) served as the main biomarkers to evaluate muscle metabolism.

Results

In treated pigs, a statistically significant increase in the apoptotic index (AI) (P = 1.17E‐4) was observed. A significant difference was found between AI at baseline (AI = 18.75%) and 8‐hours post‐treatment (AI = 35.95%). Serum levels of fat and muscle metabolism indicated trends (FFA −0.32 mmol · l−1, −28.1%; TG −0.24 mmol · l−1, −51.8%; Glycerol −5.68 mg · l−1, −54.8%; CK +67.58 μkat · l−1, +227.8%; LDH +4.9 μkat · l−1,+35.4%) suggesting that both adipose and muscle tissue were affected by HIFEM treatment. No adverse events were noted to skin and surrounding tissue.

Conclusions

Application of a high‐intensity electromagnetic field in a porcine model results in adipocyte apoptosis. The analysis of serum levels suggests that HIFEM treatment influences fat and muscle metabolism. Lasers Surg. Med. 51:47–53, 2019. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.
Clinical implementation of gene panel testing for lysosomal storage diseases
Authors: Gheldof Alexander , Seneca Sara , Stouffs Katrien , Lissens Willy , Jansen Anna , Laeremans Hilde , Verloo Patrick , Schoonjans An‐Sofie , Meuwissen Marije , Barca Diana , Martens Geert , De Meirleir Linda
Published: December 2018

Background

The diagnostic workup in patients with a clinical suspicion of lysosomal storage diseases (LSD) is often difficult due to the variability in the clinical phenotype. The gold standard for diagnosis of LSDs consists of enzymatic testing. However, due to the sequential nature of this methodology and inconsistent genotype–phenotype correlations of certain LSDs, finding a diagnosis can be challenging.

Method

We developed and clinically implemented a gene panel covering 50 genes known to cause LSDs when mutated. Over a period of 18 months, we analyzed 150 patients who were referred for LSD testing and compared these results with the data of patients who were previously enrolled in a scheme of classical biochemical testing.

Results

Our panel was able to determine the molecular cause of the disease in 22 cases (15%), representing an increase in diagnostic yield compared to biochemical tests developed for 21 LSDs (4.6%). We were furthermore able to redirect the diagnosis of a mucolipidosis patient who was initially suspected to be affected with galactosialidosis. Several patients were identified as being affected with neuronal ceroid lipofuscinosis, which cannot readily be detected by enzyme testing. Finally, several carriers of pathogenic mutations in LSD genes related to the disease phenotype were identified as well, thus potentially increasing the diagnostic yield of the panel as heterozygous deletions cannot be detected.

Conclusion

We show that the implementation of a gene panel for LSD diagnostics results in an increased yield in comparison to classical biochemical testing. As the panel is able to cover a wider range of diseases, we propose to implement this methodology as a first‐tier test in cases of an aspecific LSD presentation, while enzymatic testing remains the first choice in patients with a more distinctive clinical presentation. Positive panel results should however still be enzymatically confirmed whenever possible.
Riemann‐Hilbert problems and soliton solutions of a multicomponent mKdV system and its reduction
Authors: Ma Wen‐Xiu
Published: December 2018

An arbitrary order matrix spectral problem is introduced and its associated multicomponent AKNS integrable hierarchy is constructed. Based on this matrix spectral problem, a kind of Riemann‐Hilbert problems is formulated for a multicomponent mKdV system in the resulting AKNS integrable hierarchy. Through special corresponding Riemann‐Hilbert problems with an identity jump matrix, soliton solutions to the presented multicomponent mKdV system are explicitly worked out. A specific reduction of the multicomponent mKdV system is made, together with its reduced Lax pair and soliton solutions.
Collagen proton fraction from ultrashort echo time magnetization transfer (UTE‐MT) MRI modelling correlates significantly with cortical bone porosity measured with micro‐computed tomography (μCT)
Authors: Jerban Saeed , Ma Yajun , Wan Lidi , Searleman Adam C. , Jang Hyungseok , Sah Robert L. , Chang Eric Y. , Du Jiang
Published: December 2018

Intracortical bone porosity is a key microstructural parameter that determines bone mechanical properties. While clinical MRI visualizes the cortical bone with a signal void, ultrashort echo time (UTE) MRI can acquire high signal from cortical bone, thus enabling quantitative assessments. Magnetization transfer (MT) imaging combined with UTE‐MRI can indirectly assess protons in the bone collagenous matrix, which are inversely related to porosity. This study aimed to examine UTE‐MT MRI techniques to evaluate intracortical bone porosity. Eighteen human cortical bone specimens from the tibial and fibular midshafts were scanned using UTE‐MT sequences on a clinical 3 T MRI scanner and on a high‐resolution micro‐computed tomography (μCT) scanner. A series of MT pulse saturation powers (500°, 1000°, 1500°) and frequency offsets (2, 5, 10, 20, 50 kHz) were used to measure the macromolecular fraction (MMF) and macromolecular T2 (T2MM) using a two‐pool MT model. The measurements were made on 136 different regions of interest (ROIs). ROIs were selected at three cortical bone layers (from endosteum to periosteum) and four anatomical sites (anterior, mid‐medial, mid‐lateral, and posterior) to provide a wide range of porosity. MMF showed moderate to strong correlations with intracortical bone porosity (R = −0.67 to −0.73, p < 0.01) and bone mineral density (BMD) (R = +0.46 to +0.70, p < 0.01). Comparing the average MMF between cortical bone layers revealed a significant increase from the endosteum towards the periosteum. Such a pattern was in agreement with porosity reduction and BMD increase towards the periosteum. These results suggest that the two‐pool UTE‐MT technique can potentially serve as a novel and accurate tool to assess intracortical bone porosity.
Z scores of the fetal trachea and bronchial dimension
Authors: Cao Danming , Zeng Shi , Li Xinyan , Zhou Jiawei , Zhou Qichang
Published: December 2018

Objective

To develop Z scores for the trachea and main bronchi in normal fetuses.

Methods

This was a prospective cross‐sectional study in 823 normal singleton fetuses. The tracheal diameter immediately proximal to the bifurcation and the left and right main bronchial diameters were measured from their inner to inner edge in the coronal view. Z scores were created for the trachea and main bronchial diameters using gestational age (GA), femur length (FL), and biparietal diameter (BPD) as independent variables.

Results

Between gestational weeks 20 and 40, the inner diameters of the trachea, left principal bronchi (LPB), and right principal bronchi (RPB) increased from 1.8 to 4.7 mm, 0.8 to 2.2 mm, and 0.9 to 2.3 mm, respectively. A simple linear regression equation was fitted to model the mean of each diameter. There was however significant heteroscedasticity of the standard deviation (SD) with increasing GA, FL, or BPD. Eventually, the following formula was used to calculate Z scores for the diameters: [measured value − equation for mean]/equation for SD.

Conclusion

We have developed Z scores for the fetal trachea and main bronchi by applying standard statistical methods. These Z scores may be useful to evaluate the early development of the respiratory system.
Tramadol dispensing patterns and trends in Canada, 2007‐2016
Authors: Fischer Benedikt , Kurdyak Paul , Jones Wayne
Published: December 2018

Purpose

Opioid use and associated mortality and morbidity have substantially increased in Canada, which recent interventions have aimed to reduce. Tramadol is an atypical prescription‐only (but unscheduled under Canada's narcotics law) opioid analgesic and not subject to controls for other (eg, strong) opioids. Given experiences in different jurisdictions, tramadol may have been increasingly dispensed as a “substitute” drug during a period with increasingly restrictive controls for other (scheduled) opioids.

Methods

We examined the annual population‐level retail dispensing (as a proxy for use) of tramadol and (scheduled) “strong opioids” in Canadian provinces for 2007‐2016 based on data from a representative national sample of community pharmacies, covering the majority of episodes of opioid dispensing. Data for both aforementioned formulation categories were converted into defined daily doses (DDD)/1000 population/day and examined descriptively and by segmented regression analyses (to identify significant breakpoints in trends).

Results

Tramadol use strongly increased in all provinces until 2009. After 2009, tramadol dispensing levels either decelerated their increase or plateaued; “strong opioid” dispensing levels, in comparison, increased strongly until 2011 and decelerated or decreased for the remaining period. Tramadol was consistently dispensed at lower levels than “strong opioids.”

Conclusions

Tramadol and “strong opioids” showed similar (bifurcated) use trends, with initial increases and subsequent inflections, yet reductions in dispensing occurred earlier for tramadol than for “strong opioids” (the latter occurring following with recent interventions). Distinct from experiences with differential opioid control regimes elsewhere, there is no evidence that tramadol figured as a “substitution” drug for increasingly restricted “strong opioids” in Canada.
Validation study of colorectal cancer diagnosis in the Spanish primary care database, BIFAP
Authors: Gil Miguel , Rodríguez‐Miguel Antonio , Montoya‐Catalá Héctor , González‐González Rocío , Álvarez‐Gutiérrez Arturo , Rodríguez‐Martín Sara , García‐Rodríguez Luis A. , de Abajo Francisco J.
Published: December 2018

Purpose

To define and validate a case‐finding algorithm to identify incident colorectal cancer (CRC) in the Spanish primary care database BIFAP.

Methods

All potential incident CRC cases recorded during the study period 2001 to 2014 among patients 20 to 89 years old were identified using a defined case‐finding algorithm tailored to BIFAP database characteristics and based on codes plus text mining strategies. Potential CRC cases identified by the algorithm were classified into eight homogeneous groups according to recording characteristics. Random samples of 100 cases per group were obtained, and electronic medical records were manually reviewed by two independent researchers. Positive predictive values (PPVs) were estimated per each group and for the whole sample taking into account the stratified sampling. Standardized incidence rate (SIR) of CRC was estimated and compared with that reported by the National Cancer Registry. Negative predictive value (NPV) was also estimated in a random sample of 100 non‐CRC patients by the algorithm.

Results

A total of 17 008 potential CRC cases were identified. Most of them (14793; 87%) were recorded as incident diagnosis with linked clinical notes as free text, having this group a PPV of 92.1% (95%CI: 87.1%‐95.3%). The overall PPV including all groups was 87.3% (95%CI: 83.3%‐90.4%). SIR of CRC was 55.5 per 100.000 person‐years. SIR increased with age and was higher in men as compared with women (77.7 vs 38.1 per 100.000 py, respectively) which were in line with those reported by the Network of Cancer Registries in Spain. NPV was of 100% (96.3%‐100%).

Conclusions

This study shows a high validity of the CRC cases identified by the algorithm and a high level of CRC recording in BIFAP database and supports its appropriateness to validly identify incident CRC cases in BIFAP.
Theory of mind, directly and indirectly, facilitates kindergarten adjustment via verbal ability, executive function, and emotion knowledge
Authors: Brock Laura L. , Kim Helyn , Kelly Cara L. , Mashburn Andrew J. , Grissmer David W.
Published: December 2018

Theory of mind describes the ability to engage in perspective‐taking, understand intentions, and predict actions and emotions. Theory of mind typically achieves major developmental milestones around age of 5, coinciding with the transition to kindergarten, and is associated with a verbal ability (receptive and expressive vocabulary), executive function (inhibitory control and working memory), and emotion knowledge. Less is known about how the theory of mind operates in low‐income samples, where foundational skills (i.e., verbal ability, executive function, and emotion knowledge) tend to be delayed. Applied to classrooms, the theory of mind may support the transition to kindergarten by facilitating relationships, learning‐related behaviors, and socioemotional skills that require perspective‐taking. In a low‐income sample of 140 kindergarteners across 21 classrooms, the theory of mind was directly associated with teacher‐ratings of social and emotional skills, behavioral and academic adjustment, and closeness within the teacher–child relationship, beyond the contribution of foundational skills. Moreover, verbal ability, executive function, and emotion knowledge were indirectly associated with outcomes through the theory of mind. Findings suggest the theory of mind facilitates the transition to kindergarten and is built upon a complex set of foundational skills.
Effect of high frequency oscillatory high flow nasal cannula on carbon dioxide clearance in a premature infant lung model: A bench study
Authors: Sivieri Emidio M. , Eichenwald Eric , Bakri Salma M. , Abbasi Soraya
Published: December 2018

Objective

This study compared CO2 clearance in a premature infant lung model connected to a high flow nasal cannula (HFNC) system supplied with oscillatory versus non‐oscillatory flow.

Design/Methods

The lung model was set to compliance 1.0 mL/cmH2O, RR 60 breaths/min, and 6 mL tidal volume. A 100% CO2 was injected at a constant 15 mL/min. To create oscillation, HFNC flow was interrupted at rates of 4‐6‐8 and 10 Hz. equilibrated end‐tidal CO2 (ETCO2) was recorded with and without oscillation at set flows of 2‐8 L/min and repeated for each oscillation frequency.

Results

Overall ETCO2 decreased significantly (P < 0.001) during both non‐oscillatory and oscillatory HFNC as set flow increased from 2 to 8 L/min by 26.3% and 60.8%, respectively. Oscillatory ETCO2 levels decreased linearly compared to non‐oscillatory HFNC with negligible difference at 2 L/min and a 48.4% difference at 8 L/min (P < 0.001). There were no differences in ETCO2 levels between oscillation frequencies at any flow except at 6 Hz for which ETCO2 was significantly lower (P < 0.01) than at 4, 8, and 10 Hz for 5‐8 L/min HFNC flows. Amplitude of volume oscillations increased with increasing flow from 0.5 mL at 2 L/min to 4.0 mL at 8 L/min (P < 0.001), and decreased with increasing oscillation frequency.

Conclusion

Oscillatory HFNC as compared to non‐oscillatory was associated with significantly improved CO2 clearance in this premature infant lung model. This simple modification of the HFNC system may prove to be a useful enhancement to this mode of non‐invasive respiratory support for preterm infants at high risk for respiratory failure.
Post‐infectious bronchiolitis obliterans
Authors: Colom Alejandro J. , Teper Alejandro M.
Published: December 2018

Bronchiolitis obliterans is a rare and severe chronic lung disease resulting from a lower respiratory tract lesion. It may occur after a bone marrow or lung transplantation, infectious diseases, or less frequently after inhaling toxic substances or after connective tissue diseases. Pathology, pathogenesis, and molecular biology, as well as the best treatment of bronchiolitis obliterans, remain the subject of ongoing research. This review discusses our current knowledge of different areas of bronchiolitis obliterans associated with infectious lesions.
Analysis of the Deformation Behavior and Mechanical Properties of Slit‐Perforated Auxetic Metamaterials
Authors: Mizzi Luke , Grima Joseph N. , Gatt Ruben , Attard Daphne
Published: December 2018

Perforated systems constitute one of the most important classes of mechanical metamaterials. In this work, two types of “I”‐shaped slit perforation patterns are proposed which may be used to design perforated systems that mimic the deformation mechanisms of a variety of re‐entrant and anti‐tetrachiral honeycomb systems. Using finite element analysis, it is shown how these systems have the potential to exhibit a large spectrum of negative Poisson's ratios, ranging from extremely negative to zero, which are retained over a wide tensile strain range. A detailed analysis of the deformation behavior of these systems is also presented along with a comparison of the changes in overall expansion and Poisson's ratios of both systems observed upon loading with those predicted by previously formulated theoretical models of re‐entrant and anti‐tetrachiral systems. It is hoped that this work will be of considerable aid in the efforts of scientists to understand the underlying principles governing the production of auxetic mechanical metamaterials through the use of perforations and also stimulate further research on how these and similar mechanisms may be implemented in perforated systems to design other metamaterials with anomalous mechanical properties.
RBS/C, XRR, and XRD Studies of Damage Buildup in Er‐Implanted ZnO
Authors: Jozwik Przemyslaw , Magalhães Sergio , Ratajczak Renata , Mieszczynski Cyprian , Sequeira Miguel , Turos Andrzej , Böttger Roman , Heller Rene , Lorenz Katharina , Alves Eduardo
Published: December 2018

Accumulation and transformation of defects formed in bulk ZnO crystals at room temperature upon 300 keV Er ions bombardment have been thoroughly examined using complementary techniques: Rutherford Backscattering Spectrometry in ion Channeling mode (RBS/C), X‐Ray Reflectivity (XRR), and X‐Ray Diffraction (XRD). Evaluation of RBS/C spectra has been performed using Monte Carlo (MC) simulations (McChasy software). Two defect types have been indicated: point defects (randomly displaced atoms, RDA) and extended ones (edge dislocations, DIS). Depth‐distributions of RDA and DIS turned out to be shifted toward deeper regions of ZnO crystals (relative to Er‐ions range) while DIS are localized even deeper than RDA. The MC simulations reveal three regions of defects accumulation separated by two regions of rapid defects transformation occurring at a certain critical Er fluence. Strain, suggested to be a driving force of defect transformation, has been determined using simulations of the XRD profiles based on the dynamical theory of X‐ray diffraction (MROX software). The presented research can help to better understand the interaction between impurity Er ions and ZnO target atoms during the implantation process. Hence, implantation conditions, for example, for luminescence purpose may now be more efficiently chosen based on the results discussed.
The milk thistle (Silybum marianum) compound Silibinin stimulates leukopoiesis from mouse embryonic stem cells
Authors: Sharifpanah Fatemeh , Ali Enas Hussein , Wartenberg Maria , Sauer Heinrich
Published: December 2018

The milk thistle compound Silibinin (i.e., a 1:1 mixture of Silybin A and Silybin B) stimulates vasculogenesis of mouse embryonic stem (ES) cells. Because vasculogenesis and leukopoiesis are interrelated, the effect of Silibinin on leukopoiesis of ES cells was investigated. Treatment of differentiating ES cells with hydrosoluble Silibinin‐C‐2′,3‐dihydrogen succinate dose‐dependent increased the number of CD18+, CD45+, and CD68+ cells, indicating leukocyte/macrophage differentiation. Silibinin treatment activated phosphoinositide 3‐kinase (PI3K), AKT (protein kinase B), signal transducer and activator of transcription 3 (STAT3), stimulated hypoxia‐induced factor‐1α (HIF‐1α), and vascular endothelial growth factor receptor 2 (VEGFR2) expression and raised intracellular nitric oxide (NO). Western blot experiments showed that upon coincubation with either the PI3K inhibitor LY294002, the STAT3 inhibitor Stattic, the AKT antagonist AKT inhibitor VIII, or the NO inhibitor L‐NAME, the Silibinin‐induced expression of CD18, CD45, and CD68 was abolished. Moreover, the stimulation of HIF‐1α and VEGFR2 expression was blunted upon STAT3 and PI3K/AKT inhibition. Treatment of differentiating ES cells with L‐NAME abolished the stimulation of VEGFR2 and VE‐cadherin expression achieved with Silibinin, indicating that NO is involved in vasculogenesis and leukocyte differentiation pathways. In summary, the data of the present study demonstrate that Silibinin stimulates leukocyte differentiation of ES cells, which is associated to vasculogenesis and regulated by PI3K/AKT‐, STAT3‐, and NO‐mediated signaling.
Assimilating cloudy and rainy microwave observations from SAPHIR on board Megha Tropiques within the ARPEGE global model
Authors: Duruisseau Fabrice , Chambon Philippe , Wattrelot Eric , Barreyat Marylis , Mahfouf Jean‐François
Published: December 2018

The Megha‐Tropiques satellite was launched in 2011 with a microwave sounder called SAPHIR onboard. This instrument probes the atmosphere with six channels around the 183.31 GHz water vapour absorption band. Its observations are sensitive to water vapour as well as to hydrometeors. This instrument was proven to be useful for data assimilation by different numerical weather prediction centres, in particular for clear‐sky assimilation. At Météo‐France, SAPHIR observations have been routinely assimilated in clear sky since 2015 in the ARPEGE global model. The present article introduces a framework to complement this clear‐sky assimilation route by a new cloudy and rainy assimilation route for satellite microwave brightness temperatures. This framework is based on several steps including a Bayesian inversion of the SAPHIR brightness temperatures into relative humidity retrievals, which are then assimilated within the ARPEGE global model. This study presents the methodology of assimilation, including the development of two error models, one for the Bayesian inversion, and one for the observation errors of relative humidity retrievals within the ARPEGE 4D‐Var data assimilation system. The forecast scores obtained with this methodology over a three‐month period indicate a positive impact of SAPHIR cloudy and rainy observations within the ARPEGE system, in particular on tropical temperature and wind forecasts for which the improvements range from 0.5 to 1.7% on standard deviations with respect to the ECMWF analysis and up to a +60 h lead time.