bluuebunny/crossref_metadata_2025 huggingface dataset:
The abundance of epiphytic liverworts on the bark of Cryptomeria japonica in relation to different physical and biochemical attributes, found in Senchal Wildlife Sanctuary, Darjeeling, Eastern Himalaya
Authors: Mukhia Sumira , Mandal Palash , Singh D. K. , Singh Devendra
Published: September 2019

Background

Maintenance of biodiversity is an integral part of sustainable forest management. Epiphytic bryophytes are an important element of biodiversity. Thus, this work aims to study the role of different physical and biochemical factors in affecting the growth and proliferation of epiphytic liverworts. Fifty trees in three different plots, distributed in Senchal wildlife sanctuary, Darjeeling, were surveyed. Factors such as light intensity, moisture, and diameter at breast height (DBH) of the tree were studied to evaluate their possible role in affecting epiphytic liverworts. The effect of bark biochemical characteristics on the abundance of epiphytic liverworts was also studied by undertaking a quantitative test of pH, phenol, flavonoid, ortho-dihydric phenol, terpene, total sugar, and tannin. Multiple regression analysis and principal component analysis (PCA) were carried out to test the effects of these parameters.

Results

Light intensity, moisture, and DBH highly influenced the abundance of liverworts. Old trees had higher epiphytic liverwort cover than younger ones. Bark biochemical properties like pH, phenol, flavonoid, ortho-dihydric phenol, tannin and sugar did not have a significant effect on the epiphytic liverwort cover, while the terpenoid content of the bark reduced liverworts cover.

Conclusion

To sustain the occurrence of epiphytic liverworts in ecosystems, forest management should ensure the presence of old trees. Light intensity and moisture had a large effect on the distribution and abundance of liverworts, so it is important to maintain tree cover, shrub layer, and tree density.
Resistance and resilience to experimental gingivitis: a systematic scoping review
Authors: Zemouri Charifa , Jakubovics Nicholas S. , Crielaard Wim , Zaura Egija , Dodds Michael , Schelkle Bettina , Loos Bruno G.
Published: September 2019

Background

This systematic scoping review aimed to identify changes in biomarkers of microbiological, immunological and biochemical origin during experimental gingivitis (EG) studies that might indicate resistance and resilience.

Methods

The term ‘experimental gingivitis’ was run in PubMed from inception to April 11th, 2018. From the 411 studies retrieved, 22 studies were included for this review.

Results

Studies reporting data on biomarker changes during and after full mouth EG trial were included. Two studies reported findings on changes in biomarkers of microbiological, 12 on immunological and eight on biochemical origin. Changes were reported in the induction phase, and occasionally in the resolution phase. The microbiological composition of both supragingival and subgingival dental plaque changed over the course of EG to a more pathogenic direction, but showed a shift back to a more normal composition. This indicates resilience of the oral microbiome. For immunological biomarkers, it was challenging to retrieve a robust pattern of changes across multiple studies. IL-1β and IL-6 in saliva and in gingival crevicular fluid increased during induction phase and returned in the resolution phase below baseline values. The biochemical parameters cystatin-SN, cystatin-S and lactoferrin in saliva were increased at the end of induction phase, however also here no clear pattern emerged based on all available studies.

Conclusions

More research is needed to investigate which microbiological, immunological, and biochemical biomarkers can be useful for future investigations into the resistance and resilience of the oral cavity to experimental gingivitis.
Trends of blood pressure and heart rate in normal pregnancies: a systematic review and meta-analysis
Authors: Loerup Lise , Pullon Rebecca M. , Birks Jacqueline , Fleming Susannah , Mackillop Lucy H. , Gerry Stephen , Watkinson Peter J.
Published: September 2019

Background

Current reference ranges for blood pressure and heart rate throughout pregnancy have a poor evidence base.

Methods

This is a systematic review and meta-analysis. We included studies measuring blood pressure or heart rate from healthy pregnant women within defined gestational periods of 16 weeks or less. We analysed systolic blood pressure, diastolic blood pressure and heart rate by gestational age. We assessed effects of measurement year and method.

Results

We included 39 studies undertaken in 1967–2017, containing 124,349 systolic measurements from 36,239 women, 124,291 diastolic measurements from 36,181 women and 10,948 heart rate measurements from 8317 women. Mean (95% CI) systolic blood pressure was lowest at 10 weeks gestation, 110.4 (108.5, 112.3) mmHg, rising to 116.0 (113.6, 118.4) mmHg at 40 weeks, mean (95% CI) change 5.6 (4.0, 7.2) mmHg. Mean (95% CI) diastolic blood pressure was lowest at 21 weeks gestation, 65.9 (64.2, 67.7) mmHg; rising to 72.8 (71.0, 74.6) mmHg at 40 weeks, mean (95% CI) change 6.9 (6.2, 7.5) mmHg. Mean (95% CI) heart rate rose from 79.3 (75.5, 83.1) beats/min at 10 weeks to 86.9 (82.2, 91.6) beats/min at 40 weeks gestation, mean (95% CI) change 7.6 (1.8, 13.4) beats/min. Studies using manual measurement reported higher diastolic blood pressures than studies using automated measurement, mean (95 CI) difference 4.9 (0.8, 8.9) mmHg. Diastolic blood pressure increased by 0.26 (95% CI 0.10–0.43) mmHg/year. Including only higher-quality studies had little effect on findings, with heterogeneity remaining high (I2 statistic > 50%).

Conclusions

Significant gestational blood pressure and heart rate changes occur that should be taken into account when assessing pregnant women. Commonly taught substantial decreases in blood pressure mid-pregnancy were not seen and heart rate increases were lower than previously thought. Manual and automated blood pressure measurement cannot be used interchangeably. Increases in diastolic blood pressure over the last half-century and differences between published studies show contemporary data are required to define current normal ranges.

Study registration

PROSPERO CRD42014009673
TiHoVideos: veterinary students’ utilization of instructional videos on clinical skills
Authors: Müller Lina R. , Tipold Andrea , Ehlers Jan P. , Schaper Elisabeth
Published: September 2019

Background

The YouTube channel “TiHoVideos” was created by the University of Veterinary Medicine Hannover, Foundation (TiHo) to enable easy, public access to the university’s instructional videos as an additional support for learning clinical skills. Video production is expensive and time-consuming. To be able to optimize video production and aligning content to student needs we wanted to know if and how our students use these videos.

Results

Results show that the participating students primarily prepared for learning stations in the Clinical Skills Lab (CSL) by watching TiHoVideos at home on tablets or laptops and then concentrated at the CSL on learning the practical skills hands on. The videos available on TiHoVideos are rated as being a “very helpful” educational tool when preparing for CSL learning stations.

Conclusions

Instructional videos represent an unquestionably suitable medium to aid veterinary students learn practical skills and a contribution to animal welfare by reducing the use of live animals in undergraduate veterinary education. The university’s production of educational video material proves to be worth the effort because the videos are being used, appreciated and well-rated by TiHo students for their learning experience.
Interferon-γ enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation
Authors: Vu Tuong N. , Chen Xuesong , Foda Hussein D. , Smaldone Gerald C. , Hasaneen Nadia A.
Published: September 2019

Background

Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple pathways, and combined antifibrotic therapy is needed for future IPF therapy. Inhaled interferon-γ (IFN-γ) was recently shown to be safe and without systemic effects in patients with IPF.

Aim

To examine the in vitro effects of individual and combined treatment with IFN-γ and pirfenidone (PFD) on normal and IPF fibroblast activation and extracellular matrix remodeling after TGF-β1 and PDGF-BB stimulation.

Methods

IPF and normal human lung fibroblasts (NHLF) were treated with IFN-γ, PFD or a combination of both drugs in the presence of either TGF-β1 or PDGF-BB. The effects of TGF-β1 and PDGF-BB treatment on cell viability, proliferation, differentiation and migration were examined. The expression of collagen 1, matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) was analyzed using qPCR, Western blotting and gelatin zymography. Total collagen content in conditioned media was also measured using a Sircol assay.

Results

Compared to that of PFD, the effect of IFN-γ in downregulating normal and IPF lung fibroblast differentiation to myofibroblasts in response to TGF-β1 was more potent. Importantly, the combination of IFN-γ and PFD had a possibly synergistic/additive effect in inhibiting the TGF-β1- and PDGF-BB-induced proliferation, migration and differentiation of normal and IPF lung fibroblasts. Furthermore, both drugs reversed TGF-β1-induced effects on MMP-1, − 2, − 3, − 7, and − 9, while only PFD promoted TIMP-1 and-2 expression and release.

Conclusions

Our findings demonstrate that the antifibrotic effects of IFN-γ and PFD on normal and IPF lung fibroblasts are different and complementary. Combination therapy with inhaled IFN-γ and PFD in IPF is promising and should be further explored in IPF clinical trials.
Factors leading to failure to diagnose pulmonary malignant tumors using endobronchial ultrasound with guide sheath within the target lesion
Authors: Nishii Yoichi , Yasuma Taro , Ito Kentaro , Suzuki Yuta , Watanabe Fumiaki , Kobayashi Tetsu , Nishihama Kota , D’Alessandro-Gabazza Corina N. , Fujimoto Hajime , Gabazza Esteban C. , Asano Fumihiro , Taguchi Osamu , Hataji Osamu
Published: September 2019

Background

The diagnostic yield of peripheral pulmonary lesions has significantly increased with the use of radial endobronchial ultrasound with guide sheath within the lesion. Here, we retrospectively evaluated factors leading to misdiagnosis of pulmonary malignant tumors using endobronchial ultrasound with the guide sheath within the lesion.

Methods

We assessed the final histopathological diagnosis of biopsy samples taken from 130 patients with lung malignant tumors that underwent endobronchial ultrasound with guide sheath within the lesion.

Results

Among 130 patients, 8 (6%) showed no definite malignant findings in biopsy samples but the presence of malignant cells (primary lung cancer 7, diffuse large B cell lymphoma 1) was subsequently confirmed by histopathological study of specimens taken by computed tomography-guided needle biopsy or surgery. Of the eight cases with diagnostic failure, the size of the biopsy sample was insufficient in five due to technical difficulties during the diagnostic procedure, and the diagnosis of malignant tumor was difficult in five cases because of extensive scarring tissue or central necrosis.

Conclusions

The results of this study showed that technical difficulties and/or pathological heterogeneity of the tumor might lead to failure to diagnose lung malignant tumor in cases using endobronchial ultrasound with guide sheath within the lesion.
Long non-coding RNA LINC00485 acts as a microRNA-195 sponge to regulate the chemotherapy sensitivity of lung adenocarcinoma cells to cisplatin by regulating CHEK1
Authors: Zuo Wei , Zhang Wei , Xu Fei , Zhou Jing , Bai Wei
Published: September 2019

Background

Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs, which have the ability to influence the chemo-resistance of lung adenocarcinoma (LAC). In this study, we explored the mechanism by which LINC00485 competitively binds to microRNA-195 (miR-195) in the regulation of the chemotherapy sensitivity in LAC by regulating checkpoint kinase 1 (CHEK1).

Methods

Microarray analysis was used to screen out LAC related genes, and interaction between CHEK1 and miR-195, as well as that between miR-195 and LINC00485, was further confirmed by RNA-pull down and RIP. LINC00485 expression in LAC cells (A549 and H1299) was determined. The cells were then introduced with miR-195, anta-miR-195, LINC00485 or si-LINC00485 to identify the role of miR-195 and LINC00485 in LAC through evaluating the expression of CHEK1, CHEK1, Bax, Bcl-2, VEGF and HIF-1α in LAC cells by either RT-qPCR or Western blot analysis. After being treated with different concentration of cisplatin, cell proliferation, colony formation and apoptosis were assessed.

Results

LINC00485 acted as a competitive endogenous RNA against miR-195, and miR-195 directly targeted CHEK1. The expression of LINC00485 was higher in LAC cells. The down-regulation of LINC00485 or the up-regulation of miR-195 decreased the expression of CHEK1, Bcl-2, VEGF and HIF-1α, while also increasing the expression of Bax. Moreover, the over-expression of miR-195, or the silencing of LINC00485 enhanced the sensitivity of LAC cells to cisplatin, thereby promoting the apoptosis of LAC cells while suppressing the proliferation.

Conclusion

LINC00485 competitively binds to miR-195 to elevate CHEK1 expression in LAC cells, suggesting that LINC00485 is a novel direction for therapeutic strategies of LAC.
The role of three-dimensional reconstruction in laparoscopic partial nephrectomy for complex renal tumors
Authors: Wang Jipeng , Lu Youyi , Wu Gang , Wang Tianqi , Wang Yongqiang , Zhao Hongwei , Zhou Zhongbao , Wu Jitao
Published: September 2019

Background

To evaluate the role of three-dimensional (3D) reconstruction technique in renal function protection and ipsilateral parenchymal mass preserved after laparoscopic partial nephrectomy (LPN) in patients with complex renal tumor (R.E.N.A.L.score ≥ 8).

Methods

A retrospective study enrolling 49 patients who suffered from RCC and underwent LPN at our center, from October 1, 2017, to October 31, 2018. Twenty-one patients (group A) underwent LPN with the 3D reconstruction technique before surgery, and the other 28 patients (group B) not. Preoperative and postoperative ipsilateral parenchymal mass volume and ipsilateral glomerular filtration rate (GFR) were analyzed 3–5 days prior and 3 months after PN. In order to compare the two groups, Mann-Whitney U test and chi-square tests were performed. The main limitation of this technique is that the volume calculations are partly performed manually.

Results

All patients’ median renal score was 10 with no difference between the two groups (P = 0.89), and the median tumor size of the two groups was 3.2 cm (group A) and 3.3 cm (group B) respectively (P = 0.14). In addition, the median warm ischemia time of the two groups was 21 min (group A) and 26 min (group B) (P = 0.003). In group A and group B, the rate of preserved global GFR was 88% and 86% (P = 0.06), preserved ipsilateral GFR was 80% and 77% (P = 0.01), and preserved ipsilateral parenchymal was 84% and 80% (P = 0.03) separately.

Conclusion

3D reconstruction technique was a beneficial method for more renal function and more preserved renal parenchymal mass volume after LPN.

Trial registration

Yantai Yuhuangding Hospital, YHD[2017]212. Registered 1 January 2017 (prospectively registered), http://www.ytyhdyy.com/nav/103.htm.
Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review
Authors: Qin Jiang-Jiang , Cheng Xiang-Dong , Zhang Jia , Zhang Wei-Dong
Published: September 2019

Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.
Effectiveness of a low-value financial-incentive program for increasing vegetable-rich restaurant meal selection and reducing socioeconomic inequality: a cluster crossover trial
Authors: Nagatomo Wataru , Saito Junko , Kondo Naoki
Published: September 2019

Background

In light of recent theories in behavioural economics, an intervention program with monetary incentives could be effective for helping patrons order healthy food, even if the incentive is small and less than one’s perceived marginal value.

Methods

In this single-arm cluster crossover trial at 26 local restaurants, a 1-week campaign offered a 50-yen (approximately 0.5 US dollars) cash-back payment to customers ordering vegetable-rich meals, while no pre-order incentives were offered during the control period.

Results

In total, 511 respondents out of 7537 customers (6.8%), and 704 respondents out of 7826 customers (9.0%), ordered vegetable-rich meals during the control and intervention periods, respectively. During the intervention period, the covariate-adjusted proportion of vegetable-rich meal orders was 1.50 times higher (95% confidence interval [CI]: 1.29 to 1.75), which increased daily sales by 1.77 times (95% CI: 1.11 to 2.83), even when subtracting the cost of cash-back payments. Respondents who reported spending the least amount of money on eating out (used as a proxy measure for income) were the least likely to order vegetable-rich meals during the control period. However, these individuals increased their proportion of purchasing such meals during the intervention period (a 3.8 percentage point increase (95% CI: 2.82 to 4.76) among those spending the least vs a 2.1 percentage point increase (95% CI: 1.66 to 2.62) among those spending the most; P for interaction = 0.001). Similarly, irregular employees exhibited a larger increase (+ 5.2 percentage points, 95% CI: 4.54 to 5.76) than did regular workers (− 1.4, 95% CI: − 1.66 to − 1.05, P for interaction = 0.001).

Conclusions

A program with an immediate low-value monetary incentive could be a public health measure for reducing inequalities in making healthy food choices.

Trial registration

UMIN Clinical Trials Registry, UMIN000022396. Registered 21 May 2016.
Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective
Authors: Gao Xiujuan , Cai Yue , Wang Zhuo , He Wenjuan , Cao Sisi , Xu Rong , Chen Hui
Published: September 2019

Background

Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). However, the effect of ERs in NSCLC is still controversial and needs further investigation. A new consideration is that ERs may affect NSCLC progression through complicated molecular signaling networks rather than individual targets. Therefore, this study aims to explore the effect of ERs in NSCLC from the perspective of cancer systems biology.

Methods

The gene expression profile of NSCLC samples in TCGA dataset was analyzed by bioinformatics method. Variations of cell behaviors and protein expression were detected in vitro. The kinetic process of molecular signaling network was illustrated by a systemic computational model. At last, immunohistochemical (IHC) and survival analysis was applied to evaluate the clinical relevance and prognostic effect of key receptors in NSCLC.

Results

Bioinformatics analysis revealed that ERs might affect many cancer-related molecular events and pathways in NSCLC, particularly membrane receptor activation and signal transduction, which might ultimately lead to changes in cell behaviors. Experimental results confirmed that ERs could regulate cell behaviors including cell proliferation, apoptosis, invasion and migration; ERs also regulated the expression or activation of key members in membrane receptor signaling pathways such as epidermal growth factor receptor (EGFR), Notch1 and Glycogen synthase kinase-3β/β-Catenin (GSK3β/β-Catenin) pathways. Modeling results illustrated that the promotive effect of ERs in NSCLC was implemented by modulating the signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways; ERs maintained and enhanced the output of oncogenic signals by adding redundant and positive-feedback paths into the network. IHC results echoed that high expression of ERs, EGFR and Notch1 had a synergistic effect on poor prognosis of advanced NSCLC.

Conclusions

This study indicated that ERs were likely to promote NSCLC progression by modulating the integrated membrane receptor signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways and then affecting tumor cell behaviors. It also complemented the molecular mechanisms underlying the progression of NSCLC and provided new opportunities for optimizing therapeutic scheme of NSCLC.
Age related human T cell subset evolution and senescence
Authors: Li Mingde , Yao Danlin , Zeng Xiangbo , Kasakovski Dimitri , Zhang Yikai , Chen Shaohua , Zha Xianfeng , Li Yangqiu , Xu Ling
Published: September 2019

T cells are fundamental effector cells against viruses and cancers that can be divided into different subsets based on their long-term immune protection and immediate immune response effects. The percentage and absolute number of these subsets change with ageing, which leads to a reduced immune response in older individuals. Stem cell memory T cells (TSCM) represent a small population of memory T cells with enhanced proliferation and differentiation properties that are endowed with high potential for maintaining T cell homeostasis. However, whether these cells change with ageing and gender remains unknown. Here, we assayed the distribution of TSCM and other T cell subsets in peripheral blood from 92 healthy subjects (44 females and 48 males) ranging from 3 to 88 years old by flow cytometry. We found that CD4+ and CD8+ TSCM in the circulation have relatively stable frequencies, and the absolute number of CD8+ TSCM decreased with age; however, the ratio of TSCM to the CD4+ or CD8+ naïve population increased with age. Unlike the obvious changes in other T cell subsets with age and gender, the stable level of TSCM in peripheral blood may support their capacity for sustaining long-term immunological memory, while their importance may increase together with ageing.
Effects of extended powered knee prosthesis stance time via visual feedback on gait symmetry of individuals with unilateral amputation: a preliminary study
Authors: Brandt Andrea , Riddick William , Stallrich Jonathan , Lewek Michael , Huang He Helen
Published: September 2019

Background

Establishing gait symmetry is a major aim of amputee rehabilitation and may be more attainable with powered prostheses. Though, based on previous work, we postulate that users transfer a previously-learned motor pattern across devices, limiting the functionality of more advanced prostheses. The objective of this study was to preliminarily investigate the effect of increased stance time via visual feedback on amputees’ gait symmetry using powered and passive knee prostheses.

Methods

Five individuals with transfemoral amputation or knee disarticulation walked at their self-selected speed on a treadmill. Visual feedback was used to promote an increase in the amputated-limb stance time. Individuals were fit with a commercially-available powered prosthesis by a certified prosthetist and practiced walking during a prior visit. The same protocol was completed with a passive knee and powered knee prosthesis on separate days. We used repeated-measures, two-way ANOVA (alpha = 0.05) to test for significant effects of the feedback and device factors. Our main outcome measures were stance time asymmetry, peak anterior-posterior ground reaction forces, and peak anterior propulsion asymmetry.

Results

Increasing the amputated-limb stance time via visual feedback significantly improved the stance time symmetry (p = 0.012) and peak propulsion symmetry (p = 0.036) of individuals walking with both prostheses. With the powered knee prosthesis, the highest feedback target elicited 36% improvement in stance time symmetry, 22% increase in prosthesis-side peak propulsion, and 47% improvement in peak propulsion symmetry compared to a no feedback condition. The changes with feedback were not different with the passive prosthesis, and the main effects of device/ prosthesis type were not statistically different. However, subject by device interactions were significant, indicating individuals did not respond consistently with each device (e.g. prosthesis-side propulsion remained comparable to or was greater with the powered versus passive prosthesis for different subjects). Overall, prosthesis-side peak propulsion averaged across conditions was 31% greater with the powered prosthesis and peak propulsion asymmetry improved by 48% with the powered prosthesis.

Conclusions

Increasing prosthesis-side stance time via visual feedback favorably improved individuals’ temporal and propulsive symmetry. The powered prosthesis commonly enabled greater propulsion, but individuals adapted to each device with varying behavior, requiring further investigation.
Claudin-12 is not required for blood–brain barrier tight junction function
Authors:   German Mouse Clinic Consortium, Castro Dias Mariana , Coisne Caroline , Baden Pascale , Enzmann Gaby , Garrett Lillian , Becker Lore , Hölter Sabine M. , Hrabě de Angelis Martin , Deutsch Urban , Engelhardt Britta
Published: September 2019

Background

The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown.

Methods

We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant.

Results

Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12lacZ/lacZ C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12lacZ/lacZ C57BL/6J mice.

Conclusions

Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12lacZ/lacZ C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions.
Assessing attitudes of patient-centred care among students in international chiropractic educational programs: a cross-sectional survey
Authors: Hammerich Karin , Stuber Kent , Hogg-Johnson Sheilah , Abbas Anser , Harris Martin , Lauridsen Henrik Hein , Lemeunier Nadège , Maiers Michele , McCarthy Peter , Morales Vanessa , Myburgh Corrie , Petrini Vanessa , Pohlman Katherine , Mior Silvano
Published: September 2019

Background

Patient-centred care is internationally recognized as a foundation of quality patient care. Attitudes of students towards patient-centred care have been assessed in various health professions. However, little is known how chiropractic students’ attitudes towards patient-centred care compare to those of other health professions or whether they vary internationally, and between academic programs.

Objective

To assess the association of select variables on student attitude towards patient-centred care among select chiropractic programs worldwide.

Methods

We conducted a cross-sectional study using the Patient-Practitioner Orientation Scale (PPOS) to assess students’ patient-centred attitudes towards the doctor-patient relationship. Eighteen items were scored on a 1 to 6 Likert scale; higher scores indicating more patient-centredness. All students from seven chiropractic educational programs worldwide were invited to complete an online survey. Results were analyzed descriptively and inferentially for overall, sharing and caring subscales. General linear regression models were used to assess the association of various factors with PPOS scores.

Results

There were 1858 respondents (48.9% response rate). Student average age was 24.7 (range = 17–58) years and 56.2% were female. The average overall PPOS score was 4.18 (SD = 0.48) and average sharing and caring subscale scores were 3.89 (SD = 0.64) and 4.48 (SD = 0.52), respectively. There were small but significant differences in all PPOS scores by gender, age, and program. Year/semester of study within a program typically was not associated with scores, neither was history of previous chiropractic care nor having family members who are health professionals.

Conclusion

This is the first international study assessing students’ attitudes of patient-centred care in chiropractic educational programs. We found small but significantly different PPOS scores between chiropractic programs worldwide that did not change across year/semester of study. Scores tended to be lower than those reported among medical students. Observed differences may be related to curricular content, extent of patient exposure and/or regional cultural realities.
A perspective on Councils on Chiropractic Education accreditation standards and processes from the inside: a narrative description of expert opinion, part 2: Analyses of particular responses to research findings
Authors: Innes Stanley I. , Cope Vicki , Leboeuf-Yde Charlotte , Walker Bruce F.
Published: September 2019

Background

This is the second article reporting on a study that sought the views of people with extensive experience in Councils on Chiropractic Education (CCEs) on research that has raised concerns about variability in accreditation standards and processes for chiropractic programs (CPs) and chiropractic practice in general.

Methods

This qualitative study employed in-depth semi-structured interviews that consisted of open-ended questions asking experts about their thoughts and views on a range of issues surrounding accreditation, graduate competency standards and processes. The interviews were audio-recorded, and transcribed verbatim in June and July of 2018. The transcripts were reviewed to develop codes and themes. The study followed the COREQ guidelines for qualitative studies.

Results

The interviews revealed that these CCE experts were able to discern positive and negative elements of the accreditation standards and processes. They were, in general, satisfied with CCEs accreditation standards, graduating competencies, and site inspection processes. Most respondents believed that it was not possible to implement an identical set of international accreditation standards because of cultural and jurisdictional differences. This was thought more likely to be achieved if based on the notion of equivalence. Also, they expressed positive views toward an evidence-based CP curriculum and an outcomes-based assessment of student learning. However, they expressed concerns that an evidence-based approach may result in the overlooking of the clinician’s experience. Diverse views were found on the presence ofvitalismin CPs. These ranged from thinking vitalism should only be taught in an historical context, it was only a minority who held this view and therefore an insignificant issue. Finally, that CCEs should not regulate these personal beliefs, as this was potentially censorship. The notable absence was that the participants omitted any mention of the implications for patient safety, values and outcomes.

Conclusions

Expert opinions lead us to conclude that CCEs should embrace and pursue the widely accepted mainstream healthcare standards of an evidence-based approach and place the interests of the patient above that of the profession. Recommendations are made to this end with the intent of improving CCE standards and processes of accreditation.
Conceptualizing patient-centered care for substance use disorder treatment: findings from a systematic scoping review
Authors: Marchand Kirsten , Beaumont Scott , Westfall Jordan , MacDonald Scott , Harrison Scott , Marsh David C. , Schechter Martin T. , Oviedo-Joekes Eugenia
Published: September 2019

Background

Despite ongoing efforts aimed to improve treatment engagement for people with substance-related disorders, evidence shows modest rates of utilization as well as client-perceived barriers to care. Patient-centered care (PCC) is one widely recognized approach that has been recommended as an evidence-based practice to improve the quality of substance use disorder treatment. PCC includes four core principles: a holistic and individualized focus to care, shared decision-making and enhanced therapeutic alliance.

Aims

This scoping review aimed to explore which PCC principles have been described and how they have defined and measured among people with substance-related disorders.

Methods

Following the iterative stages of the Arksey and O’Malley scoping review methodology, empirical (from Medline, Embase, PsycINFO, CINAHL and ISI Web of Science) and grey literature references were eligible if they focused on people accessing treatment for substance-related disorders and described PCC. Two reviewers independently screened the title/abstract and full-texts of references. Descriptive analyses and a directed content analysis were performed on extracted data.

Findings

One-hundred and forty-nine references met inclusion from the 2951 de-duplicated references screened. Therapeutic alliance was the most frequent principle of PCC described by references (72%); this was consistently defined by characteristics of empathy and non-judgment. Shared decision-making was identified in 36% of references and was primarily defined by client and provider strategies of negotiation in the treatment planning process. Individualized care was described by 30% of references and included individualized assessment and treatment delivery efforts. Holistic care was identified in 23% of references; it included an integrated delivery of substance use, health and psychosocial services via comprehensive care settings or coordination. Substance use and treatment engagement outcomes were most frequently described, regardless of PCC principle.

Conclusions

This review represents a necessary first step to explore how PCC has been defined and measured for people accessing substance use disorder treatment. The directed content analysis revealed population and context-specific evidence regarding the defining characteristics of PCC-principles that can be used to further support the implementation of PCC.
Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis
Authors: Zu Yan , Mu Yue , Li Qiang , Zhang Shu-Ting , Yan Hong-Juan
Published: September 2019

Background

Osteoarthritis (OA) is the common chronic degenerative joint bone disease that is mainly featured by joint stiffness and cartilage degradation. Icariin (ICA), an extract from Epimedium, has been preliminarily proven to show anti-osteoporotic and anti-inflammatory effects in OA. However, the underlying mechanisms of ICA on chondrocytes need to be elucidated.

Methods

LPS-treated chondrocytes and monosodium iodoacetate (MIA)-treated Wistar rats were used as models of OA in vitro and in vivo, respectively. LDH and MTT assays were performed to detect cytotoxicity and cell viability. The expression levels of NLRP3, IL-1β, IL-18, MMP-1, MMP-13, and collagen II were detected by qRT-PCR and Western blotting. The release levels of IL-1β and IL-18 were detected by ELISA assay. Caspase-1 activity was assessed by flow cytometry. Immunofluorescence and immunohistochemistry were used to examine the level of NLRP3 in chondrocytes and rat cartilage, respectively. The progression of OA was monitored with hematoxylin-eosin (H&E) staining and safranin O/fast green staining.

Results

ICA could suppress LPS-induced inflammation and reduction of collagen formation in chondrocytes. Furthermore, ICA could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway to alleviate pyroptosis induced by LPS. Overexpression of NLRP3 reversed the above changes caused by ICA. It was further confirmed in the rat OA model that ICA alleviated OA by inhibiting NLRP3-mediated pyroptosis.

Conclusion

ICA inhibited OA via repressing NLRP3/caspase-1 signaling-mediated pyroptosis in models of OA in vitro and in vivo, suggesting that ICA might be a promising compound in the treatment of OA.
The impact of associated tenotomies on the outcome of incomplete phalangeal osteotomies for lesser toe deformities
Authors: Nieto-García Eduardo , Ferrer-Torregrosa Javier , Ramírez-Andrés Leonor , Nieto-González Elena , Martinez-Nova Alfonso , Barrios Carlos
Published: September 2019

Background

Partial or incomplete osteotomy (IO) of the phalanx is recently described in the literature. However, the clinical outcome and the rate of complications when applied to lesser toe deformities (LTD) have been never addressed. This study aims to find out if the association of tenotomies to incomplete or partial phalanx osteotomies has a significant impact on the clinical outcomes, the occurrence of complications, and the recovery time after surgery.

Methods

A retrospective review of two cohorts of cases operated in our institution for hallux abductus valgus (HAV) and associated LTD from 2008 to 2014 was carried out. The surgical correction of both HAV and the associated LTD was always performed by minimally invasive techniques. The study included a total of 223 patients (723 IO in 556 toes). In 129 cases, the IO for LTD correction was performed without tenotomies, and in 94, the procedure was combined with flexor and/or extensor tenotomies. Patients were assessed with the American Orthopaedic Foot and Ankle Society (AOFAS) questionnaire before surgery and at 6- and 12-month follow-up.

Results

The mean preoperative AOFAS score before surgery was similar in both cohorts. At 12-month follow-up, the cohort without tenotomies showed better recovery (95.7 ± 2.8 versus 92.5 ± 6.8; p < 0.01). AOFAS scores decreased as the number of associated LTD increased (r = − 0.814; p < 0.001). Cases operated on by PO + tenotomy showed a high rate of complications such as delayed union of the osteotomy (p < 0.01), hypertrophic callus (p < 0.01), phalangeal fracture at the osteotomy site (p < 0.01), and lack of correction (p < 0.05). The overall occurrence of adverse events was 38.6% in cases operated by PO + tenotomy and 13.9% in cases receiving PO alone (p < 0.0001). Cases operated on without tenotomy showed a shorter time to complete recovery for daily life activities (37.4 ± 2.3 versus 43.0 ± 1.7 days; p < 0.01).

Conclusion

The performance of associated tenotomies to incomplete phalanx osteotomies provides worse clinical outcomes, higher complication rates, and longer recovery time as compared to similar forefoot surgeries without tenotomies.

Trial registration

The study was based on retrospectively registered data starting on May 24, 2008.
IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression
Authors: Thiem Alexander , Hesbacher Sonja , Kneitz Hermann , di Primio Teresa , Heppt Markus V. , Hermanns Heike M. , Goebeler Matthias , Meierjohann Svenja , Houben Roland , Schrama David
Published: September 2019

Background

Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.

Methods

We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.

Results

For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53L22Q,W23S, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53L22Q,W23S in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.

Conclusions

While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance
Authors: Park So-Yeon , Lee Choong-Jae , Choi Jang-Hyun , Kim Jee-Heun , Kim Ji-Won , Kim Ji-Young , Nam Jeong-Seok
Published: September 2019

Background

Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear.

Methods

By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts.

Results

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation.

Conclusion

Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.