bluuebunny/crossref_metadata_2025 huggingface dataset:
An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes
Authors: Scott Jan , Etain Bruno , Manchia Mirko , Brichant‐Petitjean Clara , Geoffroy Pierre A. , Schulze Thomas , Alda Martin , Bellivier Frank ,   ConLiGen collaborators
Published: August 2019

Objectives

The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards.

Methods

We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale.

Results

The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score.

Conclusions

This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.
Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease
Authors: Ohm Daniel T. , Fought Angela J. , Rademaker Alfred , Kim Garam , Sridhar Jaiashre , Coventry Christina , Gefen Tamar , Weintraub Sandra , Bigio Eileen , Mesulam Marek Marsel , Rogalski Emily , Geula Changiz
Published: August 2019

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.
Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48‐linked NADPH oxidase 4 polyubiquitination and degradation
Authors: Chen Zhiquan , Sun Xiaohong , Chen Qiuhong , Lan Tian , Huang Kaipeng , Xiao Haiming , Lin Zeyuan , Yang Yan , Liu Peiqing , Huang Heqing
Published: August 2019

Background and Purpose

Nox4 is the major isoform of NADPH oxidase found in the kidney and contributes to the pathogenesis of diabetic nephropathy. However, the molecular mechanisms of increased Nox4 expression induced by hyperglycaemia remain to be elucidated. Here, the role of the connexin32–Nox4 signalling axis in diabetic nephropathy and its related mechanisms were investigated.

Experimental Approach

Diabetes was induced in mice by low‐dose streptozotocin (STZ) combined with a high‐fat diet. Effects of connexin32 on Nox4 expression and on renal function and fibrosis in STZ‐induced diabetic mice were investigated using adenovirus‐overexpressing connexin32 and connexin32‐deficient mice. Interactions between connexin32 and Nox4 were analysed by co‐immunoprecipitation and immunofluorescence assays.

Key Results

Connexin32 was down‐regulated in the kidneys of STZ‐induced diabetic mice. Overexpression of connexin32 reduced expression of Nox4 and improved renal function and fibrosis in diabetic mice, whereas connexin32 deficiency had opposite effects. Down‐regulation of fibronectin expression by connexin32 was not dependent on gap junctional intercellular communication involving connexin32. Connexin32 interacted with Nox4 and reduced the generation of hydrogen peroxide, leading to the down‐regulation of fibronectin expression. Mechanistically, connexin32 decreased Nox4 expression by promoting its K48‐linked polyubiquitination. Interestingly, Smurf1 overexpression inhibited K48‐linked polyubiquitination of Nox4. Furthermore, connexin32 interacted with Smurf1 and inhibited its expression.

Conclusion and Implications

Connexin32 ameliorated renal fibrosis in diabetic mice by promoting K48‐linked Nox4 polyubiquitination and degradation via inhibition of Smurf1 expression. Targeting the connexin32–Nox4 signalling axis may contribute to the development of novel treatments for diabetic nephropathy.
SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met
Authors: Tong Mengya , Gao Mingzhao , Xu Yongping , Fu Li , Li Yun , Bao Xubin , Fu Haoyu , Quan Haitian , Lou Liguang
Published: August 2019

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.
Targeted exosome‐encapsulated erastin induced ferroptosis in triple negative breast cancer cells
Authors: Yu Mengyu , Gai Chengcheng , Li Zihaoran , Ding Dejun , Zheng Jie , Zhang Weifen , Lv Shijun , Li Wentong
Published: August 2019

Ferroptosis is an iron‐dependent, lipid peroxide‐driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple‐negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin‐loaded exosomes labeled with folate (FA) to form FA‐vectorized exosomes loaded with erastin (erastin@FA‐exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti–tumor effect in vitro of erastin@FA‐exo were determined. Erastin@FA‐exo could increase the uptake efficiency of erastin into MDA‐MB‐231 cells; compared with erastin@exo and free erastin, erastin@FA‐exo has a better inhibitory effect on the proliferation and migration of MDA‐MB‐231 cells. Furthermore, erastin@FA‐exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA‐exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome‐based erastin preparations provide an innovative and powerful delivery platform for anti–cancer therapy.
Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis—A single‐centre experience
Authors: Fiddler Christine A. , Simler Nicky , Thillai Muhunthan , Parfrey Helen
Published: August 2019

Introduction

The optimal pharmacological management of chronic hypersensitivity pneumonitis (cHP) is unknown. Corticosteroids are often used as first line therapy but can be associated with side effects. There is a paucity of data examining the role of steroid‐sparing agents in cHP. We aimed to determine the effect of mycophenolate mofetil (MMF) and azathioprine (AZA) on lung function and prednisolone dose in cHP patients.

Methods

Retrospective analysis of patients initiated on either MMF or AZA following a multidisciplinary team diagnosis of cHP. Changes in lung function and prednisolone dose up to 12 months before and after MMF/AZA initiation were analysed.

Results

Twenty two out of 30 patients remained on treatment at 12 months (18 MMF, 4 AZA). Steroid‐sparing therapy resulted in a significant reduction in prednisolone dose from 16.2 ± 9.7 to 8.2 ± 4.2 mg daily (P = 0.002). Treatment with MMF or AZA for 12 months was associated with a significant improvement in carbon monoxide diffusing capacity (TLCO) (−0.55 ± 0.96 vs. +0.31 ± 0.58 mmol/kPa/min, P = 0.02). Although treatment reduced the rate of forced vital capacity decline (−111 ± 295 vs. +2.3 ± 319 mL), it was not significant (P = 0.22).

Conclusion

MMF or AZA therapy in cHP is associated with an improvement in TLCO and reduction in prednisolone dose. There is a need for prospective trials.
GDF‐15 in solid vs non‐solid treatment‐naïve malignancies
Authors: Arfsten Henrike , Cho Anna , Freitag Claudia , Raderer Markus , Goliasch Georg , Bartko Philipp E. , Wurm Raphael , Strunk Guido , Gisslinger Heinz , Marosi Christine , Kornek Gabriela , Zielinski Christoph , Hülsmann Martin , Pavo Noemi
Published: August 2019

Aim

GDF‐15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF‐15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF‐15 to other cardiac biomarkers and the general association of GDF‐15 on prognosis in an unselected cohort of treatment‐naïve cancer patients.

Methods

We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF‐15 concentrations were determined alongside other cardiac and routine laboratory markers. All‐cause mortality was defined as primary endpoint.

Results

GDF‐15 levels were 338 ng/L (IQR:205‐534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF‐15 [435 ng/L (IQR:279‐614) vs 266 ng/L (IQR:175‐427), P < .001]. GDF‐15 correlated positively with inflammatory status reflected by CRP, SAA and IL‐6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT‐proBNP, hsTnT, MR‐proADM and CT‐proET‐1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF‐15 was significantly associated with all‐cause mortality after multivariate adjustment [adj.HR for ln(GDF‐15) 1.78, 95%CI:1.47‐2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF‐15 with outcome in myelodysplastic and myeloproliferative disease.

Conclusions

Elevated plasma GDF‐15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment‐naïve cancer patients. GDF‐15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF‐15 represents a promising target for our pathophysiologic understanding in cardio‐oncology linking conditions of both cardiac and neoplastic disease.
Allogeneic stem cell transplantation in patients with myelofibrosis harboring the MPL mutation
Authors: Mannina Daniele , Gagelmann Nico , Badbaran Anita , Ditschkowski Markus , Bogdanov Rashit , Robin Marie , Cassinat Bruno , Heuser Michael , Shahswar Rabia , Thol Felicitas , Beelen Dietrich , Kröger Nicolaus
Published: August 2019

Introduction

Primary and post‐ET/PV myelofibrosis are myeloproliferative neoplasms harboring in most cases driving mutations in JAK2, CALR or MPL, and a variable number of additional mutations in other genes. Molecular analysis represents a powerful tool to guide prognosis and clinical management. Only about 10% of patients with myelofibrosis harbor alterations in MPL gene. No data are available about the transplantation outcome in the specific MPL‐mutated group.

Patients

We collected the data of 18 myelofibrosis patients(primary: 14; post‐ET: 4) transplanted in 4 EBMT centers (Hamburg, Paris, Essen, and Hannover) between 2005 and 2016.

Results

Before the transplant, we explored the molecular profile by NGS and reported the frequency of mutations occurring in a panel of genes including JAK2, MPL, CALR, U2AF1, SRSF2, SF3B1, ASXL1, IDH1, IDH2, CBL, DNMT3A, TET2, EZH2, TP53, IKZF1, NRAS, KRAS, FLT3, SH2B3, and RUNX1. The 1‐year transplant‐related mortality was 16.5%, 5‐years overall survival and 5‐y relapse‐free survival 83.5%. The only relapse occurred in a patient who harbored mutations in both ASXL1 and EZH2 genes.

Conclusion

These retrospective data suggest that MPL‐mutated myelofibrosis patients have a favorable outcome after allogeneic transplantation with very low rate of disease relapse (5.5%) in comparison with the available historical controls regarding myelofibrosis in all.
Gender difference in the effect of uric acid on striatal dopamine in early Parkinson's disease
Authors: Oh Y. ‐S. , Kim J. ‐S. , Yoo S. ‐W. , Hwang E. ‐J. , Lyoo C. H. , Lee K. ‐S.
Published: August 2019

Background and purpose

High uric acid (UA) levels have been shown to exert a neuroprotective effect in Parkinson's disease (PD) by inhibiting oxidative stress in the nigrostriatal pathway. However, the association between striatal dopamine activity and UA level has not been clarified.

Methods

A total of 213 patients with early PD were enrolled. All patients underwent positron emission tomography using 18F‐N‐(3‐fluoropropyl)‐2beta‐carbon ethoxy‐3beta‐(4‐iodophenyl) nortropane and a venous blood test for quantification of serum UA. All patients were stratified into either the lower UA group or the higher UA group using the median UA level. After normalizing the positron emission tomography images, differences in the regional standardized uptake value ratios (SUVRs) were analyzed with a volume‐of‐interest template. All tested SUVRs were also compared after categorizing patients by gender.

Results

The UA affected dopamine transporter SUVRs in different ways by gender. In female patients, the higher UA level group showed a smaller reduction in dopamine transporter uptake in the posterior putamen, whereas there was no such association observed in male patients.

Conclusions

Higher UA levels were correlated with higher dopamine transporter uptake in the putamen in female patients with early PD. This finding suggests that UA has a neuroprotective effect, as demonstrated by the relatively preserved striatal dopamine activity in women.
Novel signals of adaptive genetic variation in northwestern Atlantic cod revealed by whole‐genome sequencing
Authors: Clucas Gemma V. , Lou R. Nicolas , Therkildsen Nina O. , Kovach Adrienne I.
Published: August 2019

Selection can create complex patterns of adaptive differentiation among populations in the wild that may be relevant to management. Atlantic cod in the Northwest Atlantic are at a fraction of their historical abundance and a lack of recovery within the Gulf of Maine has created concern regarding the misalignment of fisheries management structures with biological population structure. To address this and investigate genome‐wide patterns of variation, we used low‐coverage sequencing to perform a region‐wide, whole‐genome analysis of fine‐scale population structure. We sequenced 306 individuals from 20 sampling locations in U.S. and Canadian waters, including the major spawning aggregations in the Gulf of Maine in addition to spawning aggregations from Georges Bank, southern New England, the eastern Scotian Shelf, and St. Pierre Bank. With genotype likelihoods estimated at almost 11 million loci, we found large differences in haplotype frequencies of previously described chromosomal inversions between Canadian and U.S. sampling locations and also among U.S. sampling locations. Our whole‐genome resolution also revealed novel outlier peaks, some of which showed significant genetic differentiation among sampling locations. Comparisons between allochronic winter‐ and spring‐spawning populations revealed highly elevated relative (FST) and absolute (dxy) genetic differentiation near genes involved in reproduction, particularly genes associated with the brain‐pituitary‐gonadal axis, which likely control timing of spawning, contributing to prezygotic isolation. We also found genetic differentiation associated with heat shock proteins and other genes of functional relevance, with complex patterns that may point to multifaceted selection pressures and local adaptation among spawning populations. We provide a high‐resolution picture of U.S. Atlantic cod population structure, revealing greater complexity than is currently recognized in management. Our genome‐scan approach likely underestimates the full suite of adaptive differentiation among sampling locations. Nevertheless, it should inform the revision of stock boundaries to preserve adaptive genetic diversity and evolutionary potential of cod populations.
Reproducibility and Replicability in Geographical Analysis
Authors: Kedron Peter , Frazier Amy E. , Trgovac Andrew B. , Nelson Trisalyn , Fotheringham A. Stewart
Published: August 2019

The scientific method is predicated on the assumption that research designs and results can be reproduced and replicated. However, recent findings in some disciplines suggest that many studies fail to reach this standard, moving issues surrounding reproducibility and replicability forward into the research agenda of those fields. While the topic has yet to become a point of controversy in geography, the intricacies of geographic phenomena and spatial data analysis make the field vulnerable to criticism. This commentary discusses how uncertainties related to the conception, measurement, analysis, and communication of geographic analyses contribute to difficulties in the reproduction and replication of geographic research. Investigating how these uncertainties collectively impact the reproducibility and replicability of spatial data analyses should be a critical focus of future Geographical Analysis research. A call to action for geographers to improve the reproducibility and replicability of their work and specific recommendations on how Geographical Analysis might facilitate this process conclude the commentary.
‘It would be much easier if we were just quiet and disappeared’: Parents silenced in the experience of caring for children with rare diseases
Authors: Currie Genevieve , Szabo Joanna
Published: August 2019

Background

Parent experiences of caring for children with neurodevelopmental disease have been silenced and constrained by social, political and health influences. There is a need to co‐construct new meanings and interpretations of parenting a child with complex disabilities by having an increased understanding of the struggles and barriers for parents.

Methods

A hermeneutic phenomenology approach was applied in this inquiry. Fifteen parents of children with rare neurodevelopmental diseases participated in semi‐structured interviews.

Results

Parents experienced silencing or being silenced within interactions with health‐care and social care systems and providers. Interpretive thematic analysis revealed three insights: (a) parents experience a sense of disconnect and silencing as little is known or understood by health‐care providers about the experience of caring for children at home; (b) parents make strong efforts to be heard and acquire services within health and social systems as fighters, saviours and navigators; and (c) parents sacrifice themselves to the caregiving role and become therapists and caregivers to their medically fragile children at the cost of losing themselves as parents.

Conclusion

An understanding of parents’ experiences in caring for a child with a rare neurodevelopmental disease may provide insight to systemic health and social support challenges faced by families and mitigate appropriate and supportive policies and services.
2D/2D SnS2/MoS2 layered heterojunction for enhanced supercapacitor performance
Authors: Wang Bo , Hu Rong , Zhang Jun , Huang Zongyu , Qiao Hui , Gong Lunjun , Qi Xiang
Published: August 2019

Two‐dimensional (2D) SnS2/MoS2 heterojunction with a 2D/2D novel structure was used as electrode material for enhanced supercapacitor performance. Compared with the sole SnS2, the as‐prepared 2D/2D SnS2/MoS2 layered heterojunction has exhibited great improvement in supercapacitor properties. This novel structure can effectively prevent agglomeration and stacking in electrochemical process, and 2D/2D structure is beneficial to intercalation and desorption of ions in electrochemical processes. The experiment result shows that MoSn5 (samples with 5% MoSn5 mole ratios) display a specific capacitance of 466.6 F/g at the current density of 1 A/g in 0.5 mol/L potassium hydroxide solution, an impressive cycling stability with 88.2% capacitance retention at current density of 4 A/g. In addition, the as‐fabricated symmetric supercapacitor exhibited high energy density of 115 Wh kg−1 at the power density of 2230 Wh kg−1. This work provides a fundamental investigation of 2D/2D layered material synergistic effect on the electrochemical process.
Measurement of central augmentation index by three different methods and techniques: Agreement among Arteriograph, Complior, and Mobil‐O‐Graph devices
Authors: Papaioannou Theodore G. , Thymis John , Benas Dimitrios , Triantafyllidi Helen , Kostelli Gavriela , Pavlidis George , Kousathana Fotini , Katogiannis Kostantinos , Vlastos Dimitrios , Lambadiari Vaia , Papadavid Evangelia , Parissis John , Tousoulis Dimitrios , Ikonomidis Ignatios
Published: August 2019

Wave reflection at central arteries consists of a major component of left ventricular afterload. Central augmentation index (AIx) is the most widely used surrogate of wave reflection. Recent technological developments now provide the ability to obtain, non‐invasively, aortic, or carotid pressure waves and measure AIx based on various algorithms of pulse wave analysis. The aim of this study was to compare AIx measurements performed by the Arteriograph, Complior, and Mobil‐O‐Graph apparatuses. Recordings by each device in randomized order were performed with 5‐minute interval at 211 individuals (age 55.1 ± 14.1 years, 67.8% males) who underwent diagnostic cardiovascular assessment. All measurements were obtained at the supine position, and AIx was calculated using the formula AIx = 100 × (Augmentation pressure)/(Pulse Pressure). Bland‐Altman analysis was performed. Mean difference (bias) ± one standard deviation of difference (with limits of agreement) of AIx between different devices was as follows: (a) Mobil‐O‐Graph vs Complior: −2.1 ± 14.8% (−31.1% to 26.9%), (b) Arteriograph vs Complior: 12.9 ± 14.6% (−15.7% to 41.5%), and (c) Mobil‐O‐Graph vs Arteriograph: −10.8 ± 16.9% (−43.9% to 22.3%). The three examined devices exerted significant differences in central AIx estimation which makes the three devices non‐interchangeable for wave reflection assessment. However, the Mobil‐O‐Graph device showed the highest agreement (lowest bias) with the Complior system as regards to the AIx measurement.
Inaccuracy of buccal bone thickness estimation on cone‐beam CT due to implant blooming: An ex‐vivo study
Authors: Vanderstuyft Tony , Tarce Mihai , Sanaan Bahoz , Jacobs Reinhilde , de Faria Vasconcelos Karla , Quirynen Marc
Published: August 2019

Aim

The aim of this article was to evaluate the accuracy of buccal bone thickness measurements around implants on CBCT.

Material and methods

Forty‐four Osseospeed EV implants (3.6 in Ø) were placed guided and flapless in five fresh frozen human cadaver heads. The buccal peri‐implant bone was measured clinically via guided bone sounding. Post‐op CBCTs were taken with two different CBCT scanners (NewTom® and Accuitomo®) on which the buccal bone was measured. Consequently, after implant removal, a new CBCT was made without implant artefacts (image reference standard) on which the real buccal bone thickness was scored.

Results

Due to an average blooming (artificial increase of implant diameter) percentage of 12%–15%, the buccal peri‐implant bone thickness was underestimated by 0.3 mm on both CBCT devices. Immediately adjacent to the implant blooming area, a doubtful zone of about 0.45 mm was observed in which the buccal bone was not always visible. Buccal bone that was thick enough to fall outside this doubtful zone could always be visualized.

Conclusion

The findings in this study may help the clinician in the decision‐making process whether or not to intervene surgically in areas with ambiguous CBCT results.
Psychometric properties of the Brief Illness Perception Questionnaire (Brief‐IPQ) in periodontal diseases
Authors: Machado Vanessa , Botelho João , Ramos Catarina , Proença Luís , Alves Ricardo , Cavacas Maria Alzira , Mendes José João
Published: August 2019

Aim

To investigate the psychometric properties of the validated Portuguese version of the Brief Illness Perception Questionnaire (Brief‐IPQ) in patients with gingivitis and periodontitis.

Material and Methods

This study enrolled 571 patients with periodontal diseases (PDs) (67 gingivitis and 504 periodontitis cases), in a population‐based epidemiologic survey conducted at the health centres in the South Lisbon Metropolitan Area. Brief‐IPQ, a 9‐item self‐reported scale, reliability was evaluated using Cronbach's alpha. Confirmatory factor analysis (CFA) was used to construct validation. Multigroup analysis tested invariance across gender.

Results

The Brief‐IPQ showed acceptable reliability (α = .80). Confirmatory factor analysis revealed good model fit (χ2 (16) = 41.236, GFI = 0.982, CFI = 0.985, RMSEA = 0.053). All factors loaded similarly to the original Brief‐IPQ scale, with the exception of the “personal control” domain. Periodontal patients downgrade its illness and likely impact. The “consequences” domain showed significant positive correlations with all factors, except “treatment control” and “understanding” domains. The “concern” and “emotional response” domains had the highest significant correlation. Multigroup analysis findings supported factor invariance across the sex groups.

Conclusion

The Brief‐IPQ revealed acceptable reliability, construct factorial validity and invariance across gender. This short instrument may be used as an easily applicable and valuable tool to determine illness perception in patients with PDs.
Expanding the clinical features of autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation by description of a novel patient
Authors: Morán‐Villaseñor E. , Saez‐de‐Ocariz M. , Torrelo A. , Arostegui J.I. , Yamazaki‐Nakashimada M.A. , Alcántara‐Ortigoza M.A. , González‐del‐Angel A. , Velázquez‐Aragón J.A. , López‐Herrera G. , Berrón‐Ruiz L. , García‐Romero M.T.
Published: August 2019

Background

Autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation (APLAID) is an exceedingly rare monogenic autoinflammatory disease. To date, only five cases have been reported with four distinct pathogenic mutations.

Objectives

We present a novel case of APLAID, corroborated by molecular analysis, with newly described clinical findings including central nervous system vasculitis (CNSV); and distinctive histopathological characteristics that may expand our knowledge of this rare disease′s phenotype.

Methods

This is a case report presentation of a 3‐year‐old boy, seen at a reference paediatric hospital in Mexico. His parents authorized the use of his clinical information and photographs.

Results

A 3‐day‐old boy presented to the emergency department with a vesiculo‐pustular rash that resolved within 1 week. Two months later, he developed widespread papules and pseudovesicles that evolved into infiltrated plaques. He also had periodical flares of conjunctivitis, diarrhoea and erythematous blistering acral plaques triggered by upper respiratory infections. By the age of 10 months, he experienced seizures and CNSV. Laboratory work‐up showed mild neutropenia, decreased serum levels of immunoglobulins and B‐cell lymphopenia. A skin biopsy revealed a dense, perivascular and interstitial histiocytic and granulomatous infiltrate, with palisading granulomas, and leucocytoclastic vasculitis with karyorrhexis. APLAID syndrome was confirmed by Sanger sequencing of PLCG2 gene [heterozygous genotype LRG_376t1:c.2543T>C or p.(Leu848Pro)].

Conclusions

Presence of CNSV has not been previously described in APLAID, however as the number of reported patients with APLAID is very small, it is possible that the overall spectrum of clinical manifestations has not been completely elucidated. The herein identified p.(Leu848Pro) variant was also documented in a Portuguese patient, suggesting that it could be a PLCG2 gene ‘hot‐spot’.
G protein‐coupled receptor 40 expression in human melanoma – correlation with tumour thickness, AJCC stage and survival
Authors: Kleemann J. , Hrgovic I. , Kleimann P. , Ter‐Nedden J. , Glaser M. , Steinhorst K. , Härle K. , Müller J. , Kaufmann R. , Kippenberger S. , Meissner M.
Published: August 2019

Background

In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein‐coupled receptor GPR40, was identified in melanoma cells.

Objectives

The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker.

Methods and Results

A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti‐GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease‐free survival (0.040).

Conclusion

The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient's survival.
Collective aggressiveness limits colony persistence in high‐ but not low‐elevation sites at Amazonian social spiders
Authors: Lichtenstein James L. L. , Fisher David N. , McEwen Brendan L. , Nondorf Daniel T. , Calvache Esteban , Schmitz Clara , Elässer Jana , Pruitt Jonathan N.
Published: August 2019

Identifying the traits that foster group survival in contrasting environments is important for understanding local adaptation in social systems. Here, we evaluate the relationship between the aggressiveness of social spider colonies and their persistence along an elevation gradient using the Amazonian spider,Anelosimus eximius. We found that colonies ofA. eximiusexhibit repeatable differences in their collective aggressiveness (latency to attack prey stimuli) and that colony aggressiveness is linked with persistence in a site‐specific manner. Less aggressive colonies are better able to persist at high‐elevation sites, which lack colony‐sustaining large‐bodied prey, whereas colony aggression was not related to chance of persistence at low‐elevation sites. This suggests that low aggressiveness promotes colony survival in high‐elevation, prey‐poor habitats, perhaps via increased tolerance to resource limitation. These data reveal that the collective phenotypes that relate to colony persistence vary by site, and thus, the path of social evolution in these environments is likely to be affected.
Prevalence and risk factors for postpartum urinary retention after vaginal delivery in Japan: A case‐control study
Authors: Kawasoe Izumi , Kataoka Yaeko
Published: August 2019

Aim

This study aimed to clarify the prevalence and risk factors of postpartum urinary retention after vaginal delivery. It also described the healing process of women who had postpartum urinary retention.

Methods

In this case‐control study, 77 women who had postpartum urinary retention were matched by age and parity with 385 women as controls. Data were analyzed by conditional logistic regression analysis. Data were collected from the women in the case group regarding their healing process and conditions for urinary retention (overt or covert urinary retention).

Results

The prevalence of postpartum urinary retention was 1.2%. The adjusted odds ratio and the 95% confidence intervals for risk factors were as follows: epidural analgesia 4.72, 95% CI 2.38, 9.39; episiotomy 2.68, 95% CI 1.40, 5.13; length of second stage of labor 1.85, 95% CI 0.98, 3.49; labor augmentation 1.78, 95% CI 0.90, 3.51; instrument delivery 0.96, 95% CI 0.43, 2.17; and Kristeller maneuver 0.93, 95% CI 0.37, 2.37. Among 59 women with overt urinary retention, 29 (49.2%) transitioned to covert urinary retention within 10 days after delivery. More than half of the women were normal within 72 hr, but there were five women whose urinary retention did not resolve 11 days following delivery.

Conclusions

The statistically significant risk factors for postpartum urinary retention were epidural analgesia and episiotomy. Initiatives for the prevention and management of postpartum urinary retention are necessary.
Injury‐preconditioning secretome of umbilical cord mesenchymal stem cells amplified the neurogenesis and cognitive recovery after severe traumatic brain injury in rats
Authors: Liu Xiao‐Yin , Wei Meng‐Guang , Liang Jun , Xu Hai‐Huan , Wang Jing‐Jing , Wang Jing , Yang Xi‐Ping , Lv Fang‐Fang , Wang Ke‐Qiang , Duan Jing‐Hao , Tu Yue , Zhang Sai , Chen Chong , Li Xiao‐Hong
Published: August 2019

Traumatic brain injury (TBI) is a dominant cause of death and permanent disability worldwide. Although TBI could significantly increase the proliferation of adult neural stem cells in the hippocampus, the survival and maturation of newborn cells is markedly low. Increasing evidence suggests that the secretome derived from mesenchymal stem cells (MSCs) would be an ideal alternative to MSC transplantation. The successive and microenvironmentally responsive secretion in MSCs may be critical for the functional benefits provided by transplanted MSCs after TBI. Therefore, it is reasonable to hypothesize that the signaling molecules secreted in response to local tissue damage can further facilitate the therapeutic effect of the MSC secretome. To simulate the complex microenvironment in the injured brain well, we used traumatically injured brain tissue extracts to pretreat umbilical cord mesenchymal stem cells (UCMSCs) in vitro and stereotaxically injected the secretome from traumatic injury‐preconditioned UCMSCs into the dentate gyrus of the hippocampus in a rat severe TBI model. The results revealed that compared with the normal secretome, the traumatic injury‐preconditioned secretome could significantly further promote the differentiation, migration, and maturation of newborn cells in the dentate gyrus and ultimately improve cognitive function after TBI. Cytokine antibody array suggested that the increased benefits of secretome administration were attributable to the newly produced proteins and up‐regulated molecules from the MSC secretome preconditioned by a traumatically injured microenvironment. Our study utilized the traumatic injury‐preconditioned secretome to amplify neurogenesis and improve cognitive recovery, suggesting this method may be a novel and safer candidate for nerve repair.

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Cover Image for this issue: doi: 10.1111/jnc.14741
The types of caregiving reactions experienced by the older spouse caregivers
Authors: Aloweni Fazila , Doshi Kinjal , Fook‐Chong Stephanie , Malhotra Rahul , Østbye Truls
Published: August 2019

Aims

To examine factors associated with the four types of caregiver reactions according to the modified Caregiver Reaction Assessment (mCRA) and assess the differences in the narrative assessment from spouse caregivers between the high‐positive and high‐negative caregiver reactions.

Background

There is a limited understanding of the factors contributing to positive and negative reactions among older spouse caregivers with chronic illnesses. Narrative assessment from spouse caregivers has not been studied before.

Design

The study design was a paired‐sample, mixed‐method survey design. Data were collected from spouse caregivers (≥55 years old) and care‐recipients in one medical institute from February 2017–December 2017. This manuscript used STROBE checklist to ensure complete reporting.

Methods

Demographic, socioeconomic, Frailty Index, perceived stress, and quality of life data were gathered from caregiver dyads. mCRA, relationship, and life satisfaction data were collected from caregivers. mCRA identified the four types of caregiver reactions: (a) high‐positive, low‐negative; (b) high‐positive, high‐negative; (c) low‐positive, high‐negative; and (d) low‐positive, low‐negative. A qualitative interview was conducted to understand the differences in the narrative and choice of words used to describe caregiving experience.

Results

Seventy‐five caregiver dyads were recruited. Total perceived stress was found to be negatively associated with high‐positive, low‐negative caregiver reaction (baseline category: low‐positive, high‐negative) by multinomial logistic regression. Content analyses showed that low‐positive and high‐negative caregivers used words that implied a lack of volition. Caregivers with positive experience viewed caregiving as a responsibility; the opposite viewed it as having ‘no choice’.

Conclusions

Perceived stress is an important indicator of caregiver reactions. Words used when describing caregiving experiences can potentially depict the spouse caregivers' current state of being as a caregiver.

Relevance to clinical practice

Spouse caregiver's narrative of their caregiving experience may provide easy and quick insights if interventions are needed. Early identification of negative reactions will allow for prompt interventions in mitigating caregivers' stress.
Establishment of reference intervals for maternal blood and umbilical cord blood procalcitonin in healthy Chinese women in late pregnancy
Authors: Ma Yan , Shao Minfang , Shao Xiaonan , Wang Yuetao , Chen Xueqin
Published: August 2019

Aim

To establish reference intervals (RIs) for maternal blood and umbilical cord blood procalcitonin (PCT) in healthy Chinese women in late pregnancy.

Methods

One hundred and twenty‐seven healthy Chinese women in late pregnancy, including 70 vaginal deliveries and 57 cesarean section deliveries, were retrospectively analyzed. These pregnant women gave birth to 58 male infants and 69 female infants. Another 127 age‐matched healthy women who were not pregnant were enrolled as the control group. PCT levels in maternal blood, umbilical cord blood and control blood were determined using electrochemiluminescence immunoassay. The RIs of PCT were defined using an intermediate 95% interval.

Results

The RIs for maternal blood and umbilical cord blood PCT were 0.020–0.075 ng/mL and 0.020–0.159 ng/mL, respectively. The cord blood PCT level was not significantly different between different delivery methods (P > 0.05). In contrast, the umbilical cord blood PCT in female newborns was higher than that in male newborns (0.088 ± 0.046 ng/mL vs 0.072 ± 0.030 ng/mL, P < 0.05).

Conclusion

Maternal blood and umbilical cord blood PCT of Chinese women in late pregnancy have different RIs, and umbilical cord blood PCT level is affected by the gender of newborns.
Neuroprotective Effects of Rasagiline in Parkinson's Disease: A Regional Cerebral Blood Flow Study
Authors: Im Jooyeon Jamie , Jeong Hyeonseok , Chung Yong‐An , Park Jong‐Sik , Heo Youngje , Oh Jin Kyoung , Song In‐Uk
Published: August 2019

BACKGROUND AND PURPOSE

Despite accumulating evidence for the clinical efficacy and neuroprotective properties of rasagiline in Parkinson's disease (PD), effects of rasagiline on brain perfusion in PD patients have not been elucidated. The present study aimed to investigate the effects of rasagiline on regional cerebral blood flow (rCBF) in patients with PD using single‐photon emission computed tomography (SPECT).

METHODS

A total of 44 PD patients were recruited and treated with dopamine agonist, either alone or in combination with levodopa. Twenty‐two of these patients (referred to as the rasagiline group) additionally received rasagiline (1 mg/day). All patients underwent brain SPECT scans and clinical assessments at baseline and follow‐up visits. The mean follow‐up period was 2.2 years. Changes in rCBF were compared between the rasagiline group and the comparison group in a voxel‐wise manner.

RESULTS

Annual change in Unified Parkinson's Disease Rating Scale motor score was lower in the rasagiline group compared to the comparison group (P = .01). A significant group‐by‐time interaction effect on rCBF was found in the right precuneus (P = .001), where rCBF was decreased in the comparison group and remained stable in the rasagiline group.

CONCLUSIONS

Our results show that adjunctive rasagiline treatment had beneficial effects on perfusion in the precuneus of PD patients, suggesting potential neuroprotective effects.
Mapping quantitative trait loci associated with southern leaf blight resistance in maize (Zea mays L.)
Authors: Kaur Maninder , Vikal Yogesh , Kaur Harleen , Pal Lalit , Kaur Kirandeep , Chawla Jasbir Singh
Published: August 2019

Southern leaf blight (SLB) caused by the fungus Cochliobolus heterostrophus (Drechs.) Drechs. is a major foliar disease of maize worldwide. Our objectives were to identify quantitative trait loci (QTL) for resistance to SLB and flowering traits in recombinant inbred line (RIL) population derived from the cross of inbred lines LM5 (resistant) and CM140 (susceptible). A set of 207 RILs were phenotyped for resistance to SLB at three time intervals for two consecutive years. Four putative QTL for SLB resistance were detected on chromosomes 3, 8 and 9 that accounted for 54% of the total phenotypic variation. Days to silking and anthesis–silking interval (ASI) QTL were located on chromosomes 6, 7 and 9. A comparison of the obtained results with the published SLB resistance QTL studies suggested that the detected bins 9.03/02 and 8.03/8.02 are the hot spots for SLB resistance whereas novel QTL were identified in bins 3.08 and 8.01/8.04. The linked markers are being utilized for marker‐assisted mobilization of QTL conferring resistance to SLB in elite maize backgrounds. Fine mapping of identified QTL will facilitate identification of candidate genes underlying SLB resistance.
TNBG-5602, a novel derivative of quinoxaline, inhibits liver cancer growth via upregulating peroxisome proliferator-activated receptor γ in vitro and in vivo
Authors: Hu Xuelian , Wan Chunmei , Gan Zongjie , Liu Rongxing , Chen Yongjie , Wang Jing , Gan Linling , Chen Yuhang , Li Yingbo , He Baicheng , Yu Yu
Published: August 2019

Objectives

TNBG-5602 is a newly synthesized compound with an isoquinoline structure. In the present study, we demonstrated the anticancer effect of TNBG-5602 in in-vitro and in-vivo models and investigated its possible anticancer mechanism.

Methods

The antiproliferation effect of TNBG-5602 in vitro was evaluated in human liver cancer cell line QGY-7701. The acute toxicity of TNBG-5602 was evaluated in mice. The anticancer activity of TNBG-5602 in vivo was assessed in a xenograft model of human liver cancer cell line QGY-7701.

Key findings

The results of CCK-8 assay showed that TNBG-5602 can effectively inhibit the proliferation of liver cancer cells in vitro. The acute toxicity test in mice showed that the LD50 of TNBG-5602 was 172 mg/kg. In a xenograft liver cancer model, TNBG-5602 could remarkably inhibit the growth of tumours. During in-vitro and in-vivo studies, we noted that TNBG-5602 could induce lipid accumulation in cancer cells and tissues. Further study indicated that the anticancer effect of TNBG-5602 may be exerted through activating peroxisome proliferator-activated receptor γ (PPARγ) and downregulating proliferating cell nuclear antigen (PCNA).

Conclusions

Our results suggested that TNBG-5602 might exert potent anticancer activity through increasing the expression of PPARγ.