bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of severe life events, attachment style, and depression – Using a new online approach
Authors: Bifulco Antonia , Kagan Lisa , Spence Ruth , Nunn Stephen , Bailey‐Rodriguez Deborah , Hosang Georgina , Taylor Matthew , Fisher Helen L.
Published: April 2019

Objectives

Severe life events are established as provoking agents for depression in combination with vulnerability factors. Identifying features of severe events improves the prediction of disorder but are rarely utilized, mainly because life event research is increasingly dominated by self‐report checklists with no capacity for inferring such characteristics. This paper investigates the association of severe life events’ features with depression and insecure attachment styles using a new online measure of life events in a clinical and control sample.

Methods

A total of 202 participants (75 clinical and 127 matched control participants), taken from an earlier national Depression Case Control genetic study and followed up after 12 years, completed the Computerised Life Events Assessment Record to assess characteristics of life events, the Vulnerable Attachment Style Questionnaire to measure attachment insecurity, and the General Health Questionnaire to measure depression.

Results

The clinical group had higher self‐reported depression, severe life events, and insecure attachment style. They also reported more loss, danger, humiliation, and trauma severe events. Intra‐respondent analysis showed individuals experiencing these types of events were more likely to report depression. Insecure attachment style and severe life events were both significantly related to recent depression and history of depressive disorder. Anxious attachment style was significantly related to relationship events and bereavements, as well as severe loss or humiliation events, whereas avoidant style was not.

Conclusions

Identifying salient features of severe life events improves associations with depression and insecure attachment style. Utilizing a new online approach can aid research and clinical approaches for depression at low cost.

Practitioner points

Salient features of severe life events (e.g., loss, humiliation) give insight into the potential impact on attachment vulnerability and depression.

Clinicians and researchers can use online methods to economically gain detailed life event information needed for clinical formulation and valid data on stressors.

The self‐reported scale for recent depression is only a proxy measure of clinical disorder, but the clinical group selection is a more robust criterion for depression history.
Validating process variables of sourcing in an assessment of multiple document comprehension
Authors: Hahnel Carolin , Kroehne Ulf , Goldhammer Frank , Schoor Cornelia , Mahlow Nina , Artelt Cordula
Published: April 2019

Background

With digital technologies, competence assessments can provide process data, such as mouse clicks with corresponding timestamps, as additional information about the skills and strategies of test takers. However, in order to use variables generated from process data sensibly for educational purposes, their interpretation needs to be validated with regard to their intended meaning.

Aims

This study seeks to demonstrate how process data from an assessment of multiple document comprehension can be used to represent sourcing, which summarizes activities for the consideration of the origin and intention of documents. The investigated process variables were created according to theoretical assumptions about sourcing, and systematically tested for differences between persons, units (i.e., documents and items), and properties of the test administration.

Sample

The sample included 310 German university students (79.4% female), enrolled in several bachelor's or master's programmes of the social sciences and humanities.

Methods

Regarding the hierarchical data structure, the hypotheses were analysed with generalized linear mixed models (GLMM).

Results

The results mostly revealed expected differences between individuals and units. However, unexpected effects of the administered order of units and documents were detected.

Conclusions

The study demonstrates the theory‐informed construction of process variables from log‐files and an approach for empirical validation of their interpretation. The results suggest that students apply sourcing for different reasons, but also stress the need of further validation studies and refinements in the operationalization of the indicators investigated.
Bendamustine for patients with indolent B cell lymphoproliferative malignancies including chronic lymphocytic leukaemia – an updated meta‐analysis
Authors: Vidal Liat , Gurion Ronit , Shargian Liat , Dreyling Martin , Gafter‐Gvili Anat
Published: April 2019

The question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B‐cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta‐analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine‐containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65–0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy‐free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible.
Impaired cellular and humoral immunity is a feature of Diamond‐Blackfan anaemia; experience of 107 unselected cases in the United Kingdom
Authors: Iskander Deena , Roberts Irene , Rees Clare , Szydlo Richard , Alikian Mary , Neale Michael , Harrington Yvonne , Kelleher Peter , Karadimitris Anastasios , de la Fuente Josu
Published: April 2019

Diamond‐Blackfan anaemia (DBA) is a rare bone marrow failure syndrome characterised by anaemia, congenital anomalies and cancer predisposition. Although infections are the second leading cause of mortality in non‐transplanted patients, immune function is largely unexplored. We identified quantitative deficits in serum immunoglobulins and/or circulating T, natural killer and B lymphocytes in 59 of 107 unselected patients (55·1%) attending our centre over a 7‐year period. Immune abnormalities were independent of ribosomal protein genotype and arose in both steroid‐treated and steroid‐untreated patients. In summary, these data highlight the high prevalence and spectrum of infections and immune defects in DBA.
Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor
Authors: Cecon Erika , Dam Julie , Luka Marine , Gautier Clément , Chollet Anne‐Marie , Delagrange Philippe , Danober Laurence , Jockers Ralf
Published: April 2019

Background and Purpose

Progressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes.

Experimental Approach

We developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction.

Key Results

We demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738.

Conclusions and Implications

Our TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs.

Linked Articles

This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
A photoswitchable GABA receptor channel blocker
Authors: Maleeva Galyna , Wutz Daniel , Rustler Karin , Nin‐Hill Alba , Rovira Carme , Petukhova Elena , Bautista‐Barrufet Antoni , Gomila‐Juaneda Alexandre , Scholze Petra , Peiretti Franck , Alfonso‐Prieto Mercedes , König Burkhard , Gorostiza Pau , Bregestovski Piotr
Published: April 2019

Background and Purpose

Anion‐selective Cys‐loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride‐selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light‐controllable modulator of GABA receptors, we constructed azobenzene‐nitrazepam (Azo‐NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group.

Experimental Approach

The experiments were carried out on cultured cells expressing Cys‐loop receptors of known subunit composition and in brain slices using patch‐clamp. Site‐directed mutagenesis and molecular modelling approaches were applied to evaluate the mechanism of action of Azo‐NZ1.

Key Results

At visible light, being in trans‐configuration, Azo‐NZ1 blocked heteromeric α1/β2/γ2 GABAA receptors, ρ2 GABAA (GABAC), and α2 glycine receptors, whereas switching the compound into cis‐state by UV illumination restored the activity. Azo‐NZ1 successfully photomodulated GABAergic currents recorded from dentate gyrus neurons. We demonstrated that in trans‐configuration, Azo‐NZ1 blocks the Cl‐selective ion pore of GABA receptors interacting mainly with the 2′ level of the TM2 region.

Conclusions and Implications

Azo‐NZ1 is a soluble light‐driven Cl‐channel blocker, which allows photo‐modulation of the activity induced by anion‐selective Cys‐loop receptors. Azo‐NZ1 is able to control GABAergic postsynaptic currents and provides new opportunities to study inhibitory neurotransmission using patterned illumination.
Age, stratigraphy, sedimentology and tectonic setting of the Sigri Pyroclastic Formation and its fossil forests, Early Miocene, Lesbos, Greece
Authors: Pe‐Piper Georgia , Piper David J.W. , Zouros Nickolas , Anastasakis George
Published: April 2019

The Petrified Forest of Lesbos comprises silicified tree fossils at multiple stratigraphic levels within the Lower Miocene Sigri Pyroclastic Formation. Our objective was to understand the interplay of tectonic setting, structural evolution, volcanological setting and basin evolution in the preservation of this remarkable natural monument. Sections were logged for lithology, sedimentary structures and hydrothermal alteration. Orientations of fallen fossil trees were measured. Samples were taken for mineralogical and geochemical analysis. 40Ar/39Ar dating was carried out on mineral separates from four samples. Widespread andesite‐dacite domes, the Eressos Formation, intrude and overlie metamorphic basement and are overlain by the Sigri Pyroclastic Formation, which comprises several hundreds of metres of pyroclastic flow tuffs (unwelded ignimbrites) interbedded with fluvial conglomerate and volcaniclastic sandstone. The Sigri Pyroclastic Formation ranges in age from 21.5 to 22 Ma, where it overlies the lacustrine Gavathas Formation, to younger than 18.4 Ma. Tuffs and fluvial conglomerates in the Sigri Pyroclastic Formation coarsen eastwards, and petrified trees and soil horizons occur throughout the Formation. The recurrence of pyroclastic flows was approximately one every 20 ka, so destructive flows were relatively infrequent, allowing the development of climax vegetation between most eruptions. Conglomerate‐filled channels show that rivers flowed westwards. Tree fall directions indicate NW to N movement of pyroclastic flows, implying a source near the younger Mesotopos–Tavari caldera to the south. The basin, which formed in a NNE‐trending dextral strike‐slip regime, provided some topographic steering. Following the Sigri Pyroclastic Formation at ca. 18 Ma, there was a rapid increase in the pace of volcanic activity, with the eruption of thick lava sequences and welded ignimbrites, and intrusion of dykes and laccoliths in SW Lesbos. Rapid burial by permeable tuffs, silica from alteration of volcanic ash, and later hydrothermal circulation all contributed to the preservation of the petrified trees.
Tumour necrosis factor alpha and interleukin‐5 inhibit olfactory regeneration via apoptosis of olfactory sphere cells in mice models of allergic rhinitis
Authors: Kim Dong‐Kyu , Choi Seung Ah , Eun Kyoung Mi , Kim Seung‐Ki , Kim Dae Woo , Phi Ji Hoon
Published: April 2019

Background

Olfactory dysfunction is frequently experienced by patients with allergic rhinitis. It is thought to result from structural and functional changes occurring in the olfactory mucosa caused by inflammation. However, the current understanding of the pathophysiology of olfactory dysfunction in allergic rhinitis remains unclear.

Objective

To investigate the mechanism by which the olfactory neural cells are damaged in allergic rhinitis.

Methods

Olfactory sphere cells (OSCs) were established after dissociation and serial cultures of cells from the mouse olfactory mucosa. Viability and proliferation of OSCs were compared between control and allergic rhinitis mice models, and olfactory stem cell markers were analysed in vivo. To elucidate which cytokines have an inhibitory effect on OSCs, viability and apoptotic markers of OSCs were investigated.

Results

Olfactory sphere cells were successfully isolated from the olfactory mucosa of mice, and these cells expressed markers of neural stem cells. To investigate the neural differentiation, we performed the immunocytochemical staining and found significantly elevated expressions of Tuji1, GFAP and O4 on OSCs. On the comparison of the characteristics of OSCs between control and allergic rhinitis model, we detected significantly fewer neurospheres, reduced clonogenic capacity and decreased expression of olfactory neural stem cell markers in allergic rhinitis model. When OSCs were treated with several major allergic cytokines were treated on OSCs, only TNF‐α showed an inhibitory effect on OSCs. Interestingly, IL‐5 had an inhibitory effect on the viability of OSCs in combination with TNF‐α, whereas IL‐5 alone does not have an effect. Moreover, TNF‐α combined with IL‐5 significantly increased the apoptotic expression, compared with TNF‐α or IL‐5 alone. Additionally, allergic rhinitis mice models showed the increased apoptotic expression.

Conclusion and Clinical Relevance

Allergic rhinitis mice models showed lower expression of OSCs, and TNF‐α combined with IL‐5 had an apoptotic effect on OSCs. Therefore, these cytokines may be therapeutic targets for olfactory dysfunction in patients with allergic rhinitis.
Clinical characteristics and leptomeningeal collateral status in pediatric and adult patients with ischemic moyamoya disease
Authors: Liu Zhi‐Wen , Han Cong , Wang Hui , Zhang Qian , Li Si‐Jie , Bao Xiang‐yang , Zhang Zheng‐Shan , Duan Lian
Published: April 2019

Aim

Previous studies have found significant differences in clinical characteristics between pediatric and adult moyamoya disease (MMD) patients, but few studies have focused on the factors underlying these differences. We aimed to investigate the differences in leptomeningeal collateral (LMC) status between pediatric and adult MMD patients and to analyze the effects of LMCs on clinical characteristics and therapeutic prognosis.

Methods

We retrospectively analyzed 214 MMD patients from January 2014 to January 2016. Clinical characteristics and LMC status were compared between the pediatric and adult patients. LMC status was graded as good or poor depending on the retrograde flow from the posterior cerebral artery (PCA) on digital subtraction angiography (DSA).

Results

A total of 83 pediatric and 131 adult (1:1.6) MMD patients were analyzed. Pediatric patients were more likely to experience a transient ischemic attack (81%), whereas adult patients were more likely to experience infarction (51%). Regarding the different MMD stages (the early, medium, and advanced stages corresponded to Suzuki stages 1‐2, 3‐4, and 5‐6, respectively), the prevalence of good LMC status was higher for pediatric patients than for adult patients in the early stage (P = 0.047) and the medium stage (P = 0.001), but there were no differences between these patient groups in the advanced stage (P = 0.547). Worse postoperative angiographic outcomes (P = 0.017) were found in adult patients than in pediatric patients in the medium stage. Poor LMC status had strong correlations with infarction (P < 0.001 and P = 0.017) and poor postoperative outcomes (P = 0.003 and P = 0.043) in both pediatric and adult patients.

Conclusions

Pediatric MMD patients have greater patency and a greater ability to establish good LMC status than adult patients, and poor LMC status has a strong correlation with severe clinical symptoms and poor postoperative outcomes. LMC status may be an important factor in the differences in clinical characteristics and prognosis between pediatric and adult MMD patients.
Effective mitigation of conservation conflicts and participatory governance: reflections on Kuboń et al.
Authors: Niedziałkowski Krzysztof , Jaroszewicz Bogdan , Kowalczyk Rafał , Kuijper Dries P.J. , Mikusiński Grzegorz , Selva Nuria , Walankiewicz Wiesław , Wesołowski Tomasz
Published: April 2019

Article impact statement: Participation is not a panacea for the Białowieża conflict; scientific evidence exists and can inform valid policy options.
The ActiGraph counts processing and the assessment of vigorous activity
Authors: Brønd Jan Christian , Aadland Eivind , Andersen Lars Bo , Resaland Geir Kåre , Andersen Sigmund Alfred , Arvidsson Daniel
Published: April 2019

The purpose of this study was to investigate the effect of different band‐pass filters on the measurement bias with ActiGraph counts during high speed running and for estimating free‐living vigorous physical activity (VPA). Two alternative band‐pass filters were designed, extending the original frequency range from 0·29 to 1·66 Hz (AG) to 0·29–4 Hz (AC4) and 0·29–10 Hz (AC10). Sixty‐two subjects in three age groups participated in a structured locomotion protocol consisting of multiple walking and running speeds. The time spent in free‐living VPA using the three different band‐pass filters were evaluated in 1121 children. Band‐pass filter specific intensity cut‐points from both linear regression and ROC analysis was identified from a calibration experiment using indirect calorimetry. The ActiGraph GT3X+ device recording raw acceleration at 30 Hz was used in all experiments. The linear association between counts and running speed was negative for AG but positive for AC4 and AC10 across all age groups. The time spent in free‐living VPA was similar for all band‐pass filters. Considering higher frequency information in the generation of ActiGraph counts with a hip/waist worn device reduces the measurement bias with running above 10 km·h−1. However, additional developments are required to accurately capture all VPA, including intermittent activities.
Cutaneous lesions of angioimmunoblastic T‐cell lymphoma: Clinical, pathological, and immunophenotypic features
Authors: Oishi Naoki , Sartori‐Valinotti Julio C. , Bennani N. Nora , Wada David A. , He Rong , Cappel Mark A. , Feldman Andrew L.
Published: April 2019

Background

Angioimmunoblastic T‐cell lymphoma (AITL) is a systemic peripheral T‐cell lymphoma with a follicular helper T‐cell (TFH) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established.

Methods

We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan‐T‐cell and TFH marker expression was evaluated by immunohistochemistry. Epstein‐Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein‐Barr virus‐encoded small RNA (EBER). T‐cell receptor (TCR) gene rearrangement was evaluated by PCR.

Results

AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium‐sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD‐1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV‐positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%).

Conclusions

Cutaneous involvement by AITL shows relatively non‐specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.
Fixed smears are better than unfixed smears of fine needle aspiration cytology for detection of acid‐fast bacilli on Ziehl‐Neelsen stain
Authors: Khairwa Anju
Published: April 2019

Alcohol (methyl alcohol) fixed smears are more sensitive and specific for AFB detection in cytology samples than unfixed air dried smears. They are also very cost effective and may be useful in developing countries.
Diagnostic challenge in a metastatic pulmonary adenocarcinoma with neuroendocrine differentiation to breast and skin
Authors: Mitra Suvradeep , Purkait Suvendu , Kundoo Aditi , Behera Gayatri , Patra Susama
Published: April 2019

This case report describes a complex differential diagnosis in an unusual case of pulmonary adenocarcinoma metastasing to breast and skin. The breast mass was misdiagnosed as infiltrating duct carcinoma, NOS in core needle biopsy. A subsequent endobronchial biopsy showed a pulmonary adenocarcinoma with neuroendocrine differentiation. The patient represented with a cutaneous metastasis. The cytological features were difficult to distinguish between related entities. Coupled with the cytomorphology was an aberrant immunoprofile making this complex case worthy of discussion.
Metastatic malignant melanoma of the oesophagus, first case diagnosed by endoscopic ultrasound‐guided fine needle aspiration
Authors: Ahsan Beena U. , Alhamar Mohamed , Pompa Robert , Schultz Daniel , Zhang Ziying
Published: April 2019

Metastatic malignant melanoma to the esophagus: an unusual metastasis. In the era of personalized medicine pathologists are more likely to receive limited tissue to make diagnosis and to perform ancillary testing on them. Thus in any patient who has a history of melanoma, including those with a very remote history, melanoma should always be considered in the differential diagnosis of a new mass at any anatomic location.
Evaluating current and future range limits of an endangered, keystone rodent (Dipodomys ingens)
Authors: Widick Ivy V. , Bean William T.
Published: April 2019

Aim

We use current models of species distribution to predict the future habitat suitability for an endangered, keystone rodent (Dipodomys ingens, giant kangaroo rat). We incorporate the possibility of local adaptation and novel competitive interactions to improve the predictive accuracy of our Maxent models.

Location

San Joaquin Valley, California, USA.

Methods

We created Maxent models of two isolated populations ofD. ingens. Using local surveys and state‐wide data, we also modelled California ground squirrels (Otospermophilus beecheyi), a potential novel competitor. Models included landscape variables (slope and soil composition) and climate variables (temperature, precipitation and climatic water deficit). We used Warren'sIto evaluate niche overlap between species as well as between isolated populations of the same species. We then projected each set of models into the future to evaluateD. ingensresponse to climate change.

Results

Niche overlap between theD. ingenspopulations was moderate (I = 0.44), suggesting that they already experience different climatic regimes and providing support for population‐level modelling. Projecting individual populations separately into the future, under a high emission climate change scenario (CCSM4, rcp8.5), resulted in less predicted range contraction than modelling the species as a whole. However, forecasted distributions showed areas of increasing niche overlap between the Panoche population ofD. ingensandO. beecheyi(I = 0.63 to 0.74), indicating competition could be a novel range limit.

Main conclusions

Modelling the distributions of isolated populations separately provides a more accurate estimation of the species’ contemporary niche, capturing not just overlap between the populations, but individually suitable areas as well. Projecting the individual contemporary and historical models into the future allows us to estimate future habitat suitability. Predicting the distribution of a novel competitor characterizes areas of potential competition. Subsequently, management can target suitable areas for preservation and avoid areas of potential novel competition.
Demystifying infant vocal imitation: The roles of mouth looking and speaker’s gaze
Authors: Imafuku Masahiro , Kanakogi Yasuhiro , Butler David , Myowa Masako
Published: April 2019

Vocal imitation plays a fundamental role in human language acquisition from infancy. Little is known, however, about how infants imitate other's sounds. We focused on three factors: (a) whether infants receive information from upright faces, (b) the infant's observation of the speaker's mouth and (c) the speaker directing their gaze towards the infant. We recorded the eye movements of 6‐month‐olds who participated in experiments watching videos of a speaker producing vowel sounds. We found that an infants’ tendency to vocally imitate such videos increased as a function of (a) seeing upright rather than inverted faces, (b) their increased looking towards the speaker's mouth and (c) whether the speaker directed their gaze towards, rather than away from infants. These latter findings are consistent with theories of motor resonance and natural pedagogy respectively. New light has been shed on the cues and underlying mechanisms linking infant speech perception and production.
Fatigue in young people with Duchenne muscular dystrophy
Authors: El‐Aloul Basmah , Speechley Kathy N , Wei Yi , Wilk Piotr , Campbell Craig
Published: April 2019

Aim

To describe fatigue in Duchenne muscular dystrophy (DMD) from patients’ and parents’ perspectives and to explore risk factors for fatigue in children and adolescents withDMD.

Method

A multicentre, cross‐sectional study design was used. Seventy‐one patients (all males; median age 12y, age range 5–17y) identified via the Canadian Neuromuscular Disease Registry, and their parents completed questionnaires. Subjective fatigue was assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale by child self‐report and parent proxy‐report.

Results

Patients withDMDacross ages and disease stages experienced greater fatigue compared to typically developing controls from published data. Sleep disturbance symptoms were associated with greater fatigue by child self‐report (ρ=–0.42;p=0.003) and parent proxy‐report (ρ=–0.51;p<0.001). Depressive symptoms were associated with greater fatigue by child self‐report (ρ=–0.46;p<0.001) and parent proxy‐report (ρ=–0.45;p<0.001). Lower functional ability was associated with greater fatigue by parent proxy‐report (ρ=0.26;p=0.03). Physical activity level, and musculoskeletal, respiratory, and cardiac function were not associated with fatigue.

Interpretation

In paediatricDMD, sleep disturbance symptoms and depressive symptoms are potentially modifiable factors associated with fatigue, warranting additional investigation to facilitate the development of therapeutic strategies to reduce fatigue.

What this paper adds

Fatigue is a major issue in paediatric Duchenne muscular dystrophy (DMD) across ages and disease stages.

Sleep disturbance and depressive symptoms are significantly associated with fatigue in paediatric DMD.
Improving the quality of life of parents of children with developmental disabilities
Authors: Funke Anne
Published: April 2019

This commentary is on the systematic review by Ogourtsova et al. on pages 1259–1265 of this issue.
PRRT2 missense mutations cluster near C‐terminus and frequently lead to protein mislocalization
Authors: Tsai Meng‐Han , Nian Fang‐Shin , Hsu Mei‐Hsin , Liu Wei‐Szu , Liu Yo‐Tsen , Liu Chen , Lin Po‐Hsi , Hwang Daw‐Yang , Chuang Yao‐Chung , Tsai Jin‐Wu
Published: April 2019

Objective

Variants in human PRRT2 cause paroxysmal kinesigenic dyskinesia (PKD) and other neurological disorders. Most reported variants resulting in truncating proteins failed to localize to cytoplasmic membrane. The present study identifies novel PRRT2 variants in PKD and epilepsy patients and evaluates the functional consequences of PRRT2 missense variations.

Methods

We investigated two families with PKD and epilepsies using Sanger sequencing and a multiple gene panel. Subcellular localization of mutant proteins was investigated using confocal microscopy and cell surface biotinylation assay in Prrt2‐transfected cells.

Results

Two novel PRRT2 variants, p.His232Glnfs*10 and p.Leu298Pro, were identified, and functional study revealed impaired localization of both mutant proteins to the plasma membrane. Further investigation of other reported missense variants revealed decreased protein targeting to the plasma membrane in eight of the 13 missense variants examined (p.Trp281Arg, p.Ala287Thr, p.Ala291Val, p.Arg295Gln, p.Leu298Pro, p.Ala306Asp, p.Gly324Glu, and p.Gly324Arg). In contrast, all benign variants we tested exhibited predominant localization to the plasma membrane similar to wild‐type Prrt2. Most likely pathogenic variants were located at conserved amino acid residues near the C‐terminus, whereas truncating variants spread throughout the gene.

Significance

PRRT2 missense variants clustering at the C‐terminus often lead to protein mislocalization. Failure in protein targeting to the plasma membrane by PRRT2 variants may be a key mechanism in causing PKD and related neurological disorders.
Randomized controlled trial of motivational interviewing for psychogenic nonepileptic seizures
Authors: Tolchin Benjamin , Baslet Gaston , Suzuki Joji , Martino Steve , Blumenfeld Hal , Hirsch Lawrence J. , Altalib Hamada , Dworetzky Barbara A.
Published: April 2019

Objective

We conducted a randomized controlled trial of motivational interviewing (MI) as an intervention to improve psychotherapy adherence and outcomes, including frequency of psychogenic nonepileptic seizures (PNES), quality of life, and emergency department utilization, among participants with PNES.

Methods

Sixty participants were randomized to receive either psychotherapy alone or MI plus psychotherapy. Participants and therapists were contacted at 16‐week follow‐up. Participants were considered adherent with psychotherapy if they attended at least eight sessions within 16 weeks following referral.

Results

Among control participants, 31.0% were adherent, whereas among MI participants, 65.4% were adherent (P = 0.015, absolute risk reduction = 34.4%, number needed to treat = 2.9). In the control arm, PNES frequency decreased by 34.8% (standard deviation [SD] = 89.7%), whereas in the MI arm, PNES frequency decreased by 76.2% (SD = 39.2%; P = 0.034, Cohen’s d = 0.59). Among control participants, 10.7% achieved PNES freedom versus 30.8% of MI participants (P = 0.095). Quality of Life in Epilepsy–10 scores (a 40‐point scale) improved by an average of 1.8 (SD = 7.9) points among control participants, and by 7.2 (SD = 10.0) points among MI participants (P = 0.047, Cohen’s d = 0.60). Monthly emergency department visits increased by 0.06 (SD = 0.47) visits per month among control participants versus a decrease of 0.15 (SD = 0.76) among MI participants (P = 0.23).

Significance

Motivational interviewing improved treatment adherence, PNES frequency, and quality of life among our participants with PNES. Our study is limited in that it was conducted at a single quaternary care medical center, and MI was provided by a single neurologist, which may limit generalization of results.
Diagnosis and treatment of confirmed and suspected primary hyperparathyroidism in equids: 17 cases (1999–2016)
Authors: Gorenberg E. B. , Johnson A. L. , Magdesian K. G. , Bertin F.‐R. , Costa L. R. R. , Theelen M. J. P. , Durward‐Akhurst S. A. , Cruz Villagrán C. , Carslake H. , Frank N. , Tomlinson J. E.
Published: April 2019

Background

Primary hyperparathyroidism is uncommon in equids.

Objectives

To describe the diagnostic findings and efficacy of treatment in equids with primary hyperparathyroidism.

Study design

Retrospective case series describing 16 horses and one mule.

Methods

Cases were identified by retrospective review of records at Cornell University and via anACVIMlistserv query. Inclusion criteria were an equid with hypercalcemia, normal renal function and high parathyroid hormone (PTH) or histopathological diagnosis of a parathyroid adenoma. Equids with normalPTHandPTH‐related protein (PTHrP) in the face of hypercalcemia were included as suspect cases.

Results

The most common presenting complaints were weight loss (12/17) and hypercalcemia (10/17).PTHwas above reference range in 12/17 cases. Suspected parathyroid tumours were localised in 12/14 equids imaged using ultrasonography alone (2/3), technetium 99m Tc sestamibi scintigraphy alone (1/1) or both modalities (9/10). Three horses did not have imaging performed. Surgical exploration successfully excised tumours in six of 10 cases. Five were located at the thoracic inlet, and surgery resulted in complete cure. One tumour was excised from the thyroid lobe, and the horse remained hypercalcemic. Four other cases explored surgically, four treated medically and three that were not treated also remained hypercalcemic.

Main limitations

The small study size prohibited statistical analysis.

Conclusions

Parathyroid adenomas in equids can be successfully localised with ultrasonography and scintigraphy. Surgical excision appears more likely to be successful for single gland disease at the thoracic inlet.
Beyond amino acid sequence: disulfide bonds and the origins of the extreme amyloidogenic properties of insulin's H‐fragment
Authors: Dec Robert , Koliński Michał , Dzwolak Wojciech
Published: April 2019

The presence of disulfide bonds affects the protein stability and therefore tendency to misfold and form amyloid‐like fibrils. Insulin's three disulfide bridges stabilize the native state and prevent aggregation. Partial proteolysis of insulin releases highly amyloidogenic and inherently disordered two‐chain ‘H‐fragment’ retaining insulin's Cys7A‐Cys7B and Cys6A‐Cys11A disulfide bonds. The abrupt self‐association of H‐fragment monomers into fibrils is suppressed in the presence of disulfide‐reducing agent. These circumstances make the H‐fragment an interesting model to study the impact of disulfide bonds on amyloidogenesis beyond the ‘stabilization‐of‐the‐native‐state’ paradigm. Here, we investigate fibrillization of various synthetic peptides derived from the H‐fragment through modifications of Cys7A‐Cys7B/Cys6A‐Cys11A bonds. In comparison to H‐fragment, aggregation of a two‐chain ‘AB’ analog lacking Cys6A‐Cys11A bond is decelerated, while the alternative removal of Cys7A‐Cys7B bond releases a non‐aggregating B‐chain and a highly amyloidogenic ‘ACC’ fragment containing the intrachain Cys6A‐Cys11A bond. Our analysis, supported by calculations of configurational entropy, suggests that Cys6A‐Cys11A bond is a key factor behind the explosive self‐association of H‐fragment. The bond restricts the conformational space probed by nucleating monomers which is reflected by an approximately 2.4 kJ·mol−1 K−1 decrease in entropy. The fact that the intact Cys6A‐Cys11A bond promotes fibrillization of the H‐fragment is remarkable in light of the previously established role of the same disulfide bond in preventing formation of insulin fibrils. Our results imply that a single disulfide bond within a folded protein and its fragment may play entirely different roles in aggregation and that this role may evolve with progressing phases of misfolding.
Long‐term loss to follow‐up in the TREAT Asia HIV Observational Database (TAHOD)
Authors: Jiamsakul A , Kiertiburanakul S , Ng OT , Chaiwarith R , Wong W , Ditangco R , Nguyen KV , Avihingsanon A , Pujari S , Do CD , Lee M‐P , Ly PS , Yunihastuti E , Kumarasamy N , Kamarulzaman A , Tanuma J , Zhang F , Choi JY , Kantipong P , Sim BLH , Ross J , Law M , Merati TP ,   the TREAT Asia HIV Observational Database of IeDEA Asia‐Pacific
Published: April 2019

Objectives

With earlier antiretroviral therapy (ART) initiation, time spent in HIV care is expected to increase. We aimed to investigate loss to follow‐up (LTFU) in Asian patients who remained in care 5 years after ART initiation.

Methods

Long‐term LTFU was defined as LTFU occurring after 5 years on ART. LTFU was defined as (1) patients not seen in the previous 12 months; and (2) patients not seen in the previous 6 months. Factors associated with LTFU were analysed using competing risk regression.

Results

Under the 12‐month definition, the LTFU rate was 2.0 per 100 person‐years (PY) [95% confidence interval (CI) 1.8–2.2 among 4889 patients included in the study. LTFU was associated with age > 50 years [sub‐hazard ratio (SHR) 1.64; 95% CI 1.17–2.31] compared with 31–40 years, viral load ≥ 1000 copies/mL (SHR 1.86; 95% CI 1.16–2.97) compared with viral load < 1000 copies/mL, and hepatitis C coinfection (SHR 1.48; 95% CI 1.06–2.05). LTFU was less likely to occur in females, in individuals with higher CD4 counts, in those with self‐reported adherence ≥ 95%, and in those living in high‐income countries. The 6‐month LTFU definition produced an incidence rate of 3.2 per 100 PY (95% CI 2.9–3.4 and had similar associations but with greater risks of LTFU for ART initiation in later years (2006–2009: SHR 2.38; 95% CI 1.93–2.94; and 2010–2011: SHR 4.26; 95% CI 3.17–5.73) compared with 2003–2005.

Conclusions

The long‐term LTFU rate in our cohort was low, with older age being associated with LTFU. The increased risk of LTFU with later years of ART initiation in the 6‐month analysis, but not the 12‐month analysis, implies that there was a possible move towards longer HIV clinic scheduling in Asia.
Unravelling the composition and envisaging the formation of sediments in traditional Chinese vinegar
Authors: Zhang Xianglong , Wu Yanfang , Zheng Yu , Xu Ying , Xia Menglei , Tu Linna , Song Jia , Wang Min
Published: April 2019

Sediments will spontaneously form in traditional Chinese vinegars (TCVs), which negatively affect the product acceptability. Here, sediments in Shanxi aged vinegar, a representative TCV, were investigated to unravel the microstructure and composition. Morphologically, crystals, amorphous substances and thalli were three common forms. Composition analysis by confocal laser scanning microscopy manifested starch/polysaccharides and proteins were present. Proteins (~30%), carbohydrates (>10%), crude fats (~17.00%) and metallic elements (~3%) were four main components determined, and polyphenols and flavonoids accounted for about 1% in the sediments. The crystals were recognised as calcium oxalate crystals by micro‐area energy‐dispersive X‐ray and micro‐Raman spectrometry, and they were mostly in dihydrate form. This is the first report on the discovery of calcium oxalate crystals in the vinegar. Crystallisation into crystals, self‐assembly and polymerisation of polymers, aggregation of particles, as well as interactions between polymers and particles form a basic model of sediments formation in TCV.
Low‐sodium roasted peanuts: effects of salt mixtures (NaCl, KCl and glycine) on consumer perception and purchase intent
Authors: Pujols Kairy Dharali , Ardoin Ryan , Chaiya Busarawan , Tuuri Georgianna , Prinyawiwatkul Witoon
Published: April 2019

The effects of ten treatment combinations of two salts (NaCl, KCl) and glycine were evaluated on low‐sodium roasted peanuts. Consumers’ (N = 330, recruited from college campus) liking, emotions, perceived saltiness and bitterness intensity, satisfaction and purchase intent (PI) of peanuts were measured following a balanced incomplete block design (t = 10, k = 3, r = 9, b = 30, λ = 2, e2 = 0.74). Emotions and PI were evaluated both before and after presenting a low‐sodium health benefit message. Sodium content of peanuts was reduced from 140 mg Na/50 g peanuts to 41.67 mg Na/50 g without significantly affecting liking scores and with positive PI over 60%. In general, high bitterness and low saltiness intensity ratings negatively affected liking and satisfaction. Consumers expressed less satisfaction when perceived saltiness intensity was ‘Not Enough’ than when ‘Too Much.’ Based on optimisation analysis, any formulation within the range of 59‐100/0‐40/0‐12.5% NaCl/KCl/Gly‐ representing a potential 37% sodium reduction past minimum ‘low sodium’ requirements‐ will yield an acceptable product.
Improving the sensory and nutritional value of gluten‐free bread
Authors: Rybicka Iga , Doba Karolina , Bińczak Olga
Published: April 2019

Bakery products, especially breads, are important part of everyday diet. Home‐made breads are all the more crucial on the gluten‐free diet, as commercially available breads without gluten are often unattractive. The study presents the recipe, nutritional characteristics (fat, protein, calcium, magnesium, sodium, potassium, copper, iron, zinc, manganese), costs and consumer acceptance of four easy to make home‐made gluten‐free breads. Partial substitution of bread‐mix based on corn and rice (control bread) with teff flour, amaranth flour or quinoa flour significantly changed the content of the most of analysed nutrients, while their price was comparable. The highest nutritional benefits were found for protein, magnesium, potassium, calcium, zinc, iron and manganese in bread with teff and for magnesium, potassium, zinc and manganese in bread with amaranth. The highest consumer acceptance of people on gluten‐free diet was noticed for breads with quinoa and teff.
Secretion of secretory phospholipase A2 into Spodoptera exigua larval midgut lumen and its role in lipid digestion
Authors: Sajjadian S. M. , Vatanparast M. , Stanley D. , Kim Y.
Published: April 2019

In insects, lipid digestion is controversial because insects have no bile salts to solubilize dietary lipids. One hypothesis is that a secretory type of phospholipase A2 (sPLA2) provides lysophospholipid (LPL) from dietary phospholipids (PLs). We identified a sPLA2, Se‐sPLA2, in beet armyworm, Spodoptera exigua, that hydrolyses PLs at sn‐2. Our goal was to investigate its role in lipid digestion. Se‐sPLA2 was expressed in the entire alimentary canal. Incubating the isolated midgut in a cell culture medium led to secretion of Se‐sPLA2 and other proteins. Ex vivo RNA interference (RNAi) of Se‐sPLA2 expression in isolated midgut culture led to significantly decreased Se‐sPLA2 secretion into the medium. Feeding double‐stranded RNA specific to Se‐sPLA2 to larvae suppressed sPLA2 activity in gut contents. A recombinant Se‐sPLA2 was susceptible to benzylideneacetone (BZA), a specific PLA2 inhibitor. After feeding BZA to larvae, we recorded significant decreases in gut content sPLA2 activity, body growth and total haemolymph lipid contents. RNAi against Se‐sPLA2 resulted in reduced digestibility. Addition of a specific LPL, 1‐palmitoyl‐sn‐glycero‐3‐phosphocholine, to BZA‐treated larvae rescued digestibility and larval growth. These results strongly bolster our hypothesis that Se‐sPLA2 secreted from the midgut acts in lipid digestion by providing necessary LPL to solubilize dietary neutral lipids.
Silencing cathepsin L expression reduces Myzus persicae protein content and the nutritional value as prey for Coccinella septempunctata
Authors: Rauf I. , Asif M. , Amin I. , Naqvi R. Z. , Umer N. , Mansoor S. , Jander G.
Published: April 2019

Gut‐expressed aphid genes, which may be more easily inhibited by RNA interference (RNAi) constructs, are attractive targets for pest control efforts involving transgenic plants. Here we show that expression of cathepsin L, which encodes a cysteine protease that functions in aphid guts, can be reduced by expression of an RNAi construct in transgenic tobacco. The effectiveness of this approach is demonstrated by up to 80% adult mortality, reduced fecundity, and delayed nymph production of Myzus persicae (green peach aphids) when cathepsin L expression was reduced by plant‐mediated RNAi. Consistent with the function of cathepsin L as a gut protease, M. persicae fed on the RNAi plants had a lower protein content in their bodies and excreted more protein and/or free amino acids in their honeydew. Larvae of Coccinella septempunctata (seven‐spotted ladybugs) grew more slowly on aphids having reduced cathepsin L expression, suggesting that prey insect nutritive value, and not just direct negative effects of the RNAi construct, needs to be considered when producing transgenic plants for RNAi‐mediated pest control.
Oral and dental findings in emanuel syndrome
Authors: Puranik Chaitanya P. , Katechia Bina
Published: April 2019

Emanuel Syndrome (ES; OMIM# 609029) is a rare disorder caused by an unbalanced chromosomal translocation [supernumerary der(22)t(11,22)] and characterized by multiple congenital abnormalities. With limited published cases and low prevalence (1:110 000), detailed ES‐associated oro‐dental findings have not previously been reported. This is a case report of a 14‐year‐old boy with ES who presented with congenital cardiac, renal, auditory, musculoskeletal problems, and global developmental delay. The patient was managed with risperidone, melatonin, omeprazole, guanfacine, and oxcarbazepine. Anxiety‐associated self‐injurious behaviour was seen along with stereotypic hand movements. Consistent with previous reports, microcephaly and micrognathia were noted. Oro‐facial cleft or gross asymmetry, however, was not observed. Significant oro‐dental findings included delayed eruption of primary and permanent teeth, oligodontia (two erupted and five unerupted permanent teeth), and short‐root anomaly of central incisors. The patient demonstrated anxiety‐triggered bruxism with generalized attrition. This case report provides a comprehensive list of systemic ES findings along with oro‐dental manifestations, which have previously not been reported in detail.