bluuebunny/crossref_metadata_2025 huggingface dataset:
Editorial: vedolizumab in pregnancy – is gut selectivity as good for baby as it is for mum? Authors’ reply
Authors: Mahadevan U. , Vermeire S. , Lasch K. , Abhyankar B. , Bhayat F. , Blake A. , Dubinsky M.
Published: April 2017

Linked Content

This article is linked to Shim and Seow, and Mahadevan et al papers. To view these articles visit https://doi.org/10.1111/apt.14027 and https://doi.org/10.1111/apt.13960.
Chenodeoxycholic acid stimulated fibroblast growth factor 19 response – a potential biochemical test for bile acid diarrhoea.
Authors: Borup C. , Wildt S. , Rumessen J. J. , Bouchelouche P. N. , Graff J. , Damgaard M. , McQuitty C. , Rainteau D. , Munck L. K.
Published: April 2017

Background

Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor‐19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation.

Aim

To explore if an impaired FGF19 response identifies primary bile acid diarrhoea.

Methods

Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme‐linked immunosorbent assay and bile acids including 7α‐hydroxy‐4‐cholesten‐3‐one by liquid chromatography‐tandem mass spectrometry.

Results

Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41–138] to 99 pg/mL (IQR: 67–147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54–512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42–79); 90 min: 48 pg/mL [IQR: 37–63); 150 min: 57 pg/mL (48–198)]. Receiver operating characteristics (ROCAUC) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α‐hydroxy‐4‐cholesten‐3‐one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation.

Conclusions

The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.
Dose sparing and the lack of a dose–response relationship with an influenza vaccine in adult and elderly patients – a randomized, double‐blind clinical trial
Authors: Vajo Zoltan , Balaton Gergely , Vajo Peter , Kalabay Laszlo , Erdman Adam , Torzsa Peter
Published: April 2017

Aims

The currently licensed seasonal trivalent influenza vaccines contain 15 μg haemagglutinin per strain for adult, and up to 60 μg for elderly patients. However, due to recent shortages, dose sparing to increase production capacity would be highly desirable. In the present study, we attempted to find a dose–response relationship for immunogenicity and, thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients.

Methods

A total of 256 subjects, including adult (aged 18–60 years) and elderly (aged over 60 years) individuals, were enrolled. Subjects were randomly assigned in a 1:1:1:1 ratio to receive a whole‐virion, aluminium‐adjuvanted trivalent influenza vaccine containing 3.5, 6, 9 or 15 μg haemagglutinin of seasonal A/H1N1, A/H3N2 and B influenza antigens manufactured by Omninvest Ltd., Hungary. Serum antibody titres against the vaccine virus strains were measured by haemagglutination inhibition.

Result

All vaccines were well tolerated. All four vaccines fulfilled all three immunogenicity licensing criteria, as determined by the European Committee for Proprietary Medicinal Products (CPMP)/Biotechnology Working Party (BWP)/214/96 guideline for all three virus strains and both age groups. The 3.5 μg vaccine showed 28% less seroconversion compared to the 15 μg dose in terms of influenza AH3N2 in the adult group (95% confidence interval –51, −3; P < 0.05). All other doses showed no significant difference in immunogenicity compared with the licensed vaccine containing 15 μg haemagglutinin.

Conclusions

Our data suggested that significant dose sparing is possible with the use of whole‐virion vaccines and aluminium adjuvants, without compromising safety. This could have significant economic and public health impacts.
Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes
Authors: Senda Asuna , Mukai Yuji , Hayakawa Toru , Kato Yuka , Eliasson Erik , Rane Anders , Toda Takaki , Inotsume Nobuo
Published: April 2017

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC50 indicate that these ARBs might inhibit the AA metabolism in the liver.
Human BJ Fibroblasts is an Alternative to Mouse BALB/c 3T3 Cells in In Vitro Neutral Red Uptake Assay
Authors: Mannerström Marika , Toimela Tarja , Sarkanen Jertta‐Riina , Heinonen Tuula
Published: April 2017

The OECD GD 129 BALB/c 3T3 neutral red uptake (NRU) assay is a standardized test method for estimating starting dose for an acute oral systemic toxicity test in rodents. Mouse BALB/c 3T3 fibroblasts are the most commonly used cells in the NRU assay. We have previously transferred and validated BALB/c 3T3 NRU assay in our GLP laboratory. Subsequently, in order to obtain more human‐relevant cytotoxicity data, we performed an intralaboratory validation using human BJ fibroblasts in the NRU assay instead of mouse BALB/c 3T3 fibroblasts. Here, we present comparative cytotoxicity data of 26 different test chemicals (pharmaceuticals, industrial chemicals, pesticides and food additives) produced with both BALB/c 3T3 NRU and BJ NRU assays.
Mathematical Modelling of Glucose‐Dependent Insulinotropic Polypeptide and Glucagon‐like Peptide‐1 following Ingestion of Glucose
Authors: Røge Rikke M. , Bagger Jonatan I. , Alskär Oskar , Kristensen Niels R. , Klim Søren , Holst Jens J. , Ingwersen Steen H. , Karlsson Mats O. , Knop Filip K. , Vilsbøll Tina , Kjellsson Maria C.
Published: April 2017

The incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), play an important role in glucose homeostasis by potentiating glucose‐induced insulin secretion. Furthermore, GLP‐1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP‐1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP‐1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP‐1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP‐1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.
Nonparametric Bayesian Covariate-Adjusted Estimation of the Youden Index
Authors: Inácio de Carvalho Vanda , de Carvalho Miguel , Branscum Adam J.
Published: April 2017

A novel nonparametric regression model is developed for evaluating the covariate-specific accuracy of a continuous biological marker. Accurately screening diseased from nondiseased individuals and correctly diagnosing disease stage are critically important to health care on several fronts, including guiding recommendations about combinations of treatments and their intensities. The accuracy of a continuous medical test or biomarker varies by the cutoff threshold (c) used to infer disease status. Accuracy can be measured by the probability of testing positive for diseased individuals (the true positive probability or sensitivity, Se(c), of the test), and the true negative probability (specificity, Sp(c)) of the test. A commonly used summary measure of test accuracy is the Youden index, , which is popular due in part to its ease of interpretation and relevance to population health research. In addition, clinical practitioners benefit from having an estimate of the optimal cutoff that maximizes sensitivity plus specificity available as a byproduct of estimating YI. We develop a highly flexible nonparametric model to estimate YI and its associated optimal cutoff that can respond to unanticipated skewness, multimodality, and other complexities because data distributions are modeled using dependent Dirichlet process mixtures. Important theoretical results on the support properties of the model are detailed. Inferences are available for the covariate-specific Youden index and its corresponding optimal cutoff threshold. The value of our nonparametric regression model is illustrated using multiple simulation studies and data on the age-specific accuracy of glucose as a biomarker of diabetes.
Measurements of immature platelets with haematology analysers are of limited value to separate immune thrombocytopenia from bone marrow failure
Authors: Cybulska Annalina , Meintker Lisa , Ringwald Jürgen , Krause Stefan W.
Published: April 2017

Detection of immature platelets in the circulation may help to dissect thrombocytopenia due to platelet destruction from bone marrow failure (BMF). We prospectively tested the predictive value of immature platelets, measured as immature platelet fraction (IPF) on the XE‐5000 (Sysmex, Kobe, Japan) or percentage of reticulated platelets (rPT) on the CD Sapphire (Abbott Diagnostics, Santa Clara, CA, USA) to separate immune thrombocytopenia (ITP) from BMF (leukaemia, myelodysplastic syndrome, aplastic anaemia). We analysed 58 samples of patients with BMF, 47 samples of patients with ITP and 97 controls. Median rPT (CD Sapphire) was increased to 9·0% in ITP and to 10·9% in BMF, compared to 1·9% in controls. Median IPF (XE‐5000) was 16·2% in ITP, 10·2% in BMF and 2·5% in controls. We found an inverse correlation between high fractions of immature platelets and low platelet counts in thrombocytopenic samples regardless of the diagnosis. In conclusion, we observed a broad overlap of immature platelets between ITP and BMF, which may be caused by an accelerated release of immature platelets in any thrombocytopenic state and decreased production in many patients with ITP. Despite this, IPF (XE‐5000) had some power to discriminate ITP from BMF, whereas rPT (CD Sapphire) was of no predictive value.
‘I call it stinkin’ thinkin’’: A qualitative analysis of metacognition in people with chronic low back pain and elevated catastrophizing
Authors: Schütze Robert , Rees Clare , Slater Helen , Smith Anne , O'Sullivan Peter
Published: April 2017

Objectives

Pain catastrophizing is widely studied in quantitative pain research because of its strong link with poor pain outcomes, although the exact nature of this construct remains unclear. Focusing on its ruminative dimension, the present qualitative study aimed to explore a nascent aspect of pain catastrophizing – metacognition – by documenting people's attitudes towards rumination and examining how these metacognitions might influence the course it takes.

Design

Qualitative interview study.

Methods

Semi‐structured interviews were conducted in a tertiary care setting with 15 adults experiencing chronic (≥6 months) low back pain who scored highly (≥30) on the Pain Catastrophising Scale. Transcripts were analysed using interpretative phenomenological analysis.

Results

The first aim of documenting pain metacognitions revealed both positive (e.g., ‘thinking helps me to cope’) and negative (e.g., ‘rumination is uncontrollable’) attitudes towards pain rumination. These were often held simultaneously, creating internal conflict. The second aim of exploring the influence of metacognition on rumination showed that both negative and positive metacognitions could fuel perseverative thinking. However, more nuanced negative metacognitions (e.g., ‘worry is pointless’) could help to end episodes of rumination by motivating the use of concrete problem‐solving or active coping behaviours.

Conclusions

While most participants described pain rumination as uncontrollable and harmful, dwelling on pain could be helpful when focused on tangible and solvable problems, thereby translating into adaptive coping behaviours that eventually interrupt rumination. Future treatments may be more effective if they are based on individualized formulations of pain catastrophizing that focus on its perseverative nature and implicit function.

Statement of contribution

What is already known on this subject?

Chronic pain affects one in five people, and psychological coping responses are key targets within gold standard biopsychosocial interventions.

People who have elevated pain catastrophizing tend to have worse pain outcomes, including increased pain, disability, and emotional distress.

What people believe about their own thinking (i.e., their metacognitions) influences how much they worry or ruminate.

What does this study add?

This is the first qualitative study exploring metacognitions in people with chronic pain and the first to target a purposive sample of people with elevated pain catastrophizing.

People with elevated pain catastrophizing often see rumination as uncontrollable and harmful but may simultaneously believe it helps them to solve problems or feel prepared for future threats.

Pain catastrophizing is not a stable and enduring trait but fluctuates both within and across individuals in response to pain, context, metacognitive beliefs about rumination, and coping behaviours.
Short Notice, Big Difference? The Effect of Temporary Employment on Firm Competitiveness across Sectors
Authors: Giuliano Romina , Kampelmann Stephan , Mahy Benoît , Rycx François
Published: April 2017

This article is one of the first to examine how the use of fixed‐term employment contracts (FTCs) affects firm competitiveness (i.e. productivity, wages and profits) while controlling for key econometric issues such as time‐invariant unobserved workplace characteristics, endogeneity and state dependence. We apply dynamic panel data estimation techniques to detailed Belgian linked employer–employee data covering all years from 1999 to 2010. Results show that the effects of FTCs on firm competitiveness vary across sectors: while temporary employment is found (at the 10 per cent significance level) to enhance productivity and profits in (labour‐intensive) services, this is not the case in manufacturing and construction.
Characterising subtypes of hippocampal sclerosis and reorganization: correlation with pre and postoperative memory deficit
Authors: Prada Jardim Anaclara , Liu Joan , Baber Jack , Michalak Zuzanna , Reeves Cheryl , Ellis Matthew , Novy Jan , de Tisi Jane , McEvoy Andrew , Miserocchi Anna , Targas Yacubian Elza Marcia , Sisodiya Sanjay , Thompson Pamela , Thom Maria
Published: April 2017

Neuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (The 2013 International League Against Epilepsy classification) are based on the qualitative assessment of patterns of neuronal loss with NeuN. In practice, some cases appear indeterminate between type 1 (CA1 and CA4 loss) and type 2 HS (CA1 loss) and we predicted that MAP2 would enable a more stringent classification. HS subtypes, as well as the accompanying alteration of axonal networks, regenerative capacity and neurodegeneration have been previously correlated with outcome and memory deficits and may provide prognostic clinical information. We selected 92 cases: 52 type 1 HS, 15 type 2 HS, 18 indeterminate‐HS and 7 no‐HS. Quantitative analysis was carried out on NeuN and MAP2 stained sections and a labeling index (LI) calculated for six hippocampal subfields. We also evaluated hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated tau) and mossy‐fiber pathway re‐organization (ZnT3). Pathology measures were correlated with clinical epilepsy history, memory and naming test scores and postoperative outcomes, at 1 year following surgery. MAP2 LI in indeterminate‐HS was statistically similar to type 2 HS but this clustering was not shown with NeuN. Moderate verbal and visual memory deficits were noted in all HS types, including 54% and 69% of type 2 HS. Memory deficits correlated with several pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus (DG) and subiculum and poor preservation of the mossy fiber pathway. Decline in memory at 1 year associated with AT8 labeling in the subiculum and DG but not HS type. We conclude that MAP2 is a helpful addition in the classification of HS in some cases. Classification of HS subtype, however, did not significantly correlate with outcome or pre‐ or postoperative memory dysfunction, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis
Authors: Salvage Samantha C , Chandrasekharan Karthik H , Jeevaratnam Kamalan , Dulhunty Angela F , Thompson Andrew J , Jackson Antony P , Huang Christopher L‐H
Published: April 2017

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)‐Ca2+ channel function. Flecainide accesses its transmembrane Nav1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Nav1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain‐of‐function modifications of Nav1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+]i through a reduced [Na+]i and/or direct open‐state RyR2‐Ca2+ channel antagonism. The consequent [Ca2+]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.

Linked Articles

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
Targeting multiple opioid receptors – improved analgesics with reduced side effects?
Authors: Günther Thomas , Dasgupta Pooja , Mann Anika , Miess Elke , Kliewer Andrea , Fritzwanker Sebastian , Steinborn Ralph , Schulz Stefan
Published: April 2017

Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ‐opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ‐opioid receptor (κ receptor), δ‐opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole‐based cebranopadol and a compound class with a piperidin‐4‐yl‐1,3‐dihydroindol‐2‐one backbone (SR16835/AT‐202 and SR14150/AT‐200). In addition, the ornivol BU08028 is an analogue of the clinically well‐established buprenorphine. Moreover, the morphinan‐based nalfurafine exerts its effect with a dominant κ receptor‐component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi‐receptor opioid ligand in that it binds to μ, κ and δ receptors. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of particular multi‐opioid receptor ligands, but not on their medicinal chemistry and design.

Linked Articles

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc
Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti‐tubercular agents using a fragment‐based drug design approach
Authors: Ryan Ali , Polycarpou Elena , Lack Nathan A , Evangelopoulos Dimitrios , Sieg Christian , Halman Alice , Bhakta Sanjib , Eleftheriadou Olga , McHugh Timothy D , Keany Sebastian , Lowe Edward D , Ballet Romain , Abuhammad Areej , Jacobs William R , Ciulli Alessio , Sim Edith
Published: April 2017

Background and Purpose

With the emergence of extensively drug‐resistant tuberculosis, there is a need for new anti‐tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG.

Experimental Approach

We generated a mutant strain of M. bovis BCG with a deletion of hsaD and tested its growth on cholesterol. Using a fragment based approach, over 1000 compounds were screened by a combination of differential scanning fluorimetry, NMR spectroscopy and enzymatic assay with pure recombinant HsaD to identify potential inhibitors. We used enzymological and structural studies to investigate derivatives of the inhibitors identified and to test their effects on growth of M. bovis BCG and M. tuberculosis.

Key Results

The hsaD deleted strain was unable to grow on cholesterol as sole carbon source but did grow on glucose. Of seven chemically distinct ‘hits’ from the library, two chemical classes of fragments were found to bind in the vicinity of the active site of HsaD by X‐ray crystallography. The compounds also inhibited growth of M. tuberculosis on cholesterol. The most potent inhibitor of HsaD was also found to be the best inhibitor of mycobacterial growth on cholesterol‐supplemented minimal medium.

Conclusions and Implications

We propose that HsaD is a novel therapeutic target, which should be fully exploited in order to design and discover new anti‐tubercular drugs.

Linked Articles

This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro‐organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc
The battle of living with obsessive compulsive disorder: a qualitative study of young people's experiences
Authors: Keyes Carly , Nolte Lizette , Williams Timothy I.
Published: April 2017

Background

There has been an abundance of studies that have employed quantitative methods to research obsessive compulsive disorder (OCD) and its neurobiology and neurochemistry. However, there appears to be a paucity of research investigating how OCD is experienced by those living with the diagnosis, particularly young people.

Method

A qualitative cross‐sectional semistructured interview design was used to address this lack of research. Ten young people, aged 14–17 years old, with a diagnosis of OCD were recruited from Child and Adolescent Mental Health Services in the United Kingdom. Thematic analysis was used to analyse the data.

Results

Four themes were identified: ‘Traumatic and stressful life events’, ‘Responses to signs of OCD’, ‘The battle of living with OCD’ and ‘Ambivalent relationship to help’. Young people reported experiencing stressful or traumatic life events prior to obsessive and compulsive behaviour. OCD behaviours were misunderstood by the young people and others, leading to delays in finding help. A sense of shame among the young people led them to keep their OCD secret due to feeling ‘crazy’. The all‐encompassing nature of OCD led the young people to withdraw socially. Most of the young people experienced an inner conflict between fighting and giving in to the compulsions.

Conclusions

Traumatic experiences may be an important factor in the development of OCD for young people, which might indicate a direction for prevention. The sense of shame and stigma needs addressing if young people are to access help earlier. Education of the public, medical professionals and educators should be a priority.
Prevalence and factors of self‐corrective intention among Hong Kong secondary school students who are self‐assessed Internet addiction cases
Authors: Lau Joseph T.F. , Wu Anise M.S. , Cheng Kit‐man , Tse Vincent W.S. , Lau Mason M.C. , Yang Xueying
Published: April 2017

Background

Adolescent Internet addiction (IA) is prevalent. No study, however, has applied the health belief model (HBM) to investigate issues on IA nor investigated factors associated with intention to correct one's perceived IA problem (self‐corrective intention). Such information facilitates design of related interventions, which are warranted.

Methods

This cross‐sectional study surveyed 9,618 Chinese secondary school students in Hong Kong; 4,111 (42.7%) self‐assessed that they had IA (self‐assessed IA cases); 1,145 of these self‐assessed IA cases (27.9%) were also classified as IA cases (concordant IA cases), as their Chen Internet Addiction Scale score exceeded 63.

Results

The prevalence of self‐corrective intention among these two subsamples was only 28.2% and 34.1%, respectively. In the self‐assessed IA subsample, the HBM constructs including perceived susceptibility to IA [adjusted odds ratio (ORa) = 1.24, 95% CI = 1.16, 1.34], perceived severity of IA (ORa = 2.28, 95% CI = 2.09, 2.48), perceived benefits for reducing Internet use (ORa = 1.21, 95% CI = 1.18, 1.24), self‐efficacy to reduce Internet use (ORa = 1.07, 95% CI = 1.03, 1.11), and cues to action to reduce Internet use (ORa = 1.15, 95% CI = 1.11, 1.20) were positively, while perceived barriers for reducing Internet use (ORa = 0.95, 95% CI = 0.94, 0.97) were negatively, associated with self‐corrective intention. Similar factors were identified in the concordant IA subsample.

Conclusions

A large proportion of the students perceived that they had IA but only about one‐third intended to correct the problem. Future interventions may consider altering students’ HBM constructs, and focus on the segment of concordant IA with self‐corrective intention, as they show readiness for changes.
Docking‐based design and synthesis of galantamine–camphane hybrids as inhibitors of acetylcholinesterase
Authors: Stavrakov Georgi , Philipova Irena , Zheleva‐Dimitrova Dimitrina , Valkova Iva , Salamanova Evdokiya , Konstantinov Spiro , Doytchinova Irini
Published: April 2017

Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE‐induced Aβ aggregation. In this study, we describe the design of a series of galantamine–camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191‐ and 369‐fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω‐loop of Aβ binds to AChE. The hybrids cross blood–brain barrier by passive diffusion and are non‐neurotoxic at the inhibitory concentrations.
A 10q21.3q22.2 microdeletion identified in a patient with severe developmental delay and multiple congenital anomalies including congenital heart defects
Authors: Shimojima Keiko , Okamoto Nobuhiko , Yamamoto Toshiyuki
Published: April 2017

Interstitial deletions in the 10q21.3q22.2 chromosomal region are rare. A de novo microdeletion in this region was identified in a patient with severe developmental delay and multiple congenital anomalies, including congenital heart defects. The identified 10.4‐Mb deletion included 84 RefSeq genes. CTNNA3 and JMJD1C have been associated with cardiomyopathy and neurological impairments (autism and/or intellectual disability), respectively. Because there is no gene which shows one‐to‐one relation to clinical features observed in this patient, combinatory deletion of the genes in this region would be causative of the clinical features in this patient.
The MiRa scale, a new standardised scale for evaluating nasal deformities before and after septorhinoplasty: A prospective study comparing patient satisfaction and the surgeon's assessment
Authors: Radulesco T. , Penicaud M. , Santini L. , Thomassin J.‐M. , Dessi P. , Michel J.
Published: April 2017

Objectives

The objective was to assess the reliability of a new standardised scale for evaluating nasal anomalies in order to compare the surgeon's assessment and patient satisfaction.

Design

Monocentric prospective cohort study.

Settings

First, we validated the reliability of the MiRa scale; then, we compared the surgeon's assessment and patient satisfaction.

Participants

Fifty‐two patients underwent septorhinoplasty surgery and gave their written consent before inclusion.

Main outcome measurements

Primary outcome measurement was to validate the reliability of the MiRa scale: two observers analysed all records twice. Intra‐observer reproducibility and interobserver reproducibility were evaluated using the intraclass correlation coefficient (ICC). Secondary outcome measurement was to compare the surgeon's assessment and patient satisfaction: MiRa and ROE (Rhinoplasty Outcome Evaluation) scores were established for each patient prior to and 6 months after surgery.

Results

Using the MiRa scale, ICC for intra‐ and interobserver reproducibility was, respectively, 95.4% and 96%, showing no statistical difference (P=.70, P=.45). Good correlation scores were, respectively, 93% and 92%. Mean ROE scores were 7.1/24 (SD=11.3) before and 19.3/24 (SD=17.3) after surgery (P<.05). We found an increase in MiRa and ROE scores of +19.75% and +51.25% (P<.05), respectively. The average postoperative ROE score in the primary septorhinoplasty group was 20.4 (SD=14.4) and 17.2 (SD=23.1) in the secondary septorhinoplasty group (P<.05).

Conclusion

MiRa scale is a reliable, standardised tool to evaluate surgical outcome in septorhinoplasty surgery. It provides an objective and reproducible score. The surgeon's assessment was more critical than patient satisfaction. Patient satisfaction is more difficult to achieve in cases involving a secondary septorhinoplasty.
Traffic Simulation in Urban Networks Using Stochastic Cell Transmission Model
Authors: Hadfi Rafik , Tokuda Sho , Ito Takayuki
Published: April 2017

The stochastic cell transmission model (SCTM) is a macroscopic traffic simulation model of high accuracy. One of its advantages is that it can represent the uncertainty of the traffic states and the changing travel demand and supply conditions. However, it has been applied to freeways and simple networks having only one origin‐destination pair. In this article, we propose a modified stochastic cell transmission model (M‐SCTM) that applies the conventional SCTM to urban networks. In M‐SCTM, we introduce vehicle agents as well as their route choice behavior on an urban network, which is more applicable to complex urban networks. Additionally, M‐SCTM was applied to networks in which the turning ratio is not priorly set through a route search algorithm. The results show that M‐SCTM can conduct simulations with as much accuracy as SCTM. Furthermore, we verified the appropriate reproducibility of the simulations based on M‐SCTM and compared the estimated value and the measured value in terms of the travel time of each vehicle.
Die histologischen Typen der lymphomatoiden Papulose – Ein Vorschlag für die Vereinfachung des Buchstabenchaos
Authors: Kempf Werner , Mitteldorf Christina , Karai Laszlo J. , Robson Alistair
Published: April 2017

Die lymphomatoide Papulose (LYP) ist klinisch durch rezidivierende papulonoduläre Läsionen charakterisiert. Im Gegensatz zu dieser stereotypen klinischen Präsentation zeigt die Erkrankung ein breites histologisches Spektrum mit verschiedenen Infiltratmustern, unterschiedlichen Tumorzellgrößen und variablen Phänotypen. Die revidierte WHO‐Klassifikation 2016 umfasst die histologischen LYP‐Typen A bis E und einen sechsten Typ, dem eine spezielle Mutation zugrunde liegt. Darüber hinaus werden jedoch immer wieder neue Typen vorgeschlagen, wobei sich die Ausweitung nicht ausschließlich auf histologische Muster bezieht, sondern sich auch auf klinische und genetische Aspekte ausdehnt. Dies führt zu einer Ausweitung der alphabetischen Liste mit zunehmender Komplexität der Terminologie und kann anstelle eines vereinfachten diagnostischen Zugangs zur Verwirrung führen. Zudem kann es zu Überschneidungen unterschiedlicher Typen kommen. Diese Entwicklung wirft die Frage auf, wie die Terminologie der lymphomatoiden Papulose vereinfacht werden kann, ohne dabei auf die histologischen Besonderheiten zu verzichten. Wir schlagen daher einen praktischen Zugang zur Terminologie der lymphomatoide Papulosen vor, welcher sich ausschließlich auf deskriptive Begriffe beschränkt und nicht auf einer alphabetischen Bezeichnung der LYP‐Typen beruht. Unser Vorschlag soll einen praktikablen und benutzerfreundlichen Zugang zur Terminologie der lymphomatoiden Papulose ermöglichen und damit den diagnostischen Prozess sowie die Kommunikation zwischen Klinikern und Pathologen vereinfachen.
Augenbeteiligung beim Pemphigus vulgaris – retrospektive Studie an einer großen spanischen Kohorte
Authors: España Agustin , Iranzo Pilar , Herrero‐González Josep , Mascaro José M. , Suárez Ricardo
Published: April 2017

Hintergrund und Ziele

Es gibt nur wenige Berichte zur Beteiligung der okulären/periokulären Region beim Pemphigus vulgaris (PV). Ziel der vorliegenden Studie war es, das Krankheitsbild des okulären PV (OPV) zu untersuchen und seinen prognostischen Wert zu definieren.

Patienten und Methodik

Zwischen 1985 und 2014 wurden insgesamt 167 Patienten mit Pemphigus vulgaris an vier tertiären spanischen Krankenhäusern behandelt. Wir haben alle Patienten mit OPV in diese retrospektive Studie aufgenommen. Klinische Daten sowie Informationen zu Begleitsymptomen wurden den Krankenakten der ­Patienten entnommen.

Ergebnisse

Lediglich 24 (14.3 %) PV‐Patienten hatten okuläre Läsionen. Meist gingen dem okulären Befall PV‐Läsionen an verschiedenen anderen Stellen voraus (durchschnittliche Dauer: 33,7 Monate). Okuläre PV‐Läsionen traten während der Schübe eines mukokutanen Pemphigus auf und waren niemals die einzige Mukosa‐Manifestation. Die häufigsten klinischen Symptome waren konjunktivale Hyperämie (87,5 %) und Erosionen an den Augenlidern (41,6 %), sowohl an der palpebralen/bulbären Konjunktiva (33,3 %) als auch am medialen Epikanthus (20,8 %). Zu den wichtigsten Begleitsymptomen gehörten lokale Schmerzen/Brennen (71,4 %), Reizung (47,6 %), Photophobie (38,1 %) und Epiphora (23,9 %). Der OPV besserte sich unter systemischer und unterstützender topischer Behandlung. Lediglich bei zwei Patienten traten Spätfolgen auf.

Schlussfolgerungen

Bei Patienten mit PV sind die Augen nur in Ausnahmefällen betroffen. Ein okulärer PV ist mit größerer Krankheitsaktivität assoziiert und hat in der Regel einen gutartigen Verlauf. Betroffen sind die Konjunktiva und/oder die Augenlider.
Subclinical enthesitis in nail psoriasis patients: a case‐control study
Authors: Klaassen Karlijn M.G. , Ploegmakers Marieke J.M. , van de Kerkhof Peter C.M. , Klein Willemijn M. , Pasch Marcel C.
Published: April 2017

Background

Patients with nail psoriasis have a higher prevalence of psoriatic arthritis; however, the pathogenetic relationship between these two disorders is as yet unclear. Entheses have been suggested as disease epicenter, which might explain the pathogenesis on an anatomical level.

Objective

To contribute to the elucidation of the hypothesis as regards the anatomical link between nail psoriasis and psoriatic arthritis, with the extensor enthesis of the distal interphalangeal joint as the epicenter.

Methods

We conducted a cross‐sectional cohort study, visualizing the distal interphalangeal (DIP) joints entheses of patients with fingernail psoriasis (n = 54), psoriasis patients without nail involvement (n = 32), and healthy controls (n = 32) using three‐dimensional ultrasound. Patients with nail psoriasis underwent repeat imaging studies after one year.

Results

Individuals with nail psoriasis had significantly thicker radial entheses than psoriasis patients without nail involvement. However, there were no significant differences in entheseal thickness between adjacent nails that were affected and those that were not (1.297 mm vs. 1.253 mm, p = 0.13). Follow‐up after one year showed no significant differences in entheseal thickness in correlation with nail psoriasis activity.

Conclusions

The present study provides evidence for subclinical enthesitis at the level of the DIP joint in patients with nail psoriasis. However, an anatomical correlation between nail psoriasis and psoriatic arthritis could not be confirmed.
Distribution of children in class I through V in functional classification systems
Authors: Gisel Erika G
Published: April 2017

This commentary is on the original article by Benfer et al. on pages 647–654 of this issue.
Reduction of left ventricular outflow tract obstruction with transcatheter mitral valve repair
Authors: Coylewright Megan , O'Neill Elizabeth S. , Robb John F. , McCullough Jock N. , Tighe Cassie M. , Callahan Joshua M. , Beaver Timothy A.
Published: April 2017

Many patients with severe mitral regurgitation cannot undergo conventional mitral valve surgery due to prohibitive surgical risk and are candidates for transcatheter repair with an edge‐to‐edge technique. Prior reports suggest efficacy with this approach for mitral regurgitation due to hypertrophic cardiomyopathy with left ventricular outflow obstruction. We present a case report of transcatheter mitral valve repair for posterior leaflet prolapse with concomitant left ventricular outflow tract obstruction due to systolic anterior motion of the mitral valve in the absence of hypertrophic cardiomyopathy.
Left atrial volume and function in patients with cardiac syndrome X assessed by real time three‐dimensional echocardiography
Authors: Acıkgoz Nusret , Yagmur Julide , Kurtoglu Ertugrul , Ermis Necip , Cansel Mehmet
Published: April 2017

Objective

The aim of this study was to evaluate left atrial (LA) volume and function using real time three‐dimensional echocardiography (RT3DE) in patients with cardiac syndrome X (CSX).

Methods

Fifty patients with CSX (28 females; mean age 50.9±10.9 years) and 50 age‐ and gender‐matched healthy controls (30 females; mean age 52.3±9.8 years) who had negative treadmill exercise test and normal coronary arteries on invasive coronary angiography were included in the study. Comprehensive two‐dimensional (2D), pulsed and tissue Doppler, speckle tracking echocardiography, and RT3DE for the assessment of LA dynamics were performed in all study participants.

Results

Cardiac syndrome X and control groups have similar clinical characteristics regarding age, sex, body mass index, hypertension, diabetes, and smoking habit. 2D echocardiographic parameters were also similar between groups. Pulsed‐ and tissue Doppler parameters, IVRT, A, and Am values, were higher in CSX group, while Em, E/A, and Em/Am ratios were higher in the control group reflecting mild diastolic dysfunction. Regarding RT3DE parameters, LA maximum volume, minimum volume, volume before atrial contraction, LA maximum volume index, total and active stroke volumes were found to be increased in CSX patients. However, LA total stroke fraction, passive stroke volume, passive stroke fraction, peak systolic, and diastolic longitudinal strains were found to be lower in CSX patients.

Conclusion

The main finding of this study was that CSX patients had altered LA booster pump, reservoir, and conduit functions. This finding may have clinical implications for early detection of abnormal LA dynamics in CSX patients.
Dental trauma prevention with mouthguard in a nose fracturing blow to the face: Case report
Authors: Gialain Ivan O. , Kobayashi‐Velasco Solange , Caldeira Celso L. , Cavalcanti Marcelo G. P.
Published: April 2017

Orofacial injuries are common in sports activities and may vary in complexity and the tissues involved. Most sports‐related trauma occurs when a player hits another player, an object or the ground. This report presents a case of an injury caused by a punchlike blow to the face during a handball college team practice session. The patient suffered a traumatic blow to the left side of the nose and mouth and promptly attended a dentist. After a clinical examination and a CBCT scan, the following injuries were diagnosed: upper lip laceration, upper left lateral incisor subluxation and anterior nasal spine fracture. More severe teeth injuries were likely prevented because the patient was wearing a mouthguard.
Using a trait‐based approach to measure the impact of dam closure in fish communities of a Neotropical River
Authors: Lima Ana C. , Sayanda Diogo , Agostinho Carlos S. , Machado Ana L. , Soares Amadeu M.V.M. , Monaghan Kieran A.
Published: April 2017

Damming is one of the main causes of the global decline in freshwater biodiversity. Yet, many hydroelectric dams are being built (or planned) in the Neotropics, where the high species diversity and lack of basic ecological knowledge provide a major obstacle to understanding the effects of this environmental change, which has been mostly described from the perspective of taxonomic change. However, this approach does not account for biological function. Trait‐based analysis provides an alternative approach to bioassessment. We assessed the impact of dam closure on the functional structure of fish communities of a Neotropical river by applying trait‐based analyses to the response of individual traits aggregated at the assemblage level. Fish data were collected during three distinct time periods (1 year before, 1 year after and 5 years after dam closure), at eight sites located downstream of the dam, in the reservoir, transition zone and upstream. The results indicated that reproduction strategies (migration and parental care) and diet (detritivores) were the trait categories mostly affected by the dam, with the response of downstream assemblages differing from upstream of the dam. A trait‐based analysis to the impact of damming on fish communities appears to be a promising approach using an initial descriptive analysis of individual traits and regression models of multiple traits that reflect species’ adaptation to the new environment. This study provides both an alternative and complementary approach to taxonomic assessment of impacts from damming, contributing towards a more robust evaluation of the response of fish communities to dams.
Dopaminergic activation anticipates daily nursing in the rabbit
Authors: Aguirre J. , Meza E. , Caba M.
Published: April 2017

Maternal care is a motivated behavior and in the rabbit it is restricted to the spontaneous return of the mother to nurse her pups for just a few minutes once a day. Previously we have reported neural activation of brain areas and neuroendocrine cells after nursing. However, this daily spontaneous return suggests that the mother is in a high motivational state to nurse her pups. Here we hypothesized that during anticipation of nursing there is an activation of dopaminergic neurons of the mesolimbic system and in their target areas. Then we explored, by the expression of FOS protein, possible activation of the mesolimbic system as well as dopaminergic cells of the A10 cell group before and after nursing and in control does. Additionally, we measured FOS expression in the preoptic area and lateral septum. We found a significant increase of FOS before nursing, and a further increase after nursing, in the mesolimbic system and dopaminergic cells as well as in the preoptic area and lateral septum. Interestingly, the medial prefrontal area shows an intense activation during anticipation of nursing, which remains after nursing. We conclude that the activation of the mesolimbic system before nursing is related to the high locomotor behavior prior to the next nursing bout and support the proposal that the mother is in a high motivational state at the time of returning to the nest. The additional activation after nursing can be related to the neuroendocrine and neural consequences of the milk ejection reflex by suckling.