bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent mapping methods reveal rotational activation near pulmonary veins where atrial fibrillation terminates before pulmonary vein isolation
Authors: Navara Rachita , Leef George , Shenasa Fatemah , Kowalewski Christopher , Rogers Albert J. , Meckler Gabriela , Zaman Junaid A. B. , Baykaner Tina , Park Shirley , Turakhia Mintu P. , Zei Paul , Viswanathan Mohan , Wang Paul J. , Narayan Sanjiv M.
Published: January 2018

Objective

To investigate mechanisms by which atrial fibrillation (AF) may terminate during ablation near the pulmonary veins before the veins are isolated (PVI).

Introduction

It remains unstudied how AF may terminate during ablation before PVs are isolated, or how patients with PV reconnection can be arrhythmia‐free. We studied patients in whom PV antral ablation terminated AF before PVI, using two independent mapping methods.

Methods

We studied patients with AF referred for ablation, in whom biatrial contact basket electrograms were studied by both an activation/phase mapping method and by a second validated mapping method reported not to create false rotational activity.

Results

In 22 patients (age 60.1 ± 10.4, 36% persistent AF), ablation at sites near the PVs terminated AF (77% to sinus rhythm) prior to PVI. AF propagation revealed rotational (n  =  20) and focal (n  =  2) patterns at sites of termination by mapping method 1 and method 2. Both methods showed organized sites that were spatially concordant (P < 0.001) with similar stability (P < 0.001). Vagal slowing was not observed at sites of AF termination.

Discussion

PV antral regions where ablation terminated AF before PVI exhibited rotational and focal activation by two independent mapping methods. These data provide an alternative mechanism for the success of PVI, and may explain AF termination before PVI or lack of arrhythmias despite PV reconnection. Mapping such sites may enable targeted PV lesion sets and improved freedom from AF.
Diagnostic approach to subcutaneous nodules in patients with neuroendocrine tumours treated with depot somatostatin analogs: a cross‐sectional study
Authors: Chicharro P. , Paniagua A. , Rodríguez‐Jiménez P. , Ibañes S. , Cortina B. , Riveiro J. , Sampedro‐Núñez M.Á. , Fraga J. , Marazuela M. , Daudén E.
Published: January 2018

Background

The presence of cutaneous nodules in patients with gastroenteropancreatic neuroendocrine tumours (GEP‐NETs) receiving depot somatostatin analogs (SSAs) is a diagnostic challenge as differential diagnosis between injection site reactions and metastases is essential.

Objective

To characterize the clinical, radiological, cytological and histopathological features of subcutaneous nodules in patients with GEP‐NETs treated with SSAs.

Materials and methods

Retrospective, cross‐sectional study of patients with GEP‐NETs treated with SSAs in whom subcutaneous nodules were detected on routine abdominal computed tomography (CT) scans. High resolution and colour Doppler ultrasonography was performed. Those patients with inconclusive radiological studies went through fine‐needle aspiration cytology (FNAC) and/or biopsy.

Results

Twelve patients (five males, seven females) were included (six midgut carcinoid NETs, six pancreatic NETs). Three patients received intramuscular depot octreotide, seven subcutaneous lanreotide, and two both treatments. CT scan findings were nonspecific. Sonography revealed a hyperechoic pattern in recent injections, and a hypoechoic pattern with a characteristic hyperechoic peripheral rim in long‐term injections (more than 3 months after injection). On colour Doppler sonography, nodules showed no signs of intralesional vascularity. Fine‐needle aspiration cytology (FNAC) was performed in five patients, revealing a characteristic acellular proteinaceous material. Biopsy in four patients showed different reactional infiltrates around the acellular material.

Conclusions

High resolution and colour Doppler ultrasonography may be very useful for the differential diagnosis of subcutaneous nodules in patients with GEP‐NETs treated with SSAs. FNAC and a biopsy are useful tests for confirmation of the diagnosis in patients with inconclusive findings. We propose a management algorithm.
Diversity of Cercomonad Species in the Phyllosphere and Rhizosphere of Different Plant Species with a Description of Neocercomonas epiphylla (Cercozoa, Rhizaria) a Leaf‐Associated Protist
Authors: Flues Sebastian , Blokker Malte , Dumack Kenneth , Bonkowski Michael
Published: January 2018

Cercomonads are among the most abundant and diverse groups of heterotrophic flagellates in terrestrial systems and show an affinity to plants. However, we still lack basic knowledge of plant‐associated protists. We isolated 75 Cercomonadida strains from the phyllosphere and rhizosphere of plants from three functional groups: grasses (Poa sp.), legumes (Trifolium sp.) and forbs (Plantago sp.), representing 28 OTUs from the genera Cercomonas, Neocercomonas and Paracercomonas. The community composition differed clearly between phyllosphere and rhizosphere, but was not influenced by plant species identity. From these isolates we describe three novel cercomonad species including Neocercomonas epiphylla that was consistently and exclusively isolated from the phyllosphere. For each new species we provide a detailed morphological description as well as an 18S rDNA gene sequence as a distinct marker of species identity. Our data contribute to a better resolution of the systematics of cercomonads and their association with plants, by describing three novel species and adding gene sequences of 10 new cercomonad genotypes and of nine previously described species. In view of the functional importance of cercozoan communities in the phyllosphere and rhizosphere of plants, a more detailed understanding of their composition, function and predator–prey interactions are clearly required.
Protistology Conferences: The Beginnings. The First International Protozoology Conference (Prague 1961) and the Tribute to Otto Jírovec, its Spiritual Father
Authors: Vávra Jiří
Published: January 2018

Two events have helped to shape protozoology/protistology as a specific scientific discipline. The first such event was the creation of the Society of Protozoologists in the U.S. in 1947 (and of its Journal of Protozoology, first published in 1954), the second event was the First International Conference on Protozoology, held in 1961 in Prague. The history of the Society of Protozoologists was comprehensively treated by Corliss (1998); the history of the Prague Conference is presented here as reminiscences and personal interpretation of events of the author, who was one of the conference organizers and a member of the organization committee. Special attention is given to the personality and scientific accomplishments of Otto Jírovec, the 1961 conference spiritual father and president. It is concluded that the Prague Conference, while establishing the tradition of protistology meetings, helped protistology to attain its present status as a fundamental science discipline, which discovers and interprets the web of life at one of its, basic, “microbial” levels. Protists literally permeate the earth biosphere and in a way represent the “dark matter” of the living world, still awaiting many discoveries.
Streamlining the Life Cycle Assessment of Buildings by Structured Under‐Specification and Probabilistic Triage
Authors: Tecchio Paolo , Gregory Jeremy , Olivetti Elsa , Ghattas Randa , Kirchain Randolph
Published: January 2018

Life cycle thinking plays an important role in sustainable development in the building sector. However, the complexity of data collection and scope definition limits life cycle assessment (LCA) applications. Even if the inventory data have already been collected, tabulated, and indexed, the method is still time‐consuming, which may be discouraging for designers. This study demonstrates how the LCA of buildings can be robustly streamlined using structured underspecification of impact data combined with an effective and efficient triage of the data collection. Tests were conducted with a series of building typologies that were analyzed with a cradle‐to‐gate approach. The probabilistic triage approach was tested to identify selected activities requiring detailed specification because they contribute most to total impact, thereby reducing data gathering effort. Impacts such as global warming, acidification, eutrophication, and smog creation were assessed, and results showed that 40% to 46% of the bill of materials components represent 75% of total impacts of single‐family houses and multifamily buildings. By specifying only a prioritized subset of the bill of materials to the highest level of specificity, results proved to be reasonably accurate and obtainable with less effort.
Sphingosine 1‐phosphate receptors regulate TLR4‐induced CXCL5 release from astrocytes and microglia
Authors: O'Sullivan Sinead A. , O'Sullivan Catherine , Healy Luke M. , Dev Kumlesh K. , Sheridan Graham K.
Published: January 2018

Sphingosine 1‐phosphate receptors (S1PR) are G protein‐coupled and compose a family with five subtypes, S1P1R–S1P5R. The drug Gilenya® (Novartis, Basel, Switzerland) (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing‐remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1‐phosphate (S1P)‐mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In this study, we investigated the regulation of pro‐inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C‐X‐C motif chemokine 5 (CXCL5), also known as LIX (lipopolysaccharide‐induced CXC chemokine) expression were quantified. Results showed that pFTY720 attenuated LPS‐induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, (i) CXCL5/LIX, (ii) C‐X‐C motif chemokine 10 (CXCL10) also known as interferon gamma‐induced protein 10 (IP10) and (iii) chemokine (C‐C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase attenuated LPS‐induced increases in mRNA levels of all three chemokines, suggesting that LPS‐TLR4 (Toll‐like receptor 4) signalling may enhance chemokine expression via S1P‐S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS‐induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

image
Assessment of the general quality of sunscreen products available in Palestine and method verification of the sun protection factor using Food and Drug Administration guidelines
Authors: Zaid Abdel Naser , Jaradat Nidal , Darwish Saja , Nairat Sura , Shamlawi Rawan , Hamad Yasmeen , Hussein Fatema , Issa Linda
Published: January 2018

Background

Sunlight exposure affects all skin types causing skin tanning, burns or even skin cancer. Sunscreens were invented to prevent these outcomes by scattering or absorbing the UV light.

Aims

This study aimed to verify the effectiveness of Mansur method in SPF measurement and to find out how much reliable the labeled sun protection factor (SPF) value for the products that are imported to Palestine knowing that they are considered as cosmetics and they don't undergo tests by the Ministry Of Health (MOH).

Materials

In this research, sun protection factor (SPF) was determined for 16 commercially available sunscreen products using Mansur equation which was also validated; moreover sunscreen classification, product phase determination and pH measurement were also done.

Results

Sun protection factor values were mostly 50, 43.75% of the analyzed samples were close to the labeled SPF, 31.25% were under the labeled value, and 25% SPF value above the labeled value. All samples exhibited a pH close to skin pH. 62% of them were found to be O/W. Cosmetic companies and importers should focus on pediatric sunscreens, since only 12.5% are pediatric sunscreens.

Conclusions

Ministry Of Health should ask prove about the quality of an SPF value of sunscreens for final registration of these products. More instructions should be available on the label regarding the proper use especially, if they are not water proof.
Association of two groups of phytoplasma with various symptoms in some wooden and herbaceous plants
Authors: Azimi Mohammad , Mehrabi‐Koushki Mehdi , Farokhinejad Reza
Published: January 2018

During 2015–2016, wooden and herbaceous plants growing in parks, boulevards, fields, gardens and forests in Khuzestan province, southwestern Iran, were visually inspected for symptoms resembling phytoplasma. Fifty‐one symptomatic samples from nine different species and one symptomless sample from each plant were collected. Leaf midribs, petioles and the parts of stem cambium were separated and freeze‐dried. Total DNA was extracted using CTAB‐based method and tested for phytoplasma using a nested PCR assay. The expected size amplicons of 16S rDNA were sequenced and compared to those of reference phytoplasmas by BLASTn search and phylogenetic analysis. The consensus 16S rDNA sequence of the detected phytoplasma in narrow cattail related to reference phytoplasma group 16SrVI, “Candidatus Phytoplasma trifolii” while in the other plants were related to reference phytoplasma subgroup 16SrII–D, “Candidatus Phytoplasma aurantifolia.” All isolates showed 98%–99% sequence identity to members of their reference groups. To our knowledge, this is the first report of “Candidatus Phytoplasma aurantifolia”‐related strains infecting the plants of Acacia salicina, Alternanthera ficoidea, Melaleuca citrine, Citrus aurantium throughout the world and Celosia christata in Iran. Furthermore, this study is the first to report the association of a “Candidatus Phytoplasma trifolii”‐related strain with Typha angustifolia worldwide.
Phylogeny and species delineation in the marine diatomPseudo‐nitzschia(Bacillariophyta) usingcox1,LSU, andITS2rRNAgenes: A perspective in character evolution
Authors: Lim Hong Chang , Tan Suh Nih , Teng Sing Tung , Lundholm Nina , Orive Emma , David Helena , Quijano‐Scheggia Sonia , Leong Sandric Chee Yew , Wolf Matthias , Bates Stephen S. , Lim Po Teen , Leaw Chui Pin
Published: January 2018

Analyses of the mitochondrialcox1, the nuclear‐encoded large subunit (LSU), and the internal transcribed spacer 2 (ITS2)RNAcoding region ofPseudo‐nitzschiarevealed that theP. pseudodelicatissimacomplex can be phylogenetically grouped into three distinct clades (Groups I–III), while theP. delicatissimacomplex forms another distinct clade (Group IV) in both theLSUandITS2 phylogenetic trees. It was elucidated that comprehensive taxon sampling (sampling of sequences), selection of appropriate target genes and outgroup, and alignment strategies influenced the phylogenetic accuracy. Based on the genetic divergence,ITS2 resulted in the most resolved trees, followed bycox1andLSU. The morphological characters available forPseudo‐nitzschia, although limited in number, were overall in agreement with the phylogenies when mapped onto theITS2 tree. Information on the presence/absence of a central nodule, number of rows of poroids in each stria, and of sectors dividing the poroids mapped onto theITS2 tree revealed the evolution of the recently diverged species. The morphologically based species complexes showed evolutionary relevance in agreement with molecular phylogeny inferred fromITS2 sequence–structure data. The data set of the hypervariable region ofITS2 improved the phylogenetic inference compared to thecox1andLSUdata sets. The taxonomic status ofP. cuspidataandP. pseudodelicatissimarequires further elucidation.
Impact of interferon‐free regimens on the glomerular filtration rate during treatment of chronic hepatitis C in a real‐life cohort
Authors: Álvarez‐Ossorio M. J. , Sarmento e Castro R. , Granados R. , Macías J. , Morano‐Amado L. E. , Ríos M. J. , Merino D. , Álvarez E. N. , Collado A. , Pérez‐Pérez M. , Téllez F. , Martín J. M. , Méndez J. , Pineda J. A. , Neukam K. ,   the HEPAVIR‐DAA, GEHEP‐MONO, RIS‐HEP07 and RIS‐HEP13 Study Groups
Published: January 2018

Little data are available on renal toxicity exerted by direct‐acting antivirals (DAAs) in real life. The aim of this study was to assess the impact of direct‐acting antivirals against hepatitis C virus infection currently used in Spain and Portugal on the estimated glomerular filtration rate (eGFR) in clinical practise. From an international, prospective multicohort study, patients treated with DAAs for at least 12 weeks and with eGFR ≥30 mL/min per 1.73 m2 at baseline were selected. eGFR was determined using the CKD‐EPI formula. A total of 1131 patients were included; 658 (58%) were HIV/HCV‐coinfected patients. Among the 901 patients treated for 12 weeks, median (interquartile range) eGFR was 100 (87‐107) at baseline vs 97 (85‐105) mL/min per 1.73 m2 at week 12 of follow‐up (FU12) post‐treatment (P < .001). For HIV‐coinfected subjects who received tenofovir plus a ritonavir‐boosted HIV protease inhibitor (PI/r), baseline vs FU12 eGFR were 104 (86‐109) vs 104 (91‐110) mL/min per 1.73 m2 (P = .913). Among subjects receiving ombitasvir/paritaprevir with or without dasabuvir, eGFR did not show any significant change. Of 1100 subjects with eGFR >60 mL/min per 1.73 m2 at baseline, 22 (2%) had eGFR <60 mL/min per 1.73 m2 at FU12, but none presented with eGFR <30 mL/min per 1.73 m2. In conclusion, eGFR slightly declines during therapy with all‐oral DAAs and this effect persists up to 12 weeks after stopping treatment in subjects with normal to moderately impaired renal function, regardless of HIV status. Concomitant use of tenofovir plus PI/r does not seem to have an impact on eGFR.
Efficacy of generic oral directly acting agents in patients with hepatitis C virus infection
Authors: Gupta S. , Rout G. , Patel A. H. , Mahanta M. , Kalra N. , Sahu P. , Sethia R. , Agarwal A. , Ranjan G. , Kedia S. , Acharya S. K. , Nayak B. , Shalimar
Published: January 2018

Novel direct‐acting antivirals (DAAs) are now the standard of care for the management of hepatitis C virus (HCV) infection. Branded DAAs are associated with high sustained virological response at 12 weeks post‐completion of therapy (SVR12), but are costly. We aimed to assess the efficacy of generic oral DAAs in a real‐life clinical scenario. Consecutive patients with known HCV infection who were treated with generic‐oral DAA regimens (May 2015 to January 2017) were included. Demographic details, prior therapy and SVR12 were documented. Four hundred and ninety patients (mean age: 38.9 ± 12.7 years) were treated with generic DAAs in the study time period. Their clinical presentations included chronic hepatitis (CHC) in 339 (69.2%) of cases, compensated cirrhosis in 120 (24.48%) cases and decompensated cirrhosis in 31 (6.32%) cases. Genotype 3 was most common (n = 372, 75.9%) followed by genotype 1 (n = 97, 19.8%). Treatment naïve and treatment‐experienced (defined as having previous treatment with peginterferon and ribavirin) were 432 (88.2%) and 58 (11.8%), respectively. Generic DAA treatment regimens included sofosbuvir in combination with ribavirin (n = 175), daclatasvir alone (n = 149), ribavirin and peginterferon (n = 80), ledipasvir alone (n = 43), daclatasvir and ribavirin (n = 37), and ledipasvir and ribavirin (n = 6). Overall SVR12 was 95.9% (470/490) for all treatment regimens. SVR12 for treatment naïve and experienced patients was 97.0% (419/432) and 87.9% (51/58), respectively, P = .005. High SVR12 was observed with various regimens, irrespective of genotype and underlying liver disease status. There were no differences in SVR12 with 12 or 24 weeks therapy. No major adverse event occurred requiring treatment stoppage. Generic oral DAAs are associated with high SVR rates in patients with HCV infection in a real‐life clinical scenario.
Decreased Clinical Severity of Strangles in Weanlings Associated with Restricted Seroconversion to OptimizedStreptococcus equisspequiAssays
Authors: Tscheschlok L. , Venner M. , Steward K. , Böse R. , Riihimäki M. , Pringle J.
Published: January 2018

Background

Streptococcus equissp.equicauses characteristic clinical signs that are most severe in young horses, including fever, purulent nasal discharge, and lymph node abscessation in the head region.

Hypothesis/Objectives

Clinical, serologic, and microbiologic factors related to unexpectedly mild disease severity in a natural outbreak of strangles in immunologically naïve weanlings were investigated.

Animals

One‐hundred and twelve warmblood weanlings.

Methods

Prospective longitudinal observational study of a natural outbreak of strangles. The entire cohort was examined at the peak of the outbreak by deep nasal swabs for culture and quantitative PCR (qPCR) for the presence ofS. equiand clinically and serologically in a sequential manner by an optimized ELISA from the index case throughout the outbreak until resolution. Descriptive statistics were calculated and comparisons made using a nondirectional Wilcoxon signed‐rank test.

Results

Outbreak morbidity was 53%, with 9 of 14 horses culture positive and 26 of 53 horses qPCR positive forS. equilacking clinical signs characteristic of strangles. By resolution, 91 of 112 had seroconverted to Antigen A by ELISA but seroconversion to antigen C (part of the SeM protein) was minimal. Sequencing of the isolates detected no alterations in the SeM protein, but identified a 61 bp deletion in the gene SEQ_0402.

Conclusions and Clinical Importance

Absence of clinical signs alone in naïve horses may be an insufficient criterion to release horses from strangles quarantine measures. Restricted seroconversion to antigen C may have been associated with decreased clinical severity. The role of a minor gene deletion in SEQ_0402 in the virulence ofS. equiwarrants further investigation.
Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN and cirrhosis regression
Authors: D'Ambrosio Roberta , Aghemo Alessio , Rumi Maria Grazia , Degasperi Elisabetta , Sangiovanni Angelo , Maggioni Marco , Fraquelli Mirella , Perbellini Riccardo , Rosenberg William , Bedossa Pierre , Colombo Massimo , Lampertico Pietro
Published: January 2018

Background and Aim

In patients with HCV‐related cirrhosis, a sustained virological response may lead to cirrhosis regression. Whether histological changes translate into prevention of long‐term complications, particularly hepatocellular carcinoma is still unknown. This was investigated in a cohort of histological cirrhotics who had been prospectively followed‐up for 10 years after the achievement of a sustained virological response to IFN.

Methods

In all, 38 sustained virological response cirrhotics who underwent a liver biopsy 5 years post‐SVR were prospectively followed to assess the impact of cirrhosis regression on clinical endpoints.

Results

During a follow‐up of 86 (30‐96) months from liver biopsy, no patients developed clinical decompensation, whilst 5 (13%) developed hepatocellular carcinoma after 79 (7‐88) months. The 8‐year cumulative probability of hepatocellular carcinoma was 17%, without differences between patients with or without cirrhosis regression (19% [95% CI 6%‐50%] vs 14% [95% CI 4%‐44%], P = .88). Patients who developed or did not an hepatocellular carcinoma had similar rates of residual cirrhosis (P = 1.0), collagen content (P = .48), METAVIR activity (P = .34), portal inflammation (P = .06) and steatosis (P = .17). At baseline, patients who developed an hepatocellular carcinoma had higher γGT (HR 1.03, 95% CI 1.00‐1.06; P = .014) and glucose (HR 1.02, 95% CI 1.00‐1.02; P = .012) values; moreover, they had increased Forns Score (HR 12.8, 95% CI 1.14‐143.9; P = .039), Lok Index (HR 6.24, 95% CI 1.03‐37.6; P = .046) and PLF (HR 19.3, 95% CI 1.72‐217.6; P = .016) values. One regressor died of lung cancer. The 8‐year cumulative survival probability was 97%, independently on cirrhosis regression (96% vs 100%, P = 1.0) or hepatocellular carcinoma (100% vs 97%, P = 1.0).

Conclusions

Post‐SVR cirrhosis regression does not prevent hepatocellular carcinoma occurrence.
A simple clinical model predicts incident hepatic steatosis in a community‐based cohort: The Framingham Heart Study
Authors: Long Michelle T. , Pedley Alison , Massaro Joseph M. , Hoffmann Udo , Ma Jiantao , Loomba Rohit , Chung Raymond T. , Benjamin Emelia J.
Published: January 2018

Background and Aims

The factors associated with incident hepatic steatosis are not definitively known. We sought to determine factors associated with incident hepatic steatosis, as measured on computed tomography, in the community.

Methods

We studied Framingham Heart Study participants without heavy alcohol use or baseline hepatic steatosis who underwent computed tomography scans between 2002‐2005 (baseline) and 2008‐2011 (follow‐up). We performed a stepwise logistic regression procedure to determine the predictors associated with incident hepatic steatosis.

Results

We included 685 participants (mean age: 45.0 ± 6.2 years, 46.8% women). The incidence of hepatic steatosis in our sample was 17.1% over a mean 6.3 years of follow‐up. Participants who developed hepatic steatosis had more adverse cardiometabolic profiles at baseline compared to those free of hepatic steatosis at follow‐up. Multivariable stepwise regression analysis showed that a simple clinical model including age, sex, body mass index, alcohol consumption and triglycerides was predictive of incident hepatic steatosis (C statistic = 0.791, 95% CI: 0.748‐0.834). A complex clinical model, which included visceral adipose tissue volume and liver phantom ratio added to the simple clinical model, and had improved discrimination for predicting incident hepatic steatosis (C statistic = 0.826, 95% CI: 0.786‐0.866, P < .0001).

Conclusions

The combination of demographic, clinical and imaging characteristics at baseline was predictive of incident hepatic steatosis. The use of our predictive model may help identify those at increased risk for developing hepatic steatosis who may benefit from risk factor modification although further investigation is warranted.
Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes
Authors: Arunagiri Anoop , Haataja Leena , Cunningham Corey N. , Shrestha Neha , Tsai Billy , Qi Ling , Liu Ming , Arvan Peter
Published: January 2018

The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7–A7, B19–A20, and A6–A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide‐linked protein complexes, is a natural by‐product of proinsulin biosynthesis, as is the case for many proteins. The steady‐state level of misfolded proinsulin—a potential ER stressor—is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene–induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.
Framework for laboratory harmonization of folate measurements in low‐ and middle‐income countries and regions
Authors: Pfeiffer Christine M. , Zhang Mindy , Jabbar Shameem
Published: January 2018

The measurement of serum and red blood cell folate, two commonly used biomarkers of folate status in populations, is complicated by analytical and data interpretation challenges. Folate results show poor comparability across laboratories, even using the same analytical technique. The folate microbiologic assay produces accurate results and requires simple instrumentation. Thus, it could be set up and maintained in low‐ and middle‐income country laboratories. However, the assay has to be harmonized through the use of common critical reagents (e.g., microorganism and folate calibrator) in order to produce comparable results across laboratories and over time, so that the same cutoff values can be applied across surveys. There is a limited need for blood folate measurements in a country owing to the periodic nature of surveys. Having a network of regional resource laboratories proficient in conducting the folate microbiologic assay and willing and able to perform service work for other countries will be the most efficient way to create an infrastructure wherein qualified laboratories produce reliable blood folate data. Continuous participation of these laboratories in a certification program can verify and document their proficiency. If the resource laboratories conduct the work on a fee‐for‐service basis, they could become self‐sustaining in the long run.
Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis
Authors: Yan Min , Xing Guang‐Lin , Xiong Wen‐Cheng , Mei Lin
Published: January 2018

Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle‐specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4—both critical for neuromuscular junction formation and maintenance—in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti‐LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well‐diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti‐agrin and anti‐LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.
Comparative effectiveness clinical trials to advance treatment of myasthenia gravis
Authors: Guptill Jeffrey T. , Raja Shruti , Sanders Donald B. , Narayanaswami Pushpa
Published: January 2018

Myasthenia gravis (MG) presents many challenges for establishing treatment efficacy through clinical trials. Among these are the rarity and heterogeneity of the disease, spontaneous fluctuations, prolonged latency to effect for many immunosuppressive drugs, and the uncertain generalizability of results from randomized controlled trials (RCTs). Prospective observational study designs may overcome some of these limitations, but attention is required to ensure that internal validity is not compromised. Observational comparative effectiveness research (CER) utilizes data obtained during routine clinical care to evaluate the effectiveness of interventions in real‐life practice conditions, thereby improving generalizability to the clinic. Compared with RCTs, observational CER studies may be less resource intensive and costly. Recent advances that have improved the feasibility of CER studies for MG are (1) the development of MG common data elements, (2) the publication of international consensus guidance for MG treatment, and (3) the development of a web‐based REDCap database that can be shared and adapted to standardize data collection. This infrastructure could be used for multisite comparisons of commonly used therapies and provides longitudinal information on patient‐ and clinician‐centered MG outcome measures. A challenge is to design studies that address the potential limitations of observational trials, such as confounding and selection and information bias.
Western lifestyle and immunopathology of multiple sclerosis
Authors: Matveeva Olga , Bogie Jeroen F.J. , Hendriks Jerome J.A. , Linker Ralf A. , Haghikia Aiden , Kleinewietfeld Markus
Published: January 2018

There is increasing evidence for a sudden and unprecedented rise in the incidence of multiple sclerosis (MS) in Westernized countries over the past decades, emphasizing the role of environmental factors. Among many candidates, rapid changes in dietary habits seem to play a role in the pathogenesis of MS. Here, we summarize and discuss the available evidence for the role of dietary nutrients, such as table salt, fatty acids, and flavonoids, in the development and pathogenesis of MS. We also discuss new and emerging risk factors accompanying Western lifestyle, such as shift work, sleep, and circadian disruption.
Serological and experimental studies in different forms of myasthenia gravis
Authors: Vincent Angela , Huda Saif , Cao Michelangelo , Cetin Hakan , Koneczny Inga , Rodriguez‐Cruz Pedro , Jacobson Leslie , Viegas Stuart , Jacob Saiju , Woodhall Mark , Nagaishi Akiko , Maniaol Angelina , Damato Valentina , Leite M. Isabel , Cossins Judith , Webster Richard , Palace Jacqueline , Beeson David
Published: January 2018

Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10–20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle‐specific kinase (MuSK). The use of cell‐based assays has extended the repertoire of antibody tests to clustered AChRs, low‐density lipoprotein receptor–related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed.
Sedation for magnetic resonance imaging using propofol with or without ketamine at induction in pediatrics—A prospective randomized double‐blinded study
Authors: Schmitz Achim , Weiss Markus , Kellenberger Christian , O`Gorman Tuura Ruth , Klaghofer Richard , Scheer Ianina , Makki Malek , Sabandal Carola , Buehler Philipp Karl
Published: January 2018

Introduction

Deep sedation using propofol has become a standard technique in children. This double‐blinded randomized clinical trial aims to compare the clinical effects of propofol‐mono‐sedation vs a combination of propofol and ketamine at induction and a reduced propofol infusion rate for maintenance in children undergoing diagnostic magnetic resonance imaging.

Methods

Children aged from 3 months to 10 years scheduled as outpatients for elective magnetic resonance imaging with deep sedation were included. They were randomized into 2 groups, receiving either 1 mg/kg ketamine at induction, then a propofol infusion rate of 5 mg/kg/h or a propofol infusion rate of 10 mg/kg/h without prior ketamine. Time to full recovery (modified Aldrete score = 10) was the primary outcome. Further outcomes were quality of induction, immobilization during image acquisition, recovery, postoperative nausea and vomiting, emergence delirium using the Pediatric Anesthesia Emergence Delirium scale, vital signs and adverse cardiorespiratory events. All patients and parents as well as anesthetists, imaging technicians, and postsedation personnel were blinded. Data are given as median (range).

Results

In total, 347 children aged 4.0 (0.25‐10.9) years, weighing 15.6 (5.3‐54) kg, ASA classification I, II, or III (141/188/18) were included. The ketamine‐propofol group showed significantly shorter recovery times (38 (22‐65) vs 54 (37‐77) minutes; median difference 14 (95% CI: 8, 20) minutes; P < .001), better quality of induction, and higher blood pressure, but higher incidence of movement requiring additional sedative drugs. There were no significant differences in respiratory side effects, cardiovascular compromise, emergence delirium, or postoperative nausea and vomiting.

Conclusion

Both sedation concepts proved to be reliable with a low incidence of side effects. Ketamine at induction with a reduced propofol infusion rate leads to faster postanesthetic recovery.
WRKY1 acts as a key component improving resistance against Alternaria solani in wild tomato, Solanum arcanum Peralta
Authors: Shinde Balkrishna A. , Dholakia Bhushan B. , Hussain Khalid , Aharoni Asaph , Giri Ashok P. , Kamble Avinash C.
Published: January 2018

Early blight (EB), caused by Alternaria solani, is a major threat to global tomato production. In comparison with cultivated tomato (Solanum lycopersicum), a wild relative, S. arcanum exhibits strong resistance against EB. However, molecular cascades operating during EB resistance in wild or cultivated tomato plants are largely obscure. Here, we provide novel insight into spatio‐temporal molecular events in S. arcanum against A. solani. Transcriptome and co‐expression analysis presented 33‐WRKYs as promising candidates of which 12 SaWRKYs displayed differential expression patterns in resistant and susceptible accessions during EB disease progression. Among these, SaWRKY1 exhibited induced expression with significant modulation in xyloglucan endotrans hydrolase 5 (XTH5) and MYB2 expressions that correlated with the disease phenotypes. Electro‐mobility shift assay confirmed physical interaction of recombinant SaWRKY1 to SaXTH5 and SaMYB2 promoters. Comparative WRKY1 promoter analysis between resistant and susceptible plants revealed the presence of crucial motifs for defence mechanism exclusively in resistant accession. Additionally, many defence‐related genes displayed significant expression variations in both the accessions. Further, WRKY1 overexpressing transgenic plants exhibited higher levels of EB resistance while RNAi silencing lines had increased susceptibility to A. solani with altered expression of XTH5 and MYB2. Overall, these findings demonstrate the positive influence of WRKY1 in improving EB resistance in wild tomato and this could be further utilized as a potential target through genetic engineering to augment protection against A. solani in crop plants.
Nuclear pseudoinclusions in melanoma cells: prognostic fact or artifact? The possible role of Golgi phosphoprotein 3 overexpression in nuclear pseudoinclusions generation
Authors: Donizy Piotr , Kaczorowski Maciej , Biecek Przemyslaw , Halon Agnieszka , Matkowski Rafal
Published: January 2018

Nuclear pseudoinclusions (NPIs) are classically found in papillary thyroid carcinoma and meningioma. Although NPIs have been described in melanocytic lesions, there is no systematic analysis of potential relationship between NPIs and other clinicopathological characteristics of melanoma. We examined the presence of NPIs in H&E‐stained tissue sections form 96 melanomas and analyzed statistical associations with important clinicopathological parameters and tissue immunoreactivity for selected proteins involved in epithelial‐mesenchymal transition (SPARC, N‐cadherin), cell adhesion and mobility (ALCAM, ADAM‐10), regulation of mitosis (PLK1), cell survival (FOXP1) and functioning of Golgi apparatus (GOLPH3, GP73). NPIs were observed in 20% of melanomas and their presence correlated with high mitotic rate and ulceration of the tumor, but not with Breslow thickness, histologic type, or presence of metastases. We observed a significant correlation with shorter cancer‐specific survival, but not disease‐free survival. Presence of NPIs was related to high expression of GOLPH3 in melanoma cells, whereas their absence was linked to enhanced immunoreactivity of GOLPH3 in tumor‐associated macrophages. NPIs are not an uncommon finding in skin melanoma and their diagnostic and prognostic utility could be helpful in the daily routine histopathological practice. The possible explanation of NPI generation is associated with enhanced activity of Golgi apparatus in melanoma cells.
The Determinants of Public Policy: What Matters and How Much
Authors: Burstein Paul
Published: January 2018

This article is a research synthesis addressing four questions critical to our understanding of the determinants of public policy. How often and how strongly do hypothetical determinants of policy—public opinion, interest groups, the party balance, and other factors—actually influence policy? Do some hypothetical determinants of policy have more influence than others? Does the way we measure policy affect our ability to explain it? And is there a connection between how strongly particular variables affect policy, and how much effort we devote to studying them? It turns out that variables hypothesized to influence policy more often than not have no effect. When variables do affect policy, researchers very seldom say anything about how much impact they have. Variables that convey the most information to policymakers about what the public wants have a greater impact than other variables, but it is less clear how the measurement of policy affects our findings. Researchers pay much attention to hypothetical determinants of policy unlikely to matter very much, and little attention to those likely to be the most important. Implications for future research are considered.
Injuries in Dutch elite field hockey players: A prospective cohort study
Authors: Delfino Barboza S. , Nauta J. , van der Pols M. J. , van Mechelen W. , Verhagen E. A. L. M.
Published: January 2018

This study describes the prevalence, incidence density, severity, and nature of injuries in elite field hockey players over the Dutch 2015–2016 season. Eighty players answered a baseline questionnaire and were subsequently followed up every 2 weeks to report the hours spent on training/competition and experienced injuries, which were registered using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Of the 74 players included in the analysis, 52 (70%) reported 112 injuries. Eighty‐seven injuries (78%) received medical attention, and 56 (50%) led to training/competition time‐loss. Thirty‐four injuries (30%) hampered players’ availability to train and compete. Most of the injuries (74%) were not caused by any contact. The mean prevalence of injury was 29% (95% confidence interval [CI] 3–55) for all, 9% (95% CI 0–20) for acute, and 14% (95% CI 0–36) for overuse injuries. Players sustained 3.5 (95% CI 2.5–4.5) new acute injuries per 1000 hours of training and 12.3 (95% CI 7.6–17.0) per 1000 hours of competition. The median of the severity score was 28 from 100 (25%–75% interquartile range [IQR] 16–42) for all, 35 (IQR 23–53) for acute, and 21 (IQR 16–31) for overuse injuries. On average, 1 in 4 elite field hockey players experiences an injury within a 2‐week period during the season. Although acute injuries are common, overuse injuries pose a comparable problem in elite field hockey. As injuries are a burden on players’ health and may hamper performance and availability to train and compete, prevention is of great importance.
3D imaging of cleared human skin biopsies using light‐sheet microscopy: A new way to visualize in‐depth skin structure
Authors: Abadie S. , Jardet C. , Colombelli J. , Chaput B. , David A. , Grolleau J.‐L. , Bedos P. , Lobjois V. , Descargues P. , Rouquette J.
Published: January 2018

Background

Human skin is composed of the superimposition of tissue layers of various thicknesses and components. Histological staining of skin sections is the benchmark approach to analyse the organization and integrity of human skin biopsies; however, this approach does not allow 3D tissue visualization. Alternatively, confocal or two‐photon microscopy is an effective approach to perform fluorescent‐based 3D imaging. However, owing to light scattering, these methods display limited light penetration in depth. The objectives of this study were therefore to combine optical clearing and light‐sheet fluorescence microscopy (LSFM) to perform in‐depth optical sectioning of 5 mm‐thick human skin biopsies and generate 3D images of entire human skin biopsies.

Materials and Methods

A benzyl alcohol and benzyl benzoate solution was used to successfully optically clear entire formalin fixed human skin biopsies, making them transparent. In‐depth optical sectioning was performed with LSFM on the basis of tissue‐autofluorescence observations. 3D image analysis of optical sections generated with LSFM was performed by using the Amira® software.

Results

This new approach allowed us to observe in situ the different layers and compartments of human skin, such as the stratum corneum, the dermis and epidermal appendages. With this approach, we easily performed 3D reconstruction to visualise an entire human skin biopsy. Finally, we demonstrated that this method is useful to visualise and quantify histological anomalies, such as epidermal hyperplasia.

Conclusion

The combination of optical clearing and LSFM has new applications in dermatology and dermatological research by allowing 3D visualization and analysis of whole human skin biopsies.
Optical clearing agent reduces scattering of light by the stratum corneum and modulates the physical properties of coenocytes via hydration
Authors: Lee S.‐H. , Jun S.‐H. , Yeom J. , Park S.‐G. , Lee C.‐K. , Kang N.‐G.
Published: January 2018

Background

The interaction between light and the skin determine how the skin looks to the human eye. Light can be absorbed, scattered, and reflected by different components of the skin in a variety of different ways. Here, we focus on the scattering properties of the outmost layer, the stratum corneum (SC). However, we currently have limited methods with which to distinguish the scattering of light by SC from the changes due to other components of the skin.

Materials and methods

Dark‐field images of tape‐striped corneocytes were used in vitro to study the differences in light scattered by the SC and other skin components. Several optical clearing agents (OCAs) were tested for their ability to reduce light scattering. Physical properties of the SC (water content, keratin configuration, and volume) after OCA treatment were investigated using FT‐IR, confocal Raman microscopy, and 3D laser microscopy.

Results

Urea derivatives, several reducing sugars, and sugar alcohols, which were used as OCA in optics and also used as humectants in cosmetic area, could reduce scattering. However, unlike dehydration in optics, penetration of water into the keratin was increased at low OCA concentrations. In such conditions, the volume of corneocytes was increased but their stiffness was reduced.

Conclusion

By analyzing the tape‐striped SC, we were able to measure the changes in the optical and physical properties of corneocytes in response to OCAs. Hydration of the SC layer by OCAs reduces light scattering from the corneocytes and would be helpful in moisturizing the skin and helping the skin look healthy.