bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic exposure of metformin in patients with non‐alcoholic fatty liver disease
Authors: Sundelin Elias Immanuel Ordell , Gormsen Lars Christian , Heebøll Sara , Vendelbo Mikkel Holm , Jakobsen Steen , Munk Ole Lajord , Feddersen Søren , Brøsen Kim , Hamilton‐Dutoit Stephen Jacques , Pedersen Steen Bønløkke , Grønbæk Henning , Jessen Niels
Published: April 2019

Aims

Metformin is first‐line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome, but whether NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies.

Methods

Eighteen patients with biopsy‐proven NAFLD were investigated using 11C‐metformin PET/CT technique. Gene transcripts of OCTs were determined by real‐time polymerase chain reaction (PCR).

Results

We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non‐alcoholic steatohepatitis (NASH) (Vd 2.38 ± 0.56 vs. 2.10 ± 0.39, P = 0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription.

Conclusion

Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings imply that metformin action in liver in patients with NAFLD may be preserved.
Bone marrow characterization in sickle cell disease: inflammation and stress erythropoiesis lead to suboptimal CD34 recovery
Authors: Leonard Alexis , Bonifacino Aylin , Dominical Venina M. , Luo Min , Haro‐Mora Juan J. , Demirci Selami , Uchida Naoya , Pierciey Francis J. , Tisdale John F.
Published: April 2019

Stress erythropoiesis and chronic inflammation in subjects with sickle cell disease (SCD) may have an impact on the bone marrow (BM) haematopoietic stem and progenitor cell (HSPC) quality and yield necessary for effective autologous, ex vivo HSPC gene therapy. BM from 19 subjects with SCD and five volunteers without SCD (non‐SCD) was collected in different anticoagulants and processed immediately (day 0) or the following day (day 1). Inflammatory, contamination and aggregation markers within the mononuclear layer, and CD34, CD45 and Glycophorin‐A (GPA) expression on HSPCs after CD34+ selection were analysed by conventional and imaging flow cytometry. Compared to non‐SCD BM, multiple markers of inflammation, contamination (red cells, P < 0·01; platelets, P < 0·01) and aggregates (platelet/granulocytes, P < 0·01; mononuclear/red cells, P < 0·01) were higher in SCD BM. Total CD34+ cell count was lower in SCD BM (P < 0·05), however CD34+ count was higher in SCD BM when collected in acid citrate dextrose‐A (ACDA) versus heparin (P < 0·05). Greater than 50% of CD34+ HSPCs from SCD BM are CD34dim due to higher erythroid lineage expression (P < 0·01) as single cell CD34+CD45+GPA+ (P < 0·01) and CD34+CD45−GPA+ (P < 0·01) HSPCs. SCD BM is characterized by increased inflammation, aggregation and contamination contributing to significant differences in HSPC quality and yield compared to non‐SCD BM.
Anthropometric factors and risk of myeloid leukaemias and myelodysplastic syndromes: a prospective study and meta‐analysis
Authors: Teras Lauren R. , Patel Alpa V. , Carter Brian D. , Rees‐Punia Erika , McCullough Marjorie L. , Gapstur Susan M.
Published: April 2019

There is insufficient evidence linking excess body weight to risk of myeloid malignancies. We investigated this association using data from the Cancer Prevention Study‐II(CPS‐II), and a meta‐analysis of published cohort studies. Among 152 090CPS‐IIparticipants, 387 acute myeloid leukaemias (AML), 100 chronic myeloid leukaemias (CML) and 170MDSwere identified over 21 years of follow‐up. InCPS‐II, body mass index (BMI) was weakly associated with risk ofCML(hazard ratio [HR] = 1·04, 95% confidence interval [CI]: 0·99–1·09 per 1 unit increase inBMI),AML(HR = 1·01, 95%CI: 0·98–1·03) andMDS(HR = 1·03, 95%CI: 0·99–1·07). After controlling for other anthropometric factors, no clear association was observed for height,BMIat age 18 years or weight change. In the meta‐analysis (n = 7117 myeloid leukaemias),BMI25–29·9 kg/m2(HRpooled = 1·36, 95%CI: 1·12–1·59) andBMI≥30 kg/m2(HRpooled = 1·43, 95%CI: 1·18–1·69) were associated with higher risk of myeloid leukaemia overall, compared to aBMI<25 kg/m2. Likewise,BMI≥25 kg/m2was positively associated with bothAMLandCMLrisk individually in the meta‐analysis. These results underscore the need for large studies to detect associations with rare cancers, and show a modest, but positive association between excess body weight and myeloid malignancy risk.
Transport infrastructure, growth and persistence: The rise and demise of the Sui Canal
Authors: Flückiger Matthias , Ludwig Markus
Published: April 2019

This paper investigates the effect of transport infrastructure on the spatial distribution of population over two millennia. Focusing on the Sui Canal, one of history's greatest infrastructure projects, we show that its completion in the 7th century CE led to a strong increase in population concentration along the newly established transport artery. We exploit the fact that large parts of the canal fell into disrepair after the 12th century to analyze the persistence of this effect. We find that in 2010, more than 800 years after the Sui Canal fell into disuse, regions once directly connected to the canal are still more populous than areas that never had access. However, this population concentration is not mirrored in economic development. GDP per capita is lower in areas that lay along the course of the canal. One potential explanation for this finding is a change in the value of locational fundamentals as well as a shift in investments to the benefit of coastal regions since the initiation of the Open Door Policy in 1978.
Epidermal growth factor receptor‐targeted molecular imaging of colorectal tumors: Detection and treatment evaluation of tumors in animal models
Authors: Miyamoto Yoshihiko , Muguruma Naoki , Fujimoto Shota , Okada Yasuyuki , Kida Yoshifumi , Nakamura Fumika , Tanaka Kumiko , Nakagawa Tadahiko , Kitamura Shinji , Okamoto Koichi , Miyamoto Hiroshi , Sato Yasushi , Takayama Tetsuji
Published: April 2019

To overcome the problem of overlooking colorectal tumors, a new and highly sensitive modality of colonoscopy is needed. Moreover, it is also important to establish a new modality to evaluate viable tumor volume in primary lesions of colorectal cancer (CRC) during chemotherapy. Therefore, we carried out molecular imaging of colorectal tumors targeting epidermal growth factor receptor (EGFR), which is highly expressed on tumor cells, for evaluating chemotherapeutic efficacy and for endoscopic detection of colorectal adenomas. We first attempted to image five CRC cell lines with various levels of EGFR expression using an Alexa Fluor‐labeled anti‐EGFR monoclonal antibody (AF‐EGFR‐Ab). A strong fluorescence signal was observed in the cells depending on the level of EGFR expression. When nude mice xenografted with LIM1215 CRC cells, which highly express EGFR, were i.v. injected with AF‐EGFR‐Ab, a strong fluorescence signal appeared in the tumor with a high signal to noise ratio, peaking at 48 hours after injection and then gradually decreasing, as shown using an IVIS Spectrum system. When the xenografted mice were treated with 5‐fluorouracil, fluorescence intensity in the tumor decreased in proportion to the viable tumor cell volume. Moreover, when the colorectum of azoxymethane‐treated rats was observed using a thin fluorescent endoscope with AF‐EGFR‐Ab, all 10 small colorectal adenomas (≤3 mm) were detected with a clear fluorescence signal. These preliminary results of animal experiments suggest that EGFR‐targeted fluorescent molecular imaging may be useful for quantitatively evaluating cell viability in CRC during chemotherapy, and also for detecting small adenomas using a fluorescent endoscope.
T‐score differences and nonprogression in lumbar vertebrae as predictors of vertebral fractures
Authors: Lajlev Siv E. , Rejnmark Lars , Harsløf Torben
Published: April 2019

Purpose

In case of a vertebral fracture, the area of the vertebrae decreases with a concomitant increase in BMD, as assessed by a DXA scanning. Furthermore, a vertebral fracture may disrupt the normal increase in vertebral body area from L1 to L4 (nonprogression). We aimed to examine associations between T‐score difference and nonprogression of vertebral area and vertebral fractures.

Methods

We identified 100 patients with 1 or more fractures in L1‐L4 and 106 patients without fractures. All patients had undergone a DXA scan and a lumbar spine X‐ray. In fracture patients, we recorded T‐score difference between the fractured vertebra and the adjacent vertebra, and whether the fractured vertebra was smaller than the one above (nonprogression). In nonfracture patients, the greatest positive T‐score difference was recorded, and nonprogression was present if vertebral area did not increase successively from L1 to L4.

Results

With a T‐score difference ≥1 SD odds ratio for fracture was 1.30 (0.74‐2.29). Sensitivity and specificity were 0.40 and 0.66, respectively. With T‐score difference ≥1.5 SD, odds ratio for fracture was 2.26 (1.08‐4.73). Sensitivity and specificity were 0.24 and 0.88, respectively. Nonprogression was very common in the no‐fracture group (38%), while only 23% of X‐ray verified fractures had nonprogression.

Conclusion

A randomly found T‐score difference ≥1.5 SD between adjacent vertebrae on a DXA scan is associated with a small increased risk of compression fracture. Nonprogression is very common in patients without fractures.
Trueness of cone beam computed tomography versus intra‐oral scanner derived three‐dimensional digital models: An ex vivo study
Authors: Al‐Rimawi Ali , Shaheen Eman , Albdour Emad A. , Shujaat Sohaib , Politis Constantinus , Jacobs Reinhilde
Published: April 2019

Objectives

To compare the trueness of 3D digital models derived from CBCT and IOS and to evaluate their accuracy for implementation in oral implant rehabilitation.

Materials and methods

A dry human mandible with a full set of intact teeth was included in the study. The mandible was scanned using Trios IOS and four different CBCT machines with various protocols for generation of 3D digital models. A µCT was utilized to scan each tooth individually. Following registration and segmentation, the trueness evaluation of 3D digital models was carried out by part comparison analysis and color‐coded mapping of the superimposed teeth surfaces.

Results

The four CBCT‐derived 3D digital models with different protocols had better trueness than Trios IOS. NewTom VGi evo (110 KV), ProMax 3D (90 kV), 3D Accuitomo 170 (90 kV), Green 21 (110 kV), and Green 21 (90 kV) showed significantly better trueness than IOS. However, 3D Accuitomo 170 and ProMax 3D CBCT devices with 70 kV protocol showed better trueness without any significant difference with IOS.

Conclusion

CBCT‐derived 3D digital models showed better trueness when compared with IOS. When CBCT data are available for preoperative planning for oral implant rehabilitation, it may preclude the need for IOS for obtaining 3D study models.
Changing trends of contact allergens in Thailand: A 12‐year retrospective study
Authors: Sukakul Thanisorn , Chaweekulrat Pichanee , Limphoka Pichaya , Boonchai Waranya
Published: April 2019

Background

Contact allergen prevalences often change. Continual surveillance is necessary to detect trends in sensitization rates and emerging allergens.

Objective

To identify the prevalence of, and trends in, the positive reactions to each allergen in the baseline series during a 12‐year period in Thailand.

Methods

The medical records of 2803 patients who underwent patch testing at the Contact Dermatitis Clinic, Siriraj Hospital, between 2006 and 2018, were retrospectively reviewed. The baseline series used by the clinic was adapted from the European and the International baseline series. The patch testing results were subdivided into 2‐year blocks in order to compare the prevalences of each allergen.

Results

The prevalences of positive reactions to nickel, fragrance mixes I and II, dichromate, cobalt, carba mix, methyldibromo glutaronitrile, paraben mix, neomycin sulfate, methylisothiazolinone (MI), epoxy resin, N‐isopropyl‐N‐phenyl‐4‐phenylenediamine and the corticosteroids significantly decreased. Methylchloroisothiazolinone (MCI)/MI was the only allergen associated with a significant increase of positive reactions, from 2.4% to 10.7%. However, the proportion of positive reactions to MCI/MI decreased in the final 2‐year period.

Conclusions

Approximately half of the substances in the screening patch test series showed a decline in the number of positive reactions, whereas MCI/MI showed an increasing prevalence.
HETEROGENEOUS EFFECTS OF THE ACA MEDICAID EXPANSION ON HOSPITAL FINANCIAL OUTCOMES
Authors: Rhodes Jordan H. , Buchmueller Thomas C. , Levy Helen G. , Nikpay Sayeh S.
Published: April 2019

This study examines the effect of the Affordable Care Act's Medicaid expansion on hospital financial outcomes. A key innovation relative to prior studies is that we explicitly account for heterogeneity across states in the timing and extent of the expansion as well as across hospital types. We find that Medicaid expansion led to a decrease in uncompensated care expenditures and an increase in average operating margins. The effects were larger in states where the Medicaid expansion led to a greater increase in program eligibility. Operating margins improved most for public hospitals and facilities located in rural areas. (JEL I11, I13, I18)
Human parvovirus B19 in solid organ transplantation: Guidelines from the American society of transplantation infectious diseases community of practice
Authors: Eid Albert J. , Ardura Monica I. ,   the AST Infectious Diseases Community of Practice
Published: April 2019

Clinical manifestations of human parvovirus B19 infection can vary widely and may be atypical in solid organ transplant (SOT) recipients. However, disease is apparent when there is destruction of erythrocyte progenitor cells leading to severe acute or chronic anemia with lack of an appropriate reticulocyte response in the setting of active parvovirus B19 infection. Serology may not reliably establish the diagnosis. High‐level viremia is more likely to be associated with symptomatic disease. Conversely, ongoing DNAemia after infection may not be clinically significant, if detected at low levels. Despite lack of robust data, intravenous immunoglobulin (IVIG) is frequently used for the treatment of SOT recipients with symptomatic parvovirus B19 infection. Although the optimal dosage and duration of IVIG is not known, most patients receive a total of 2 g/kg over a period of 2‐5 days. A daily dose of 1 g/kg or more seems to be associated with higher incidence of toxicity. Application of standard and droplet isolation precautions remains the cornerstone for preventing human parvovirus B19 transmission. Additional research is needed to assess the efficacy of current and novel therapies and to develop a safe and effective parvovirus B19 vaccine.
A rare variant of extraskeletal osteosarcoma presenting as a clinically benign subcutaneous neoplasm
Authors: Ryan Michael P. , Woolridge Katelyn F. , Sedrak Michael , Berlingeri‐Ramos Alma C. , Group Ashley R.
Published: April 2019

Extraskeletal osteosarcoma (ESOS) is a rare variant of osteosarcoma that arises without attachment to the underlying skeleton. These cancers are typically found embedded in deeper tissues, most commonly the muscle or fascia, and are rarely found within the skin or subcutis. Most tumors are large in size upon initial presentation, and carry a poor prognosis. We discuss the case of a 48‐year‐old Caucasian woman who presented to a dermatology clinic with an asymptomatic, small, mobile, subcutaneous mass that appeared clinically benign. After elective removal and histopathologic examination, the patient was diagnosed with ESOS. ESOS presenting in this manner is exceedingly rare, and this case highlights the importance of sending all excised specimens, even those with a benign presentation, for pathologic examination.
Effect of dual versus mono antiplatelet therapy on recurrent stroke modulated by activated partial thromboplastin time
Authors: Xie X. , Wang X. , Laskowitz D. T. , Zhao X. , Miao Z. , Liu L. , Li H. , Meng X. , Wang Y. , Wang Y. ,   the CHANCE investigators
Published: April 2019

Background and purpose

The efficacy of dual antiplatelet treatment may be modified by many factors. The aim was to assess whether the effect of clopidogrel plus aspirin versus aspirin alone on recurrent stroke would be affected by admission activated partial thromboplastin time (aPTT).

Methods

Data were derived from the Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A total of 5074 patients were categorized into three groups based on the aPTT distribution according to the 15th and 85th percentile. The primary outcome was any stroke within 90 days. The interaction of aPTT with antiplatelet therapy on stroke risk was assessed with a Cox proportional hazards model with adjustment for covariates.

Results

In the high aPTT group (defined as ≥35.9 s), stroke occurred in 6.7% of patients in the clopidogrel–aspirin arm and 11.9% in the aspirin arm [adjusted hazard ratio (HR) 0.50; 95% confidence interval (CI) 0.29–0.85]. In the medium aPTT group (24.6–35.8 s), stroke occurred in 7.7% of patients in the clopidogrel–aspirin arm and 11.8% in the aspirin arm (adjusted HR 0.62; 95% CI 0.50–0.75). Furthermore, in the low aPTT group (≤24.5 s), stroke occurred in 11.2% of patients in the clopidogrel–aspirin arm and 9.9% in the aspirin arm (adjusted HR 1.07; 95% CI 0.65–1.62). The interaction P value of antiplatelet therapy with aPTT level at the cut‐point of approximately 25 s or below was significant (P < 0.05).

Conclusions

Dual antiplatelet therapy was superior to single antiplatelet therapy in the high or medium aPTT group but not in the low aPTT group.
Fundamental rights and private enforcement in the digital age
Authors: Bassini Marco
Published: April 2019

This article addresses the shift inthe paradigm of fundamental rights protection on the Internet. More and morethe enforcement of such rights is being delegated to private Internet operators, and the urgent question is how the task of balancing conflicting rights affects the status of Internet Service Providers (ISPs). The article examines the increasing privatisation of fundamental rights enforcementon the Internet, highlighting the impact of this trend. Following the analysisof recent developments, it argues that the pillars governing ISP liability should not be altered. In particular, the early determination that ISPs should not be presumptively saddled with content monitoring tasks should not be called into question. Therefore, the regulatory pressure on ISPs shouldbe lowered, as the spectre of liability, combined with ISPs' increasing role indeciding the proper balance between conflicting rights, unduly burdens the activity of ISPs and generates incentives to delete even lawful content.
Privacy as Europe's first Amendment
Authors: Petkova Bilyana
Published: April 2019

The protection of universal principles varies across jurisdictions: the prominence of free speech in the United States is undisputed. My argument is that the First Amendment took off only during the New Deal and later, the Civil Rights revolution as an identity‐formation and unifying tool in a deeply divided society. The symbolic significance of free speech in the US remains central to this day. In the midst of its identity crisis with looming Brexit, Europe is now experimenting with privacy‐as‐constitutional identity in a similar way. This article seeks to unpack the values encompassed in privacy and freedom of speech, looking into the different functional responses that two different democratic societies place their bets on. As data protection and privacy come to a clash with important trade and security interests in an evermore‐globalized world, the power of the outward‐oriented European privacy discourse is likely to remain above all rhetorical.
Melanosome maturation proteins Oca2, Mitfa and Vps11 are differentially required for cisplatin resistance in zebrafish melanocytes
Authors: Peterson Kersten A. , Neuffer Samantha , Bean Miranda E. , New Leslie , Coffin Allison B. , Cooper Cynthia D.
Published: April 2019

Melanoma is the deadliest form of skin cancer, partially due to its inherent resistance to therapy. Here, we test in live larvae the hypothesis that mature melanosomes contribute to resistance to chemotherapeutic drug, cisplatin, via drug sequestration. We also compare three melanosome biogenesis proteins—microphthalmia‐associated transcription factor (Mitfa), vacuolar protein sorting 11 (Vps11) and oculocutaneous albinism 2 (Oca2) to determine their respective contributions to chemoresistance. Melanocytes in zebrafish larvae harbouring loss‐of‐function mutations in the mitfa, vps11 or oca2 genes are more sensitive to cisplatin damage than wild‐type larvae. As a comparison, we examined sensory hair cells of the lateral line, which are sensitive to cisplatin. Hair cells in oca2 and mitfa mutants do not show increased cisplatin sensitivity when compared to wild‐type larvae, suggesting the increase in cisplatin sensitivity could be melanocyte specific. However, hair cells in vps11 mutants are more sensitive to cisplatin than their wild‐type counterparts, suggesting that this mutation increases cisplatin susceptibility in multiple cell types. This is the first in vivo study to show an increase in chemotherapeutic drug sensitivity when melanosome maturation mutations are present. The proteins tested, especially Oca2, represent novel drug targets for increasing the efficiency of melanoma chemotherapy treatment.
Dissecting the role of hyaluronan synthases in the tumor microenvironment
Authors: Passi Alberto , Vigetti Davide , Buraschi Simone , Iozzo Renato V.
Published: April 2019

The tumor microenvironment is becoming a crucial factor in determining the aggressiveness of neoplastic cells. The glycosaminoglycan hyaluronan is one of the principal constituents of both the tumor stroma and the cancer cell surfaces, and its accumulation can dramatically influence patient survival. Hyaluronan functions are dictated by its ability to interact with several signaling receptors that often activate pro‐angiogenic and pro‐tumorigenic intracellular pathways. Although hyaluronan is a linear, non‐sulfated polysaccharide, and thus lacks the ability of the other sulfated glycosaminoglycans to bind and modulate growth factors, it compensates for this by the ability to form hyaluronan fragments characterized by a remarkable variability in length. Here, we will focus on the role of both high and low molecular weight hyaluronan in controlling the hallmarks of cancer cells, including cell proliferation, migration, metabolism, inflammation, and angiogenesis. We will critically assess the multilayered regulation of HAS2, the most critical hyaluronan synthase, and its role in cancer growth, metabolism, and therapy.
The impact of psychosocial determinants on caregivers’ burden of children with haemophilia (results of the BBC study)
Authors: von Mackensen Sylvia , Myrin Westesson Linda , Kavakli Kaan , Klukowska Anna , Escuriola Carmen , Uitslager Nanda , Santoro Cristina , Holland Mike , Khair Kate
Published: April 2019

Introduction

Caring for a child with haemophilia is burdensome and impacting on caregivers’ emotional and financial status. This paper assesses the impact of psychosocial determinants on caregivers’ burden across European countries.

Methods

This non‐interventional study enrolled caregiver/child dyads at haemophilia treatment centres (HTCs) using the “HEMOphilia associated CAregiver Burden scale” (HEMOCAB). Socio‐demographic characteristics and clinical data were collected.

Results

A total of 144 dyads from Germany (n = 19), Italy (n = 19), Netherlands (n = 19), Turkey (n = 20), Sweden (n = 21), UK (n = 21) and Poland (n = 25) participated. Caregivers’ mean age was 39.84 ± 7 (range 24‐57); 81.3% were mothers, married (80.4%), living with a partner (86.6%), had a college/university degree (66.5%) and worked (74.2%). Around two thirds of caregivers (66.2%) reported that haemophilia affected their life; 26.8% reported an economic impact; 57.6% reported their child cannot do certain things because of his condition. Caregivers lost an average of 8.35 ± 14.5 days due to haemophilia. The highest burden was reported in the HEMOCAB domains “Perception of Child” (37.9 ± 24.7), “Emotional Stress” (37.4 ± 22.6) and “Medical Management” (33.1 ± 22.8). Significantly, higher burden was found in caregivers who reported that haemophilia “affects their life” (P < 0.0001), “has an economic impact” (P < 0.0001), “their child cannot do certain things” (P < 0.0001), “they spent ≥5 h/mo infusing” (P < 0.003) and “they needed ≥3 h/mo to reach the HTC” (P < 0.0001).

Conclusion

This “snapshot” analysis of burden related to caring for a child with haemophilia across Europe revealed the greatest burdens are economic, including days lost from work, and things that a child cannot do, impacting on both child and caregiver.
Loss of expression of MLH1 in non‐dysplastic crypts is a harbinger of neoplastic progression in sessile serrated adenomas/polyps
Authors: Yozu Masato , Kem Marina , Cenaj Odise , Mino‐Kenudson Mari , Odze Robert D , Misdraji Joseph
Published: April 2019

Aims

Dysplasia in colonic sessile serrated adenomas (SSAs)/sessile serrated polyps often shows loss of MLH1 expression as determined with immunohistochemistry, but the significance of loss of MLH1 expression in non‐dysplastic crypts in these polyps is less well studied. The purpose of this study was to evaluate the prevalence of loss of MLH1 expression in non‐dysplastic crypts in SSAs, and to evaluate its significance with regard to progression of these polyps.

Methods and results

Four hundred SSAs, including 158 SSAs without dysplasia, 219 SSAs with dysplasia (SSAD), and 23 SSAs with invasive adenocarcinoma (SSAC), were evaluated immunohistochemically for loss of MLH1 expression in both non‐dysplastic and dysplastic portions of the polyps. Seventy‐one of 400 (18%) SSAs showed loss of MLH1 expression in non‐dysplastic crypts. The prevalence of MLH1‐deficient non‐dysplastic crypts was higher in polyps with dysplasia or carcinoma (7%, 22%, and 52% in SSAs, SSADs, and SSACs, respectively; P < 0.0001). When SSAs with MLH1‐deficient dysplasia and those with MLH‐1‐proficient dysplasia were compared, those with MLH1‐deficient dysplasia were more likely to have MLH1‐deficient non‐dysplastic crypts (66% versus 8.1%, P < 0.0001) and a greater number of discrete foci (3.6 foci versus 1.1 foci, P = 0.008). Also, non‐dysplastic crypts with loss of MLH1 expression were more likely to be contiguous with the dysplasia when the dysplasia also showed loss of MLH1 expression (26% versus 0%, P = 0.02).

Conclusions

Our results suggest that loss of MLH1 expression in non‐dysplastic crypts in SSAs precedes the development of MLH1‐deficient dysplasia and adenocarcinoma, and may be a biomarker of an advanced serrated polyp even in the absence of dysplasia.
Numerical and experimental study of blow and blow for perfume bottles to predict glass thickness and blank mold influence
Authors: Biosca Adrià , Borrós Salvador , Pedret Clemente Vicenç , Hyre Matthew R. , García Granada Andrés‐Amador
Published: April 2019

Glass forming to produce perfume bottles with specific thickness distribution profiles is based on trial and error and requires several tests in production line. These tests are expensive and time‐consuming, which increases time to market. The use of a numerical model aims to reduce the number of prototypes by performing virtual tests of the mold equipment and the process conditions. This article presents results of numerical simulations of the blow and blow forming process to predict glass thickness distribution. Correlation of the simulation results of the glass temperature with experimental infrared measurements on the glass skin and experimental validation of glass forming simulations and influence of the blank mold cavity in the thickness distributions of perfume bottles are provided. Finally validation of the results of axisymmetrical and three‐dimensional models for axisymmetric bottles defining a useful technique to use the right blank mold for desired thickness distribution while reducing the trial and error testing.
Fibroblastic reticular cells at the nexus of innate and adaptive immune responses
Authors: Perez‐Shibayama Christian , Gil‐Cruz Cristina , Ludewig Burkhard
Published: April 2019

Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune‐interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat‐associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses.
Compartmentalization of dendritic cell and T‐cell interactions in the lymph node: Anatomy of T‐cell fate decisions
Authors: León Beatriz , Lund Frances E.
Published: April 2019

Upon receiving cognate and co‐stimulatory priming signals from antigen (Ag)‐presenting dendritic cells (DCs) in secondary lymphoid tissues, naïve CD4+ T cells differentiate into distinct effector and memory populations. These alternate cell fate decisions, which ultimately control the T‐cell functional attributes, are dictated by programming signals provided by Ag‐bearing DCs and by other cells that are present in the microenvironment in which T‐cell priming occurs. We know that DCs can be subdivided into multiple populations and that the various DC subsets exhibit differential capacities to initiate development of the different CD4+ T‐helper populations. What is less well understood is why different subanatomic regions of secondary lymphoid tissues are colonized by distinct populations of Ag‐presenting DCs and how the location of these DCs influences the type of T‐cell response that will be generated. Here we review how chemokine receptors and their ligands, which position allergen and nematode‐activated DCs within different microdomains of secondary lymphoid tissues, contribute to the establishment of IL‐4 committed follicular helper T and type 2 helper cell responses.
T‐cell positioning by chemokines in autoimmune skin diseases
Authors: Richmond Jillian M. , Strassner James P. , Essien Kingsley I. , Harris John E.
Published: April 2019

Autoimmune skin diseases are complex processes in which autoreactive cells must navigate through the skin tissue to find their targets. Regulatory T cells in the skin help to mitigate autoimmune inflammation and may in fact be responsible for the patchy nature of these conditions. In this review, we will discuss chemokines that are important for global recruitment of T cell populations to the skin during disease, as well as signals that fine‐tune their localization and function. We will describe prototypical disease responses and chemokine families that mediate these responses. Lastly, we will include an overview of chemokine‐targeting drugs that have been tested as new treatment strategies for autoimmune skin diseases.
Studying the multilevel impact of cohesion versus structural holes in knowledge networks on adaptation to IT‐enabled patient‐care practices
Authors: Raman Roopa , Grover Varun
Published: April 2019

We investigate the impact of cohesion versus structural holes in two different types of knowledge networks—help‐seeking networks and voluntary contribution networks—on adaptation to health IT‐enabled patient‐care practices. In a multimethod study conducted within a large hospital system, qualitative and quantitative data were collected from 806 clinicians working with electronic medical record systems in 27 inpatient patient‐care units. Multilevel analysis of the data revealed that overall network cohesiveness versus location in structural hole positions related to adaptation differently, depending on the type of network. In help‐seeking networks, location in structural hole positions was negatively related to adaptation, while network cohesion had a bell‐shaped curvilinear relationship with adaptation; in voluntary contribution networks, the overall cohesiveness of the network was negatively related to adaptation, but location in structural hole positions was irrelevant to adaptation. Our findings suggest a more nuanced way of monitoring and utilising different sets of informal social interactions at work to maximise employees' adaptation to IT‐enabled work.
Triggering efficient photocatalytic water oxidation reactions over BaNbO2N by incorporating Ca at B site
Authors: Wei Shunhang , Jin Shu , Pan Guoxiang , Li Zuxin , Liu Gang , Xu Xiaoxiang
Published: April 2019

Although BaNbO2N has visible light absorption as far as 740 nm, its photocatalytic activity is generally very poor under ordinary conditions, being incommensurate to its light absorption properties. In this work, we introduce Ca into the B site of BaNbO2N to form a complex perovskite BaNb1−x/3Cax/3O2+yN1−y (0 ≤ x, y ≤ 1). The presence of Ca in BaNbO2N has great impact on a number of important properties such as band gap value, nitrogen content, surface hydrophilicity, and defects levels. In particular, defects such as Nb4+ species are effectively suppressed in Ca‐modified BaNbO2N. More importantly, photocatalytic activity of BaNbO2N for water oxidation reactions is substantially improved after Ca modifications. Compared with pristine BaNbO2N, more than twofold enhancement in photocatalytic oxygen evolution is observed for BaNb0.8Ca0.2O2+yN1−y (x = 0.6). Such improvements probably stem from the suppression of Nb4+ species in the structure as well as enhanced surface hydrophilicity after Ca modification. The facile approach by incorporating alkaline earth cations into crystal structure can be well extended to other perovskite oxynitrides whose photocatalytic activity is subject to those defective species.
Retrospective chart review of spectacle prescription prevalence in adults with learning disabilities in Scotland
Authors: Butchart Maggie , Colahan Craig
Published: April 2019

Background

Evidence suggests that people with learning disabilities are less likely to have an up‐to‐date eye examination as sight loss is characteristically underdiagnosed in people with complex needs.

Method

A retrospective study of records from 576 Service Users of RNIB UK Vision, learning disability and Complex Needs Services was carried out.

Results

The record review found a higher prevalence of spectacle prescription in a learning disability (LD) population in agreement with findings from other LD studies. There was a higher prevalence of severe myopia in people with LD compared with a general adult population.

Conclusion

This study found a higher prevalence of spectacle prescription in people with learning disabilities compared to a general adult population, which has implications for people with learning disabilities to ensure that they have access to eye care and regularly attended eye tests. It also has implications for healthcare professionals working with people with complex needs to ensure they have access to eye care.
Association of thyroid function with white coat hypertension and sustained hypertension
Authors: Cai Peng , Peng Yan , Chen YuXi , Li Li , Chu Wei , Wang Yan , Wang Xukai
Published: April 2019

This study aimed to explore the relationship of thyroid‐stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) levels with hypertension subtypes. 1056 euthyroid adults were included as research samples. They underwent measurement of clinic blood pressure and 24‐hours ambulatory blood pressure monitoring. Then, they were divided into normotension (NT), white coat hypertension (WCH), masked hypertension (MHT), and sustained hypertension (SHT) groups. The 24‐hours dynamic electrocardiogram was performed to analyze the heart rate variability (HRV), so as to reflect the cardiac autonomic function. The relationship between hypertension subtypes, thyroid function, and HRV was analyzed. The TSH concentration was significantly higher in the SHT group than in the NT group (P = 0.001). The FT3 concentration was higher in the SHT group than in the NT and MHT groups (P = 0.013, P = 0.008), while the FT4 concentration was significantly higher in the WCH group than in the NT group (P = 0.002). The changes in HRV were observed between the SHT, WCH, and MHT groups and the NT groups, as well as between the SHT and the MHT groups. The multiple linear regression analysis also showed that FT3, HRV (RMSSD and PNN50), and blood pressure levels linearly correlated with one another (P < 0.05). Meanwhile, the linear regression analysis showed a linear negative correlation between FT4 and HRV (SDANN) in the WCH + NT group (P = 0.001). Thyroid function was closely related to hypertension subtypes such as WCH probably due to the changes in the cardiac autonomic function.
The role of autophagy in the pathogenesis of exposure keratitis
Authors: Wang Guoliang , Xue Yuhua , Wang Yanzi , Dong Fei , Shen Mei , Zong Rongrong , Liu Zuguo , Li Cheng
Published: April 2019

Incomplete tear film spreading and eyelid closure can cause defective renewal of the ocular surface and air exposure‐induced epithelial keratopathy (EK). In this study, we characterized the role of autophagy in mediating the ocular surface changes leading to EK. Human corneal epithelial cells (HCECs) and C57BL/6 mice were employed as EK models, respectively. Transmission electron microscopy (TEM) evaluated changes in HCECs after air exposure. Each of these models was treated with either an autophagy inhibitor [chloroquine (CQ) or 3‐methyladenine (3‐MA)] or activator [Rapamycin (Rapa)]. Immunohistochemistry assessed autophagy‐related proteins, LC3 and p62 expression levels. Western blotting confirmed the expression levels of the autophagy‐related proteins [Beclin1 and mammalian target of rapamycin (mTOR)], the endoplasmic reticulum (ER) stress‐related proteins (PERK, eIF2α and CHOP) and the PI3K/Akt/mTOR signalling pathway‐related proteins. Real‐time quantitative PCR (qRT‐PCR) determined IL‐1β, IL‐6 and MMP9 gene expression levels. The TUNEL assay detected apoptotic cells. TEM identified autophagic vacuoles in both EK models. Increased LC3 puncta formation and decreased p62 immunofluorescent staining and Western blotting confirmed autophagy induction. CQ treatment increased TUNEL positive staining in HCECs, while Rapa had an opposite effect. Similarly, CQ injection enhanced air exposure‐induced apoptosis and inflammation in the mouse corneal epithelium, which was inhibited by Rapa treatment. Furthermore, the phosphorylation status of PERK and eIF2α and CHOP expression increased in both EK models indicating that ER stress‐induced autophagy promoted cell survival. Taken together, air exposure‐induced autophagy is indispensable for the maintenance of corneal epithelial physiology and cell survival.
Oral hygiene phase revisited: How different study designs have affected results in intervention studies
Authors: Preus Hans R. , Maharajasingam Nisha , Rosic Jovana , Baelum Vibeke
Published: April 2019

Every periodontal researcher have been taught, and every textbook in periodontics have advocated, that a phase in which the patient is meticulously motivated and instructed in proper oral hygiene—the oral hygiene phase—must be included in any periodontal intervention. However, how is this oral hygiene phase actually portrayed in periodontal intervention studies, and how much space have this important phase received in the planning and carry‐through of intervention studies? The purpose of this letter to the editor was to review current literature in the period 1975/01/01–2017/12/31 on periodontal, mechanical intervention studies in order to see what focus the oral hygiene phase had received in these articles. The result showed that the oral hygiene phase is variable in length and content, variable in claimed result, insufficiently described, and invariably amalgamated with the scaling and root planing which is the intervention or part of an intervention. The consequences of these findings are discussed and suggestions proposed for more harmonized and calibrated oral hygiene phase introduced to avoid biased and inflated results of interventions.
External validation and comparison of four confocal microscopic scores for melanoma diagnosis on a retrospective series of highly suspicious melanocytic lesions
Authors: Pampena R. , Borsari S. , Lai M. , Benati E. , Longhitano S. , Mirra M. , Kyrgidis A. , Pellacani G. , Longo C.
Published: April 2019

Background

In vivo reflectance confocal microscopy significantly improves melanoma diagnosis as compared to clinical/dermoscopic examination alone. Several confocal criteria have been described allowing to differentiate melanoma from nevi; by combining different criteria, three pure confocal scores (Pellacani 2005, Segura 2009 and Pellacani 2012) and one mixed dermoscopic/confocal score (Borsari 2018) were constructed.

Objective

Our aim was to externally validate and compare the performance of these confocal scores.

Methods

We retrospectively enrolled excised melanocytic lesions which underwent confocal examination in a 2‐year period. Lesions located on the face and acral sites were excluded. Both dermoscopic and confocal criteria considered in the four scores were evaluated by experts. Subsequently, specificity and sensitivity levels for each score were calculated, together with the positive and negative predictive values and likelihood ratios; also, receiver operating characteristic curves were constructed.

Results

A total of 389 patients with 422 lesions were retrospectively enrolled, of which 162 (38.4%) were melanomas and 260 (61.6%) were nevi (189 common and 71 Spitz/Reed nevi). The highest sensitivity levels were recorded for Segura 2009 with cut‐off ≥−1 (92.0%), while Pellacani 2005 with cut‐off ≥5 achieved the highest specificity (69.6%). The score by Borsari et al. showed the highest levels of positive and negative predictive values (59.8% and 91.5%) and likelihood ratios (2.4 and 0.1) as well as the highest area under the curve values (0.76; 95% CI 0.72–0.81; P < 0.001).

Conclusions

High levels of accuracy were found for each of the four considered scores. No differences were found among scores in confirming melanoma diagnosis when positive; however, the score by Borsari 2018 was the best in excluding melanoma diagnosis when negative.
Ochroconis globalis infecting Atlantic salmon (Salmo salar), with a review of Ochroconis species in cold‐blooded animals
Authors: Samerpitak Kittipan , Alfjorden Anders , Seyedmousavi Seyedmojtaba , Rijs Antonius J. M. M. , Gerrits van den Ende Albertus Hendrikus Gerardus , de Hoog Gert Sybren
Published: April 2019

Necropsy examination of an adult Atlantic salmon (Salmo salar) from the Dalälven River in Sweden revealed numerous large, white nodules, with spherical cysts and granulomata in kidney and liver. Histopathology showed dark, septate, thin‐walled hyphae. The aetiologic agent was found to be an Ochroconis species (Venturiales) that differed from known fish‐associated species of the genus. Molecular phylogenetic studies of the culture (strain UIII09 = CBS 135766) demonstrated that Ochroconis globalis was concerned. The isolate proved to be susceptible to all investigated antifungals, as it is known for another Ochroconis species. The role of Ochroconis in opportunism of cold‐blooded animals was discussed, and the diagnostic methods using DNA sequences for routine identification of the fungus were proposed.
Development of piscirickettsiosis in Atlantic salmon (Salmo salar L.) smolts after intraperitoneal and cohabitant challenge using an EM90‐like isolate: A comparative study
Authors: Meza Karla , Inami Makoto , Dalum Alf S. , Bjelland Ane M. , Sørum Henning , Løvoll Marie
Published: April 2019

Piscirickettsiosis, caused by the intracellular Gram‐negative bacteria Piscirickettsia salmonis, is at present the most devastating disease in the Chilean salmon industry. The aim of this study was to analyse disease development after challenge with a P. salmonis strain (EM90‐like) under a controlled environment by comparing intraperitoneal challenge with cohabitation challenge. The P. salmonis EM90‐like isolate was cultured in a liquid medium for the challenge of 400 Atlantic salmon (Salmo salar) smolts. Cumulative mortality was registered, necropsy was performed, and bacterial distribution in the tissues and histopathological changes were analysed. The results revealed a similar progression of the disease for the two different challenge models. Pathological and histopathological changes became more visible during the development of the clinical phase of the disease. Bacterial DNA was identified in all the analysed tissues indicating a systemic infection. Bacterial tropism to visceral organs was demonstrated by real‐time quantitative PCR and immunohistochemistry. Better knowledge of disease development during P. salmonis infection may contribute to further development of challenge models that mimic the field situation during piscirickettsiosis outbreaks. The models can be used to develop and test future preventive measures against the disease.