bluuebunny/crossref_metadata_2025 huggingface dataset:
A simple morphometric analysis method for dermal microstructure using color thresholding and moments
Authors: Hong Ji Hyuck , Kim Dai Hyun , Rhyu Im Joo , Kye Young Chul , Ahn Hyo Hyun
Published: September 2019

Background

Proper assessment of dermal collagen fibers by dermatologists and researchers is essential. Histologic evaluation methods have limitations. We present a simple method for measurement of collagen fibers in human skin using Masson's trichrome staining.

Materials and Methods

Normal skin specimens from a cadaver were processed with Masson's trichrome, which can effectively stain collagen fibers blue with aniline dye. Optical photomicrographs of these slides were analyzed using ImageJ software. Color image processing, a histogram‐based function of ImageJ for image segmentation, was performed with color moments thresholding technique. We selected blue areas by adjusting the blue channel to include specific values. The selected areas were highlighted and evaluated. We divided the image into layers of 0.09‐mm2 areas from the top to bottom of the dermis. Each area was cropped and evaluated.

Results

Quantitative assessment yielded the quantitative size occupied by collagen fibers in an area of 0.09 mm2. Calculation of the percentage in each area can be used to determine the density of collagen fibers.

Conclusion

Measurements obtained with our method can be applied to research on dermal collagen fibers. We present a convenient quantitative assessment method for the dermal constituents in Masson's trichrome‐stained slides.
Salt décollement and rift inheritance controls on crustal deformation in orogens
Authors: Grool Arjan R. , Huismans Ritske S. , Ford Mary
Published: September 2019

We investigate the factors that control the shortening distribution and its evolution through time in orogenic belts using numerical models. We present self‐consistent high‐resolution numerical models that simulate the inversion of a rift to generate an upper crustal antiformal stack, a wide outer pro‐wedge fold‐and‐thrust belt, characterised by a two‐phase evolution with early symmetric inversion followed by formation of an asymmetric doubly‐vergent orogen. We show that a weak viscous salt décollement promotes gravitational collapse of the cover. When combined with efficient erosion of the orogenic core and sedimentation in adjacent forelands, it ensures the thick‐skinned pro‐wedge taper remains subcritical, promoting formation of an upper crustal antiformal stack. Rift inheritance promotes a two‐phase shortening distribution evolution regardless of the shallow structure and other factors. Comparison to the Pyrenees strongly suggests that this combination of factors led to a very similar evolution and structural style.
Intra‐bone bone marrow transplantation from hCD47 transgenic pigs to baboons prolongs chimerism to >60 days and promotes increased porcine lung transplant survival
Authors: Watanabe Hironosuke , Ariyoshi Yuichi , Pomposelli Thomas , Takeuchi Kazuhiro , Ekanayake‐Alper Dilrukshi K. , Boyd Lennan K. , Arn Scott J. , Sahara Hisashi , Shimizu Akira , Ayares David , Lorber Marc I. , Sykes Megan , Sachs David H. , Yamada Kazuhiko
Published: September 2019

Background

We have recently demonstrated that human‐CD47 (hCD47) expressed on endothelial cells of porcine lung xenografts extended median graft survival from 3.5 days to 8.7 days in baboons. Intra‐bone bone marrow transplantation (IBBMTx) in a pig‐to‐baboon model was previously shown to markedly prolong the duration of macrochimerism up to 21 days from 1 to 4 days by intravenous BMTx. We now examined whether the use of hCD47 transgenic (Tg) BM further prolonged the duration of chimerism following IBBMTx. We then tested if lung xenograft survival was prolonged following IBBMTx.

Methods

Baboons received GalTKO‐hCD47/hCD55Tg (n = 5) or ‐hCD55Tg (n = 1) or ‐hCD46/HLA‐E Tg (n = 1) pig IBBMTx. Macrochimerism, anti‐pig T cells and antibody responses were assessed. Animals received lung xenografts from either hCD47+ or hCD47‐ porcine lungs 1‐3 months later.

Results

All baboons that received hCD47Tg porcine IBBM maintained durable macrochimerism >30 days, and two maintained chimerism for >8 weeks. Notably, anti‐pig antibody levels decreased over time and anti‐pig cellular unresponsiveness developed following IBBMTx. Lungs from hCD47Tg IBBMTx matched pigs were transplanted at day 33 or day 49 after IBBMTx. These animals showed extended survival up to 13 and 14 days, while animals that received lungs from hCD47 negative pigs displayed no prolonged survival (1‐4 days).

Conclusion

This is the first report demonstrating durable macrochimerism beyond 8 weeks, as well as evidence for B cell tolerance in large animal xenotransplantation. Using hCD47Tg pigs as both IBBMTx and lung donors prolongs lung xenograft survival. However, additional strategies are required to control the acute loss of lung xenografts.
Residual intersections are Koszul–Fitting ideals
Authors: Bouça Vinicius , Hassanzadeh S. Hamid
Published: September 2019

We describe generators of disguised residual intersections in any commutative Noetherian ring. It is shown that, over Cohen–Macaulay rings, the disguised residual intersections and algebraic residual intersections are the same, for ideals with sliding depth. This coincidence provides structural results for algebraic residual intersections in a quite general setting. It is shown how the DG-algebra structure of Koszul homologies affects the determination of generators of residual intersections. It is shown that the Buchsbaum–Eisenbud family of complexes can be derived from the Koszul–Čech spectral sequence. This interpretation of Buchsbaum–Eisenbud families has a crucial rule to establish the above results.
Transbronchial Invasion and Proliferation of Leptospira interrogans in Lung without Inflammatory Cell Infiltration in a Hamster Model
Authors: Nikaido Yasuhiko , Ogawa Midori , Fukuda Kazumasa , Yokoyama Mitsuru , Kanemaru Takaaki , Nakayama Toshiyuki , Saito Mitsumasa
Published: September 2019

Leptospirosis caused by pathogenic
Leptospira
is one of the most common zoonoses in the world. It is believed that humans become infected with it mainly through their skin and mucous membranes by contact with water or soil that is contaminated with urine excreted from infected animals. Recently, outbreaks have frequently occurred in the tropics, especially after flooding, but how leptospires cause mass infection remains poorly understood.
Initial Laramide tectonism recorded by Upper Cretaceous paleoseismites in the northern Bighorn Basin, USA: Field indicators of an applied end load stress
Authors: Jackson W.T. , McKay M.P. , Bartholomew M.J. , Allison D.T. , Spurgeon D.L. , Shaulis B. , VanTongeren J.A. , Setera J.B.
Published: September 2019

Soft-sediment deformational structures associated with paleoseismicity (e.g., planar clastic dikes) exist within Upper Cretaceous Mesaverde Group strata in the Laramide Elk Basin anticline, northern Bighorn Basin (Wyoming, USA). Retrodeformation of the Elk Basin anticline to a horizontal Mesaverde Group position indicates that all basement offset is removed and that clastic dikes exhibit a dominant northeast trend. The trend of clastic dikes corresponds to the interpreted northeast-southwest direction of early Laramide layer-parallel shortening, suggesting that the development of clastic dikes recorded initiation of basement deformation and Laramide tectonism. To determine the timing of clastic dike development, we present zircon U-Pb geochronology from the stratigraphically lowest sand-source bed generating upwardly injected clastic dikes and a volcanic bentonite bed (Ardmore bentonite) above the stratigraphic interval containing clastic dikes. Weighted mean ages bracket clastic dike development between 82.4 and 78.0 Ma. Our results imply initiation of basement deformation ∼8–15 m.y. prior than other estimates in the Bighorn Basin. Therefore, we interpret the development of clastic dikes in the Elk Basin anticline to represent an initial phase of Laramide tectonism associated with an applied end load stress transmitted from the southwestern North American plate margin in response to the collision of the conjugate Shatsky Rise oceanic plateau ca. 90–85 Ma. Results demonstrate how sedimentary responses in the foreland can be used to understand tectonic processes at plate boundaries and provide spatial-temporal parameters for models of Laramide deformation.
Cohort profile: the DANish LIFE course (DANLIFE) cohort, a prospective register-based cohort of all children born in Denmark since 1980
Authors: Bengtsson Jessica , Dich Nadya , Rieckmann Andreas , Hulvej Rod Naja
Published: September 2019

Purpose

The DANish LIFE course (DANLIFE) cohort is a prospective register-based study set up to investigate the complex life course mechanisms linking childhood adversities to health and well-being in childhood, adolescence and young adulthood including cumulative and synergistic actions and potentially sensitive periods in relation to health outcomes.

Participants

All children born in Denmark in 1980 or thereafter have successively been included in the cohort totalling more than 2.2 million children. To date, the study population has been followed annually in the nationwide Danish registers for an average of 16.8 years with full data coverage in the entire follow-up period. The information is currently updated until 2015.

Findings to date

DANLIFE provides information on a wide range of family-related childhood adversities (eg, parental separation, death of a parent or sibling, economic disadvantage) with important psychosocial implications for health and well-being in childhood, adolescence and young adulthood. Measurement of covariates indicating demographic (eg, age, sex), social (eg, parental education) and health-related factors (eg, birth weight) has also been included from the nationwide registers. In this cohort profile, we provide an overview of the childhood adversities and covariates included in DANLIFE. We also demonstrate that there is a clear social gradient in the exposure to childhood adversities confirming clustering of adverse experiences within individuals.

Future plans

DANLIFE provides a valuable platform for research into early life adversity and opens unique possibilities for testing new research ideas on how childhood adversities affect health across the life course.
Comparative thromboembolic risk in atrial fibrillation with and without a secondary precipitant—Danish nationwide cohort study
Authors: Gundlund A , Kümler Thomas , Bonde Anders Nissen , Butt Jawad Haider , Gislason Gunnar Hilmar , Torp-Pedersen Christian , Køber Lars , Olesen Jonas Bjerring , Fosbøl Emil Loldrup
Published: September 2019

Objectives

We compared long-term outcomes in patients with atrial fibrillation (AF) with and without a secondary precipitant.

Design and setting

Retrospective cohort study based on Danish nationwide registries.

Participants

Patients with AF with and without secondary precipitants (1996–2015) were matched 1:1 according to age, sex, calendar year, CHA2DS2-VASc score and oral anticoagulation therapy (OAC), resulting in a cohort of 39 723 patients with AF with a secondary precipitant and the same number of patients with AF without a secondary precipitant. Secondary precipitants included alcohol intoxication, thyrotoxicosis, myocardial infarction, surgery and infection in conjunction with AF.

Primary and secondary outcomes

The primary outcome in this study was thromboembolic events. Secondary outcomes included AF rehospitalisation and death. Long-term risks of outcomes were examined by multivariable Cox regression analysis.

Results

The most common precipitants were infection (55.0%), surgery (13.2%) and myocardial infarction (12.0%). The 5-year absolute risk of thromboembolic events (taking death into account as a competing risk) in patients with AF grouped according to secondary precipitants were 8.3% (alcohol intoxication), 8.5% (thyrotoxicosis), 12.1% (myocardial infarction), 11.6% (surgery), 12.2% (infection), 10.1% (>1 precipitant) and 12.3% (no secondary precipitant). In the multivariable analyses, AF with a secondary precipitant was associated with the same or an even higher thromboembolic risk than AF without a secondary precipitant. One exception was patients with AF and thyrotoxicosis: those not initiated on OAC therapy carried a lower thromboembolic risk the first year of follow-up than matched patients with AF without a secondary precipitant and no OAC therapy.

Conclusions

In general, AF with a secondary precipitant was associated with the same thromboembolic risk as AF without a secondary precipitant. Consequently, this study highlights the need for more research regarding the long-term management of patients with AF associated with a secondary precipitant.
The impact of a named GP scheme on continuity of care and emergency hospital admission: a cohort study among older patients in England, 2012–2016
Authors: Tammes Peter , Payne Rupert A , Salisbury Chris , Chalder Melanie , Purdy Sarah , Morris Richard W
Published: September 2019

Objective

To investigate whether the introduction of a named general practitioner (GP, family physician) improved patients’ healthcare for patients aged 75 and over in England.

Setting

Random sample of 27 500 patients aged 65 to 84 in 2012 within 139 English practices from the Clinical Practice Research Datalink linked with Hospital Episode Statistics.

Design

Prospective cohort approach, measuring patients’ GP consultations and emergency hospital admissions 2 years before/after the intervention. Patients were grouped in (i) aged over 74 and (ii) younger than 75 in both periods in order to compare who were or were not subject to the intervention. Adjusted associations between the named GP scheme, continuity of care and emergency hospital admission were examined using multilevel modelling.

Intervention

National Health Service policy to introduce a named accountable GP for patients aged over 74 in April 2014.

Main outcome measures

(A) Continuity of care index-score, (B) risk of emergency hospital admissions, (C) number of emergency hospital admissions.

Results

The intervention was associated with a decrease in continuity index-scores of −0.024 (95% CI −0.030 to −0.018, p<0.001); there were no differences in the decrease between the two age groups (−0.005, 95% CI −0.014 to 0.005). In the pre-intervention and post-intervention periods, respectively, 15.4% and 19.4% patients had an emergency admission. The probability of an emergency hospital admission increased after the intervention (OR 1.156, 95% CI 1.064 to 1.257, p=0.001); this increase was bigger for patients over 74 (relative OR 1.191, 95% CI 1.066 to 1.330, p=0.002). The average number of emergency hospital admissions increased after the intervention (rate ratio (RR) 1.178, 95% CI 1.103 to 1.259, p<0.001); this increase was greater for patients over 74 (relative RR 1.143, 95% CI 1.052 to 1.242, p=0.001).

Conclusion

The introduction of the named GP scheme was not associated with improvements in either continuity of care or rates of unplanned hospitalisation.
Critical appraisal of clinical practice guidelines for the diagnosis and treatment of stress urinary incontinence using AGREE II instrument: a systematic review protocol
Authors: Yang Xiaowei , Zhang AiXia , Tan Yanquan , Zhang Zhengbao , Zhang Jie
Published: September 2019

Introduction

Stress urinary incontinence is a major health problem, and several clinical guidelines have been formulated and released regarding this in different countries. However, the recommendations in these guidelines formulated by different organisations and countries are inconsistent. This review aims to conduct a critical appraisal of clinical practice guidelines for the diagnosis and treatment of stress urinary incontinence.

Methods and analysis

We will conduct a comprehensive search in the following databases: PubMed, Embase, Medline, Cochrane Library, three Chinese databases and six guideline databases. The databases will be searched from January 2003, and the comprehensive search will be done again to include all the qualified guidelines before making conclusions. The quality of clinical practice guidelines will be assessed by three appraisers using the Appraisal of Guidelines Research and Evaluation II instrument, and this will be scored. The recommendation available in the guidance will also be summarised in different domains including the diagnosis standard, recommended examination and questionnaire for assessment, conservative treatment and surgical treatment.

Ethics and dissemination

This review will be disseminated through peer-reviewed publications. The results will help inform the health practitioners about the recommendations in clinical practice guidelines.

PROSPERO registration number

CRD42018115743.
Clinicopathological risk factors for gastric cancer: a retrospective cohort study in China
Authors: Hu Kongwang , Wang Shuaili , Wang Zikun , Li Longlong , Huang Zhiguo , Yu Weiqiang , Chen Zhongxue , Wu Qing-Fa
Published: September 2019

Objective

To examine the potential clinicopathological factors affecting the prognosis of patients with gastric cancer after surgical treatment in China.

Methods

Between 1 January 2001 and 31 December 2012, a total of 716 patients aged 22–84 years with gastric cancer were enrolled in the study. Survival analysis techniques including log rank test and Cox proportional hazard regression model were applied to evaluate the prognostic significance of clinicopathological characteristics in terms of survival time.

Results

Of the 24 demographic and pathological variables collected in the data, 16 prognostic factors of gastric cancer were found to have statistically significant influences on survival time from the unadjusted analyses. The adjusted analysis furtherly revealed that age, age square, lymph node metastasis rate group, tumour size group, surgical type II, number of cancer nodules, invasion depth group and the interaction between surgical type II and tumour size group were important prognosis and clinicopathological factors for gastric cancer in Chinese.

Conclusion

Our study with relatively large sample size and many potential risk factors enable us to identify independent risk factors associated with the prognosis of gastric cancer. Findings from the current study can be used to assist clinical decision-making, and serve as a benchmark for the planning of future prognosis and therapy for patients with gastric carcinoma.
Appropriateness of initial dose of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation in the UK
Authors: García Rodríguez Luis Alberto , Martín-Pérez Mar , Vora Pareen , Roberts Luke , Balabanova Yanina , Brobert Gunnar , Fatoba Samuel , Suzart-Woischnik Kiliana , Schaefer Bernhard , Ruigomez Ana
Published: September 2019

Objective

To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK.

Design

Population-based cross-sectional study.

Setting

UK primary care.

Population

30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016.

Main outcome measures

Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed—including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status.

Results

A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%.

Conclusion

Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.
Short-term outcomes of rapid initiation of antiretroviral therapy among HIV-positive patients: real-world experience from a single-centre retrospective cohort in Taiwan
Authors: Huang Yi-Chia , Sun Hsin-Yun , Chuang Yu-Chung , Huang Yu-Shan , Lin Kuan-Yin , Huang Sung-Hsi , Chen Guan-Jhou , Luo Yu-Zheng , Wu Pei-Ying , Liu Wen-Chun , Hung Chien-Ching , Chang Shan-Chwen
Published: September 2019

Objectives

Rapid initiation of antiretroviral therapy (ART) engenders faster viral suppression but with suboptimal rates of durable viral suppression and engagement in care, as reported by clinical trials in resource-limited settings. Real-world experience with rapid ART initiation remains limited in resource-rich settings.

Design

Retrospective cohort study.

Setting

A tertiary hospital in metropolitan Taipei, Taiwan.

Participants

We included 631 patients newly diagnosed as having HIV infection between March 2014 and July 2018.

Main outcome measures

Rapid ART initiation was defined as starting ART within 7 days after HIV diagnosis confirmation. HIV diagnosis, ART initiation and viral suppression dates and clinical outcome data were collected by reviewing medical records. The rates of loss to follow-up (LTFU), engagement in care and virological rebound at 12 months were compared between patients with rapid ART initiation and those with standard initiation.

Results

Rapid ART initiation increased from 33.8% in 2014 to 68.3% in 2017, and the median interval between HIV diagnosis and viral suppression (HIV RNA load <200 copies/mL) decreased from 138 to 47 days. Patients with rapid ART initiation had a significantly higher rate of engagement in care at 12 months than did those with standard initiation (88.3% vs 79.0%; p=0.002). Patients aged <30 years had a higher risk of LTFU (HR: 2.19; 95% CI 1.20 to 3.98); and rapid ART initiation was associated with a lower risk of LTFU (HR: 0.41; 95% CI 0.24 to 0.83). Patients aged <30 years were more likely to acquire incident sexually transmitted infections (STIs) before achieving viral suppression.

Conclusions

Rapid ART initiation was associated with a higher rate of engagement in care at 12 months and shortened interval from diagnosis to HIV suppression. Delayed ART initiation may increase onwards HIV transmission considering the high rates of STIs.

Ethics approval

The study was approved by the Research Ethics Committee of National Taiwan University Hospital (Registration No. 201003112R).
Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia
Authors: Graham Neil SN , Sharp David J
Published: September 2019

Traumatic brain injury (TBI) leads to increased rates of dementia, including Alzheimer’s disease. The mechanisms by which trauma can trigger neurodegeneration are increasingly understood. For example, diffuse axonal injury is implicated in disrupting microtubule function, providing the potential context for pathologies of tau and amyloid to develop. The neuropathology of post-traumatic dementias is increasingly well characterised, with recent work focusing on chronic traumatic encephalopathy (CTE). However, clinical diagnosis of post-traumatic dementia is problematic. It is often difficult to disentangle the direct effects of TBI from those produced by progressive neurodegeneration or other post-traumatic sequelae such as psychiatric impairment. CTE can only be confidently identified at postmortem and patients are often confused and anxious about the most likely cause of their post-traumatic problems. A new approach to the assessment of the long-term effects of TBI is needed. Accurate methods are available for the investigation of other neurodegenerative conditions. These should be systematically employed in TBI. MRI and positron emission tomography neuroimaging provide biomarkers of neurodegeneration which may be of particular use in the postinjury setting. Brain atrophy is a key measure of disease progression and can be used to accurately quantify neuronal loss. Fluid biomarkers such as neurofilament light can complement neuroimaging, representing sensitive potential methods to track neurodegenerative processes that develop after TBI. These biomarkers could characterise endophenotypes associated with distinct types of post-traumatic neurodegeneration. In addition, they might profitably be used in clinical trials of neuroprotective and disease-modifying treatments, improving trial design by providing precise and sensitive measures of neuronal loss.
Flavour types used by youth and adult tobacco users in wave 2 of the Population Assessment of Tobacco and Health (PATH) Study 2014–2015
Authors: Rose Shyanika W , Johnson Amanda L , Glasser Allison M , Villanti Andrea C , Ambrose Bridget K , Conway Kevin , Cummings K. Michael , Stanton Cassandra A. , Delnevo Cristine , Wackowski Olivia A , Edwards Kathryn C , Feirman Shari P , Bansal-Travers Maansi , Bernat Jennifer , Holder-Hayes Enver , Green Victoria , Silveira Marushka L , Zhou Yitong , Abudayyeh Haneen , Hyland Andrew
Published: September 2019

Background

Most youth and young adult (YA) tobacco users use flavoured products; however, little is known about specific flavours used.

Methods

We report flavour types among US tobacco users from the Population Assessment of Tobacco and Health Study, wave 2, 2014–2015. At wave 2, we examined (1) flavour use and type at past 30-day use; (2) new flavoured tobacco product use and type; (3) product-specific flavour patterns across youth (ages 12–17) (n=920), YA (18–24) (n=3726) and adult (25+) (n=10 346) past 30-day and new tobacco users and (4) concordance between self-coded and expert-coded brand flavour type among all adults (18+).

Results

Prevalence of flavoured tobacco product use was highest among youth, followed by YA and adult 25+ any tobacco users. Within each age group, flavoured use was greatest among hookah, e-cigarette and snus users. Overall, menthol/mint, fruit and candy/sweet were the most prevalent flavour types at first and past 30-day use across age groups. For past 30-day use, all flavour types except menthol/mint exhibited an inverse age gradient, with more prevalent use among youth and YAs, followed by adults 25+. Prevalence of menthol/mint use was high (over 50% youth, YAs; 76% adults 25+) and exhibited a positive age gradient overall, though the reverse for cigarettes. Brand-categorised and self-reported flavour use measures among adults 18+ were moderately to substantially concordant across most products.

Conclusions

Common flavours like menthol/mint, fruit and candy/sweet enhance appeal to young tobacco users. Information on flavour types used by product and age can inform tobacco flavour regulations to addess flavour appeal especially among youth.
Extracellular pyruvate kinase M2 facilitates cell migration by upregulating claudin-1 expression in colon cancer cells
Authors: Kim Hyunju , Kim Seong Ho , Hwang Dohyeon , An Jinsu , Chung Hak Suk , Yang Eun Gyeong , Kim So Yeon
Published: September 2019

Extensive studies have been reported the non-canonical functions of pyruvate kinase M2 (PKM2) as a kinase, transcriptional regulator, and even cell-to-cell communicator, emphasizing its importance in various signaling pathways. However, the role of secreted PKM2 in cancer progression and its signaling pathway is yet to be elucidated. In this study, we found that extracellular PKM2 enhanced the migration of low-metastatic, benign colon cancer cells by upregulating claudin-1 expression and internalizing it to the cytoplasm and nucleus. Knock-down of claudin-1 significantly reduced extracellular PKM2-induced cell migration. Inhibition of either protein kinase C (PKC) or epidermal growth factor receptor (EGFR) resulted in a reduction of extracellular PKM2-mediated claudin-1 expression, suggesting EGFR–PKC–claudin-1 as a signaling pathway in the extracellular PKM2-mediated tumorigenesis of colon cancer cells.
Systemic Lupus Erythematosus Presented with Bilateral Orbital Edema and Negative Serology
Authors: Al-Khaldi Manal , Alsabbagh Manal
Published: September 2019

Isolated bilateral periorbital edema with negative serology is an extremely rare presentation of cutaneous lupus erythematosus that may lead to eyelid scarring, infection, or even corneal involvement. The treatment usually comprises a combination of hydroxychloroquine and a tapering dose of systemic steroids. Patients require long-term follow-up as they may develop systemic lupus erythematosus with positive serology later in life. We report a case of a 32-year-old female who presented with chronic bilateral periorbital edema, and the histopathology confirmed cutaneous lupus erythematosus.
Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance)
Authors: Yuan Chen , Sato Kaori , Hollis Bruce W. , Zhang Sui , Niedzwiecki Donna , Ou Fang-Shu , Chang I-Wen , O'Neil Bert H. , Innocenti Federico , Lenz Heinz-Josef , Blanke Charles D. , Goldberg Richard M. , Venook Alan P. , Mayer Robert J. , Fuchs Charles S. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: September 2019

Purpose:

Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.

Experimental Design:

We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.

Results:

At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20–<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.

Conclusions:

In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.
Phosphoinositide 3-Kinase Signaling Can Modulate MHC Class I and II Expression
Authors: Chandrasekaran Sanjay , Sasaki Maiko , Scharer Christopher D. , Kissick Haydn T. , Patterson Dillon G. , Magliocca Kelly R. , Seykora John T. , Sapkota Bishu , Gutman David A. , Cooper Lee A. , Lesinski Gregory B. , Waller Edmund K. , Thomas Susan N. , Kotenko Sergei V. , Boss Jeremy M. , Moreno Carlos S. , Swerlick Robert A. , Pollack Brian P.
Published: September 2019

Molecular events activating the PI3K pathway are frequently detected in human tumors and the activation of PI3K signaling alters numerous cellular processes including tumor cell proliferation, survival, and motility. More recent studies have highlighted the impact of PI3K signaling on the cellular response to interferons and other immunologic processes relevant to antitumor immunity. Given the ability of IFNγ to regulate antigen processing and presentation and the pivotal role of MHC class I (MHCI) and II (MHCII) expression in T-cell–mediated antitumor immunity, we sought to determine the impact of PI3K signaling on MHCI and MHCII induction by IFNγ. We found that the induction of cell surface MHCI and MHCII molecules by IFNγ is enhanced by the clinical grade PI3K inhibitors dactolisib and pictilisib. We also found that PI3K inhibition increases STAT1 protein levels following IFNγ treatment and increases accessibility at genomic STAT1-binding motifs. Conversely, we found that pharmacologic activation of PI3K signaling can repress the induction of MHCI and MHCII molecules by IFNγ, and likewise, the loss of PTEN attenuates the induction of MHCI, MHCII, and STAT1 by IFNγ. Consistent with these in vitro studies, we found that within human head and neck squamous cell carcinomas, intratumoral regions with high phospho-AKT IHC staining had reduced MHCI IHC staining.

Implications:

Collectively, these findings demonstrate that MHC expression can be modulated by PI3K signaling and suggest that activation of PI3K signaling may promote immune escape via effects on antigen presentation.
Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults
Authors: Gregory Michael A. , Manuel-Apolinar Leticia  , Sánchez-Garcia Sergio , Villa Romero Antonio R. , de Jesús Iuit Rivera Jaime , Basurto Acevedo Lourdes , Grijalva-Otero Israel , Cuadros-Moreno Juan , Garcia-de la Torre Paola , Guerrero Cantera Jose , Garcia Dominguez Juana Angélica , Martínez Gallardo Sergio , Vega Garcia Sara , Mejía Alonso Laura Alejandra , Sánchez-Arenas Rosalinda
Published: September 2019

Background: Endothelial dysfunction and subsequent inflammation contribute to the development of vascular cognitive impairment (VCI). Soluble intercellular adhesion molecule-1 (sICAM-1) is upregulated in endothelial dysfunction and promotes an inflammatory response; however, the relationship between sICAM-1 and VCI remains equivocal. Objective: To determine whether sICAM-1 contributes to the prediction of VCI. Methods: Community-dwelling older adults (n = 172) from the “Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults” (COSFOMA) study were identified as VCI or controls using standard neuropsychological evaluations and neuroimaging. sICAM-1 was quantified using ELISA, and multivariate logistic regression determined the association between sICAM-1 and VCI. Results: A total of 31 VCI cases were identified. sICAM-1 was higher in VCI (VCI: 450.7 [241.6] ng/mL vs. controls: 296.9 [140.9] ng/mL). sICAM-1 concentrations above the 90th percentile (464.1 ng/mL) were associated with VCI group membership in all models (OR: 6.9, 95% CI: 1.1–42.2). The final saturated model explained 64% of the variance in VCI group membership. Conclusion: High concentrations of sICAM-1 are independently associated with VCI group membership. Efforts to further characterize the relationship between indices of endothelial dysfunction and pathological changes to the aging brain should be further pursued.
Reactions to Synthetic Membranes Dialyzers: Is there an Increase in Incidence?
Authors: Martin-Navarro Juan , Esteras Raquel , Castillo Esmeralda , Carriazo Sol , Fernández-Prado Raúl , Gracia-Iguacel Carolina , Mas Fontao Sebastian , Ortíz Alberto , González-Parra Emilio
Published: September 2019

Background: Reactions to dialyzers used in dialysis have been reported more frequently in recent years. Evidence, however, shows that the reaction rate has remained stable for years. Summary: One explanation for the apparent increase in publication frequency could be the lack of knowledge that dialyzer reactions may well occur with biocompatible membranes. Studies showed that the cause of these reactions is very diverse and varied, involving multiple materials. However, polyvinylpyrrolidone continues to be the main suspect, but without conclusive results. There are no differences between the different fibers, and although polysulfone is the most described, it is also the most used. Key Messages: The change to cellulose triacetate continues to be the most appropriate form of treatment. The classification of these reactions into type A and B complicates the diagnosis, and its true usefulness is in doubt.
Ultraviolet Radiation Exposure of One Eye Stimulates Sympathizing Expression of Neurokinin-1 Receptor but Not Monocyte Chemoattractant Protein-1 in the Partner Eye
Authors: Gross Janine , Willimsky Eva , Wegener Alfred R. , Kronschläger Martin , Schönfeld Carl-Ludwig , Holz Frank G. , Meyer Linda M.
Published: September 2019

Purpose: To investigate the influence of unilateral ultraviolet radiation (UVR) exposure on the unexposed, partner eye in vivo. To characterize the immunological cross-talk between the eyes and verify a sympathizing reaction of the partner eye via a neurokinin-dependent signaling pathway of substance P and its neurokinin-1 receptor (NKR-1) and/or monocyte chemoattractant protein-1 (MCP-1). Methods: C57BL/6 mice were unilaterally exposed in vivo to UVR-B to a 5-fold cataract threshold equivalent dose of 14.5 kJ/m2 with a UV irradiation Bio-Spectra system. The unexposed contralateral eye was completely shielded during irradiation. After 3 and 7 days post exposure, eyes were stained with fluorescence-coupled antibody for substance P NKR-1. The same was performed in control animals receiving only anesthesia but no UVR-B exposure. NKR-1 and MCP-1 levels in ocular tissue lysates were quantified by enzyme-linked immunosorbent assay. Results: UVR-B induces NKR-1 upregulation after 3 and 7 days in the exposed and in the unexposed, contralateral mouse eye. NKR-1 protein level was upregulated in the exposed and contralateral iris/ciliary body complex, choroidea and in the contralateral retina as well as in the exposed cornea. MCP-1 levels were elevated in the exposed cornea, iris/ciliary body complex, and aqueous humor but not in contralateral ocular tissues. Conclusions: UVR-B exposure triggers NKR-1 upregulation not only in the exposed but also in the unexposed, partner eye in various ocular tissues. Following UVR-B exposure, MCP-1 protein levels are upregulated in the exposed eye, but the contralateral side remains unaffected.
Randomized Controlled Trial on the Effects of Morning versus Evening Primary Vaccination on Episodes of Hypoxemia and Bradycardia in Very Preterm Infants
Authors: Gottlob Stefan , Gille Christian , Poets Christian F.
Published: September 2019

Background: Hypoxemia and bradycardia occur frequently in preterm infants, but are incompletely understood. They are more prevalent during infections and following immunization. Data on adults suggested an increased immune response if subjects slept following vaccination, suggesting an interaction between circadian rhythm and the immune system. Whether this holds true for preterm infants with their less well-established circadian rhythm is unclear. Objective: Do infants born at 26–30 weeks’ gestation and having received their first routine hexavalent vaccination in the morning have a lower cardiorespiratory event rate (CER) after vaccination than those receiving it in the evening? Methods: Twenty-six infants were randomized to an evening versus morning vaccination group in a pilot and main study with 10 and 16 participants, respectively. Pulse oximeter saturation, actigraphy, and rectal temperature were obtained for 24 h before and after vaccination. Blood samples for vaccination titers were taken before vaccination and during a follow-up examination in our outpatient clinic; another blood sample was taken 24 h after vaccination to determine inflammatory markers. Results: Vaccination led to an increase in CER in both groups, but there was no difference in CER between the morning and evening groups. Vaccination titers for Bordetella pertussis were increased in both groups, with no difference in inflammatory markers 24 h after vaccination. Body temperature increased in both groups after vaccination. Participants in the evening group slept longer after vaccination. Conclusions: We did not identify a difference in CER between morning and evening vaccination but could confirm increased body temperatures and vaccination titers following vaccination.
Microstructural Correlates and Laterality Effect of Prospective Memory in Non-Demented Adults with Memory Complaints
Authors: Hsu Yen-Hsuan , Huang Ching-Feng , Huang Wen-Hui , Deng Jie-Fu , Tu Min-Chien
Published: September 2019

Background: An increasing number of studies suggest the importance of prospective memory (ProM) due to its functional relevance and sensitivity to neuropathology. However, its relevant neural substrates have not been sufficiently explored. Objectives: The present study aimed to investigate the relationship between structural connectivity and both objective and subjective ProM measures in a group of non-demented people with subjective memory complaints, and to examine the potential of ProM measures to detect the difference between subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in the pre-dementia stage. Method: Thirty-sevennon-dementedparticipants aged above 50 years were recruited from an outpatient Neurology Clinic; 13 of them fulfilled the criteria of MCI and 24 of SCD. All subjects received comprehensive neuropsychological tests, including the adapted version of the Cambridge Prospective Memory Test, as well as the Taiwan version of the Prospective and Retrospective Memory Questionnaire. The diffusion tensor imaging technique with tract-based spatial statistics was applied to measure cerebral microstructural changes. Results: Time-based ProM performance was significantly correlated with microstructural integrity of the right superior longitudinal fasciculus, while the event-based one was associated with that of the left superior longitudinal fasciculus and the genu of the corpus callosum among all participants and in the SCD group. After controlling for age, the correlation remained significant between event-based ProM performance and the left superior longitudinal fasciculus among all participants and in the MCI group, as well as between event-based ProM performance and the genu among all participants. Although self-reported ProM failures in real life was associated with fiber disruption of the left superior longitudinal fasciculus among all participants and within the MCI group, an inverse relationship was also observed with that of the corpus callosum in the SCD group even after controlling for age. As compared to the SCD group, people with MCI performed significantly worse on time-based ProM tasks and reported more ProM failures in daily life. Conclusions: ProM was related to the integrity of interhemispheric commissural fibers and association fibers that connect the frontal lobe with posterior regions, with a task-specific laterality effect. Time-based ProM tasks and self-reported ProM questionnaire may be sensitive to early pathological cognitive deterioration, while the concomitant aging process and individual awareness level may respectively confound the results of evaluation.
How Is Endoscopic Submucosal Dissection for Gastrointestinal Lesions Being Implemented? Results from an International Survey
Authors: Araújo-Martins Miguel , Pimentel-Nunes Pedro , Libânio Diogo , Borges-Canha Marta , Dinis-Ribeiro Mário
Published: September 2019

Background and Study Aim: Superficial gastrointestinal (GI) neoplasms can be treated with endoscopic mucosal resection (EMR) and/or endoscopic submucosal dissection (ESD). These techniques are widely used in Eastern countries; however, its use in the West is limited. The aim of this study was to evaluate the current implementation of ESD in Western countries. Methods: Western endoscopists (n = 279) who published papers related to EMR/ESD between 2005 and 2017 were asked to complete an online survey from December 2017 to February 2018. Results: A total of 58 endoscopists (21%) completed the survey. Thirty performed ESD in the esophagus (52%), 45 in the stomach (78%), 36 in the co­lorectum (62%), and 6 in the duodenum (10%). The median total number of lesions ever treated per endoscopist was 190, with a median number per endoscopist in 2016 of 41 (7 [IQR 1–21], 6 [IQR 4–16], and 28 [5–63] in the esophagus, in the stomach, and in the colon and rectum, respectively). En bloc resection rates were 97% in the esophagus, 95% in the stomach, and 84% in the colorectum. Complete resection (R0) was achieved in 88, 91, and 81%, respectively. Curative rates were 69, 70, and 67%, respectively. Major complications (perforation or delayed bleeding) occurred more often in colorectal ESD (12 vs. 6% in the esophagus and 7% in the stomach). In the upper GI tract, the majority of resected lesions were intramucosal adenocarcinoma (59% in the esophagus; 47% in the stomach), while in the colorectum the majority were adenomas (59%). Conclusion: ESD seems to be performed by a large number of centers and endoscopists. Our results suggest that ESD is being successfully implemented in Western countries, achieving a good rate of efficacy and safety according to European guidelines.
Joint Association of Serum Homocysteine and High-Sensitivity C-Reactive Protein with Arterial Stiffness in Chinese Population: A 12-Year Longitudinal Study
Authors: Wang Keke , Wang Yang , Chu Chao , Hu Jiawen , Zheng Wenling , Yan Yu , Ma Qiong , Gao Ke , Yuan Yue , Mu Jianjun
Published: September 2019

Background: Elevated plasma homocysteine (Hcy) and high-sensitivity C-reactive protein (hsCRP) levels are independent risk factors for cardiovascular diseases. However, it is unclear whether the coexistence of these conditions accelerates the risk of arterial stiffness. Our study aimed to evaluate the association of combined Hcy and hsCRP with arterial stiffness in Chinese middle-aged adults. Material/Methods: We conducted a 12-year longitudinal study in 220 individuals in Hanzhong, China, from 2005 to 2017. The average age at follow-up was 41.83 ± 3.10 years. Demographic information, medical history, anthropometric measurements, and blood pressure as well as urine and fasting blood samples, including Hcy, hsCRP, and brachial-ankle pulse wave velocity (baPWV) were measured and analyzed. Results: BaPWV levels showed a linear growth trend with the increasing of hsCRP (p for trend <0.01). The ORs in the highest quartile compared to the lowest quartile were 1.985 (95% CI 0.776–5.077; p = 0.152) and 3.960 (95% CI 1.468–10.684; p= 0.007) for Hcy and hsCRP, respectively. When Hcy and hsCRP were combined, subjects in both the highest quartile of Hcy and hsCRP (Hcy ≥15.50 μmol/L and hsCRP ≥0.82 μmol/L) had a 12.68-fold increased risk of developing arterial stiffness at the 12-year follow-up compared to those in the lowest quartile of Hcy and hsCRP (Hcy ≤9.91 μmol/L and hsCRP ≤0.19 μmol/L) after adjusting for potential confounders. Conclusions: The present study demonstrated that the combination of elevated serum Hcy and hsCRP may contribute to an increased risk of arterial stiffness.