bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prenatal Histological, Cellular and Molecular Anomalies in Down Syndrome Lung
Authors: Danopoulos Soula , Bhattacharya Soumyaroop , Deutsch Gail , Mariani Thomas , Alam Denise Al 
Published: April 2020

RationaleDown Syndrome (DS), from trisomy 21 (T21), is the most common human chromosomal anomaly in the United States. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin.MethodsPrenatal DS lung histology (n=15) was assessed by H&E. Comprehensive gene expression assessment in prenatal DS lungs (n=19), and age‐matched controls (n=19), was performed using high‐throughput RNA sequencing (RNAseq) and validated by qPCR. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC) and in situ hybridization (ISH).ResultsHistopathological abnormalities were observed in approximately half of DS (T21) prenatal lung tissue samples analyzed, and included dilated airway terminal airways/acinar tubules, dilated lymphatics and muscularized arteries. RNAseq identified 316 genes significantly dysregulated in DS lung tissue (FDR <0.05), when adjusted for age. Ontology analysis showed IFN pathway genes were significantly up‐regulated and extracellular matrix pathway genes were significantly down‐regulated. qPCR confirmed increased expression of interferon (IFN) pathway genes (MX1, IFIT27), COL6A1, and FABP4, and lower expression of SOX2 in prenatal DS lungs. ISH indicated increased IFN receptor expression in DS lung tissue. IHC for KI67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in those tissues displaying pathology. Airway smooth muscle was reduced and discontinuous in the proximal airway. Reduction in SOX2 was confirmed by IHC, suggesting a reduction in prenatal airway progenitor cells.ConclusionsOur data demonstrate for the first time that specific histological, cellular and molecular abnormalities occur prenatally in the human DS lung.Support or Funding InformationFunding Source: NIH/NHLBI HL141856 and Program in Pediatric Molecular and Personalized Medicine of University of Rochester.
Reflection & Self‐Assessment Cycles in a Medical School Anatomy Course
Authors: Patitucci Teresa Noel , Fritz Jeffery D. 
Published: April 2020

Looking beyond medical knowledge into developing character traits like professionalism, self‐awareness, and empathy is a current focus in medical education. Critical reflection and self‐assessment can be used as tools to develop these skills. The aim of this study was to use repeated critical reflection and self‐assessment in a cadaver‐based first‐year medical school human gross anatomy course to develop professional identity and emotional intelligence.First, learners wrote a critical reflection in response to their choice of writing prompt and received faculty feedback. Learners then completed a self‐assessment of growth in areas of emotional intelligence, listed personal growth fronts, and developed a SMART goal, again receiving faculty feedback. This paradigm was repeated for each block of the course, resulting in 4 cycles total. Reflections were blinded and evaluated using qualitative analysis by two independent coders into three themes: emotional intelligence, teamwork, and wellness/well‐being. At the end of the semester, learners completed a voluntary perception survey using Qualtrics. This project was approved by the Medical College of Wisconsin Institutional Review Board (PRO00032535).In the area of emotional intelligence, students described struggling with perfectionism in the beginning of the course but by the end reported increased confidence. Learners also described empathy for their “first patient”. In the area of teamwork, students started the year skeptical to work as a group for so long but later appreciated the need to openly acknowledge strengths and weaknesses. An appreciation for the importance of trust amongst team members was also reported at the end of the year. In the well‐being theme, learners began the semester dealing with the concept of death which makes sense given the nature of the course. Around the middle of the semester they really struggled with social and physical wellness. Data on the Emotional Intelligence Inventory suggest that learners found the reflective process to have a positive influence on their growth in the 5 domains of emotional intelligence. Learners most frequently identified self‐care, teamwork, confidence, wellness, time‐management, empathy and adaptability as growth fronts throughout the duration of the course. Follow‐up surveys were completed by 71% of participants where 86.7% of respondents recommended continuing reflective writing assignments in the anatomy course, and two‐thirds could see themselves adapting the reflection/self‐assessment process outside of clinical human anatomy.In this study, we learned that the first year of medical school is filled with transitions where ongoing personal development of emotional intelligence and goal‐setting can be beneficial. Our learners reported the most growth in areas of self‐awareness and teamwork with continued challenges in the areas of physical & social wellbeing, and personal identity formation (imposter syndrome).Support or Funding InformationMedical College of Wisconsin Learning Resource Fund
Analyzing Murine Microglial Cell Response to Different Types of Particulate Matter
Authors: Merrill Lucas , Buchmann Kelsey , Stadem Nathan , Street Mikayla , Mazzer Paula 
Published: April 2020

Alzheimer’s and other neurodegenerative diseases affect nearly 24.3 million individuals globally— a number that will likely increase with the rising world population [1]. Studies conducted in Mexico City, Mexico suggest there may be a link between air pollution and chronic inflammation in the brain [4;5]. Research by Lillian Calderón‐Garcidueñas et al. showed that dogs and humans living in Mexico City, Mexico, a city with high amounts of air pollution, developed higher amounts of inflammation in the brain compared to humans and dogs residing in more rural areas [2;3]. Two hallmarks of Alzheimer’s and other related neurodegenerative diseases are the accumulation of β‐amyloid plaques and oxidative stress resulting in apoptosis. Exposing diesel exhaust particulate (DEP) from an industrial forklift engine (NIST, Boulder, CO) and urban dust (UD) filtered from Washington, D.C. (NIST, Boulder, CO) to cultured murine microglial cells (CRL‐2467; ATCC, Manassas, VA), we measured for the activation, production of reactive oxygen species (ROS), and apoptosis in microglial cells. We measured for caspase‐3 activity using a Caspase‐3/CPP32 Colorimetric Kit (Life Technologies, Fredrick, MD), activation by measuring for TNF‐α using mouse tumor necrosis factor α Elisa Kit (Sigma Aldrich, St. Louis, MO), and measured for ROS using an amplex red assay (ThermoFisher Scientific, Minneapolis, MN). We found a possible increase in TNF‐α production in cells cultured with DEP and no increase in ROS in our cells cultured with neither DEP nor UD.Support or Funding InformationSouth Dakota Biomedical Research Infrastructure Network
Development of a dopaminergic neurodegeneration assay using laser cytometry of Caenorhabditis elegans models of Parkinson’s disease
Authors: Akano Emmanuel O. , Casazza Julia A. , Dranchak Patricia , Moritz Amy E. , Free R Benjamin , Inglese James , Sibley David R. 
Published: April 2020

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons resulting in bradykinesia, tremor, gait abnormalities, and numerous non‐motor complications. The prevalence and economic burden of PD is increasing due to an aging population. However, there are currently no drugs to halt the progression of this disease. Although loss of dopamine in the basal ganglia is recognized as the hallmark of PD, the molecular mechanisms underlying this loss and subsequent brain dysfunction remain poorly characterized. The majority of PD animal models involve the administration of neurotoxins that target dopaminergic neurons leading to their degeneration, however these models correlate poorly with the disease progression in humans. More accurate models may utilize genetic modulation of PD‐related genes and exhibit progressive neurodegeneration. Here, we report the development of a high‐throughput assay for monitoring dopaminergic neurodegeneration in Caenorhabditis elegans (C. elegans). Two strains of C. elegans containing human PD‐linked genes were used, one expressing mutant (A53T) alpha‐synuclein, and the other expressing mutant (G2019S) leucine‐rich repeat kinase 2 (LRRK2). Both strains express GFP in their dopaminergic neurons and the lines were further crossed into a neuronal RNAi‐sensitive background strain expressing mCherry under a pharyngeal promoter. This allows for the accurate measurement of dopaminergic neurons (via GFP) and a normalization and sorting control of the total number of worms plated (via mCherry). Daily measurements of GFP/mCherry fluorescence intensity were performed using laser cytometry of worms sorted into 384‐well microplates. Robust temporal degeneration of dopaminergic neurons was found to occur within the first eight days of adulthood in the C. elegans models of PD, but not in a wild‐type control strain. The LRRK2 model was particularly severe as total GFP intensity dropped by 75–85% during the time of assay. We determined a signal (cell loss) to baseline ratio of approximately 4‐fold, sufficient for screening applications. Our results indicate that this assay provides a reproducible high‐throughput measurement of dopaminergic neurodegeneration using an in vivo model. Future studies may exploit this model to conduct quantitative high‐throughput screens to identify small molecules capable of inhibiting this neurodegeneration or to use RNAi libraries to identify genes mediating the neurodegenerative response, and hence new drug targets for the treatment of PD.Support or Funding InformationThis study is supported by the intramural program of the NINDS/NIH
Essential role of NFATC4‐S‐palmitoylation to promote IP3R1‐expression required for lysosomal Ca++ homeostasis dysregulated in INCL mice
Authors: Mondal Avisek , Sadhukhan Tamal , Appu Abhilash P. , Bagh Maria B. , Mukherjee Anil B. 
Published: April 2020

Infantile Neuronal Ceroid Lipofuscinosis (INCL), commonly known as infantile Batten disease, is a devastating neurodegenerative lysosomal storage disease caused by inactivating mutations in the CLN1 gene. CLN1 encodes palmitoyl‐protein thioesterases‐1 (PPT1), a lysosomal depalmitoylating enzyme essential for degradation of S‐palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Despite this discovery more than two decades ago, the precise molecular mechanism of INCL pathogenesis has remained elusive. Here we report that in the brain of Cln1−/− mice, a reliable animal model of INCL, lysosomal Ca++ levels were significantly lower compared with those of their WT littermates. Moreover, in Cln1−/− mice the levels of inositol 1, 4, 5‐triphosphate receptor type‐1 (IP3R1), which facilitates the transport of Ca++ from the ER to the lysosome, were also substantially lower. We found that NFATC4, the transcription factor that regulates Ip3R1‐expression, requires S‐palmitoylation for its translocation from the cytosol to the nucleus. Notably, we identified ZDHHC2 and ZDHHC4 are the palmitoyl acyl transferases that S‐palmitoylate NFATC4. Moreover, the lower levels of these ZDHHCs, S‐palmitoylation of NFATC4 in Cln1−/− mice was significantly decreased suppressing its translocation from the cytosol to the nucleus. Consequently, low IP3R1 expression in Cln1−/− mouse brain significantly reduced lysosomal Ca++ levels. Notably, the enzymatic activities of Ca++‐dependent lysosomal proteases such as cathepsin D (CD) and tripeptidyl peptidase‐1 (TPP1) were markedly inhibited causing lysosomal accumulation of undegraded substrates. Interestingly, mutations in TPP1 (CLN2) and CD (CLN10), cause late infantile NCL (LINCL) and congenital NCL (CNCL), respectively. Our results reveal a previously unrecognized role of Cln1/Ppt1 in regulating lysosomal Ca++ homeostasis and suggest that dysregulation of lysosomal Ca++ homeostasis may compromise its degradative function and contribute to INCL pathogenesis. Studies to determine whether a brain‐penetrant, PPT1‐mimetic, small molecule, NtBuHA, ameliorates this defect are ongoing.Support or Funding InformationNIH intramural Fund
Ribosomal DNA Transcription Induced by Acute Resistance Exercise is Dependent on rDNA Gene Dosage but not Promoter Methylation
Authors: von Walden Ferdinand , Figueiredo Vandré , Fernandez-Gonzalo Rodrigo , Murach Kevin , Mobley Brooks , Norrbom Jessica , McCarthy John , Alkner Björn 
Published: April 2020

Ribosome biogenesis has been shown to increase following resistance exercise; yet, it is currently unknown how promoter methylation and dosage of rDNA genes influence translational capacity, as well as basal and post‐exercise rDNA transcription rates in skeletal muscle. Moreover, whether ribosome biogenesis is induced in response to acute aerobic exercise is not well characterized in skeletal muscle.Healthy volunteers (n=30; 18 men and 12 women; 31 ±8 yrs, 25 ±4 kg/m2) were randomized to an acute bout of either aerobic (AE, 45 min biking, 70% VO2max) or resistance exercise (RE, 4 x 7 x 2 exercises), or control (no exercise). Skeletal muscle biopsies were obtained before and at 30 min, 3‐, 8‐and 24 hrs following the exercise session, and RNA/DNA was extracted. Ribosomal DNA transcription and rDNA copy number were assessed using qRT‐PCR. Average methylation of the rDNA promoter (−189 to +47) was investigated using the Agena massARRAY EpiTYPER.rDNA transcription at baseline was negatively associated with rDNA copy number (r=−0,44, p<0.05) but not with average rDNA promoter methylation. Total RNA was not related to rDNA copy number or degree of methylation of the promoter. RE significantly induced rDNA transcription, whereas AE and control did not. Average methylation of the rDNA promoter (mean: 23%, range: 10–35%) varied among volunteers; however, it was not influenced by exercise at any timepoint. Gene dosage of rDNA strongly correlated to fold‐change in rDNA transcription at the 24h timepoint (r=0.85, p<0.01).Transcription of the rRNA genes increased following resistance exercise but not following aerobic exercise, indicating specificity of exercise modality in stimulating ribosome biogenesis following exercise. Average rDNA promoter methylation varied between subjects but was not affected by exercise. Dosage of the rRNA genes strongly correlated to resistance exercise induced rDNA transcription suggesting the importance of rDNA copy number for ribosome biogenesis, and likely hypertrophic potential.Support or Funding InformationSwedish Research Council for Sport Science (FvW); Futurum – the Academy for Health and Care, Region Jönköping County (BA)
Unplanned ICU Admission From Hospital Wards After Rapid Response Team Review in Australia and New Zealand
Authors: Orosz Judit , Bailey Michael , Udy Andrew , Pilcher David , Bellomo Rinaldo , Jones Daryl 
Published: April 2020

Objectives:
To evaluate what proportion of unplanned ICU admissions from hospital wards occurred after rapid response team review and compare baseline characteristics and outcomes of patients admitted after rapid response team review with non-rapid response team-related admissions.

Design:
Multicenter binational retrospective cohort study.

Setting:
One-hundred seventy-eight ICUs across Australia and New Zealand.

Patients:
All adults (≥ 17 yr) in the Australian and New Zealand Intensive Care Society Adult Patient Database between 2012 and 2017.

Interventions:
None.

Measurements and Main Results:
Among 97,181 unplanned ICU admissions from the ward, prior rapid response team review occurred in 55,084 cases (56.7%). Rapid response team patients were slightly older (65.4 [16.9] vs 63.3 [18]), had a higher Acute Physiology and Chronic Health Evaluation III score (64.6 [27.1] vs 54.7 [25.3]) and more frequently had limitations of medical treatment (13.1% vs 8.5%) compared with patients with no rapid response team review. The strongest independent associations with ICU admission following rapid response team review included age, ICU admission diagnosis (especially sepsis-, neurologic-, respiratory-, and cardiovascular-related), tertiary ICU status, and presence of limitations of medical treatment (p < 0.0001 all comparisons). Rapid response team-related ICU admissions had a longer median ICU (2.4 d [1.2–4.6 d] vs 2.1 d [1.0–4.2 d]) and hospital (12.8 d [7.0–23.6 d] vs 10.8 d [5.9–20.3 d]) length of stay, and were more likely to die in the ICU (12.3% vs 7.5%) and in-hospital (20.8% vs 13.5%) (p < 0.0001). After adjusting for illness severity and institution, patients admitted following rapid response team review stayed longer in hospital but were not at increased risk of dying in-hospital (adjusted odds ratio, 1.03; 0.98–1.07).

Conclusions:
In Australia and New Zealand, hospital ward patients admitted to ICU following rapid response team review represent the majority of ward-based ICU admissions, are more chronically and acutely ill, and more frequently have sepsis than those admitted from the ward without rapid response team review. Their unadjusted outcomes are worse, but after adjustment their mortality is similar.
New information flows for cancer registries: testing the use of laboratory data in the province of Reggio Emilia, Italy
Authors: Roncaglia Francesca , Mancuso Pamela , Vicentini Massimo , Vitiello Antonio , Vecchia Luigi , Luminari Stefano , Mangone Lucia , Zorzi Manuel , La Vecchia Carlo , Giorgi Rossi Paolo 
Published: April 2020

Introduction
Haematological malignancies often escape the standard information flows of cancer registries because diagnosis is not always based on bone marrow histology but, rather, on other laboratory tests.

Objective
To quantify incident haematological malignancies identified exclusively through the laboratory information system and to measure the impact of that source on the sensitivity and accuracy of registering these malignancies.

Methods
We collected data from the only provincial laboratory of Reggio Emilia on molecular biology, flow cytometry tests and bone marrow smears to detect specific markers of some chronic haematological malignancies. We carried out a record linkage between laboratory reports (period 2013–2017) of patients resident in the province of Reggio Emilia and the Cancer Registry of Reggio Emilia.

Results
Of the 303 patients who underwent at least one of these tests, 85 were not included in our Cancer Registry. Of these 85 patients, 42 had received a diagnosis of cancer: 34 myeloproliferative neoplasms, 3 chronic myeloid leukaemias, 3 myelodysplastic neoplasms, 1 multiple myeloma and 1 chronic lymphocytic leukaemia. We recovered 4.2% of the total number of chronic haemolymphopoietic cancers registered in the study period, accounting for 15% of myeloproliferative neoplasms. For 30% of prelinkage cases, the specificity of the morphological code improved.

Conclusions
Although the laboratory information system’s contribution to the completeness of Cancer Registry incident cases was modest, it is useful to add laboratory data to routine cancer registry information flows due to the increasing use of molecular characterisation and to the phenomenon of dehospitalisation.
Role of sex steroid hormones in pelvic organ prolapse
Authors: Reddy Ravali A. , Cortessis Victoria , Dancz Christina , Klutke John , Stanczyk Frank Z. 
Published: April 2020

Abstract

Objective:
Pelvic organ prolapse (POP) affects a significant percentage of women and contributes to major healthcare costs both in the United States and worldwide. This review examines the current understanding of the role of sex steroid hormones (estrogens, androgens, and progesterone) in POP in premenopausal, perimenopausal, and postmenopausal women.

Methods:
We reviewed the relevant studies on POP related to estrogens, androgens, and progesterone in both animal models and humans.

Results:
Estrogen has a profound influence on the synthesis and metabolism of pelvic connective tissues, and may have the ability to both prevent POP and improve prognosis if used therapeutically. There is limited research regarding the role of androgens and progesterone and their receptors in POP and results so far have been contradictory, warranting further study to determine whether changes in androgen and progesterone receptor expression are a cause or effect of POP.

Conclusions:
Because of the role that estrogen plays in maintaining the integrity of pelvic floor connective tissues, we propose that rigorous and well-controlled studies are needed on the role of exogenous estrogen administration as a form of POP prevention.

Video Summary:
http://links.lww.com/MENO/A583.
IBS Patients’ Treatment Expectancy and Motivation Impacts Quality of the Therapeutic Alliance With Provider
Authors: Lackner Jeffrey M. , Quigley Brian M. , Radziwon Christopher D. , Vargovich Alison M. 
Published: April 2020

Background:
In the absence of a satisfactory medical or dietary treatment, the quality of the therapeutic alliance between irritable bowel syndrome (IBS) patients and their provider is deemed critical to managing refractory IBS. Surprisingly, little research has been conducted on the nature of the therapeutic alliance, factors that influence it, or practical strategies to improve it. This study sought to identify actionable variables that impact therapeutic alliance in patients with refractory IBS.

Methods:
Subjects included a total of 436 Rome III-diagnosed IBS patients (80% female, mean age=41.39 y) who completed a battery of clinical measures at the beginning of the acute treatment phase of an National Institutes of Health (NIH) behavioral trial. Pretreatment candidate predictor variables were organized into 4 categories: sociodemographic, extraintestinal, interpersonal, clinical (eg, symptom severity, pain intensity), cognitive (eg, treatment motivation, expectancy for improvement). Alliance was assessed by patient and clinician-rated measures of the Working Alliance Inventory after first treatment session.

Results:
Patient reports of alliance were most strongly and consistently predicted by patient access to interpersonal support [β=0.16; 95% confidence interval (CI)=0.07-0.25], motivation for IBS symptom improvement (β=0.12; 95% CI=0.02-0.21), and expectancy of IBS symptom improvement (β=0.35; 95% CI=0.25-0.44). Therapist ratings of alliance also were predicted by patient expectancy of IBS symptom improvement (β=0.16; 95% CI=0.05-0.26).

Conclusion:
When managing IBS, a focus on dynamic factors of treatment motivation, social support, and treatment expectancy may be useful in improving the quality of the therapeutic alliance between patient and clinical gastroenterologist.