bluuebunny/crossref_metadata_2025_split huggingface dataset:
The histological microstructure and in vitro mechanical properties of pregnant and postmenopausal ewe perineal body
Authors: Kochová Petra , Hympánová Lucie , Rynkevic Rita , Cimrman Robert , Tonar Zbyněk , Deprest Jan , Kalis Vladimir 
Published: September 2019

Abstract

Objective:
The mechanical properties and microstructure of the perineal body are important for the improvement of numerical models of pelvic organs. We determined the mechanical parameters and volume fractions of the ewe perineal body as an animal model.

Methods:
The 39 specimens of 13 pregnant swifter ewes delivering by cesarean section (aged 2 years, weight 61.2 ± 6.2 kg (mean ± standard deviation) and 24 specimens of 8 postmenopausal swifter ewes 150 days after surgical ovariectomy (aged 7 years, 58.6 ± 4.6 kg)) were loaded uniaxially to determine Young's moduli of elasticity in the small (E0) and large (E1) deformation regions, and ultimate stresses and strains. The 63 adjacent tissue samples were processed histologically to assess volume fractions of smooth and skeletal muscle, adipose cells, elastin, and type I collagen using a stereological point testing grid. We compared the structural and mechanical differences along the ewe perineal body, and between pregnant and postmenopausal groups.

Results:
The pregnant/postmenopausal perineal body was composed of smooth muscle (12/14%; median), skeletal muscle (12/16%), collagen (10/23%), elastin (8/7%), and adipose cells (6/6%). The E0 was 37/11 kPa (median), E1 was 0.97/1.04 MPa, ultimate stress was 0.55/0.59 MPa, and ultimate strain was 0.90/0.87 for pregnant/postmenopausal perineal body. The perineal body showed a structural and mechanical stability across the sites. The pregnant ewes had a higher amount of skeletal muscle, higher E0, and a less amount of collagen when compared with postmenopausal ewes.

Conclusions:
The data can be used as input for models simulating vaginal delivery, pelvic floor prolapsed, or dysfunction.
Histological Corneal Alterations in Keratoconus After Crosslinking—Expansion of Findings
Authors: Müller Philipp L. , Loeffler Karin U. , Messmer Elisabeth , Holz Frank G. , Perdikakis Georgios , Kohlhaas Markus , Herwig-Carl Martina C. 
Published: September 2019

Purpose:
To investigate histopathologic, immunohistochemical, and electron microscopic findings in 8 keratoplasty specimens with a history of corneal collagen crosslinking (CXL) for keratoconus. Five new (hitherto unreported) and 3 previously published specimens were analyzed.

Methods:
Corneal buttons of 8 keratoconus corneas (5–114 months after CXL) were compared with 5 keratoconus specimens without CXL and 5 normal corneas for morphological alterations. Corneal buttons were evaluated by light microscopy and immunohistochemistry using antibodies against CD34, PGP 9.5, nestin, telomerase reverse transcriptase, and Ki67 as well as by transmission electron microscopy.

Results:
Keratoconus corneas after CXL showed a significant keratocyte loss (except 1 specimen with an increased keratocyte number), whereas keratoconus corneas without CXL revealed a higher keratocyte density compared with healthy controls. Keratocyte loss could be clinically correlated with corneal opacification and corneal perforation. In corneas after CXL, the remaining keratocytes appeared more polymorphic and revealed a different expression of surface markers similar to keratocytes in corneal scars. The presence of proteoglycans, nerves, and endothelial cells was unaffected by CXL.

Conclusions:
CXL may cause permanent keratocyte loss or repopulation of altered keratocytes, resulting in clinical complications such as corneal opacification or perforation. Despite its good safety profile and high effectiveness in progressive keratoconus, CXL should be performed in accordance with current guidelines strictly adhering to protocol and safety standards.
Programmed Death Ligand 1 Testing of Endobronchial Ultrasound–guided Transbronchial Needle Aspiration Samples Acquired For the Diagnosis and Staging of Non–Small Cell Lung Cancer
Authors: Smith Allister , Wang Hangjun , Zerbo Alix , Beaudoin Stéphane , Ofiara Linda , Fiset Pierre-Olivier , Benedetti Andrea , Gonzalez Anne V. 
Published: September 2019

Rationale:
Immunotherapy has become an integral part of management in patients with advanced non–small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression in at least 50% of tumor cells on histologic samples has been correlated with improved efficacy of the immune checkpoint inhibitor pembrolizumab. A limited number of studies have examined the suitability of endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) specimens for assessment of PD-L1 status.

Objective:
We sought to examine the feasibility and results of PD-L1 testing performed on EBUS-TBNA samples acquired for the diagnosis and staging of NSCLC.

Materials and Methods:
Patients were identified from a prospectively maintained pathology database. Baseline characteristics were tabulated. Hematoxylin and eosin slides were reviewed to categorize cellularity between <100, 100 to 500, and >500 viable tumor cells. Samples were tested using Dako’s PD-L1 IHC 22C3 pharmDx kit, with a minimum of 100 viable tumor cells. For patients in whom additional tissue samples were available, the results of PD-L1 testing were compared.

Results:
PD-L1 testing was attempted on 120 EBUS-TBNA samples. The most common NSCLC subtype was adenocarcinoma (78%). Seventy-six specimens (63%) had a cellularity >500 tumor cells. Among 110 of 120 (92%) patients with an adequate endobronchial ultrasound (EBUS) sample, 53 of 110 (48.2%) had high PD-L1 expression, defined as a Tumor Proportion Score ≥50%. EBUS PD-L1 results were concordant with an available histologic sample in 14 of 18 patients (78%), with no false-negative results.

Conclusion:
PD-L1 testing was feasible in the majority of EBUS-TBNA samples acquired for the diagnosis and staging of NSCLC. Comparison of EBUS results with histologic samples revealed moderate concordance, with no false-negative results.
Diphenhydramine Use in End-Stage Kidney Disease
Authors: Nguyen Timothy , Polyakova Beatrice , Cerenzio John , Ramilo Josh Renzo 
Published: September 2019

Background:
Diphenhydramine is commonly used in patients with kidney disease and end-stage kidney disease (ESKD) for sleep, allergic reactions, itching, and dialysis treatment related complications, and misuse associated with diphenhydramine is also reported. Diphenhydramine's pharmacokinetics property is reviewed and discussed.

Areas of Uncertainty:
Diphenhydramine is highly bound to albumin. The safety profile and dosing information of diphenhydramine use in ESKD population is lacking. The purpose of this study is to provide an overview of diphenhydramine pharmacokinetic properties and evaluate diphenhydramine use in ESKD population.

Data Sources:
A literature search was conducted during Spring 2019 using PubMed, CINAHL, Cochrane, Ovid, and Google Scholar. Search terms used include “diphenhydramine abuse,” “diphenhydramine dialysis,” and “diphenhydramine kidney disease.”

Results:
There is lack of studies available for diphenhydramine, kidney disease, and dialysis. There were case reports of diphenhydramine abuse and toxicity due to overdose. Diphenhydramine is highly bound to protein that limits its ability to dialyze, and therefore, it may predispose to side effects. Information on diphenhydramine used in the dialysis population is scarce, and dosing toxicity is unknown.

Conclusions:
The data available for use of diphenhydramine in ESKD and dialysis are limited. Clinicians should use caution with the use of diphenhydramine in this population.
Brief Report: Decreased JC Virus-Specific Antibody-Dependent Cellular Cytotoxicity in HIV-Seropositive PML Survivors
Authors: Tan Chen S. , Ghofrani Joshua , Geiger Emma , Koralnik Igor J. , Jost Stephanie 
Published: September 2019

Background:
Progressive multifocal leukoencephalopathy (PML) is an often fatal disease caused by JC virus (JCV) in severely immunocompromised patients, including HIV patients. Development of therapeutics to prevent or treat PML is an urgent medical need. While JCV-specific T cells are crucial to control JCV and recover from PML, the role played by antibodies remains unclear. Anti-JCV antibodies, including potent neutralizing antibodies, can be detected in most infected adults, yet in PML patients, JCV seems to escape from neutralization. Whether antibodies can contribute to JCV control by eliciting Fc-mediated effector functions activity has not been evaluated.

Methods:
We measured the capacity of plasma anti-JCV VP1 antibodies to recruit Fc receptor (FcR)-bearing effector cell functions in 28 HIV patients, comparing subjects without PML with PML survivors (PML S) who were alive 1 year after disease onset or PML progressors (PML P) who succumbed within the first year. Antibody titers against JCV VP1 and HIV gp140 trimer were determined by end-point titer dilution ELISA. FcR–mediated natural killer cell degranulation and IFN-γ production were measured as surrogate for in vitro antibody-dependent cellular cytotoxicity (ADCC).

Results:
PML S had higher JCV antibody titers than PML P and patients without PML. However, anti-JCV antibodies had a higher ability to functionally engage FcR in PML P than PML S. Antibody titers and ADCC activity did not vary over time in PML S. Anti-HIV antibody titers and ADCC activity were similar among groups.

Conclusions:
The ability of anti-JCV antibodies to stimulate FcR-bearing effector cell activity might contribute to the outcome of PML. Further studies are warranted to define Fc-mediated functions of anti-JCV antibodies and evaluate whether ADCC can contain JCV replication.
Microbiology of Implant-Based Breast Reconstruction Infections
Authors: Banuelos Joseph , Abu-Ghname Amjed , Asaad Malke , Vyas Krishna , Sohail M. Rizwan , Sharaf Basel 
Published: September 2019

Background
Postsurgical complications have been an increasing concern for hospitals, particularly in light of payment reform. The costs to the health care system are increasing in light of Medicare penalties for readmissions for certain conditions. Surgical site infection following implant-based breast reconstruction (IBR) remains challenging. The rates of positive cultures and isolated microorganisms in IBR are unknown. This systematic review summarizes the reported microorganisms and positive culture rates in the existing literature.

Methods
A systematic review was performed using the guidelines outlined in Preferred Reporting Items for Systematic Reviews and Meta-analyses. Articles were included if breast implant infection rates and culture results were reported. Further subgroup analysis of culture positive infections was performed.

Results
A total of 25 studies were included, encompassing 25,177 IBR. Implant infections were reported in 1356 reconstructions (5.4%). Cultures were positive in 74.5% of infections. Gram-positive bacteria were the most common (68.6%), of which Staphylococcus species (51%) was the most isolated pathogen, followed by Pseudomonas. A subgroup analysis showed that early infections (63% vs 88%), radiotherapy (82% vs 93%), and acellular dermal matrix use (90% vs 100%) were associated with lower positive culture rates than their respective counterparts. Patients who received chemotherapy had higher positive culture results (94% vs 83%). Isolated microorganisms also varied among the subgroups.

Conclusions
This systematic review outlines reported microorganisms in IBR. Staphylococcus species and Pseudomonas were the most frequently reported microorganism. Negative cultures were reported in up to 25.5% of infections. Patients with early infections, radiotherapy, and acellular dermal matrix demonstrated higher negative culture rates. This review can help guide the use of empirical antimicrobial therapy in IBR.
Adjustable Fat Repositioning With Intraoral Anchoring
Authors: Gao Wei , Qiao Congzhen , Lin Xiaoxi 
Published: September 2019

Background
Prominent tear trough deformity and midfacial depression are the first priority in periorbital rejuvenation. To achieve harmonious lower eyelid improvement, we developed a novel approach to reposition infraorbital fat using intraoral anchoring in transconjunctival lower eyelid blepharoplasty.

Methods
Fourteen patients were included. Blepharoplasty involved infraorbital fat repositioning by intraoral anchoring via a transconjunctival incision to address depression and grooves deformities. Optimal fat repositioning can be achieved by intraorally manipulating suture tension. Photographs were taken both preoperatively and postoperatively. Time of operation, complications, recovery time, and postoperative outcomes were evaluated.

Results
Fourteen patients underwent blepharoplasty between August of 2018 and December of 2018. Their mean age was 36.9 ± 6.1 years. Grooves deformities and depression were eliminated, and the periorbital contour significantly improved. All patients were satisfied with postoperative outcomes. There were no major complications observed.

Conclusions
Intraoral anchoring of the infraorbital fat pedicles yields a significantly improved lower eyelid appearance and requires minimum clinic visits and an extremely short recovery time. In addition, the maneuverable intraoral anchoring allows for customization of patient aesthetics. This approach can be regarded as a true alternative for lower lid rejuvenation, and the outcome is straightforward and predictable.
Triamcinolone Acetonide Suppresses Keloid Formation Through Enhancing Apoptosis in a Nude Mouse Model
Authors: Chen Austin D. , Chen Rong-Fu , Li Yun-Ting , Huang Yu-Ting , Lin Sin-Daw , Lai Chung-Sheng , Kuo Yur-Ren 
Published: September 2019

BackgroundCurrent understanding of steroid treatments for keloids is in regards to modulation of inflammation, proliferation, and apoptosis, with no in vivo study on the latter. Using a nude mouse model, we investigated whether triamcinolone acetonide (TA) injections induce keloids regression through enhancing apoptosis.Materials and MethodsThirty-six keloid specimens (1 × 1 cm) were harvested from 6 patients and separated into sets of 2 from the same patient: no treatment and intralesional TA injection (0.4 mg/mL/kg) at 8 weeks of postimplantation. One set was implanted in each of 18 randomly selected nude mice, which were separated into 3 groups based on time of keloid harvesting after treatment: group A, 2 weeks; group B, 8 weeks; and group C, 14 weeks. Each group had 1 set of specimen from each patient. Histological staining was performed with hematoxylin and eosin stain. Immunohistochemistry staining was performed for human-prolyl 4-hydroxylase (hPH4) and caspase 3 protein, along with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay.ResultsAll keloid specimens survived, with no noted overgrowth. Hematoxylin and eosin staining revealed dense extracellular matrix and viable fibroblasts, and hPH4 immunohistochemistry revealed strong expression, demonstrating keloid viability. Caspase 3 protein and TUNEL expressions were significantly increased in the treatment versus control groups, demonstrating that TA injections induced apoptosis.ConclusionsTriamcinolone acetonide intralesional injections significantly increased apoptosis in keloids, represented by increased caspase 3 protein and TUNEL expressions, supporting that steroids suppress keloids in part owing to enhancement of apoptosis.
Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study
Authors: Watanabe Eizo , Nishida Osamu , Kakihana Yasuyuki , Odani Motoi , Okamura Tatsuaki , Harada Tomohiro , Oda Shigeto 
Published: September 2019

ABSTRACT

Background:
Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers.

Methods:
In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]).

Results:
Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0–163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred.

Conclusions:
A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time.

Trial registration:

JAPIC, JapicCTI-173600.
Early Axonal Injury and Delayed Cytotoxic Cerebral Edema are Associated with Microglial Activation in a Mouse Model of Sepsis
Authors: Pang Diana , Wu Yijen L. , Alcamo Alicia M. , Cummings Jessica , Di Caro Valentina , Walko Thomas , Hsue Victor , Clark Robert S. B. , Panigrahy Ashok , Kochanek Patrick M. , Aneja Rajesh K. 
Published: September 2019

ABSTRACT
Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in preclinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI) to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP). Sepsis was induced in 6–10-week-old male C57/BL6 mice by CLP. We used immunohistochemistry (IHC) to define neuropathology in a mouse model of sepsis along with parallel studies using MRI, focusing on cerebral edema, blood–brain barrier (BBB) disruption, and microglial activation on days 1 and 4 days after CLP. We demonstrate that septic mice had evidence of early axonal injury, inflammation, and robust microglial activation on day 1 followed by cytotoxic edema on day 4 in the cortex, thalamus, and hippocampus in the absence of BBB disruption. We note the superiority of the MRI to detect subtle brain injury and cytotoxic cerebral edema in comparison with the traditional gold standard assessment, i.e., percent brain water (wet-dry weight method). We conclude that inflammatory changes in the septic brain can be detected in real time, and further studies are needed to understand axonal injury and the impact of inhibition of microglial activation on the development of cerebral edema.
The relationship between misfolding avoidance hypothesis and protein evolutionary rates in the light of empirical evidence
Authors: Usmanova Dinara R. , Plata Germán , Vitkup Dennis 
Published: September 2019

AbstractFor more than a decade the misfolding avoidance hypothesis (MAH) and related theories have dominated evolutionary discussions aimed at explaining the variance of molecular clock across cellular proteins. In this study we use various experimental data to further investigate the consistency of the MAH predictions with empirical evidence. We also critically discuss experimental results that motivated the MAH development and that are often viewed as evidence of its major contribution to constraining protein evolution. We demonstrate, in Escherichia coli and Homo sapiens, the lack of a substantial negative correlation between protein evolutionary rates and Gibbs free energies of unfolding, a direct measure of protein stability. We then analyze multiple new genome-scale datasets describing protein aggregation and interaction propensities, which are likely optimized in evolution to alleviate deleterious effects associated with toxic protein misfolding and misinteractions. Our results demonstrate that the propensity of proteins to aggregate, the fraction of charged amino acids, and protein stickiness do correlate with protein abundances. Nevertheless, across multiple organisms and datasets we do not observe substantial correlations between proteins aggregation- and stability-related properties and evolutionary rates. Therefore, diverse empirical data support the conclusion that the MAH and similar hypotheses are unlikely to play a major role in mediating a strong negative correlation between protein expression and molecular clock, and thus in explaining the variability of evolutionary rates across cellular proteins.Significance statementEvolutionary rates vary substantially across cellular proteins. Understanding the nature of molecular clock and its variability across proteins is a foundational question in molecular evolution. The popular and currently dominant theory to explain the molecular clock variability is the misfolding avoidance hypothesis (MAH). The role of the MAH is currently under active debate. In the manuscript we discuss how to appropriately test the MAH based on available empirical data, and then rigorously test the hypothesis using more than a dozen of new genome-wide datasets of protein stability and aggregation propensities. Our results suggest that the MAH is unlikely to play a major role in explaining the variability of molecular clock across proteins.
Expression of endoplasmic reticulum mannosyl-oligosaccharide α1, 2-mannosidase regulates tumorigenicity of prostate cancer cells
Authors: Toonstra Christian , Wang Xiangchun , Höti Naseruddin , Pan Jianbo , Zhang Hui 
Published: September 2019

AbstractIt has been previously demonstrated that glycogenes can function as important pleiotropic regulators of tumorigenesis. In this study, we investigated the function of endoplasmic reticulum mannosyl-oligosaccharide 1, 2-alpha-mannosidase (MAN1B1) on the behavior of prostate cancer cells and found that overexpression of MAN1B1 in androgen-independent PC3 cells reduced cellular migration. We extended the analysis to an androgen dependent cell line, LNCaP, and another androgen independent cell line, LNCaP-AI, observing a similar migratory phenotype. By using quantitative proteomics, we found the downregulation of vimentin expression when PC3 or LNCaP-AI cells with overexpressed MAN1B1. The current study suggests that MAN1B1 may regulate cellular migration and promote epithelial-to-mesenchymal transition (EMT) phenotype in prostate cancer cells.