Endoscopic ultrasound guided brush/fine-needle aspiration cytology: A 15-month study

Background

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become increasingly popular for the diagnosis and staging of gastrointestinal diseases and peri-gastrointestinal lesions. The application of FNA/Brush has dramatically expanded the clinical utility of EUS.

Aims and objective

To evaluate the diagnostic accuracy, study the spectrum of lesions encountered in EUS-FNAC/brush cytology of gastrointestinal and peri-gastrointestinal lesions.

Materials and methods

Total of 124 patients during the period from August 2015 to November 2016 was included in the study. Routine staining was done.

Results

A total of 124 cases were studied with 86% (107 cases) being satisfactory for evaluation. M:F ratio was 1:1.03, mean age of 50.5 years. The most common site was common bile duct (CBD) (37%) followed by lymph node (21%), pancreas (17.7%), esophagus (17%), stomach (3.5%), liver (1.8%), gallbladder (1%), and spleen (1%). In total, 53.4% lesions were benign, in 6.5% atypical cells were seen, 12.1% were suspicious for malignancy, and 28% cases were positive for malignancy. Follow-up was available in 102 cases with cyto-histopathological concordance rate of 90%.

Conclusion

EUS-FNA/Brush is a reliable, sensitive, specific and minimally invasive way to establish a diagnosis. It can be utilized as a pre-operative procedure for the management of many intra-abdominal lesions and prevent unnecessary invasive procedures.

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Surface-Enhanced Raman Scattering for Rapid Detection and Characterization of Antibiotic-Resistant Bacteria

Abstract

As the prevalence of antibiotic-resistant bacteria continues to rise, biosensing technologies are needed to enable rapid diagnosis of bacterial infections. Furthermore, understanding the unique biochemistry of resistance mechanisms can facilitate the development of next generation therapeutics. Surface-enhanced Raman scattering (SERS) offers a potential solution to real-time diagnostic technologies, as well as a route to fundamental, mechanistic studies. In the current review, SERS-based approaches to the detection and characterization of antibiotic-resistant bacteria are covered. The commonly used nanomaterials (nanoparticles and nanostructured surfaces) and surface modifications (antibodies, aptamers, reporters, etc.) for SERS bacterial detection and differentiation are discussed first, and followed by a review of SERS-based detection of antibiotic-resistant bacteria from environmental/food processing and clinical sources. Antibiotic susceptibility testing and minimum inhibitory concentration testing with SERS are then summarized. Finally, recent developments of SERS-based chemical imaging/mapping of bacteria are reviewed.

Surface-enhanced Raman scattering (SERS)-based approaches to detect and characterize antibiotic-resistant bacteria are reviewed in this contribution. SERS technologies hold promise to enable rapid detection and fundamental understanding of resistance mechanisms. This review focuses on SERS-active nanomaterials (nanoparticles and nanostructured surfaces) for bacterial detection and SERS-based detection of antibiotic-resistant bacteria. Recent developments in SERS-based antibiotic susceptibility testing and bacterial mapping are also covered.

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Graphene Materials in Antimicrobial Nanomedicine: Current Status and Future Perspectives

Abstract

Graphene materials (GMs), such as graphene, graphene oxide (GO), reduced GO (rGO), and graphene quantum dots (GQDs), are rapidly emerging as a new class of broad-spectrum antimicrobial agents. This report describes their state-of-the-art and potential future covering both fundamental aspects and biomedical applications. First, the current understanding of the antimicrobial mechanisms of GMs is illustrated, and the complex picture of underlying structure–property–activity relationships is sketched. Next, the different modes of utilization of antimicrobial GMs are explained, which include their use as colloidal dispersions, surface coatings, and photothermal/photodynamic therapy agents. Due to their practical relevance, the examples where GMs function as synergistic agents or release platforms for metal ions and/or antibiotic drugs are also discussed. Later, the applicability of GMs in the design of wound dressings, infection-protective coatings, and antibiotic-like formulations ("nanoantibiotics") is assessed. Notably, to support our assessments, the existing clinical applications of conventional carbon materials are also evaluated. Finally, the key hurdles of the field are highlighted, and several possible directions for future investigations are proposed. We hope that the roadmap provided here will encourage researchers to tackle remaining challenges toward clinical translation of promising research findings and help realize the potential of GMs in antimicrobial nanomedicine.

This report explains the current state and potential research directions of antimicrobial graphenes focusing on three major aspects: (i) the mechanisms of antimicrobial activity referring to structure–property–activity relationships, (ii) proposed modes for utilization in biomedical antimicrobial applications, (iii) remaining questions concerning the fundamental understanding and critical considerations for future use in clinical settings.

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Biomarkers in Cardiorenal Syndromes

There is a consensus that cardiorenal syndromes (CRS) are defined as the disorders of heart and kidney where acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in another. Patients with CRS have increased hospitalization and mortality rates, and thus their identification is of great implication. Biomarkers are not only predictive in heart failure or renal diseases, but also useful in identifying cardiac dysfunction in renal diseases and renal injury in heart failure. Thus, they may be applied in order to identify patients with CRS and even assess prognosis and guide therapy in these patients. However, studies on biomarkers have just begun in CRS. Future studies are essential to observe current biomarkers and find novel biomarkers in CRS so as to improve diagnosis, therapy, and prognosis of CRS.

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Salivary Markers and Microbial Flora in Mouth Breathing Late Adolescents

Objective. This is a 6-month observational case-control study that aims to estimate plaque index (PI), salivary flow, buffering capacity of saliva, and specific Streptococcus mutans (S. mutans) and Lactobacillus rates in a mouth breathing late adolescents sample, after a professional oral hygiene procedure and home oral hygiene instructions. Subjects and Methods. A sample of 20 mouth breathing late adolescents/young adults (average: ; range: 18–23 years) and a matched control group of nose breathing subjects (average: ; range 18–23 years) were included in the study. All the participants were subjected to a professional oral hygiene procedure and appropriate home oral hygiene instructions (t0). After three months (t1) and six months (t2), the PI, salivary flow, buffering capacity of saliva, and S. mutans and Lactobacilli rates were recorded. Results. The mean buffering capacity of saliva and the salivary flow rate showed no significant difference between the two groups, all over the observational period. For PI, a significantly higher mode (score 1 of PI) was observed in the study group at t1 (score 0 = 35% of subjects; score 1 = 60%; score 2 = 5%) and t2 (score 1 = 65% of subjects, score 2 = 35%), with respect to control group. Furthermore, mouth breathing subjects show a significant 4 times higher risk to develop S. mutans CFU > 105 (CI lower limit: 0.95; CI upper limit: 9.48; chi-square: 4.28; ), with respect to the control subjects. Conclusions. Mouth breathing late adolescents show a significantly higher risk to develop S. mutans CFU > 105 and an increased level of PI. Interceptive orthodontic treatments in growing subjects, like palatal expansion, are encouraged to improve the nasal air flow. In older subjects, orthodontic treatments should be performed with removable appliances like clear aligners, in order to allow a better oral hygiene level.

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Metal–Organic-Framework-Assisted In Vivo Bacterial Metabolic Labeling and Precise Antibacterial Therapy

Abstract

Bacterial infection is one of the most serious physiological conditions threatening human health. There is an increasing demand for more effective bacterial diagnosis and treatment through noninvasive theranostic approaches. Herein, a new strategy is reported to achieve in vivo metabolic labeling of bacteria through the use of MIL-100 (Fe) nanoparticles (NPs) as the nanocarrier for precise delivery of 3-azido-d-alanine (d-AzAla). After intravenous injection, MIL-100 (Fe) NPs can accumulate preferentially and degrade rapidly within the high H₂O₂ inflammatory environment, releasing d-AzAla in the process. d-AzAla is selectively integrated into the cell walls of bacteria, which is confirmed by fluorescence signals from clickable DBCO-Cy5. Ultrasmall photosensitizer NPs with aggregation-induced emission characteristics are subsequently designed to react with the modified bacteria through in vivo click chemistry. Through photodynamic therapy, the amount of bacteria on the infected tissue can be significantly reduced. Overall, this study demonstrates the advantages of metal–organic-framework-assisted bacteria metabolic labeling strategy for precise bacterial detection and therapy guided by fluorescence imaging.

A novel strategy for in vivo bacterial metabolic labeling and precise antibacterial therapy is developed based on the combination of a metal–organic framework (MOF) as a carrier for amino acid delivery and photosensitizers with aggregation-induced emission characteristics for image and therapy. The formulated MOF-assisted strategy represents a promising alternative to antibiotics in image-guided antibacterial therapy.

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The “Rust” Challenge: On the Correlations between Electronic Structure, Excited State Dynamics, and Photoelectrochemical Performance of Hematite Photoanodes for Solar Water Splitting

Abstract

In recent years, hematite's potential as a photoanode material for solar hydrogen production has ignited a renewed interest in its physical and interfacial properties, which continues to be an active field of research. Research on hematite photoanodes provides new insights on the correlations between electronic structure, transport properties, excited state dynamics, and charge transfer phenomena, and expands our knowledge on solar cell materials into correlated electron systems. This research news article presents a snapshot of selected theoretical and experimental developments linking the electronic structure to the photoelectrochemical performance, with particular focus on optoelectronic properties and charge carrier dynamics.

Hematite is a promising photoanode material for photoelectrochemical water splitting. The main challenges toward achieving efficient hematite photoanodes are reviewed. Particular focus is placed on linking the electronic structure to the processes of light absorption, charge transport, and the surface electrochemical reaction. The main losses are identified and discussed, while promising avenues for future research are highlighted.

http://ift.tt/2FcJM43

Template Conversion of Covalent Organic Frameworks into 2D Conducting Nanocarbons for Catalyzing Oxygen Reduction Reaction

Abstract

Progress over the past decades in porous materials has exerted great effect on the design of metal-free carbon electrochemical catalysts in fuel cells. The carbon material must combine three functions, i.e., electrical conductivity for electron transport, optimal pores for ion motion, and abundant heteroatom sites for catalysis. Here, an ideal carbon catalyst is achieved by combining two strategies—the use of a 2D covalent organic framework (COF) and the development of a suitable template to guide the pyrolysis. The COF produces nanosized carbon sheets that combine high conductivity, hierarchical porosity, and abundant heteroatom catalytic edges. The catalysts achieve superior performance to authentic Pt/C with exceptional onset potential (0 V vs −0.03 V), half-wave potentials (−0.11 V vs −0.16 V), high limit current density (7.2 mA cm⁻² vs 6.0 mA cm⁻²), low Tafel slope (110 mV decade⁻¹ vs 121 mV decade⁻¹), long-time stability, and methanol tolerance. These results reveal a novel material platform based on 2D COFs for designing novel 2D carbon materials.

Two-dimensional nanosized carbon materials are made by a new strategy in which 2D covalent organic frameworks (COFs) are used as precursors in conjunction with a template carbonization methodology. This strategy enables the production of 2D carbons that combine high conductivity, hierarchical porosity, and abundant edge active sites, and that achieve exceptional catalytic activity in oxygen reduction reaction.

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Advanced Materials through Assembly of Nanocelluloses

Abstract

There is an emerging quest for lightweight materials with excellent mechanical properties and economic production, while still being sustainable and functionalizable. They could form the basis of the future bioeconomy for energy and material efficiency. Cellulose has long been recognized as an abundant polymer. Modified celluloses were, in fact, among the first polymers used in technical applications; however, they were later replaced by petroleum-based synthetic polymers. Currently, there is a resurgence of interest to utilize renewable resources, where cellulose is foreseen to make again a major impact, this time in the development of advanced materials. This is because of its availability and properties, as well as economic and sustainable production. Among cellulose-based structures, cellulose nanofibrils and nanocrystals display nanoscale lateral dimensions and lengths ranging from nanometers to micrometers. Their excellent mechanical properties are, in part, due to their crystalline assembly via hydrogen bonds. Owing to their abundant surface hydroxyl groups, they can be easily modified with nanoparticles, (bio)polymers, inorganics, or nanocarbons to form functional fibers, films, bulk matter, and porous aerogels and foams. Here, some of the recent progress in the development of advanced materials within this rapidly growing field is reviewed.

Nanocelluloses, with their hydrogen bonded internal structures, are colloidal and fibrillar materials with attractive mechanical properties, functionability, and economics toward sustainable nanoconstruction. Beyond the already emerging mainstream applications, potential novel concepts for nanocellulose-based advanced materials that exploit self-assembly, directed self-assembly, supramolecular and supracolloidal chemistry, and protein engineering are reviewed.

http://ift.tt/2Fgg9io

Nanomaterials for Cancer Precision Medicine

Abstract

Medical science has recently advanced to the point where diagnosis and therapeutics can be carried out with high precision, even at the molecular level. A new field of "precision medicine" has consequently emerged with specific clinical implications and challenges that can be well-addressed by newly developed nanomaterials. Here, a nanoscience approach to precision medicine is provided, with a focus on cancer therapy, based on a new concept of "molecularly-defined cancers." "Next-generation sequencing" is introduced to identify the oncogene that is responsible for a class of cancers. This new approach is fundamentally different from all conventional cancer therapies that rely on diagnosis of the anatomic origins where the tumors are found. To treat cancers at molecular level, a recently developed "microRNA replacement therapy" is applied, utilizing nanocarriers, in order to regulate the driver oncogene, which is the core of cancer precision therapeutics. Furthermore, the outcome of the nanomediated oncogenic regulation has to be accurately assessed by the genetically characterized, patient-derived xenograft models. Cancer therapy in this fashion is a quintessential example of precision medicine, presenting many challenges to the materials communities with new issues in structural design, surface functionalization, gene/drug storage and delivery, cell targeting, and medical imaging.

Cancer precision therapy necessitates the following critical components: new cancer classification based on oncogene identification; specific-oncogene-targeted therapy by noncoding RNAs; gene-delivery via advanced and programmable nanocarriers, and accurate assessment of drug efficacy by genetically characterized patient-derived xenograft (PDX) models. The major critical issues involved in all aspects of cancer precision medicine and nanomaterials science are addressed.

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Chemical and Morphological Control of Interfacial Self-Doping for Efficient Organic Electronics

Abstract

Solution-based processing of materials for electrical doping of organic semiconductor interfaces is attractive for boosting the efficiency of organic electronic devices with multilayer structures. To simplify this process, self-doping perylene diimide (PDI)-based ionene polymers are synthesized, in which the semiconductor PDI components are embedded together with electrolyte dopants in the polymer backbone. Functionality contained within the PDI monomers suppresses their aggregation, affording self-doping interlayers with controllable thickness when processed from solution into organic photovoltaic devices (OPVs). Optimal results for interfacial self-doping lead to increased power conversion efficiencies (PCEs) of the fullerene-based OPVs, from 2.62% to 10.64%, and of the nonfullerene-based OPVs, from 3.34% to 10.59%. These PDI–ionene interlayers enable chemical and morphological control of interfacial doping and conductivity, demonstrating that the conductive channels are crucial for charge transport in doped organic semiconductor films. Using these novel interlayers with efficient doping and high conductivity, both fullerene- and nonfullerene-based OPVs are achieved with PCEs exceeding 9% over interlayer thicknesses ranging from ≈3 to 40 nm.

Self-doping of perylene-diimide-based ionenes enables chemical and morphological control of interfacial doping and conductivity in organic electronic devices. Using these materials provides a straightforward and controllable method to modulate the interface between electrodes and active layers, affording both fullerene- and nonfullerene-based solar cells with high efficiencies over a wide range of doped interlayer thicknesses.

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Oxidoreductase-Initiated Radical Polymerizations to Design Hydrogels and Micro/Nanogels: Mechanism, Molding, and Applications

Abstract

Due to their 3D cross-linked networks and tunable physicochemical properties, polymer hydrogels with different sizes are applied widely in tissue engineering, drug-delivery systems, pollution regulation, ionic conducting electrolytes, agricultural drought-resistance, cosmetics, and the food industry. Novel, environmentally friendly, and efficient oxidoreductase-initiated radical polymerizations to design hydrogels and micro/nanogels have gained increasing attention. Herein, the recent advances on the use of novel enzyme-initiated systems for hydrogel polymerization, including the mechanisms, and molding of polymeric and hybrid-polymeric networks are reviewed. Preliminary progress related to interfacial enzymatic polymerization for the generation of hybrid micro/nanogels is introduced as an emerging initiating approach. In addition, certain biological applications in tissue engineering, bioimaging, and therapy are demonstrated step by step. Finally, some perspectives on the safety profile of enzymatic formed hydrogels, new enzymatic systems, and potential theranostic applications are discussed.

Environmentally friendly, efficient enzymatic polymerization and hydrogelation has attracted increasing attention. A systematic overview of the mechanisms of oxidoreductase-initiated radical polymerization is provided. With respect to the unique characteristics of enzymatic reactions, recent research on enzymatic molding and biomedical applications of hydrogels and micro/nanogels are also summarized.

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Lithiation/Delithiation Synthesis of Few Layer Silicene Nanosheets for Rechargeable Li–O2 Batteries

Abstract

Silicene has recently received increasing interest due to its unique properties. However, the synthesis of silicene remains challenging, which limits its wide applications. In this work, a top-down lithiation and delithiation process is developed to prepare few layer silicene-like nanosheets from ball-milled silicon nanopowders. It is found that delithiation solvent plays a critical role in the structure evolution of the final products. The use of isopropyl alcohol renders 2D silicene-like products 30–100 nm in length and ≈2.4 nm in thickness. The electrochemical characterization analysis suggests that the product shows high performance for rechargeable Li–O₂ batteries with 73% energy efficiency and high stability. The top-down synthesis strategy proposed in this work not only provides a new solution to the challenging preparation issue of few layer silicene but also demonstrates the feasibility of producing 2D materials from nonlayered starting structures.

Few layer silicene nanosheets are successfully prepared by a lithiation/delithiation approach with controlled lithiation extent and selected delithiation agent. These crystal nanosheets with 30–100 nm length and ≈2.4 nm thickness are attached with oxygen molecules and oxygen-containing groups on their surfaces. They exhibit high catalytic performance for rechargeable Li–O₂ batteries.

http://ift.tt/2H73jQ6

Electroconductive Biohybrid Collagen/Pristine Graphene Composite Biomaterials with Enhanced Biological Activity

Abstract

Electroconductive substrates are emerging as promising functional materials for biomedical applications. Here, the development of biohybrids of collagen and pristine graphene that effectively harness both the biofunctionality of the protein component and the increased stiffness and enhanced electrical conductivity (matching native cardiac tissue) obtainable with pristine graphene is reported. As well as improving substrate physical properties, the addition of pristine graphene also enhances human cardiac fibroblast growth while simultaneously inhibiting bacterial attachment (Staphylococcus aureus). When embryonic-stem-cell-derived cardiomyocytes (ESC-CMs) are cultured on the substrates, biohybrids containing 32 wt% graphene significantly increase metabolic activity and cross-striated sarcomeric structures, indicative of the improved substrate suitability. By then applying electrical stimulation to these conductive biohybrid substrates, an enhancement of the alignment and maturation of the ESC-CMs is achieved. While this in vitro work has clearly shown the potential of these materials to be translated for cardiac applications, it is proposed that these graphene-based biohybrid platforms have potential for a myriad of other applications—particularly in electrically sensitive tissues, such as neural and neural and musculoskeletal tissues.

A biohybrid material containing collagen and pristine graphene is prepared. This biohybrid material displays electroconductivity matching native heart levels, and heart stem cells grown on this material begin to display characteristics of adult heart cells. Applying electrical stimulation across the biohybrid material then allows the cells to align and further mature toward functional cardiac activity.

http://ift.tt/2oQkTQL

DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control.

Torsional stress, and supercoiling generated by transcription, shape the topology of DNA. Furthermore, the resultant secondary DNA structures and their interacting partners provide feedback to regulate gene expression. Emerging evidence suggests these mechanisms, identified through analysis of the MYC promoter, are applicable genome-wide.

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Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years

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Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity

ABSTRACT

Aim

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients.

Methods

Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated.

Results

UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P=0.002, P=0.037 and P=0.041, respectively). One patient who was UGT1A1*28/*37 presented grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity.

Conclusions

We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.

http://ift.tt/2FgoDlF

Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers doi: 10.3390/cancers10030064

Authors: Cosimo Lobello Vasilis Bikos Andrea Janikova Sarka Pospisilova

Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.

http://ift.tt/2tfjEjD

Myeloid-derived suppressor cells suppress CD4+ T cell activity and prevent the development of type 2 diabetes

Abstract

CD4⁺ T cells play an important role in the progression of type 2 diabetes mellitus (T2DM). It is known that T cell responses can be suppressed by myeloid-derived suppressor cells (MDSCs). In this study, we aimed to explore the potential role of MDSCs in the progression of T2DM, and to examine whether the underlying mechanism was associated with CD4⁺ T cells. Peripheral blood samples were obtained from T2DM patients and healthy controls, as well as C57BL6J db/db mice and control heterozygous (db/-) mice. The frequency of MDSCs and CD4⁺ T cells was analyzed using flow cytometry. Serum levels of the cytokines interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were quantified using ELISA kits. Cell proliferation was assessed using carboxyfluorescein succinimidyl ester (CFSE) labeling. In addition, the severity of insulitis was assessed using H&E staining of the pancreata. The data showed an increased frequency of CD11b⁺/CD33⁺ MDSCs and CD4⁺ T cells in the peripheral blood of T2DM patients. In addition, there were decreased IL-4 level and increased TNF-α and IFN-γ levels in the serum from T2DM patients. In db/db mice, an increased frequency of CD11b⁺/Gr-1⁺ MDSCs and CD4⁺ T cells was found in splenocytes, as well as in the peripheral blood. MDSCs inhibited the proliferation and modulated the cytokine secretion of CD4⁺ T cells in vitro and delayed the development of diabetes in NOD/SCID mice. In conclusion, MDSCs suppress CD4⁺ T cell activity and prevent the development of T2DM.

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An Enlarging Lung Nodule in an Immunocompromised Host

(See pages 978–9 for the Answer to the Photo Quiz)

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Cover

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News

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In the Literature

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An Enlarging Lung Nodule in an Immunocompromised Host

(See page 977 for the Photo Quiz.)

http://ift.tt/2oJoVeB

Assessing Viral Transfer During Doffing of Ebola-Level Personal Protective Equipment in a Biocontainment Unit

Abstract

Background

Personal protective equipment (PPE) protects healthcare workers (HCWs) caring for patients with Ebola virus disease (EVD), and PPE doffing is a critical point for preventing viral self-contamination. We assessed contamination of skin, gloves, and scrubs after doffing Ebola-level PPE contaminated with surrogate viruses: bacteriophages MS2 and Φ6.

Methods

In a medical biocontainment unit, HCWs (n = 10) experienced in EVD care donned and doffed PPE following unit protocols that incorporate trained observer guidance and alcohol-based hand rub (ABHR). A mixture of Φ6 (enveloped), MS2 (nonenveloped), and fluorescent marker was applied to 4 PPE sites, approximating body fluid viral load (Φ6, 10⁵; MS2, 10⁶). They performed a patient care task, then doffed. Inner gloves, face, hands, and scrubs were sampled for virus, as were environmental sites with visible fluorescent marker.

Results

Among 10 HCWs there was no Φ6 transfer to inner gloves, hands, or face; 1 participant had Φ6 on scrubs at low levels (1.4 × 10²). MS2 transfer (range, 10¹–10⁶) was observed to scrubs (n = 2), hands (n = 1), and inner gloves (n = 7), where it was highest. Most (n = 8) had only 1 positive site. Environmental samples with visible fluorescent marker (n = 21) were negative.

Conclusions

Among experienced HCWs, structured, observed doffing using ABHR protected against hand contamination with enveloped virus. Nonenveloped virus was infrequent on hands and scrubs but common on inner gloves, suggesting that inner gloves, but not necessarily ABHR, protect against hand contamination. Optimizing doffing protocols to protect against all types of viruses may require reinforcing careful handling of scrubs and good glove/hand hygiene with effective agents.

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Human Factors Risk Analyses of a Doffing Protocol for Ebola-Level Personal Protective Equipment: Mapping Errors to Contamination

Abstract

Background

Doffing protocols for personal protective equipment (PPE) are critical for keeping healthcare workers (HCWs) safe during care of patients with Ebola virus disease. We assessed the relationship between errors and self-contamination during doffing.

Methods

Eleven HCWs experienced with doffing Ebola-level PPE participated in simulations in which HCWs donned PPE marked with surrogate viruses (ɸ6 and MS2), completed a clinical task, and were assessed for contamination after doffing. Simulations were video recorded, and a failure modes and effects analysis and fault tree analyses were performed to identify errors during doffing, quantify their risk (risk index), and predict contamination data.

Results

Fifty-one types of errors were identified, many having the potential to spread contamination. Hand hygiene and removing the powered air purifying respirator (PAPR) hood had the highest total risk indexes (111 and 70, respectively) and number of types of errors (9 and 13, respectively). ɸ6 was detected on 10% of scrubs and the fault tree predicted a 10.4% contamination rate, likely occurring when the PAPR hood inadvertently contacted scrubs during removal. MS2 was detected on 10% of hands, 20% of scrubs, and 70% of inner gloves and the predicted rates were 7.3%, 19.4%, 73.4%, respectively. Fault trees for MS2 and ɸ6 contamination suggested similar pathways.

Conclusions

Ebola-level PPE can both protect and put HCWs at risk for self-contamination throughout the doffing process, even among experienced HCWs doffing with a trained observer. Human factors methodologies can identify error-prone steps, delineate the relationship between errors and self-contamination, and suggest remediation strategies.

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Global Trends in CD4 Cell Count at the Start of Antiretroviral Therapy: Collaborative Study of Treatment Programs

Abstract

Background

Early initiation of combination antiretroviral therapy (cART), at higher CD4 cell counts, prevents disease progression and reduces sexual transmission of human immunodeficiency virus (HIV). We describe the temporal trends in CD4 cell counts at the start of cART in adults from low-income, lower-middle-income, upper-middle-income, and high-income countries (LICs, LMICs, UMICs, and HICs, respectively).

Methods

We included HIV-infected individuals aged ≥16 years who started cART between 2002 and 2015 in a clinic participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) or the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). Missing CD4 cell counts at the start of cART were estimated through multiple imputation. Weighted mixed-effect models were used to smooth trends in median CD4 cell counts.

Results

A total of 951855 adults from 16 LICs, 11 LMICs, 9 UMICs, and 19 HICs were included. Overall, the modeled median CD4 cell count at the start of cART increased from 2002 to 2015, from 78/µL (95% confidence interval, 58–104/µL) to 287/µL (250–328/µL) in LICs, from 99/µL (71–140/µL) to 234/µL (192–285/µL) in LMICs, from 71/µL (49–104/µL) to 311/µL (255–379/µL) in UMICs, and from 161/µL (143–181/µL) to 327/µL (286–372/µL) in HICs. In LICs, LMICs, and UMICs, the increase was more pronounced in women; in HICs, the opposite was observed.

Conclusions

Median CD4 cell counts at the start of cART increased in all income groups, but generally remained below 350/μL in 2015. Substantial additional efforts and resources are required to achieve earlier diagnosis, linkage to care, and initiation of cART.

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Erratum

An error appeared in the 15 October 2016 issue of the journal [Hanna DB, Ramaswamy C, Kaplan RC, et al. Trends in Cardiovascular Disease Mortality Among Persons with HIV in New York City, 2001–2012. Clin Infect Dis 2016; 63(8):1122–9]. The financial support section is missing information. It should read:

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Erratum

An error appeared in the 15 March 2016 issue of the journal [Polizzotto MN, Uldrick TS, Wyvill KM, et al. Clinical Features and Outcomes of Patients with Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS). Clin Infect Dis 2016; 62: 730–8]. The units for C reactive protein were improperly listed as g/dL, when they should be mg/L. This error appears in number 2 of Table 1, the "C-reactive protein" in Table 4, panel E in Figure 1, the upper right panel in Figure 2, and at the end of the first sentence under the heading "Systemic Inflammation in KICS Subjects."

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Combating Global Antibiotic Resistance: Emerging One Health Concerns in Lower- and Middle-Income Countries

Abstract

Antibiotic misuse in lower- and middle-income countries (LMICs) contributes to the development of antibiotic resistance that can disseminate globally. Strategies specific to LMICs that seek to reduce antibiotic misuse by humans, but simultaneously improve antibiotic access, have been proposed. However, most approaches to date have not considered the growing impact of animal and environmental reservoirs of antibiotic resistance, which threaten to exacerbate the antibiotic resistance crisis in LMICs. In particular, current strategies do not prioritize the impacts of increased antibiotic use for terrestrial food-animal and aquaculture production, inadequate food safety, and widespread environmental pollution. Here, we propose new approaches that address emerging, One Health challenges.

http://ift.tt/2oLtXXR

Infectious Diseases, Weather, and Climate

infectionclimate changeweatherrisk factors

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The Human Immunodeficiency Virus Care Continuum in China: 1985–2015

Abstract

Background

Human immunodeficiency virus (HIV) care continuum attrition is a major global public health challenge. Few studies have examined this problem in resource-limited settings. We aimed to assess cumulative, current, and historical achievement along China's HIV continuum of care.

Methods

A nationwide, serial cross-sectional study of all individuals with HIV infection diagnosed in China between 1 January 1985 and 31 December 2015 was conducted using data from China's HIV/AIDS information systems. Biennial estimates of the number of persons living with HIV were also used. We defined 7 steps in HIV care continuum as infected (estimated), diagnosed, linked, retained, enrolled, receiving antiretroviral therapy (ART), and virally suppressed. Cumulative, 30-year performance, and biennial performance during the most recent 10 years were examined.

Results

A total of 573529 persons diagnosed with HIV infection were included. Cumulatively, 94% were linked, 88% were retained, 73% were enrolled, 67% were receiving ART, and 44% were suppressed. Greatest attrition was observed for adolescents, minorities, and those who reported injecting drug use as their route of infection. Improvement was observed from 2005 to 2015. As of the end of 2015, 68% among those infected were diagnosed, 67% among diagnosed were receiving ART, and 65% among those receiving ART were virally suppressed. After adjusting for those without viral load testing, the proportion suppressed increased to 89%.

Conclusions

Despite dramatic improvements, China faces serious challenges in achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets, because of substantial attrition along its continuum of HIV care.

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Reply to Raoult

To the Editor—We thank Professor Raoult for his interest in our study and for his remarks, which underline the role of patients' oral status and dental hygiene in the genesis of streptococcal infective endocarditis [1, 2]. He suggests that we analyze our data to assess antibiotic prophylaxis efficacy, which we purposely did not perform for the following reasons:

http://ift.tt/2tffrw9

Endocarditis Prophylaxis

To the Editor—The work by Duval and colleagues [1] is interesting because it shows that patients' oral health and dental hygiene play an important role in the etiology of streptococcal endocarditis. It is also likely that the continuous improvement of the dental condition of modern populations explains the very significant decrease of endocarditis with streptococci of buccal origin [2]. However, the careful reanalysis of their data does not support the conclusion that antibiotic prophylaxis before dental care plays a role, which is currently the most debated subject [3]. In fact, the analysis of their data, obtained from supplementary material online, makes it possible to confirm or not whether antibiotic prophylaxis could prevent streptococcal endocarditis in a patient with underlying valvulopathy. Indeed, among the 12 patients with oral streptococcal endocarditis, 3 had no known valvulopathy, and the one who had known valvulopathy received antibiotic prophylaxis. These 4 are outside the purpose of this study. Therefore, only 8 patients among a cohort of 73 patients with oral streptococcal endocarditis could be analyzed vs 11 patients with endocarditis due to another microorganism in a cohort of 192 patients. This difference is not significant. Following this analysis, this work confirms that there is no evidence in the literature showing an even slight effect of prophylaxis of oral streptococcal endocarditis by the use of antibiotic prophylaxis before dental care.

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Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic

Abstract

We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died.

http://ift.tt/2tgIHmj

Frequent Undetected Ward-Based Methicillin-Resistant Staphylococcus aureus Transmission Linked to Patient Sharing Between Hospitals

Abstract

Background

Recent evidence suggests that hospital transmission of methicillin-resistant Staphylococcus aureus (MRSA) is uncommon in UK centers that have implemented sustained infection control programs. We investigated whether a healthcare-network analysis could shed light on transmission paths currently sustaining MRSA levels in UK hospitals.

Methods

A cross-sectional observational study was performed in 2 National Health Service hospital groups and a general district hospital in Southeast London. All MRSA patients identified at inpatient, outpatient, and community settings between 1 November 2011 and 29 February 2012 were included. We identified genetically defined MRSA transmission clusters in individual hospitals and across the healthcare network, and examined genetic differentiation of sequence type (ST) 22 MRSA isolates within and between hospitals and inpatient or outpatient and community settings, as informed by average and median pairwise single-nucleotide polymorphisms (SNPs) and SNP-based proportions of nearly identical isolates.

Results

Two hundred forty-eight of 610 (40.7%) MRSA patients were linked in 90 transmission clusters, of which 27 spanned multiple hospitals. Analysis of a large 32 patient ST22-MRSA cluster showed that 26 of 32 patients (81.3%) had multiple contacts with one another during ward stays at any hospital. No residential, outpatient, or significant community healthcare contacts were identified. Genetic differentiation between ST22 MRSA inpatient isolates from different hospitals was less than between inpatient isolates from the same hospitals (P ≤ .01).

Conclusions

There is evidence of frequent ward-based transmission of MRSA brought about by frequent patient admissions to multiple hospitals. Limiting in-ward transmission requires sharing of MRSA status data between hospitals.

http://ift.tt/2oLtTHB

Prosthetic Valve Candida spp. Endocarditis: New Insights Into Long-term Prognosis—The ESCAPE Study

Abstract

Background

Prosthetic valve endocarditis caused by Candida spp. (PVE-C) is rare and devastating, with international guidelines based on expert recommendations supporting the combination of surgery and subsequent azole treatment.

Methods

We retrospectively analyzed PVE-C cases collected in Spain and France between 2001 and 2015, with a focus on management and outcome.

Results

Forty-six cases were followed up for a median of 9 months. Twenty-two patients (48%) had a history of endocarditis, 30 cases (65%) were nosocomial or healthcare related, and 9 (20%) patients were intravenous drug users. "Induction" therapy consisted mainly of liposomal amphotericin B (L-amB)–based (n = 21) or echinocandin-based therapy (n = 13). Overall, 19 patients (41%) were operated on. Patients <66 years old and without cardiac failure were more likely to undergo cardiac surgery (adjusted odds ratios [aORs], 6.80 [95% confidence interval [CI], 1.59–29.13] and 10.92 [1.15–104.06], respectively). Surgery was not associated with better survival rates at 6 months. Patients who received L-amB alone had a better 6-month survival rate than those who received an echinocandin alone (aOR, 13.52; 95% CI, 1.03–838.10). "Maintenance" fluconazole therapy, prescribed in 21 patients for a median duration of 13 months (range, 2–84 months), led to minor adverse effects.

Conclusion

L-amB induction treatment improves survival in patients with PVE-C. Medical treatment followed by long-term maintenance fluconazole may be the best treatment option for frail patients.

http://ift.tt/2tje8fC

High Human Immunodeficiency Virus Incidence and Prevalence and Associated Factors Among Adolescent Sexual Minority Males—3 Cities, 2015

Abstract

Background

Much has been written about the impact of human immunodeficiency virus (HIV) among young (13–24) sexual minority men (SMM). Evidence for concern is substantial for emerging adult (18–24 years) SMM. Data documenting the burden and associated risk factors of HIV among adolescent SMM (<18 years) remain limited.

Methods

Adolescent SMM aged 13–18 years were recruited in 3 cities (Chicago, New York City, and Philadelphia) for interview and HIV testing. We used χ² tests for percentages of binary variables and 1-way analysis of variance for means of continuous variables to assess differences by race/ethnicity in behaviors. We calculated estimated annual HIV incidence density (number of HIV infections per 100 person-years [PY] at risk). We computed Fisher's exact tests to determine differences in HIV prevalence by selected characteristics.

Results

Of 415 sexually active adolescent SMM with a valid HIV test result, 25 (6%) had a positive test. Estimated annual HIV incidence density was 3.4/100 PY; incidence density was highest for blacks, followed by Hispanics, then whites (4.1, 3.2, and 1.1/100 PY, respectively). Factors associated with higher HIV prevalence included black race; ≥4 male partners, condomless anal sex, and exchange sex in the past 12 months; and a recent partner who was older, black, HIV-infected, or had ever been in jail or prison (P < .05).

Conclusions

HIV-related risk behaviors, prevalence, and estimated incidence density for adolescent SMM were high, especially for minority SMM. Our findings suggest that initiating intervention efforts early may be helpful in combating these trends.

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Vancomycin Is Ineffective in Eliminating Methicillin-Resistant Staphylococcus aureus Colonization of Respiratory Secretions in Ventilated Intensive Care Unit Patients: A Clinical and Pharmacokinetic Perspective

To the Editor—We read Stulik and colleagues' article with much interest, and some aspects deserve comment [1]. In intubated adults in the intensive care unit (ICU), airway colonization is common, with aerobic gram-negative bacilli (GNB) or Staphylococcus aureus often persisting for prolonged periods without progression to ventilator-associated pneumonia (VAP) [2].

http://ift.tt/2tc2Olm

Marshaling the Translational Potential of MC1R for Precision Risk Assessment of Melanoma

Melanoma rates have been increasing in the United States, and neither primary (sun protection and avoidance) nor secondary (skin examination) prevention is practiced consistently, even by those with melanoma risk factors. Inherited variation at MC1R is a robust marker for increased risk of melanoma, even among individuals with "sun-resistant" phenotypes. Although MC1R conveys important information about inherited melanoma risk for a broad spectrum of individuals, concerns that MC1R feedback could have negative consequences, including increased distress about melanoma, inappropriate use of health services, and development of a false sense of security, are valid and require empirical examination. The time is right for high-quality research focusing on the translation of MC1R genotype into clinical and public health practice. If studies show MC1R genetic risk screening is effective at motivating behavior change, more melanomas may be detected at earliest stages for which surgical excision is highly curative or a large number of melanomas may be prevented altogether. While other genetic markers for melanoma susceptibility may emerge in the coming years, the burgeoning research agenda on the public health translational potential of MC1R genetic risk screening will inform and usefully advance current and future precision risk assessment of melanoma. Cancer Prev Res; 11(3); 121–4. ©2017 AACR.

http://ift.tt/2FgNcP8

Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity

We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (P < 0.05) and mutagenesis (P = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (P < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly (P < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. Cancer Prev Res; 11(3); 157–64. ©2017 AACR.

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Targeting Epigenetics to Prevent Obesity Promoted Cancers

Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue–promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity–cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125–8. ©2018 AACR.

See related article by Chakraborty et al., p. 129

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Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143–56. ©2017 AACR.

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A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo. We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivo. Cancer Prev Res; 11(3); 129–42. ©2017 AACR.

See related editorial by Berger and Scacheri, p. 125

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Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21-39 Years

Cervical intraepithelial neoplasia grade 2 (CIN2) frequently regresses, is typically slow-growing, and rarely progresses to cancer. Some women forgo immediate treatment, opting for conservative management (heightened surveillance with cytology and colposcopy), to minimize overtreatment and increased risk of obstetric complications; however, there are limited data examining clinical outcomes in these women. We performed a retrospective cohort analysis of younger women diagnosed with initially untreated CIN1/2, CIN2 and CIN2/3 lesions at Kaiser Permanente Northern California between 2003 and 2015. Clinical outcomes were categorized into five mutually exclusive hierarchical groups: cancer, treated, returned to routine screening, persistent high-grade lesion, or persistent low-grade lesion. Median follow-up for the 2,417 women was 48 months. Six women were diagnosed with cancer (0.2%), all with history of high-grade cytology, and none after a negative cotest. Thirty percent of women were treated, and only 20% returned to routine screening; 50% remained in continued intensive follow-up, of which 86% had either low-grade cytology/histology or high-risk human papillomavirus (HPV) positivity, but not necessarily persistence of a single HPV type. No cancers were detected after a single negative cotest in follow-up. Almost half of initially untreated women did not undergo treatment, but remained by protocol in colposcopy clinic for 2 or more years in the absence of persisting CIN2⁺. Their incomplete return to total negativity was possibly due to sequential new and unrelated low-grade abnormalities. The prolonged colposcopic surveillance currently required to return to routine screening in the absence of persisting CIN2⁺ might not be necessary after a negative cotest.

Significance: Many younger women under conservative management following an initial CIN2 result remain in a clinical protocol of prolonged intensified surveillance without a subsequent diagnosis of CIN2 or more severe diagnoses. More research is needed to determine whether such prolonged management might be unnecessary following a negative cotest for those women with an initial CIN2 but otherwise only low-grade findings. Cancer Prev Res; 11(3); 165–70. ©2018 AACR.

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Tough job market pushes more surgical specialists to extend training [News]

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Deans of medicine urge provincial action on residency mismatch [News]

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Narrowing the treatment gap in managing opioid use disorder [Commentary]

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Opioids for chronic pain [Letters]

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The status quo bias and decisions to withdraw life-sustaining treatment [Humanities]

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Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study [Research]

BACKGROUND:

Case fatality after total anterior circulation stroke is high. Our objective was to describe the experiences and needs of patients and caregivers, and to explore whether, and how, palliative care should be integrated into stroke care.

METHODS:

From 3 stroke services in Scotland, we recruited a purposive sample of people with total anterior circulation stroke, and conducted serial, qualitative interviews with them and their informal and professional caregivers at 6 weeks, 6 months and 1 year. Interviews were transcribed for thematic and narrative analysis. The Palliative Care Outcome Scale, EuroQol-5D-5L and Caregiver Strain Index questionnaires were completed after interviews. We also conducted a data linkage study of all patients with anterior circulation stroke admitted to the 3 services over 6 months, which included case fatality, place of death and readmissions.

RESULTS:

Data linkage (n = 219) showed that 57% of patients with total anterior circulation stroke died within 6 months. The questionnaires recorded that the patients experienced immediate and persistent emotional distress and poor quality of life. We conducted 99 interviews with 34 patients and their informal and professional careers. We identified several major themes. Patients and caregivers faced death or a life not worth living. Those who survived felt grief for a former life. Professionals focused on physical rehabilitation rather than preparation for death or limited recovery. Future planning was challenging. "Palliative care" had connotations of treatment withdrawal and imminent death.

INTERPRETATION:

Major stroke brings likelihood of death but little preparation. Realistic planning with patients and informal caregivers should be offered, raising the possibility of death or survival with disability. Practising the principles of palliative care is needed, but the term "palliative care" should be avoided or reframed.

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Management of opioid use disorders: a national clinical practice guideline [Guideline]

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Professional writers can help to improve clarity of medical writing [Letters]

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Diffuse skin thickening, myalgias and joint stiffness in a 41-year-old man [Practice]

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Canada and US going opposite directions on conscientious objection for doctors [News]

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Who needs palliative care? [Commentary]

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Jamestown Canyon virus meningoencephalitis mimicking migraine with aura in a resident of Manitoba [Practice]

http://ift.tt/2FcB2eg

Effect of Vitrification on Functional Morphology and Viability of the Ovarian Tissue

The results of a complex morphofunctional study with markers of proliferation (PCNA and Ki-67), angiogenesis (CD31 and CD34), and structural integrity of mesenchymal cells (vimentin) suggest that the pool of primordial follicles was well preserved in vitrified ovarian tissue and that viability of its cellular components can be rapidly restored during incubation at 37°C within 4 h after thawing.

http://ift.tt/2H6S4Hb

Intracellular Reorganization of Cardiomyocytes in Dyslipidemic Cardiomyopathies

The study examined the myocardial ultrastructural alterations in rats maintained on various atherogenic diets. It revealed the complex ultrastructural alterations of cardiomyocytes and endotheliocytes (including the lytic and destructive changes of the intracellular organelles, upregulation of the autophagocytosis in the cardiomyocytes, and necrobiosis with apoptosis of endotheliocytes) reflecting the cytopathic features of circulating cholesterol and lipoproteins, whose elevation determined the intensity of destructive processes. The revealed peculiarities in the changes of lipid inclusions (their osmiophilic transformation) in cardiomyocytes can be provoked by entry of cholesterol into the cells and its further metabolic modifications. During moderate dyslipidemia, the cardiomyocytes demonstrated the ultrastructural signs of induction of intracellular regeneration (marked with the clusters of polysomes in the intermyofibrillar and subsarcolemmal spaces with appearance of neogenic myofilaments) and upregulated pinocytotic activity. In all cases, up-regulated autophagocytosis in cardiomyocytes was accompanied by accumulation of myelin- and vacuole-like structures in the intercellular spaces and capillary lumens paralleled with appearance of activated forms of macrophages and fibroblasts in the myocardium.

http://ift.tt/2Fk3OsJ

Induction of Alternative Splicing and Inhibition of Activity of Telomerase Catalytic Subunit by Apoptotic Endonuclease EndoG in Human T, B, and NK Cells

The effect of apoptotic endonuclease EndoG on alternative splicing of mRNA of human telomerase catalytic subunit hTERT (human telomerase reverse transcriptase) and telomerase activity in normal human lymphocytes were studied. Human CD4⁺, CD8⁺, B, and NK cells were transfected with a plasmid pEndoG-GFP containing EndoG gene or control plasmid pGFP. The levels of mRNA of EndoG or hTERT splicing variants were analyzed by real-time PCR. Protein content was assessed by Western blotting. Telomerase activity was measured by the telomere repeats amplification protocol. EndoG overexpression reduced the expression of active full-length hTERT and increased the expression of inactive splice variant. Shifted balance of hTERT splice variants in cells led to a significant decrease in telomerase activity within 72 h after transfection.

http://ift.tt/2H2E9Sy

Studying the Phenotypic and Genotypic Expression of Antibiotic Resistance in Campylobacter jejuni under Stress Conditions

Specific features for the development of resistance in Campylobacter jejuni strains were studied after treatment with antibiotics of 6 pharmacological groups. Populations of 18 native strains of C. jejuni (isolated from raw poultry products) and their subcultures (obtained after 2-3-fold stress exposures to antimicrobial agents in subinhibitory doses) were examined to evaluate the expression of phenotypic antibiotic resistance. Genotypic properties of strains were studied by the PCR with primers that detect the presence of genes for resistance to aminoglycosides (aphA-1, aphA-3, and aphA-7), tetracyclines (tetO), and quinolones (GZgyrA). The majority of test strains of C. jejuni exhibited a high resistance to nalidixic acid, ciprofloxacin, and tetracycline, which reached the maximum value after numerous passages. The expression of antibiotic resistance was greatest in the presence of nalidixic acid and tetracycline. Ciprofloxacin resistance of 33% strains, which were initially resistant to this antibiotic, was increased after 2-3-fold treatment. We revealed a high degree of correspondence between phenotypic and genotypic profiles of antibiotic resistance in food isolates of Campylobacter. One, two, or more genes of aphA were identified in 85% strains phenotypically resistant to aminoglycosides. The tetO gene was found nearly in all strains resistant to tetracycline. Studying the biofilm matrix in C. jejuni after culturing with antibiotics in subinhibitory doses showed that quinolones (particularly nalidixic acid) and tetracyclines potentiate the formation of biofilms and increase the tolerance of Campylobacter to stress exposures. The intensity of biofilm growth was shown to depend little on the effect of macrolides and aminoglycosides. Therefore, the presence of these agents in residual concentrations is associated with a lower risk for the development of antibiotic resistance in C. jejuni populations.

http://ift.tt/2FkhV1d

Preparation of Human Olfactory Ensheathing Cells for the Therapy of Spinal Cord Injuries

We developed an optimal protocol for preparing and culturing of olfactory ensheathing cells from human olfactory mucosa. Using this protocol, we obtained a culture enriched with human olfactory ensheathing cells. Immunofluorescence analysis by simultaneous expression of GFAP and p75NTR markers showed that the content of ensheathing cells was maximum in passage 3 and 4 cultures (94 and 89.5%, respectively). The developed protocol can be recommended for obtaining autologous preparations of human ensheathing cells for cell therapy of spinal cord injuries.

http://ift.tt/2H2E2X8

Survival of Mesenchymal Stem Cells in Different Methods of Nebulization

We compared survival of bone marrow mesenchymal stem cells after compressor, ultrasound, and mesh nebulization of the cell suspension over 10 min. Viability of stromal cells was best preserved after compressor nebulization (72%). Cell survival after ultrasonic nebulization was significantly lower (20%). After mesh nebulization, no live cells were found. Thus, compressor nebulization is the most preferable method of the production of cell aerosol for their delivery to the lower respiratory tract.

http://ift.tt/2Fl4HB7

Analysis of Dynamic Geometric Configuration of the Aortic Channel from the Perspective of Tornado-Like Flow Organization of Blood Flow

Analysis of the data of morphometry of aortic casts, aortography at different pressures, and multispiral computer tomography of the aorta with contrast and normal pulse pressure showed that geometric configuration of the flow channel of the aorta during the whole cardiac cycle corresponded to the conditions of self-organization of tornado-like quasipotential flow described by exact solutions of the Navier—Stokes equation and continuity of viscous fluid typical for this type of fluid flows. Increasing pressure in the aorta leads to a decrease in the degree of approximation of the channel geometry to the ratio of exact solution and increases the risk of distortions in the structure of the flow. A mechanism of evolution of tornado-like flow in the aorta was proposed.

http://ift.tt/2H0ax88

Monocytes with Oncogenic Mutation JAK2 V617F as a Tool for Studies of the Pathogenic Mechanisms of Myelofibrosis

We analyzed previously generated stable monocyte-derived cell line carrying mutation JAK2 V617F. Evaluation of the expression of pro- and antifibrotic factors revealed changes in the production of MMPs and their inhibitors, growth factors, galectin-3, and pentraxin 3 in cells carrying mutation JAK2 in comparison with control non-modified cells.

http://ift.tt/2Fmu7hJ

Analysis of IL-1α, bFGF, TGF-β1, IFNγ, MMP-1, and CatD Expression in Multinuclea Macrophages In Vitro

The incidence of mono- and multinuclear cells and their expression of pro- and antifibrotic factors were studied in cultured peritoneal macrophages from intact and BCG-infected mice. Generally, the expression of factors increased with an increase in the number of nuclei per cell. However, the expression was higher in macrophages from BCG infected mice, except the cells with 3 and more nuclei, extremely rarely expressing IL-1α in cultures from intact and BCG-infected animals. The number of macrophages with 3 and more nuclei, expressing CatD, was comparable with the number of mono- and binuclear macrophages. Presumably, this was determined by various mechanisms of formation of multinuclear (3-5 and more nuclei) macrophages, for example, by amitosis.

http://ift.tt/2H5lo0N

L-Lysine-α-Oxidase: Acidovorax citrulli Bacterium Inhibitor

Studies of the effects of Trichoderma harzianum Rifai F-180 culture fluid concentrate containing L-lysine-α-oxidase antitumor enzyme produced by the fungus and the homogenous enzyme, on ultrahazardous bacterium Acidovorax citrulli demonstrated the antibacterial activity of the concentrate. Trichoderma harzianum Rifai F-180 producing L-lysine-α-oxidase was cultured in a technological device at G. K. Skryabin Institute of Biochemistry and. Physiology of Microorganisms, Russian Academy of Sciences. Activity of L-lysine-α-oxidase in the resulted culture fluid concentrate was 0.54 U/ml, activity of the homogenous enzyme was 50 U/mg.

http://ift.tt/2FoJJ4v

Expression of Adhesion Molecules in Activated Endothelium after Interaction with Mesenchymal Stromal Cells

The studied the expression of intercellular adhesion molecules and transcription of the corresponding genes in intact and activated endothelial cells both in monoculture and during interaction with mesenchymal stromal cells. It was found that the levels of integrin-α1 and VE-cadherin mRNA increased during co-culturing. TNFα-induced activation of endothelial cells enhanced expression of integrin-α1 both at the mRNA and protein synthesis stages and had no effect on the level of VE-cadherin. Direct contact with mesenchymal stromal cells did not eliminate the effect of endothelial cell activation, but expression of integrin-α1 and VE-cadherin in activated endothelial cells tended to decrease.

http://ift.tt/2H6LYXj

Experimental Evaluation of the Effects of Low-Dose Heparin on the Behavior and Morphofunctional Status of the Liver in Wistar Rats with Posttraumatic Stress Disorders

Posttraumatic stress disorders were induced in Wistar rats by modeling predatory stress. Animals tested in elevated plus-maze demonstrated signs of high anxiety and difficulties in space orientation. Behavioral disorders were paralleled by degenerative changes in hepatocytes. A course of low-dose high-molecular heparin after stress exposure promoted effective adaptation and normalization of behavioral and morphofunctional disorders. Analysis of the results indicated good prospects of heparin as an effective drug under conditions of exposure to extreme factors of psychotraumatic type.

http://ift.tt/2Fl4G01

Changes in Canonical β-Catenin/Wnt Signaling Activation in the Adrenal Cortex of Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Prenatal and Postnatal Ontogeny

Prenatal and postnatal exposure to low doses of the endocrine disruptor dichlorodiphenyltrichloroethane (DDT) leads to delayed activation of the canonical β-catenin/Wnt signaling in zona glomerulosa and zona reticularis of the adrenal cortex in rats, which changed the rate of their postnatal development. Suppression of the Wnt pathway in zona fasciculata promotes its regeneration after DDT-induced blood circulation disorders and cell death.

http://ift.tt/2H4lciv

Role of Matrix Metalloproteinase-2 in the Development of Cyclophosphamide-Induced Cardiomyopathy

Immunohistochemical assay was employed to determine localization of MMP-2 in cardiomyocytes of WAG rats and changes in MMP-2 expression during modeled cardiomyopathy induced by single intraperitoneal injection of cyclophosphamide (125 mg/kg) alone or in combination with preventive intraperitoneal administration of an equal dose of asparcam-L (potassium-magnesium asparaginate) 30 min prior to the cytostatic. In the myocardium of control and experimental rats, MMP-2 was mostly located in cardiomyocyte nuclei. During the development of cyclophosphamide-induced cardiomyopathy (in 3 days after injection), the index of MMP-2-positive cardiomyocyte nuclei increased by 76%. In contrast to control hearts, MMP-2 was also expressed in the cardiomyocyte sarcoplasm. Preventive injection of asparcam-L moderated the cardiotoxic effect of cyclophosphamide, which manifested in less pronounced increase in the volume density of cardiomyocytes with lytic changes (by 42%) and index of MMP-2⁺ cardiomyocyte nuclei (by 23%) in comparison with the rats exposed to cyclophosphamide alone.

http://ift.tt/2FmIVNq

Analysis of the Basic Characteristics of Osteogenic and Chondrogenic Cell Lines Important for Tissue Engineering Implants

We isolated and characterized cultures of bone and cartilage tissue cells of laboratory minipigs. The size and morphological features of adherent osteogenic and chondrogenic cells were specified. During long-term culturing under standard conditions, the studied cultures expressed specific markers that were detected by immunohistochemical staining: alkaline phosphatase and calcium deposits in osteoblasts and type II collagen and cartilage extracellular matrix in chondrogenic cells. Proliferative potential (mitotic index) of both cell types was 4.64% of the total cell number. Cell motility, i.e. the mean velocity of cell motion was 49 pixels/h for osteoblasts and 47 pixels/h for chondroblasts; the mean migration distance was 2045 and 2118 pixels for chondroblasts and osteoblasts, respectively. The obtained cell lines are now used as the control for evaluation of optimal biocompatibility of scaffold materials in various models. Characteristics of the motility of the bone and cartilage tissue cells can be used for modeling and estimation of the rate of cells population of 3D scaffolds made of synthetic and biological polymers with different internal structure and physicochemical properties during designing in vitro tissue implants.

http://ift.tt/2H4VeLo

Infrared Fluorescent Angiography during Experimental Trachea Transplantation

Indocyanine green fluorescence was used for evaluation of the degree of trachea revascularization after its autotransplantation in rabbits (transplantation of 1- and 2-cm segment of the trachea). Intravenous administration of indocyanine green was followed by a significant fluorescence of the substance in microvessels of the trachea over 30-40 sec. Immediately after surgery, fluorescence in the implanted segment was absent, but within 7 days it was completely restored in rabbits receiving transplantation of a 1-cm segment. After transplantation of 2-cm segment of the trachea, fluorescence did not recover, which corresponded to the clinical picture and autopsy results. Thus, fluorescent angiography is an informative method for evaluation of trachea revascularization.

http://ift.tt/2FoHTk3

Matrix Metalloproteinases MMP-1 and MMP-9 and Their Inhibitor TIMP-1 as Markers of Dilated Cardiomyopathy in Patients of Different Age

We studied the expression of MMP-2, MMP-9, and inhibitor TIMP-1 in myocardial autopsy samples from subjects of different age and in cardiomyocyte cultures in the norm and in dilated cardiomyopathy. In autopsy samples of normal myocardium and in cardiomyocyte cultures, expression of molecules involved in extracellular matrix remodeling did not change during aging. In dilation cardiomyopathy, expression of MMP-2, MMP-9, and TIMP-1 and their ratios in autopsy material and in cultures was elevated by 1.5-9 times. Remodeling of extracellular matrix plays an important role in the pathogenesis of dilated cardiomyopathy. MMP-2, MMP-9, and their inhibitor TIMP-1 and the MMP/TIMP ratios can be regarded as promising predictors of dilated cardiomyopathy and used for evaluation of the effectiveness of treatment of this conditions in patients of different ages.

http://ift.tt/2H4laqT

Role of Endogenous Melatonin in the Regulation of Th17/Treg Balance during Pregnancy

We studied the role of endogenous melatonin in the development and functioning of T cells that produce IL-17 (Th17) and regulatory T cells (Treg) during pregnancy. The study was performed ex vivo and in vitro with auto-serum as the source of endogenous melatonin under conditions of blockade of melatonin-dependent signaling. Participation of the hormone in the regulation of differentiation of both CD4⁺RORγt⁺ and CD4⁺FoxP3⁺T cells and their key products IL-17A and TGF-β was demonstrated. It is known that the normal gestational process is accompanied by a decrease in Th17/Treg ratio due to hormonal changes. The sensitivity of the studied subpopulations to melatonin during pregnancy can affect its outcome.

http://ift.tt/2Fpy1qm

Machine learning aided exploration of relationship between strength and elastic properties in ascending thoracic aneurysm

Summary

Machine learning was applied to classify tension-strain curves harvested from inflation tests on ascending thoracic aneurysm samples. The curves were classified into rupture and non-rupture groups using pre-rupture response features. Two groups of features were used as the basis for classification. The first was the constitutive parameters fitted from the tension-strain data and the second was geometric parameters extracted from the tension-strain curve. Based on the importance scores provided by the machine learning, implications of some features were interrogated. It was found that (1) the value of a constitutive parameter is nearly the same for all members in the rupture group, and (2) the strength correlates strongly with a tension in the early phase of response as well as with the end stiffness. The study suggests that the strength, which is not available without rupturing the tissue, may be indirectly inferred from pre-rupture response features. This article is protected by copyright. All rights reserved.

http://ift.tt/2FWMdoJ

Issue Information

No abstract is available for this article.

http://ift.tt/2CYxR3N

Outcomes of laparoscopic sleeve gastrectomy in Crohn's disease patients: an initial Australian experience

Background

Crohn's disease (CD) in association with obesity is becoming an increasing issue in Australia and worldwide. This report looks at outcomes for patients with CD undergoing laparoscopic sleeve gastrectomy.

Methods

This is a retrospective analysis of our database of patients undergoing laparoscopic sleeve gastrectomy from 2007 to 2016. Patients with concurrent CD were included.

Results

Eight patients with CD underwent laparoscopic sleeve gastrectomy with a mean preoperative body mass index of 43.8. There were no identified intraoperative or post-operative complications. The mean excess weight loss was 55.7% and 56.5% at 6 months and 1 year, respectively.

Conclusion

Laparoscopic sleeve gastrectomy can be achieved in CD patients. No complications and effective weight loss was observed in the eight reported patients.

http://ift.tt/2HZzlyF

Corrigendum

http://ift.tt/2oPYsLw

Exploring the Pharmacological Mechanism of Danzhi Xiaoyao Powder on ER-Positive Breast Cancer by a Network Pharmacology Approach

Background. Breast cancer is the most common malignancy among women worldwide, but the long-term endocrine therapy is frequently associated with adverse side effects. Danzhi Xiaoyao powder (DXP) is a herbal formula that has an effect on breast cancer, especially ER-positive breast cancer. However, the active compounds, potential targets, and pharmacological and molecular mechanism of its action against cancer remain unclear. Methods. A network pharmacology approach comprising drug-likeness evaluation, oral bioavailability prediction, Caco-2 permeability prediction, multiple compound target prediction, multiple known target collection, breast cancer genes collection, and network analysis has been used in this study. Results. Four networks are set up—namely, ER-positive breast cancer network, compound-compound target network of DXP, DXP-ER-positive breast cancer network, and compound-known target-ER-positive breast cancer network. Some ER-positive breast cancer and DXP related targets, clusters, biological processes, and pathways, and several potential anticancer compounds are found. Conclusion. This network analysis successfully predicted, illuminated, and confirmed the molecular synergy of DXP for ER-positive breast cancer, got potential anticancer active compounds, and found the potential ER-positive breast cancer associated targets, cluster, biological processes, and pathways. This work also provides clues to the researcher who explores ethnopharmacological or/and herbal medicine's or even multidrugs' various synergies.

http://ift.tt/2FdzZGT

Specificity of Good Manufacturing Practice (GMP) for Biomedical Cell Products

The article describes special aspects of Good Manufacturing Practice (GMP) for biomedical cell products (BMCP) that imply high standards of aseptics throughout the entire productio process, strict requirements to donors and to the procedure of biomaterial isolation, guaranty of tracing BMCP products, defining processing procedures which allow to identify BMCP as minimally manipulated; continuous quality control and automation of the control process at all stages of manufacturing, which will ensure product release simultaneously with completion of technological operations.

http://ift.tt/2H2WDCf

Some Peculiarities of Local Distribution of Multipotent Mesenchymal Stromal Cells after Their Injection into Intact Muscle Tissue in Experiment

Changes in the muscular tissue after subcutaneous injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and additionally stained with cell membrane dye Vybrant CM-Dil in the projection of ligated femoral vein were studied by light microscopy with luminescence. Stromal cells injected through the skin can appear not only in the damaged tissue where acceleration of regeneration processes is required, but also in intact structures located in superficial or deeper layers. In intact muscular tissue, stromal cells spreading in the perivascular tissue initiate inflammation and migration of macrophages, activate and even trigger sclerotic processes due to differentiation into connective tissue cells (fibroblasts) and stimulation of proliferation and collagen synthesis by host fibroblasts. Injected multipotent mesenchymal stromal cells are gradually phagocytized by macrophages.

http://ift.tt/2Fm0E7H

Measuring of Adhesion Force in the Cell—Cell System Based on Atomic Force Microscopy Technology

We developed and tested a method for fabrication of a biosensor chip based on native human whole blood lymphocyte and a titanium tipless cantilever. The biosensor can be used for measuring intermolecular adhesion forces in the cell—cell system by using atomic force spectroscopy. The developed biosensor chip was applied for measuring adhesion force between lymphocyte and granulocyte and between lymphocyte and erythrocyte in healthy individuals and in patients with acute lymphoblastic leukemia (before treatment, during standard treatment, and during relapse). It was found that adhesion force between lymphocyte and granulocyte and between lymphocyte and erythrocyte increased almost twice during relapse, which is an important diagnostic marker of early cytological abnormalities indicating progression of the disease.

http://ift.tt/2H3zAaA

Isolation and Characterization of Human Myoblast Culture In Vitro for Technologies of Cell and Gene Therapy of Skeletal Muscle Pathologies

We analyzed cultures of 5 independent myoblast lines from human skeletal muscles. It was shown that the content of desmin-positive cells in cultures at early passages exceeds 90%. Typical morphofunctional signs of myogenic differentiation disturbances were identified and their dynamics was studied. Signs of alternative adipogenic and chondrogenic differentiation of cells were revealed. Based on these data, limitations for the use of myoblast cultures of certain passages for biomedical research and cell therapy were evaluated.

http://ift.tt/2FotioL

Peculiarities of Cyto- and Chemoarchitectonics of Human Entorhinal Cortex during the Fetal Period

We studied peculiarities of the structure of human entorhinal cortex at weeks 20-26 of gestation (10 hemispheres). The samples were Nissl-stained and immunohistochemically treated with antibodies to parvalbumin, calretinin, calbindin, and cytoskeleton proteins (MAP2 and N200). 3D-reconstruction of the entorhinal cortex from serial sections was performed, caudomedial and rostrolateral areas were isolated. Parvalbumin⁺ cells in layer I, discrete distribution of layer II cells with colocalization of MAP2 and calretinin at the border with layer I, and two sublayers Va and Vb with MAP2⁺ neurons were typical for the caudomedial area. Rostrolateral area was characterized by the homogenous layer II with big amount of cells, high density of MAP2⁺ neurons only in layer III, and the unique layer V. Reelin⁺ Cajal—Retzius cells and N200⁺ fiber plexus in layer I were observed in the caudomedial and rostrolateral areas of the entorhial cortex. Layer IV was represented by a cell-free desiccant.

http://ift.tt/2H3zwaQ

Co-Culturing of Multipotent Mesenchymal Stromal Cells with Autological and Allogenic Lymphocytes

We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged. Priming of multipotent mesenchymal stromal cells with IFN did not affect these changes. In turn, lymphocytes underwent activation, expression of HLA-DR increased, subpopulation composition of lymphocytes changed towards the increase in the content of naïve T cells. These findings are important for cell therapy.

http://ift.tt/2Fm0tt3

In Vitro Modeling of Co-Transplantation of Multipotent Stromal Mesenchymal Cells from Orbital Fat Pad and Lipoaspirate of Human Subcutaneous Adipose Tissue in Organ Culture in Collagen Gel

The interplay of multipotent stromal cells derived from the orbital fat pads and cells of the lipoaspirate from the subcutaneous adipose tissue was studied using in vitro co-transplantation model in an organ culture in a collagen gel. Microscopy findings and intensity of apoptosis and cell proliferation in cultures of lipoaspirate with and without multipotent stromal cells showed that the cells maintained their viability, proliferation capacity, and cytokine secretion activity. Higher proliferatitive activity of cells in cocultures promotes renewal of fat transplant cells and can help to maintain its stable volume in delayed terms after transplantation.

http://ift.tt/2H3zrUA

KrioBlast TM as a New Technology of Hyper-fast Cryopreservation of Cells and Tissues. Part I. Thermodynamic Aspects and Potential Applications in Reproductive and Regenerative Medicine

Kinetic (dynamic) vitrification is a promising trend in cryopreservation of biological materials because it allows avoiding the formation of lethal intracellular ice and minimizes harmful effects of highly toxic penetrating cryoprotectants. A uniform cooling protocol and the same instruments can be used for practically all types of cells. In modern technologies, the rate of cooling is essentially limited by the Leidenfrost effect. We describe a novel platform for kinetic vitrification of biological materials KrioBlast^TM that realizes hyper-fast cooling and allows overcoming the Leidenfrost effect. This opens prospects for creation of a novel technology of cell cryopreservation for reproductive and regenerative medicine.

http://ift.tt/2Fm0pJP

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization (FISH).

http://ift.tt/2oTtmTo

Phosphaturic Mesenchymal Tumor Without Osteomalacia: Additional Confirmation of the “Non-Phosphaturic” Variant, with Emphasis on the Roles of FGF23 Chromogenic in situ Hybridization and FN1-FGFR1 Fluorescence in situ Hybridization

Phosphaturic Mesenchymal Tumor (PMT) is a rare, histologically distinctive neoplasm, which classically presents with phosphaturia and tumor-induced osteomalacia (TIO) (i.e., oncogenic osteomalacia). Both the phosphaturia and TIO are due to paraneoplastic production of FGF23 (a phosphatonin) by the neoplastic cells, which are genetically characterized by rearrangements of FN1 (most often with FGFR1 – and less frequently with FGF1). However, rare cases of PMT present without phosphaturia and TIO (i.e., the "non-phosphaturic" variant) – and are therefore much more challenging to diagnose.

http://ift.tt/2HZlQih

A case report of atypical Spitz tumor harboring a novel MLPH-ALK gene fusion with discordant ALK immunohistochemistry results

Frequent kinase fusions have been reported in spitzoid neoplasms, approximately 10% of which involve ALK rearrangements. Herein, we report a case of atypical Spitz tumour (AST) with a novel MLPH-ALK fusion, which has not been previously reported to contribute to cancer development. The tumour was detected in the right arm of a 40-year-old woman. The novel ALK fusion was identified by a 5′-rapid amplification of cDNA ends-based system optimised for formalin-fixed paraffin-embedded tissue. Initially, ALK expression was detected by immunohistochemistry (IHC) using 5A4 antibodies for both sensitive and conventional polymer detection method.

http://ift.tt/2oTtiD8

Propranolol prevents liver cirrhosis by inhibiting hepatic stellate cell activation mediated by the PDGFR/Akt pathway

Propranolol is known to reduce portal pressure by decreasing blood flow to the splanchnic circulation and the liver. However, it is unknown if propranolol improves fibrogenesis and sinusoidal remodeling in the cirrhotic liver. The aim of this study was to investigate the therapeutic effects of propranolol on carbon tetrachloride (CCl4)-induced liver fibrosis in a mouse model and the intrinsic mechanisms underlying those effects. In this study, a hepatic cirrhosis mouse model was induced by CCl4 administration for 6weeks.

http://ift.tt/2I1JnPT

Clinical-oriented Three-dimensional Gait Analysis Method for Evaluating Gait Disorder

In this study, a clinician-friendly three-dimensional gait analysis method, which was designed to be performed in the rehabilitation clinic, is presented. The method consists of a simplified measurement method and intuitive figures to facilitate clinicians' understanding of the results.

http://ift.tt/2Fobf23

Cryopreservation of Zebrafish Spermatogonia by Whole Testes Needle Immersed Ultra-Rapid Cooling

The main purpose of this study was to adapt the needle immersed vitrification (NIV) procedure to cryopreserve whole zebrafish testes. Additionally, the repeatability of the method in five different zebrafish strains was tested.

http://ift.tt/2Fe2zYK

Usage and Usability of a Web-based Program for Family Caregivers of Older People in Three European Countries: A Mixed-Methods Evaluation

InformCare is a European Web platform that supports informal caregivers of older people by providing access to online information and professional and peer support. The aim of this study was to assess the usage and usability of a psychosocial Web-based program carried out in three European countries (Italy, Sweden, and Germany). A mixed-methods sequential explanatory design was adopted, comprising baseline and postintervention assessments, as well as combined thematic content analysis of results and focus group findings. A convenience sample of 118 caregivers was enrolled, of whom 94 used the services offered by the program at least once. The subsamples in the three countries used the platform in different ways, with a predominance of passive strategies (eg, seeking information and reading other people's comments) for Italian caregivers, and more active usage by Swedish and German caregivers. The usability assessment showed that the platform was perceived well by Italian and German caregivers, whereas technical problems affected the Swedish sample's experiences. Focus group data highlighted user satisfaction with the online support and reliability of the environment. Recommendations for practitioners are to ensure digital training for caregivers who have lower confidence in use of the Internet, to involve different healthcare professionals in the provision of professional support, and to adequately manage online community building. The research leading to these results has received funding from the European Union's Seventh Framework Programme for Research and Technological Development (FP7/2007–2013) under grant agreement no. 306058 (HEALTH-F3-2012-306058) for the INNOVAGE project. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Corresponding author: Francesco Barbabella, PhD, Linnaeus University, Universitetsplatsen 1, 351 95 Växjö, Sweden (francesco.barbabella@lnu.se). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2CWmppv

Antidiabetic Effects of a Chinese Herbal Medicinal Compound Sangguayin Preparation via PI3K/Akt Signaling Pathway in db/db Mice

Sangguayin (SGY), comprising four types of Chinese herbs, can be used as both food and medicine and has been clinically used to treat type 2 diabetes mellitus (T2DM) for a long time. Our previous study demonstrated the antidiabetic effect of SGY in experimental T2DM rats fed with a high-fat diet and treated with a low dose of streptozotocin. However, its mechanism of action is questionable. In this study, we refined the traditional SGY decoction and investigated its antidiabetic activity in db/db mice. We evaluated the possible molecular mechanism using skeletal muscle tissues. The results show that the treatment with SGY preparation resulted in a decrease in the blood glucose, glycated serum protein, and blood lipid levels and an improvement in the glucose tolerance as well as insulin resistance. In addition, SGY preparation remarkably upregulated the expression of insulin receptor, insulin receptor substrate-1, phosphoinositide 3 kinase (PI3K), protein kinase B (Akt), and glucose transporter type 4 (GLUT4). Thus, SGY preparation is an effective agent for the treatment of T2DM, and its molecular mechanism may be related to the regulation of PI3K/Akt signaling in the skeletal muscle.

http://ift.tt/2CXMu7B