Sharp Force Trauma to a 1,000‐year‐old Skull from the Jerusalem Mountains

International Journal of Osteoarchaeology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D7NMlF

Assisted phytostabilisation of As, Pb and Sb-contaminated Technosols with mineral and organic amendments using Douglas fir ( Pseudotsuga menziesii (Mirb.) Franco)

Abstract

Phytoremediation of metal(loid)s by conifers is not widely studied, although conifers may be interesting, particularly in temperate-cold areas and/or on acidic soils. In this study, seeds of Douglas fir were sown in greenhouse and cultivated for 3 months on two Technosols highly contaminated with different concentrations of Pb, As and Sb and collected in two French old former mines located in massif Central or close to it: a mine of gold at La Petite Faye and a mine of lead and silver at Pontgibaud. Two amendments, a nutrient solution (NS) and composted sewage sludge (CSS), were tested in order to stimulate Douglas fir growth and to reduce the metal(loid)s mobility and phytoavailability. The speciation determined by sequential extractions as well as mineralogy highlight different geochemical behaviours of Pb, As and Sb as a function of the Technosol. In all cases, CSS amendments significantly reduced Pb phytoavailability as well as the uptake and translocation of Pb and As. Moreover, CSS stimulated the growth of Douglas firs highlighting that this amendment could be a good strategy for a better phytostabilisation of these metal(loid)s.

https://ift.tt/2peDC98

Deep sequencing of SMPD1 gene revealed a heterozygous frameshift mutation (p.Ser192Alafs) in a Palestinian infant with Niemann–Pick disease type A: a case report

Niemann–Pick disease is caused by reduced level of the lysosomal enzyme acid sphingomyelinase. Children can survive between 2 and 12 years based on the disease type. Two main types are well known: type A and B...

https://ift.tt/2MHuUJY

Acquired thrombotic thrombocytopenia purpura associated with severe ADAMTS13 deficiency in a 3-year-old boy: a case report and review of the literature

Acquired thrombotic thrombocytopenia purpura is very rarely encountered in children. It is often misdiagnosed initially when the condition is not inherited.

https://ift.tt/2pitUme

Feasibility of desensitizing children highly allergic to peanut by high‐dose oral immunotherapy

Allergy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xuc9DZ

Tolerability of iobitridol in patients with non‐immediate hypersensitivity reactions to iodinated contrast media

Allergy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NPqc1i

Debunking the Myths: Mental Illness and Mass Shootings

Violence and Gender, Ahead of Print.


https://ift.tt/2PIVlkg

Early Identification of Grooming and Targeting in Predatory Sexual Behavior on College Campuses

Violence and Gender, Ahead of Print.


https://ift.tt/2xqQgqj

Compassion: Without It—The Shame Is Ours to Bear

Violence and Gender, Volume 5, Issue 3, Page 125-127, September 2018.


https://ift.tt/2PMFzoK

Epstein–Barr Virus Lytic Reactivation Induces IgG4 Production by Host B Lymphocytes in Graves' Disease Patients and Controls: A Subset of Graves' Disease Is an IgG4-Related Disease-Like Condition

Viral Immunology, Ahead of Print.


https://ift.tt/2MHWmad

Differential Activation of NLRP3, AIM2, and IFI16 Inflammasomes in Humans with Acute and Chronic Hepatitis B

Viral Immunology, Ahead of Print.


https://ift.tt/2pfTkRm

A Comparison of Toll-Like Receptor 5 and 21 Ligands as Adjuvants for a Formaldehyde Inactivated H9N2 Avian Influenza Virus Vaccine in Chickens

Viral Immunology, Ahead of Print.


https://ift.tt/2MDL07m

Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

Viral Immunology, Ahead of Print.


https://ift.tt/2phHztO

Immunology of West Nile Virus Infection and the Role of Alpha-Synuclein as a Viral Restriction Factor

Viral Immunology, Ahead of Print.


https://ift.tt/2MMX5r2

Interleukin-6 Rescues Lymphocyte from Apoptosis and Exhaustion Induced by Chronic Hepatitis C Virus Infection

Viral Immunology, Ahead of Print.


https://ift.tt/2pgpdct

Safety and efficacy of a novel high‐intensity focused electromagnetic technology device for noninvasive abdominal body shaping

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NnZSfv

In vivo dynamic thermal imaging of skin radiofrequency treatment

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D3PF32

Effects of radiofrequency on adipose tissue: A systematic review with meta‐analysis

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NnZNbH

Procedural management of rhinophyma: A comprehensive review

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D4LYK7

Histological findings correlated with clinical outcomes in telangiectasia treated with ohmic thermolysis and 940 nm laser

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NitjiO

Comparison of novel dual mode vs conventional single pass of a 1450‐nm diode laser in the treatment of acne vulgaris for Korean patients: A 20‐week prospective, randomized, split‐face study

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D7TIvb

Safety and efficacy of a novel high‐intensity focused electromagnetic technology device for noninvasive abdominal body shaping

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NnZSfv

In vivo dynamic thermal imaging of skin radiofrequency treatment

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D3PF32

Effects of radiofrequency on adipose tissue: A systematic review with meta‐analysis

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NnZNbH

Procedural management of rhinophyma: A comprehensive review

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D4LYK7

Histological findings correlated with clinical outcomes in telangiectasia treated with ohmic thermolysis and 940 nm laser

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2NitjiO

Comparison of novel dual mode vs conventional single pass of a 1450‐nm diode laser in the treatment of acne vulgaris for Korean patients: A 20‐week prospective, randomized, split‐face study

Journal of Cosmetic Dermatology, EarlyView.


https://ift.tt/2D7TIvb

Screening for Syphilis with Dual Algorithms: Analysis of Discordant and Concordant Serology Results in a Population with a Low Prevalence of Syphilis

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xiGkif

Type IV allergy to antimalarials can mimic cutaneous manifestations of lupus erythematosus

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PEbl6Y

Morphological Classification System of Hair Regrowth Patterns in Alopecia Areata Patches: DIMT Classification

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xiGdmP

Association of Irisin Circulating Level with Diabetic Retinopathy: A Case-Control Study

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0723-3749

Obesity and obesity induced diabetes (DM II) development and progression have been associated with sedentary lifestyle. Irisin, a newly discovered myokine, has been demonstrated at lower levels in obese and DM II patients compared to controls. The main aim of this study is to explore association of Irisin with diabetic retinopathy (DR). A total of 233 healthy and DM II adults participated in this study. Participants were divided into four categories: a healthy control group and an age-match subset of patients with DM II; a positive control group of patients with DM II not affected by DR (No DR); and patients with DM II affected by DR (non-proliferative DR (NPDR) and proliferative DR (PDR)). Plasma samples were quantified for Irisin measurement, lipid profile and HbA1c. Comparison of the age-matched groups of healthy controls and patients with DM II revealed lower Irisin plasma level in DM II group. Analyses revealed negative correlations of Irisin to HbA1c and LDL levels and positive correlation to HDL level. Comparing Irisin level in No DR and DR groups revealed a higher level in No DR group and analysis per DR classification indicated higher Irisin level in NPDR group. Our results demonstrate not only correlation of plasma Irisin level with DR stages, but also significantly different Irisin level among them. This is promising in terms of researching Irisin as a potential associating marker for DM II and DR development and progression.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2DeS1fA

Diagnostic Performance of HMGA2 Gene Expression for Differentiation of Malignant Thyroid Nodules; A Systematic Review and Meta‐analysis

Clinical Endocrinology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Qym04u

Coexisting pituitary and non‐pituitary gigantism in the same family

Clinical Endocrinology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xnsf2m

P.Ventricosus detection in a baby skin folds

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xsiTT5

Pro-inflammatory effects of extracted urban fine particulate matter on human bronchial epithelial cells BEAS-2B

Abstract

Atmospheric particulate matter (PM) constitutes the major part of urban air pollution and is a heterogeneous mixture of solid and liquid particles of different origin, size, and chemistry. Human exposure to PM in urban areas poses considerable and significant adverse effects on the respiratory system and human health in general. Major contributors to PM content are combustion-related sources such as diesel vehicles, household, and industrial heating. PM is composed of thousands of different high molecular weight organic compounds, including poly-aromatic hydrocarbons (PAHs). The aim of this study was to clarify the cytotoxic effects of the extract of actual urban PM1 with high benzo[a]pyrene (BaP) content collected in Eastern European mid-sized city during winter heating season on human bronchial epithelial cells (BEAS-2B). Decreased cell viability, alteration of cell layer integrity, increased apoptosis, and oxidative stress were observed during the 3-day exposure to the PM extract. In addition, following PM exposure pro-inflammatory cytokine expression was upregulated at gene and protein levels. Morphology and motility changes, i.e., decreased cells' ability to cover scratch area, were also documented. We report here that the extract of urban PM1 may induce bronchial epithelium changes and render it pro-inflammatory and compromised within 3 days.

https://ift.tt/2xiehjb

Detection of high‐grade dysplasia, carcinoma in situ and squamous cell carcinoma in the upper aerodigestive tract: recommendations for optimal use and interpretation of Narrow Band Imaging

Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2QDMnpB

A mixed methods study of the management of hearing loss associated with otitis media with effusion in children with Down syndrome

Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PFbOWK

Controversial Issues In Vitiligo patients: a review of old and recent treatments

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D4vL7M

Intravenous immunoglobulin for treatment of necrobiotic xanthogranuloma

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pgbEdl

Biphasic Amyloidosis involved in the face: Effective Treatment with 30% Salicylic Acid

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D4v8Ls

Development of hidradenitis suppurativa in a patient treated with ustekinumab for her psoriasis: a potential paradox reaction?

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pfKUtb

Controversial Issues In Vitiligo patients: a review of old and recent treatments

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D4vL7M

Intravenous immunoglobulin for treatment of necrobiotic xanthogranuloma

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pgbEdl

Biphasic Amyloidosis involved in the face: Effective Treatment with 30% Salicylic Acid

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D4v8Ls

Development of hidradenitis suppurativa in a patient treated with ustekinumab for her psoriasis: a potential paradox reaction?

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pfKUtb

Acquired disorders with hypopigmentation: A clinical approach to diagnosis and treatment

Acquired hypopigmented skin changes are commonly encountered by dermatologists. Although hypopigmentation is often asymptomatic and benign, occasional serious and disabling conditions present with cutaneous hypopigmentation. A thorough history and physical examination, centered on disease distribution and morphological findings, can aid in delineating the causes of acquired hypopigmented disorders. Part II of this two-part series focuses on conditions with a hypopigmented phenotype. Early diagnosis and appropriate management of these disorders can improve a patient's quality of life, halt disease progression, and prevent irreversible disability.

https://ift.tt/2xijBTw

Acquired disorders with depigmentation: A systematic approach to vitiliginoid conditions

Acquired disorders with depigmentation are commonly encountered by dermatologists and present with a wide differential diagnosis. Vitiligo, the most common disorder of acquired depigmentation, is characterized by well-defined depigmented macules and patches. Other conditions, such as chemical leukoderma, can present with similar findings, and are often easily mistaken for vitiligo. Key clinical features can help differentiate between acquired disorders of depigmentation. Part I of this two-part series focuses on conditions with a vitiligo-like phenotype.

https://ift.tt/2OAL1Lf

In regards to Girard et a.l Occurrence of vismodegib-induced cramps (muscular spasms) in the treatment of basal cell carcinoma: A prospective study in 30 patients

https://ift.tt/2xkJu59

Necrolytic migratory erythema (glucagonoma syndrome) associated with pancreatic neuroendocrine tumor presenting with superimposed cellulitis

Introduction: Necrolytic migratory erythema (NME) is a paraneoplastic dermatologic phenomenon classically associated with glucagon-producing tumors from the pancreatic alpha cells. It is characterized by an abnormally elevated blood level of glucagon and skin findings of NME in the setting of glucagon-secreting pancreatic neuroendocrine tumor. Erythematous scaly lesions with centrifugal growth commonly on perineum, distal extremities, lower abdomen, and face characterize the clinical appearance of the disease.

https://ift.tt/2OAKTeJ

What are the best exercises for bat wings?

Strengthening the arms can help improve the muscles and promote fat loss. This can help to improve the shape of the arms and reduce excess and drooping skin that is there. This excess skin is sometimes known as "bat wings" or "bingo wings." Learn more about how to get rid of bat wings.

https://ift.tt/2D11yXg

Hair loss: Scientists test wearable regrowth device

A study investigating ways to promote hair regrowth takes a look at micro LEDs. The scientists believe that they could be used as a wearable solution.

https://ift.tt/2pdTvwL

What are the best exercises for bat wings?

Strengthening the arms can help improve the muscles and promote fat loss. This can help to improve the shape of the arms and reduce excess and drooping skin that is there. This excess skin is sometimes known as "bat wings" or "bingo wings." Learn more about how to get rid of bat wings.

https://ift.tt/2D11yXg

Hair loss: Scientists test wearable regrowth device

A study investigating ways to promote hair regrowth takes a look at micro LEDs. The scientists believe that they could be used as a wearable solution.

https://ift.tt/2pdTvwL

A prospective, randomized, single‐blinded trial for improving health outcomes in rhinology by the use of personalized video recordings

International Forum of Allergy &Rhinology, EarlyView.


https://ift.tt/2QEfJ7j

Correction: Influenza A Virus Negative Strand RNA Is Translated for CD8+ T Cell Immunosurveillance [CORRECTIONS]

https://ift.tt/2MJzNCp

Epidermal Growth Factor (EGF) Autocrine Activation of Human Platelets Promotes EGF Receptor-Dependent Oral Squamous Cell Carcinoma Invasion, Migration, and Epithelial Mesenchymal Transition [TUMOR IMMUNOLOGY]

Activated platelets release functional, high m.w. epidermal growth factor (HMW-EGF). In this study, we show platelets also express epidermal growth factor (EGF) receptor (EGFR) protein, but not ErbB2 or ErbB4 coreceptors, and so might respond to HMW-EGF. We found HMW-EGF stimulated platelet EGFR autophosphorylation, PI3 kinase-dependent AKT phosphorylation, and a Ca²⁺ transient that were blocked by EGFR tyrosine kinase inhibition. Strong (thrombin) and weak (ADP, platelet-activating factor) G protein-coupled receptor agonists and non–G protein-coupled receptor collagen recruited EGFR tyrosine kinase activity that contributed to platelet activation because EGFR kinase inhibition reduced signal transduction and aggregation induced by each agonist. EGF stimulated ex vivo adhesion of platelets to collagen-coated microfluidic channels, whereas systemic EGF injection increased initial platelet deposition in FeCl₃-damaged murine carotid arteries. EGFR signaling contributes to oral squamous cell carcinoma (OSCC) tumorigenesis, but the source of its ligand is not established. We find individual platelets were intercalated within OSCC tumors. A portion of these platelets expressed stimulation-dependent Bcl-3 and IL-1β and so had been activated. Stimulated platelets bound OSCC cells, and material released from stimulated platelets induced OSCC epithelial–mesenchymal transition and stimulated their migration and invasion through Matrigel barriers. Anti-EGF Ab or EGFR inhibitors abolished platelet-induced tumor cell phenotype transition, migration, and invasion; so the only factor released from activated platelets necessary for OSCC metastatic activity was HMW-EGF. These results establish HMW-EGF in platelet function and elucidate a previously unsuspected connection between activated platelets and tumorigenesis through rapid, and prolonged, autocrine-stimulated release of HMW-EGF by tumor-associated platelets.

https://ift.tt/2NkFXxN

Autocrine IL-10 Signaling Promotes Dendritic Cell Type-2 Activation and Persistence of Murine Cryptococcal Lung Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

The substantial morbidity and mortality caused by invasive fungal pathogens, including Cryptococcus neoformans, necessitates increased understanding of protective immune responses against these infections. Our previous work using murine models of cryptococcal lung infection demonstrated that dendritic cells (DCs) orchestrate critical transitions from innate to adaptive immunity and that IL-10 signaling blockade improves fungal clearance. To further understand interrelationships among IL-10 production, fungal clearance, and the effect of IL-10 on lung DCs, we performed a comparative temporal analysis of cryptococcal lung infection in wild type C57BL/6J mice (designated IL-10^+/+) and IL-10^–/– mice inoculated intratracheally with C. neoformans (strain 52D). Early and sustained IL-10 production by lung leukocytes was associated with persistent infection in IL-10^+/+ mice, whereas fungal clearance was improved in IL-10^–/– mice during the late adaptive phase of infection. Numbers of monocyte-derived DCs, T cells, and alveolar and exudate macrophages were increased in lungs of IL-10^–/– versus IL-10^+/+ mice concurrent with evidence of enhanced DC type-1, Th1/Th17 CD4 cell, and classical macrophage activation. Bone marrow–derived DCs stimulated with cryptococcal mannoproteins, a component of the fungal capsule, upregulated expression of IL-10 and IL-10R, which promoted DC type-2 activation in an autocrine manner. Thus, our findings implicate fungus-triggered autocrine IL-10 signaling and DC type-2 activation as important contributors to the development of nonprotective immune effector responses, which characterize persistent cryptococcal lung infection. Collectively, this study informs and strengthens the rationale for IL-10 signaling blockade as a novel treatment for fungal infections.

https://ift.tt/2xhd6k6

Sialic Acid Ligand Binding of CD22 and Siglec-G Determines Distinct B Cell Functions but Is Dispensable for B Cell Tolerance Induction [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Siglec-G and CD22 are inhibitory receptors on B cells and play an important role in the maintenance of tolerance. Although both molecules are expressed on all B cell populations at a similar level, Siglec-G was found to regulate exclusively B1a cells, whereas CD22 functions as an inhibitory receptor specifically on B2 cells. It is known that the mechanistic function of both Siglecs is regulated by sialic acid binding in a reciprocal manner, although it was not known until now how B cells would act when both Siglec-G and CD22 lack their ability to bind sialic acids. We answered this question by analyzing Siglec-G R120E x CD22 R130E mice. These mice show decreased numbers of mature recirculating B cells in the bone marrow similar to mice with mutations in CD22. Also, they show an increased B1a cell population in peritoneal cavity and a skewed BCR repertoire in peritoneal B1a cells, which is characteristic for mice with mutated Siglec-G. Ca²⁺ mobilization was strongly reduced in B2 cells and was altered in peritoneal B1a cells, whereas B cell survival was neither affected in B2 cells nor in B1a cells. Also, aging Siglec-G R120E x CD22 R130E mice do neither develop a general hyperactivated immune status nor autoimmunity. This demonstrates that Siglec binding to sialic acids as abundant self-ligands cannot be a dominant mechanism for the Siglec-mediated B cell tolerance induction.

https://ift.tt/2MMhZGM

Human NK Cells Lyse Th2-Polarizing Dendritic Cells via NKp30 and DNAM-1 [INNATE IMMUNITY AND INFLAMMATION]

Cross-talk between NK cells and dendritic cells (DCs) is important in Th1 immune responses, including antitumor immunity and responses to infections. DCs also play a crucial role in polarizing Th2 immunity, but the impact of NK cell–DC interactions in this context remains unknown. In this study, we stimulated human monocyte-derived DCs in vitro with different pathogen-associated molecules: LPS or polyinosinic–polycytidylic acid, which polarize a Th1 response, or soluble egg Ag from the helminth worm Schistosoma mansoni, a potent Th2-inducing Ag. Th2-polarizing DCs were functionally distinguishable from Th1-polarizing DCs, and both showed distinct morphology and dynamics from immature DCs. We then assessed the outcome of autologous NK cells interacting with these differently stimulated DCs. Confocal microscopy showed polarization of the NK cell microtubule organizing center and accumulation of LFA-1 at contacts between NK cells and immature or Th2-polarizing DCs but not Th1-polarizing DCs, indicative of the assembly of an activating immune synapse. Autologous NK cells lysed immature DCs but not DCs treated with LPS or polyinosinic–polycytidylic acid as reported previously. In this study, we demonstrated that NK cells also degranulated in the presence of Th2-polarizing DCs. Moreover, time-lapse live-cell microscopy showed that DCs that had internalized fluorescently labeled soluble egg Ag were efficiently lysed. Ab blockade of NK cell–activating receptors NKp30 or DNAM-1 abrogated NK cell lysis of Th2-polarizing DCs. Thus, these data indicate a previously unrecognized role of NK cell cytotoxicity and NK cell–activating receptors NKp30 and DNAM-1 in restricting the pool of DCs involved in Th2 immune responses.

https://ift.tt/2xhIDSU

Human Lymph Nodes Maintain TCF-1hi Memory T Cells with High Functional Potential and Clonal Diversity throughout Life [SYSTEMS IMMUNOLOGY]

Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes [LN]) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. In this study, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors and identify a subset of memory CD8⁺ T cells in LN, which maintain a distinct differentiation and functional profile compared with memory CD8⁺ T cells in blood, spleen, bone marrow, and lungs. Whole-transcriptome and high-dimensional cytometry by time-of-flight profiling reveals that LN memory CD8⁺ T cells express signatures of quiescence and self-renewal compared with corresponding populations in blood, spleen, bone marrow, and lung. LN memory T cells exhibit a distinct transcriptional signature, including expression of stem cell–associated transcription factors TCF-1 and LEF-1, T follicular helper cell markers CXCR5 and CXCR4, and reduced expression of effector molecules. LN memory T cells display high homology to a subset of mouse CD8⁺ T cells identified in chronic infection models that respond to checkpoint blockade immunotherapy. Functionally, human LN memory T cells exhibit increased proliferation to TCR-mediated stimulation and maintain higher TCR clonal diversity compared with memory T cells from blood and other sites. These findings establish human LN as reservoirs for memory T cells with high capacities for expansion and diverse recognition and important targets for immunotherapies.

https://ift.tt/2D6b2AB

miR-143 Regulates Memory T Cell Differentiation by Reprogramming T Cell Metabolism [TUMOR IMMUNOLOGY]

MicroRNAs are an important regulator for T cell immune response. In this study, we aimed to identify microRNAs with the potential to regulate T cell differentiation. The influence of miR-143 on differentiation and function of CD8⁺ T cells from healthy donors were detected, and it was found that miR-143 overexpression could significantly increase the differentiation of central memory T (Tcm) CD8⁺ cells, decrease cell apoptosis, and increase proinflammatory cytokine secretion. Furthermore, the specific killing of HER2-CAR T cells against esophageal cancer cell line TE-7 was enhanced by miR-143 overexpression. Glucose transporter 1 (Glut-1) was identified as the critical target gene of miR-143 in the role of T cell regulation. By inhibition Glut-1, miR-143 inhibited glucose uptake and glycolysis in T cell to regulated T cell differentiation. Tcm cell populations were also suppressed in parallel with the downregulation of miR-143 in tumor tissues from 13 patients with esophagus cancer. IDO and its metabolite kynurenine in the tumor microenvironment were screened as an upstream regulator of miR-143. IDO small interfering RNA significantly increased the expression of miR-143 and Tcm cell population. In conclusion, our results show that miR-143 enhanced antitumor effects of T cell by promoting memory T cell differentiation and metabolism reprogramming through Glut-1. Our findings will encourage the development of new strategies targeting miR-143 in both cancer cells and T cells.

https://ift.tt/2D6aRoV

Significance of neck dissection for the treatment of clinically-evident medullary thyroid carcinomas: A systematic review

The survival benefit of prophylactic lateral neck dissection in medullary thyroid carcinomas remains unclear; thus, recent clinical guidelines have deferred the recommendation of lateral neck dissection. This review is to assess the role of lateral neck dissection in treatment of clinically overt medullary thyroid carcinoma.

https://ift.tt/2OwBLrl

Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2Rα, IL-2Rβ, and common [_c]). IL-2Rα, which is highly expressed on regulatory T (T_Reg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward T_Reg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating T_Reg expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease.

https://ift.tt/2NOF7J4

Crystal Structure of the Labile Complex of IL-24 with the Extracellular Domains of IL-22R1 and IL-20R2 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Crystal structure of the ternary complex of human IL-24 with two receptors, IL-22R1 and IL-20R2, has been determined at 2.15 Å resolution. A crystallizable complex was created by a novel approach involving fusing the ligand with a flexible linker to the presumed low-affinity receptor, and coexpression of this construct in Drosophila S2 cells together with the presumed high-affinity receptor. This approach, which may be generally applicable to other multiprotein complexes with low-affinity components, was necessitated by the instability of IL-24 expressed by itself in either bacteria or insect cells. Although IL-24 expressed in Escherichia coli was unstable and precipitated almost immediately upon its refolding and purification, a small fraction of IL-24 remaining in the folded state was shown to be active in a cell-based assay. In the crystal structure presented here, we found that two cysteine residues in IL-24 do not form a predicted disulfide bond. Lack of structural restraint by disulfides, present in other related cytokines, is most likely reason for the low stability of IL-24. Although the contact area between IL-24 and IL-22R1 is larger than between the cytokine and IL-20R2, calculations show the latter interaction to be slightly more stable, suggesting that the shared receptor (IL-20R2) might be the higher-affinity receptor.

https://ift.tt/2xqForj

Three-Dimensional Ameliorated Biologics Elicit Thymic Renewal in Tumor-Bearing Hosts [IMMUNOTHERAPY AND VACCINES]

Cancer-initiating/sustaining stem cell subsets (CSCs) have the potential to regenerate cancer cell populations and are resistant to routine therapeutic strategies, thus attracting much attention in anticancer research. In this study, an innovative framework of endogenous microenvironment-renewal for addressing such a dilemma has been just developed. CSCs in three-dimensional multipotent spheroid-engineered biologics were prepared with 150 Gy radiation and inoculated into 15-mo-old BALB/c and C57BL/6 mice bearing diverse advanced tumors covering Mammary 4T1, liver Hepa, lung LL/2, and colon C26 tumors and distant metastases. Subsequently, the systematic microenvironment of tumor-bearing hosts was rapidly remodeled to resettle thymic cortex and medulla rudiment as an endogenous foxn1-thymosin reprogramming TCR-repertoire for resetting MHC-unrestricted multifunction renewal. Postrenewal V4T-subsets would bind and lead migrating CSCs into apoptosis. Moreover, TCR repertoire multifunction renewal could reverse tumor metastases from tumoricidal resistance into eventual regression as a blockade of cancer-sustaining Bmi-1/Nanog-Oct4-Sox2 renewal loop with sequent multivalent depletion of both migrating/in situ CSCs and non–stem terminal cancer cell subsets. This study represents a promising start to set up a generalizable strategy of three-dimensional biologics evoking an endogenous integral microenvironment into pluripotent renewal versus advanced cancer.

https://ift.tt/2NOEWgS

Activation of Th1 Immunity within the Tumor Microenvironment Is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia [IMMUNOTHERAPY AND VACCINES]

Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response. Within days of starting lenalidomide, T cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pretreatment and on-treatment lymph node biopsy specimens revealed upregulation of IFN- and many of its target genes in response to lenalidomide. The IFN-–mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of TCR genes revealed decreasing diversity of the T cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.

https://ift.tt/2OsydGu

Absence of Surface IgD Does Not Impair Naive B Cell Homeostasis or Memory B Cell Formation in IGHD Haploinsufficient Humans [CLINICAL AND HUMAN IMMUNOLOGY]

Surface IgD is coexpressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 y after its initial discovery. In this study, we examined the in vivo role of surface IgD in human B cell homeostasis and Ab responses in four individuals with heterozygous nonsense mutations in IGHD. All IGHD heterozygous individuals had normal numbers of B cells and serum Igs and did not show signs of immunodeficiency or immune dysregulation. IgD⁺ and IgD^– naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD^– subset. Furthermore, both IgD⁺ and IgD^– naive mature B cells had normal replication histories and similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig class–switched memory B cells showed similar levels of somatic hypermutations. Thus, human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restrictedly in regulating of B cell activation to specific antigenic structures.

https://ift.tt/2pfX855

Activation of NF-{kappa}B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression [CLINICAL AND HUMAN IMMUNOLOGY]

The aim was to assess the activation and association of the NF-B system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-B subunit RelA in nuclear and cytosolic fractions and NF-B1–DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase–quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-B1–DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-B1–DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-B1–DNA binding, and SM nuclear NF-B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-B–triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

https://ift.tt/2xqFajX

Innate T Cells Govern Adipose Tissue Biology [BRIEF REVIEWS]

During the past 25 y, the immune system has appeared as a key regulator of adipose tissue biology and metabolic homeostasis. In lean animals, adipose-resident leukocytes maintain an anti-inflammatory microenvironment that preserves the proper functioning of the tissue. In this review, we describe two populations of innate T cells enriched in adipose tissue, invariant NKT and T cells, and how they serve overlapping and nonredundant roles in controlling adipose tissue functions. These cells interact with and expand anti-inflammatory regulatory T cells and M2 macrophages, thereby driving a metabolically beneficial tissue milieu. Surprisingly, we have found that adipose invariant NKT and T cells also promote weight loss and heat production in a process called "nonshivering thermogenesis." The data surrounding these two cell types highlight their powerful ability to regulate not only other leukocytes, but also tissue-wide processes that affect an entire organism.

https://ift.tt/2pipLOZ

IL-2-Anti-IL-2 Monoclonal Antibody Immune Complexes Inhibit Collagen-Induced Arthritis by Augmenting Regulatory T Cell Functions [AUTOIMMUNITY]

IL-2 induces regulatory T cells (Tregs) and reduces disease severity, such as in graft-versus-host disease and systemic lupus erythematosus. To investigate the regulatory network of IL-2 in rheumatoid arthritis, we examined the effects of IL-2–anti–IL-2 mAb immune complexes (IL-2ICs) in a rheumatoid arthritis model of collagen-induced arthritis (CIA). CIA was induced in male DBA/1 mice by two immunizations with type II collagen at 3-wk intervals. IL-2ICs were prepared by mixing 5 μg of an anti–IL-2 mAb (clone JES6-1D) with 1 μg of mouse IL-2 and were injected i.p. every day for 3 d. Mouse paws were scored for arthritis using a macroscopic scoring system. Th1, Th2, Th17, and Tregs were analyzed by flow cytometry. Joint histopathology was examined by H&E and immunohistochemical staining. Treg functions were examined by studying in vitro suppression using flow cytometry. IL-2IC administration effectively elicited a 1.6-fold expansion of CD4⁺Foxp3⁺ Tregs in peripheral blood cells relative to that found in control mice. IL-2IC treatment significantly inhibited arthritis in CIA mice. Histopathological examination of joints revealed inhibited synovial cell proliferation and IL-17, IL-6, and TNF-α levels but increased Foxp3⁺ Tregs after IL-2IC treatment. Flow cytometric examination of spleen cells revealed reduced IFN-– and IL-17–producing cells and increased IL-10–producing Tregs after IL-2IC treatment. The suppressive activities of CD4⁺CD25⁺ Tregs induced by IL-2ICs were stronger than those in untreated mice. IL-2ICs inhibited arthritis by augmenting not only Treg numbers but also Treg functions, which play regulatory roles in autoimmune arthritis.

https://ift.tt/2OxfklQ

Cutting Edge: Elevated Leptin during Diet-Induced Obesity Reduces the Efficacy of Tumor Immunotherapy [CUTTING EDGE]

Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti–CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient (ob/ob) obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present.

https://ift.tt/2NMzmf7

The PGI2 Analog Cicaprost Inhibits IL-33-Induced Th2 Responses, IL-2 Production, and CD25 Expression in Mouse CD4+ T Cells [IMMUNE REGULATION]

IL-33 has pleiotropic functions in immune responses and promotes the development of allergic diseases and asthma. IL-33 induces Th2 differentiation and enhances type 2 cytokine production by CD4⁺ T cells. However, the regulation of IL-33–driven type 2 cytokine responses is not fully defined. In this study, we investigated the effect of PGI₂, a lipid mediator formed in the cyclooxygenase pathway of arachidonic acid metabolism, on naive CD4⁺ T cell activation, proliferation, and differentiation by IL-33. Using wild-type and PGI₂ receptor (IP) knockout mice, we found that the PGI₂ analog cicaprost dose-dependently inhibited IL-33–driven IL-4, IL-5, and IL-13 production by CD4⁺ T cells in an IP-specific manner. In addition, cicaprost inhibited IL-33–driven IL-2 production and CD25 expression by CD4⁺ T cells. Furthermore, IP knockout mice had increased IL-5 and IL-13 responses of CD4⁺ T cells to Alternaria sensitization and challenge in mouse lungs. Because IL-33 is critical for Alternaria-induced type 2 responses, these data suggest that PGI₂ not only inhibits IL-33–stimulated CD4⁺ Th2 cell responses in vitro but also suppresses IL-33–induced Th2 responses caused by protease-containing allergens in vivo.

https://ift.tt/2MFFL7f

Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation [ALLERGY AND OTHER HYPERSENSITIVITIES]

As adults, women are twice as likely as men to have asthma; however, the mechanisms explaining this sexual dimorphism remain unclear. Increased type 2 cytokines and/or IL-17A, leading to increased airway eosinophils and neutrophils, respectively, are associated with asthma. Previous studies showed that testosterone, signaling through the androgen receptor (AR), decreased Th2-mediated allergic inflammation and type 2 innate immune responses during allergic inflammation. Therefore, we hypothesized that testosterone and AR signaling attenuate type 2 and IL-17A–mediated airway inflammation. To test our hypothesis, sham-operated and gonadectomized female and male mice were intranasally challenged with house dust mite (HDM) or vehicle (PBS) for 3 wk. Testosterone decreased and ovarian hormones increased HDM-induced eosinophilic and neutrophilic inflammation, IgE production, and airway hyperresponsiveness, as well as decreased the numbers of IL-13⁺ CD4 Th2 cells and IL-17A⁺ CD4 Th17 cells in the lung. Next, using wild-type male and female mice and AR^tfm male mice that are unable to signal through the AR, we determined AR signaling intrinsically attenuated IL-17A⁺ Th17 cells but indirectly decreased IL-13⁺ CD4 Th2 cells in the lung by suppressing HDM-induced IL-4 production. In vitro Th2 and Th17 differentiation experiments showed AR signaling had no direct effect on Th2 cell differentiation but decreased IL-17A protein expression and IL-23R mRNA relative expression from Th17 cells. Combined, these findings show AR signaling attenuated type 2 and IL-17A inflammation through different mechanisms and provide a potential explanation for the increased prevalence of asthma in women compared with men.

https://ift.tt/2D38iDW

Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis [AUTOIMMUNITY]

Arthritis in a genetically susceptible SKG strain of mice models a theoretical paradigm wherein autoimmune arthritis arises because of interplay between preexisting autoreactive T cells and environmental stimuli. SKG mice have a point mutation in ZAP-70 that results in attenuated TCR signaling, altered thymic selection, and spontaneous production of autoreactive T cells that cause arthritis following exposure to microbial β-glucans. In this study, we identify Nod2, an innate immune receptor, as a critical suppressor of arthritis in SKG mice. SKG mice deficient in Nod2 (Nod2^–/–SKG) developed a dramatically exacerbated form of arthritis, which was independent of sex and microbiota, but required the skg mutation in T cells. Worsened arthritis in Nod2^–/–SKG mice was accompanied by expansion of Th17 cells, which to some measure coproduced TNF, GM-CSF, and IL-22, along with elevated IL-17A levels within joint synovial fluid. Importantly, neutralization of IL-17A mitigated arthritis in Nod2^–/–SKG mice, indicating that Nod2-mediated protection occurs through suppression of the Th17 response. Nod2 deficiency did not alter regulatory T cell development or function. Instead, Nod2 deficiency resulted in an enhanced fundamental ability of SKG CD4⁺ T cells (from naive mice) to produce increased levels of IL-17 and to passively transfer arthritis to lymphopenic recipients on a single-cell level. These data reveal a previously unconsidered role for T cell–intrinsic Nod2 as an endogenous negative regulator of Th17 responses and arthritogenic T cells. Based on our findings, future studies aimed at understanding a negative regulatory function of Nod2 within autoreactive T cells could provide novel therapeutic strategies for treatment of patients with arthritis.

https://ift.tt/2D6U0CB

The Canonical but Not the Noncanonical Wnt Pathway Inhibits the Development of Allergic Airway Disease [ALLERGY AND OTHER HYPERSENSITIVITIES]

Asthma is a syndrome with multifactorial causes, resulting in a variety of different phenotypes. Current treatment options are not curative and are sometimes ineffective in certain disease phenotypes. Therefore, novel therapeutic approaches are required. Recent findings have shown that activation of the canonical Wnt signaling pathway suppresses the development of allergic airway disease. In contrast, the effect of the noncanonical Wnt signaling pathway activation on allergic airway disease is not well described. The aim of this study was to validate the therapeutic effectiveness of Wnt-1–driven canonical Wnt signaling compared with Wnt-5a–driven noncanonical signaling in murine models. In vitro, both ligands were capable of attenuating allergen-specific T cell activation in a dendritic cell–dependent manner. In addition, the therapeutic effects of Wnt ligands were assessed in two different models of allergic airway disease. Application of Wnt-1 resulted in suppression of airway inflammation as well as airway hyperresponsiveness and mucus production. In contrast, administration of Wnt-5a was less effective in reducing airway inflammation or goblet cell metaplasia. These results suggest an immune modulating function for canonical as well as noncanonical Wnt signaling, but canonical Wnt pathway activation appears to be more effective in suppressing allergic airway disease than noncanonical Wnt activation.

https://ift.tt/2pd4RRk

A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice [AUTOIMMUNITY]

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8⁺ T cells recognizing pancreatic β cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-K^d and/or H2-D^b class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8⁺ T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8⁺ T cells. Using an inducible model of thymic negative selection and mRNA transcript analyses, we initially identified an elevated Nfkbid expression variant as a likely NOD-proximal chromosome 7 region gene contributing to impaired thymic deletion of diabetogenic CD8⁺ T cells. CRISPR/Cas9–mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8⁺ T cells. These results indicated that allelic variants of Nfkbid contribute to the efficiency of intrathymic deletion of diabetogenic CD8⁺ T cells. However, although enhancing thymic deletion of pathogenic CD8⁺ T cells, ablating Nfkbid expression surprisingly accelerated T1D onset that was associated with numeric decreases in both regulatory T and B lymphocytes in NOD mice.

https://ift.tt/2xspOvy

Differential Influence on Regulatory B Cells by TH2 Cytokines Affects Protection in Allergic Airway Disease [ALLERGY AND OTHER HYPERSENSITIVITIES]

The role of regulatory B cells (Bregs) in modulating immune responses and maintaining tolerance are well established. However, how cytokines present during immune responses affect Breg growth and function are not as well defined. Previously, our laboratory reported IL-5– and mCD40L-expressing fibroblast (mCD40L-Fb) stimulation induced IL-10 production from murine B cells. The current study investigated the phenotype and functional relevance of IL-10– producing B cells from this culture. We found IL-5/mCD40L-Fb stimulation induced IL-10 production exclusively from CD5⁺ splenic B cells of naive mice. After stimulation, the resulting IL-10⁺ B cells displayed markers of multiple reported Breg phenotypes. Interestingly, when investigating effects of IL-4 (a critical T_H2 cytokine) on IL-5/mCD40L-Fb–induced IL-10 production, we found IL-4 inhibited IL-10 production in a STAT6-dependent manner. Upon adoptive transfer, CD5⁺ B cells previously stimulated with IL-5/mCD40L-Fb were able to reduce development of OVA-induced allergic airway disease in mice. Using B cells from IL-10 mutant mice differentiated by IL-5/mCD40L-Fb, we found protection from allergic airway disease development was dependent on the IL-10 production from the transferred B cells. Bregs have been shown to play crucial roles in the immune tolerance network, and understanding stimuli that modulate their growth and function may be key in development of future treatments for diseases of immune dysregulation.

https://ift.tt/2D6a0EJ

Cytosolic Processing Governs TAP-Independent Presentation of a Critical Melanoma Antigen [ANTIGEN RECOGNITION AND RESPONSES]

Cancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway critical for CD8 T cell–mediated tumor clearance. TAP and tapasin, both key players in the pathway, are frequently downregulated in human cancers, correlating with poor patient survival. Reduced dependence on these factors may promote vaccine efficiency by limiting immune evasion. In this study, we demonstrate that PMEL_209–217, a promising phase 3 trial–tested antimelanoma vaccine candidate, is robustly presented by various TAP- and/or tapasin-deficient cell lines. This striking characteristic may underlie its potency as a vaccine. Surprisingly, cytosolic proteasomes generate the peptide even for TAP-independent presentation, whereas tripeptidyl peptidase 2 (TPP2) efficiently degrades the epitope. Consequently, inhibiting TPP2 substantially boosts PMEL_209–217 presentation, suggesting a possible strategy to improve the therapeutic efficacy of the vaccine.

https://ift.tt/2NOGuaD

Characterization of an NLRP1 Inflammasome from Zebrafish Reveals a Unique Sequential Activation Mechanism Underlying Inflammatory Caspases in Ancient Vertebrates [IMMUNOGENETICS]

NLRP1 inflammasome is one of the best-characterized inflammasomes in humans and other mammals. However, the existence of this inflammasome in nonmammalian species remains poorly understood. In this study, we report the molecular and functional identification of an NLRP1 homolog, Danio rerio NLRP1 (DrNLRP1) from a zebrafish (D. rerio) model. This DrNLRP1 possesses similar structural architecture to mammalian NLRP1s. It can trigger the formation of a classical inflammasome for the activation of zebrafish inflammatory caspases (D. rerio Caspase [DrCaspase]–A and DrCaspase-B) and maturation of D. rerio IL-1β in a D. rerio ASC (DrASC)–dependent manner. In this process, DrNLRP1 promotes the aggregation of DrASC into a filament with DrASC^CARD core and DrASC^PYD cluster. The assembly of DrNLRP1 inflammasome depends on the CARD–CARD homotypic interaction between DrNLRP1 and DrASC^CARD core, and PYD–PYD interaction between DrCaspase-A/B and DrASC^PYD cluster. The FIIND domain in DrNLRP1 is necessary for inflammasome assembly. To understand the mechanism of how the two DrCaspases are coordinated in DrNLRP1 inflammasome, we propose a two-step sequential activation model. In this model, the recruitment and activation of DrCaspase-A/B in the inflammasome is shown in an alternate manner, with a preference for DrCaspase-A followed by a subsequent selection for DrCaspase-B. By using morpholino oligonucleotide–based knockdown assays, the DrNLRP1 inflammasome was verified to play important functional roles in antibacterial innate immunity in vivo. These observations demonstrate that the NLRP1 inflammasome originated as early as in teleost fish. This finding not only gives insights into the evolutionary history of inflammasomes but also provides a favorable animal model for the study of NLRP1 inflammasome-mediated immunology and diseases.

https://ift.tt/2xqE7k1

Collateral Damage: What Effect Does Anti-CD4 and Anti-CD8{alpha} Antibody-Mediated Depletion Have on Leukocyte Populations? [NOVEL IMMUNOLOGICAL METHODS]

Anti-CD4 or anti-CD8α Ab–mediated depletion strategies are widely used to determine the role of T cell subsets. However, surface expression of CD4 and CD8α is not limited to T cells and occurs on other leukocyte populations as well. Using both unbiased t-distributed stochastic neighbor embedding of flow cytometry data and conventional gating strategies, we assessed the impact of anti-CD4 and anti-CD8α Ab–mediated depletion on non–T cell populations in mice. Our results show that anti-CD4 and anti-CD8α Ab injections not only resulted in depletion of T cells but also led to depletion of specific dendritic cell subsets in a dose-dependent manner. Importantly, the extent of this effect varied between mock- and virus-infected mice. We also demonstrate the importance of using a second, noncompeting Ab (clone CT-CD8α) to detect CD8α⁺ cells following depletion with anti-CD8α Ab clone 2.43. Our study provides a necessary caution to carefully consider the effects on nontarget cells when using Ab injections for leukocyte depletion in all experimental conditions.

https://ift.tt/2NLx9Az

PPAR{gamma} Deficiency Suppresses the Release of IL-1{beta} and IL-1{alpha} in Macrophages via a Type 1 IFN-Dependent Mechanism [INNATE IMMUNITY AND INFLAMMATION]

Obesity and diabetes modulate macrophage activation, often leading to prolonged inflammation and dysfunctional tissue repair. Increasing evidence suggests that the NLRP3 inflammasome plays an important role in obesity-associated inflammation. We have previously shown that activation of the lipotoxic inflammasome by excess fatty acids in macrophages occurs via a lysosome-dependent pathway. However, the mechanisms that link cellular lipid metabolism to altered inflammation remain poorly understood. PPAR is a nuclear receptor transcription factor expressed by macrophages that is known to alter lipid handling, mitochondrial function, and inflammatory cytokine expression. To undercover novel links between metabolic signaling and lipotoxic inflammasome activation, we investigated mouse primary macrophages deficient in PPAR. Contrary to our expectation, PPAR knockout (KO) macrophages released significantly less IL-1β and IL-1α in response to lipotoxic stimulation. The suppression occurred at the transcriptional level and was apparent for multiple activators of the NLRP3 inflammasome. RNA sequencing revealed upregulation of IFN-β in activated PPARKO macrophages, and this was confirmed at the protein level. A blocking Ab against the type 1 IFNR restored the release of IL-1β to wild type levels in PPARKO cells, confirming the mechanistic link between these events. Conversely, PPAR activation with rosiglitazone selectively suppressed IFN-β expression in activated macrophages. Loss of PPAR also resulted in diminished expression of genes involved in sterol biosynthesis, a pathway known to influence IFN production. Together, these findings demonstrate a cross-talk pathway that influences the interplay between metabolism and inflammation in macrophages.

https://ift.tt/2xn4O9e

Prime-and-Trap Malaria Vaccination To Generate Protective CD8+ Liver-Resident Memory T Cells [IMMUNOTHERAPY AND VACCINES]

Tissue-resident memory CD8⁺ T (Trm) cells in the liver are critical for long-term protection against pre-erythrocytic Plasmodium infection. Such protection can usually be induced with three to five doses of i.v. administered radiation-attenuated sporozoites (RAS). To simplify and accelerate vaccination, we tested a DNA vaccine designed to induce potent T cell responses against the SYVPSAEQI epitope of Plasmodium yoelii circumsporozoite protein. In a heterologous "prime-and-trap" regimen, priming using gene gun–administered DNA and boosting with one dose of RAS attracted expanding Ag-specific CD8⁺ T cell populations to the liver, where they became Trm cells. Vaccinated in this manner, BALB/c mice were completely protected against challenge, an outcome not reliably achieved following one dose of RAS or following DNA-only vaccination. This study demonstrates that the combination of CD8⁺ T cell priming by DNA and boosting with liver-homing RAS enhances formation of a completely protective liver Trm cell response and suggests novel approaches for enhancing T cell–based pre-erythrocytic malaria vaccines.

https://ift.tt/2NTotrG

Valaciclovir: a culprit drug for DRESS not to be neglected. Three cases

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pcnyF0

Oral propranolol in the treatment of proliferating infantile haemangiomas: British Society for Paediatric Dermatology consensus guidelines

British Journal of Dermatology, Volume 179, Issue 3, Page 582-589, September 2018.


https://ift.tt/2DebRHQ

Image Gallery: Wyburn–Mason syndrome with a chronic wound

British Journal of Dermatology, Volume 179, Issue 3, Page e134-e134, September 2018.


https://ift.tt/2pfy91L

Core outcome sets in dermatology: next steps

British Journal of Dermatology, Volume 179, Issue 3, Page 549-550, September 2018.


https://ift.tt/2D5BDOk

Applying the phenotype approach for rosacea to practice and research

British Journal of Dermatology, Volume 179, Issue 3, Page e148-e148, September 2018.


https://ift.tt/2pgkfwE

Issue Information

British Journal of Dermatology, Volume 179, Issue 3, Page i-vi, September 2018.


https://ift.tt/2D7asCO

Cost‐effectiveness of omalizumab in chronic spontaneous urticaria

British Journal of Dermatology, Volume 179, Issue 3, Page e144-e144, September 2018.


https://ift.tt/2pgkeZC

异位性皮肤压力源对NMF和皮肤细胞因子的作用

British Journal of Dermatology, Volume 179, Issue 3, Page e160-e160, September 2018.


https://ift.tt/2D53EFz

Effect of atopic skin stressors on NMFs and skin cytokines

British Journal of Dermatology, Volume 179, Issue 3, Page e145-e145, September 2018.


https://ift.tt/2pe3QbJ

Is methotrexate an effective and safe treatment for maintaining hair regrowth in people with alopecia totalis? A critically appraised topic

British Journal of Dermatology, Volume 179, Issue 3, Page e147-e147, September 2018.


https://ift.tt/2D3Ng8r

BSPD guidelines for treatment of IH with propranolol

British Journal of Dermatology, Volume 179, Issue 3, Page e146-e146, September 2018.


https://ift.tt/2pdMtIc

奥马珠单抗治疗自发慢性荨麻疹的成本效益

British Journal of Dermatology, Volume 179, Issue 3, Page e159-e159, September 2018.


https://ift.tt/2D3MsAr

Improvements in quality of life and work productivity make omalizumab cost‐effective for the treatment of chronic spontaneous urticaria

British Journal of Dermatology, Volume 179, Issue 3, Page 562-563, September 2018.


https://ift.tt/2D53ldT

使用普萘洛尔治疗IH的BSPD指南

British Journal of Dermatology, Volume 179, Issue 3, Page e161-e161, September 2018.


https://ift.tt/2pmq23P

Subtyping, phenotyping or endotyping rosacea: how can we improve disease understanding and patient care?

British Journal of Dermatology, Volume 179, Issue 3, Page 551-552, September 2018.


https://ift.tt/2D3N0Gv

皮肤癣菌病和STAT3突变

British Journal of Dermatology, Volume 179, Issue 3, Page e158-e158, September 2018.


https://ift.tt/2pmq7Vb

New therapeutics for itch in dermatomyositis

British Journal of Dermatology, Volume 179, Issue 3, Page 559-560, September 2018.


https://ift.tt/2D53D4t

人体测量因素和Breslow厚度

British Journal of Dermatology, Volume 179, Issue 3, Page e157-e157, September 2018.


https://ift.tt/2pe3NN5

润肤剂和局部糖皮质激素治疗成人湿疹

British Journal of Dermatology, Volume 179, Issue 3, Page e156-e156, September 2018.


https://ift.tt/2pfy4uZ

Interventional management of hyperhidrosis in secondary care: where do we go from here?

British Journal of Dermatology, Volume 179, Issue 3, Page 555-556, September 2018.


https://ift.tt/2D538HD

Fetal exposure to mitotane/Op’DDD: post‐natal study of four children

Clinical Endocrinology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NmJL1t

Issue Information ‐ Instructions for Authors

Clinical Endocrinology, Volume 89, Issue 4, Page 530-531, October 2018.


https://ift.tt/2MHyGTz

Issue Information ‐ TOC and Editorial Board

Clinical Endocrinology, Volume 89, Issue 4, Page 383-384, October 2018.


https://ift.tt/2NgDrZv

Valaciclovir: a culprit drug for DRESS not to be neglected. Three cases

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pcnyF0

Oral propranolol in the treatment of proliferating infantile haemangiomas: British Society for Paediatric Dermatology consensus guidelines

British Journal of Dermatology, Volume 179, Issue 3, Page 582-589, September 2018.


https://ift.tt/2DebRHQ

Image Gallery: Wyburn–Mason syndrome with a chronic wound

British Journal of Dermatology, Volume 179, Issue 3, Page e134-e134, September 2018.


https://ift.tt/2pfy91L

Core outcome sets in dermatology: next steps

British Journal of Dermatology, Volume 179, Issue 3, Page 549-550, September 2018.


https://ift.tt/2D5BDOk

Applying the phenotype approach for rosacea to practice and research

British Journal of Dermatology, Volume 179, Issue 3, Page e148-e148, September 2018.


https://ift.tt/2pgkfwE

Issue Information

British Journal of Dermatology, Volume 179, Issue 3, Page i-vi, September 2018.


https://ift.tt/2D7asCO

Cost‐effectiveness of omalizumab in chronic spontaneous urticaria

British Journal of Dermatology, Volume 179, Issue 3, Page e144-e144, September 2018.


https://ift.tt/2pgkeZC

异位性皮肤压力源对NMF和皮肤细胞因子的作用

British Journal of Dermatology, Volume 179, Issue 3, Page e160-e160, September 2018.


https://ift.tt/2D53EFz

Effect of atopic skin stressors on NMFs and skin cytokines

British Journal of Dermatology, Volume 179, Issue 3, Page e145-e145, September 2018.


https://ift.tt/2pe3QbJ

Is methotrexate an effective and safe treatment for maintaining hair regrowth in people with alopecia totalis? A critically appraised topic

British Journal of Dermatology, Volume 179, Issue 3, Page e147-e147, September 2018.


https://ift.tt/2D3Ng8r

BSPD guidelines for treatment of IH with propranolol

British Journal of Dermatology, Volume 179, Issue 3, Page e146-e146, September 2018.


https://ift.tt/2pdMtIc

奥马珠单抗治疗自发慢性荨麻疹的成本效益

British Journal of Dermatology, Volume 179, Issue 3, Page e159-e159, September 2018.


https://ift.tt/2D3MsAr

使用普萘洛尔治疗IH的BSPD指南

British Journal of Dermatology, Volume 179, Issue 3, Page e161-e161, September 2018.


https://ift.tt/2pmq23P

Subtyping, phenotyping or endotyping rosacea: how can we improve disease understanding and patient care?

British Journal of Dermatology, Volume 179, Issue 3, Page 551-552, September 2018.


https://ift.tt/2D3N0Gv

皮肤癣菌病和STAT3突变

British Journal of Dermatology, Volume 179, Issue 3, Page e158-e158, September 2018.


https://ift.tt/2pmq7Vb

New therapeutics for itch in dermatomyositis

British Journal of Dermatology, Volume 179, Issue 3, Page 559-560, September 2018.


https://ift.tt/2D53D4t

人体测量因素和Breslow厚度

British Journal of Dermatology, Volume 179, Issue 3, Page e157-e157, September 2018.


https://ift.tt/2pe3NN5

Improvements in quality of life and work productivity make omalizumab cost‐effective for the treatment of chronic spontaneous urticaria

British Journal of Dermatology, Volume 179, Issue 3, Page 562-563, September 2018.


https://ift.tt/2D53ldT

润肤剂和局部糖皮质激素治疗成人湿疹

British Journal of Dermatology, Volume 179, Issue 3, Page e156-e156, September 2018.


https://ift.tt/2pfy4uZ

Interventional management of hyperhidrosis in secondary care: where do we go from here?

British Journal of Dermatology, Volume 179, Issue 3, Page 555-556, September 2018.


https://ift.tt/2D538HD

Alopecia areata and overt thyroid diseases: A nationwide population‐based study

The Journal of Dermatology, EarlyView.


https://ift.tt/2PEXPQK

Comparison of oxidative stress on DNA, protein and lipids in patients with actinic keratosis, Bowen's disease and squamous cell carcinoma

The Journal of Dermatology, EarlyView.


https://ift.tt/2NOxq5E

Acquisition of resistance to vemurafenib leads to interleukin‐10 production through an aberrant activation of Akt in a melanoma cell line

The Journal of Dermatology, EarlyView.


https://ift.tt/2PJrrw9

Intestinal barrier integrity in patients with plaque psoriasis

The Journal of Dermatology, EarlyView.


https://ift.tt/2NOxgey

Oral exfoliative cytology and corrosion of metal piercings. Tissue implications

Abstract

Objectives

A group of adolescents with oral piercings was studied to determine the presence of metallic particles in cells exfoliated from the mucosa surrounding their metal oral piercings and the association between such particles and the metal jewelry, and to evaluate subsequent tissue implications.

Materials and methods

Sixteen teenage patients who had tongue and/or lip piercings were included. The clinical features of the oral mucosa and lip skin were evaluated. Exfoliative cytology was performed in the area surrounding the piercing. The surface of used and unused jewelry was studied by scanning electron microscopy and energy dispersive X-ray analysis.

Results

Hyperplastic, leukoedematous, and lichenoid lesions were observed in the mucosa, as well as lesions associated with metallosis of the lip skin. Cytological smears showed the presence of particles inside the epithelial cells; the particles were found to contain aluminum, tungsten, and molybdenum. In one case requiring surgical removal of the piercing, histological examination of the tissue associated with the piece of jewelry showed the presence particles containing aluminum, iron, and tin inside multinucleated giant cells. Although surface finish defects were observed on both unused and used piercing jewelry, they were more evident on the used pieces.

Conclusions

Ion particles are released from the metal piercings and could have been adjuvant factors in the development of the observed lesions. Cells exfoliated from the oral mucosa surrounding metal piercings may serve as bioindicators of corrosion processes.

Clinical relevance

We propose the use of exfoliative cytology to monitor corrosion processes and for routine clinical follow up.

https://ift.tt/2PLuLqW

Dentinal tubule penetration of AH Plus, BC Sealer and a novel tricalcium silicate sealer: a confocal laser scanning microscopy study

Abstract

Objectives

The aim of this in vitro study was to assess the dentinal tubule penetration of three different sealers, AH Plus, BC Sealer and a novel tricalcium silicate sealer (NTS).

Materials and methods

Ninety-six human maxillary central incisors were divided into three experimental groups (n = 32) and were filled with gutta-percha using a single-cone technique in conjunction with one of the three sealers: AH Plus, BC Sealer or NTS. The roots in each group were cross-sectioned at 1 and 5 mm from the root apex, and the surfaces were examined under confocal laser scanning microscopy (CLSM). The sealer penetration depths were measured at their maximum depths and at four circumferential depths (12, 3, 6 and 9 o'clock) and were evaluated using ImageJ software (ImageJ, NIH).

Results

The maximum and mean penetration depths were significantly higher at 5 mm compared to 1 mm from the apex in the AH Plus (p < 0.001), BC Sealer (p < 0.001) and NTS groups (p < 0.001). No significant difference was observed between the groups at 1 mm for both parameters. The maximum and mean penetration depths were significantly lower at 5 mm for AH Plus compared with the other two groups (p = 0.012).

Conclusions

Within the study limitations, the BC Sealer and NTS demonstrated better tubule penetration results than the AH Plus sealer.

Clinical relevance

Although no study has confirmed a relationship between the penetration depth of root canal sealers and the prevention of apical periodontitis, dentinal tubule sealer penetration may improve obturation quality.

https://ift.tt/2NS3TIe

Exertional heat illness: knowledge and behavior among construction workers

Abstract

Construction workers are considered one of the most vulnerable health group workers. Exertional heat illness (EHI) is a well-recognized health hazard that causes significant sickness and death. The purpose of this study was to assess construction workers' environment and hydration status and to evaluate the effect of health education program on workers. An interventional study was conducted on 89 construction workers in Port Said City. Assessments of workplace environment and workers' hydration status were done by using workplace evaluation checklist, wet-bulb globe temperature, urine specific gravity, and urine color chart. A pre-post-test design was used in the evaluation of workers' knowledge and behavior regarding EHI. A health education program was conducted to improve workers' knowledge and behavior; then, evaluation was done after 1 month. The most reported symptoms of heat illness were sweating (100.0%), dizziness (98.0%), and muscle pain (82.0%). Most workers showed signs of minimal dehydration (78.7%). There was a significant improvement in workers' knowledge about EHI and behavioral action for prevention after health education. Construction workers are at high risk of exposure to EHI which raised the attention to provide educational programs which can guide workers to follow healthy behaviors and prevent EHI.

https://ift.tt/2pdOXq3

TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis-

Abstract

Background

Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement.

Patients/Methods

46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height.

Results

Patients were divided into groups (Group I – slightly affected, n = 36; Billiau severity 0–2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II – severely affected, N = 10; Billiau severity 3–4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I.

Conclusions

Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results.

https://ift.tt/2MGGwg7

Analysis of soil risk characteristics by comprehensive assessment in an industrial area of China

Abstract

Soil pollution in industrial areas poses a major challenge for China's environmental protection. In this study, comprehensive assessment methodologies for soil risk in industrial areas were developed. The comprehensive assessment covered ecological and human health risks of soil pollution, as well as vulnerability of different types of risk receptors. Comprehensive ecological risk assessment integrated potential ecological risk assessment and landscape vulnerability assessment. Comprehensive social risk assessment specialized human health risk assessment by introducing spatial distribution of population. A typical industrial area in China was studied, and the quantitative and spatial assessments of the comprehensive soil risk were presented. The results showed that the spatial distribution of soil comprehensive ecological and social risks differed. High-risk areas of soil comprehensive ecological risk in the study area were mainly farmlands and nature reserves. Inhabited areas and industrial zones were less affected by comprehensive ecological risk of soil. By contrast, the spatial distribution of soil comprehensive social risk and human activities showed a clear trend of convergence. Vulnerability assessment of the risk receptors provided a suitable complement to the risk assessment of soil pollution.

https://ift.tt/2NQDOcA

Effective dose of remifentanil for intubation in children

https://ift.tt/2OtC6Lh

Rice single cropping or ratooning agro-system: which one is more environment-friendly?

Abstract

Sustainable development of food production depends on damping the environmental impacts of agricultural production. The aim of this study was to investigate the environmental performance of rice production in single crop and ratooning (main rice + ratoon crop) agro-systems through life cycle assessment (LCA) methodology in Guilan province, Northern Iran, in 2015. The flooding irrigation regime was the dominant irrigation method for single cropping system and main crop rising in ratooning agro-system. The data were gathered through a face to face interview with 215 single crop and 115 ratoon breeder paddy farmers. The environmental risks were determined in six impact categories including global warming, terrestrial eutrophication, acidification, and depletion of fossil fuels, phosphate, and potash resources. The functional unit (FU) was set as 100 kg protein. Results indicated that the CO₂, N₂O, and CH₄ emissions of the rice ratooning agro-system (661.44, 1.96, and 5.42 kg 100 kg⁻¹ protein) were less than the corresponding values in the rice single cropping agro-system (1341.63, 2.88, and 9.20 kg 100 kg⁻¹ protein, respectively). Among all the environmental impact categories, the terrestrial eutrophication had the widest negative environmental effect followed by depletion of phosphate resources in single cropping agro-system with weighted indices of 0.51 and 0.41, respectively. Moreover, the terrestrial eutrophication had the largest negative environmental effect followed by acidification in rice ratooning agro-system with weighted indices of 0.48 and 0.29, respectively. Overall, the results highlighted that the rice ratooning ago-system is more environmentally beneficial than the single cropping system, particularly in terms of depletion of fossil fuels, global warming, and depletion of phosphate and potash resources categories. This priority may be improved through adopting proper management of agronomic practices for main and ratoon rice in ratooning agro-system.

Graphical abstract

ᅟ

https://ift.tt/2NQZ16d

POLLAR: Impact of air POLLution on Asthma and Rhinitis; a European Institute of Innovation and Technology Health (EIT Health) project

Allergic rhinitis (AR) is impacted by allergens and air pollution but interactions between air pollution, sleep and allergic diseases are insufficiently understood. POLLAR (Impact of air POLLution on sleep, As...

https://ift.tt/2D4Iis2

A systematic approach to the recurrent laryngeal nerve dissection at the cricothyroid junction

Abstract

Background

To describe and evaluate a four step systematic approach to dissecting the recurrent laryngeal nerve (RLN) starting at the cricothyroid junction during thyroid surgery (subsequently referred to as the retrograde medial approach).

Methods

All thyroidectomies completed by the senior author between August 2014 and January 2016 were retrospectively reviewed. Patients were excluded if concurrent lateral or central neck dissection was performed. A follow up period of 1 year was included.

Results

Surgical photographs and illustrations demonstrate the four steps in the retrograde medial approach to dissection of the RLN in thyroid surgery.

Three hundred forty-two consecutive thyroid surgeries were performed in 17 months, including 213 hemithyroidectomies, 91 total thyroidectomies, and 38 completion thyroidectomies. The rate of temporary and permanent hypocalcemia was 13% (95% confidence interval [CI]: 8–20%) and 3% (95% CI: 1–8%) respectively. The rate of temporary and permanent vocal cord palsy was 9% (95% CI: 6–12%) and 0.3% (95%CI: 0.01–2%) respectively. The median surgical times for hemithyroidectomy, total thyroidectomy, and completion thyroidectomy were 39 min (Interquartile range [IQR]: 33–47 min), 48 min (IQR: 40–60 min), and 40 min (IQR: 35–51 min) respectively. 1% of cases required conversion to an alternative surgical approach.

Conclusion

In a tertiary endocrine head and neck practice, the routine use of the retrograde medial approach to RLN dissection is safe and results in a short operative time, and a low conversion rate to other RLN dissection approaches.

https://ift.tt/2pe5cDq

Carcinoembryonic antigen levels correlated with advanced disease in medullary thyroid cancer

Abstract

Background

Medullary thyroid cancer (MTC) cells are capable of secreting various tumor markers including calcitonin and carcinoembyronic antigen (CEA). The purpose of this study is to determine whether abnormal CEA levels may be used as a tumor marker to predict the severity of disease in MTC.

Methods

A retrospective analysis was completed for 33 patients with MTC who had preoperative serum CEA levels. Univariate and multivariate analyses were used to quantify the relationship between serum CEA levels and tumor stage and prognosis.

Results

On multivariate analysis, elevated preoperative CEA levels were significantly associated with the size and stage of tumor, distant metastasis, decreased biochemical cure, and mortality. There was a significant association between tumor size greater than 37 mm and elevated CEA levels (> 271 ng/ml). There was also a positive correlation with increased cancer stage (> 377 ng/ml), distant metastasis (> 405 ng/ml), and contralateral compartment location of lymph node metastasis (> 162 ng/ml). When pre-operative CEA levels are > 500 ng/ml, patient mortality was 67%.

Conclusion

In this study, both pre-operative calcitonin and CEA levels were significantly correlated with the extent of disease in MTC. While calcitonin has a linear relationship with disease progression, abnormal CEA levels were a better indicator of advanced disease. CEA levels > 271 ng/ml are significant for advanced tumor size and staging, metastasis to the central compartment, and decreased chance of biochemical cure. CEA levels greater than 500 ng/ml are associated with significant patient mortality.

https://ift.tt/2MF9nkZ

Improving vaccination uptake in pediatric Cochlear implant recipients

Abstract

Background

An Infectious Disease vaccine specialist joined our institution's Cochlear Implant Team in 2010 in order to address the high percentage of non-compliance to immunization prior to surgery identified previously from an internal review. The purpose of this study was to (1) review the immunization status of cochlear implant recipients in 2010–2014, (2) assess if introducing a vaccine specialist made a significant change in vaccination compliance and (3) elucidate any barriers to vaccination compliance.

Methods

Retrospective chart review and a telephone survey. Medical records of 116 cochlear implant recipients between 2010 and 2014 were reviewed. A telephone survey was conducted to obtain the current vaccination status in children who required post-operative vaccinations with incomplete records on chart review and, if applicable, the reason for non-compliance.

Results

Between 2010 and 2014, 98% of children were up-to-date at the time of surgery, compared to 67% up-to-date at the time of surgery between 2002 and 2007. 27 children were included in our post-operative immunization analysis. 29.6% (8/27) failed to receive necessary vaccinations post-surgery. Pneumovax-23, a vaccine for high-risk patients (such as cochlear implant candidates) was missed in all cases.

Conclusion

Pre-operative vaccination for cochlear implant recipients improved dramatically with the addition of a vaccine specialist. However, a significant proportion of patients requiring vaccinations post-surgery did not receive them. The main reason for non-compliance was due to parents being unaware that their children required this vaccine postoperatively by being "high-risk".

Although improvement was demonstrated, a communication gap continued to impede the adequacy of vaccination uptake in pediatric cochlear implant recipients following surgery at age 2 when the high-risk vaccine was due.

https://ift.tt/2peWc13

Efficacy of an agonist of α‐MSH, the palmitoyl tetrapeptide‐20, in hair pigmentation

International Journal of Cosmetic Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2pfT7h0

Maintenance Immune Check-point Inhibitor Following Post-operative Chemo-radiation in Subjects With HPV-negative HNSCC

Condition:   Squamous Cell Head and Neck Carcinoma
Interventions:   Drug: Durvalumab;   Radiation: radiotherapy;   Drug: Placebo;   Drug: Cisplatin
Sponsor:   European Organisation for Research and Treatment of Cancer - EORTC
Not yet recruiting

https://ift.tt/2MIt5MZ

Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination With Pembrolizumab

Condition:   Advanced Cancer
Interventions:   Drug: FLX475;   Drug: Pembrolizumab
Sponsor:   FLX Bio, Inc.
Recruiting

https://ift.tt/2xppUoD

Telestroke for Comprehensive Stroke Care in Acute Stroke Ready Hospitals

Condition:   Stroke
Intervention:   Other: Telestroke
Sponsor:   University of Minnesota, MN
Not yet recruiting

https://ift.tt/2MF2tMM

Maintenance Immune Check-point Inhibitor Following Post-operative Chemo-radiation in Subjects With HPV-negative HNSCC

Condition:   Squamous Cell Head and Neck Carcinoma
Interventions:   Drug: Durvalumab;   Radiation: radiotherapy;   Drug: Placebo;   Drug: Cisplatin
Sponsor:   European Organisation for Research and Treatment of Cancer - EORTC
Not yet recruiting

https://ift.tt/2MIt5MZ

Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination With Pembrolizumab

Condition:   Advanced Cancer
Interventions:   Drug: FLX475;   Drug: Pembrolizumab
Sponsor:   FLX Bio, Inc.
Recruiting

https://ift.tt/2xppUoD

Telestroke for Comprehensive Stroke Care in Acute Stroke Ready Hospitals

Condition:   Stroke
Intervention:   Other: Telestroke
Sponsor:   University of Minnesota, MN
Not yet recruiting

https://ift.tt/2MF2tMM

A prospective multicenter evaluation of immediately functionalized tapered conical connection implants for single restorations in maxillary anterior and premolar sites: 3-year results

Abstract

Objectives

This multicenter prospective clinical trial investigated immediately provisionalized, anodized, conical connection, tapered implants with platform shifting in maxillary anterior and premolar sites.

Materials and methods

Patients requiring single-tooth implant-supported restorations in maxillary anterior and premolar sites were enrolled. Implants were immediately provisionalized and evaluated at insertion, 6 months, and annually thereafter. Outcome measures were marginal bone level change (ΔMBL), cumulative survival rate (CSR), and success rate, soft-tissue parameters, and oral health impact profile (OHIP). ΔMBL and Pink Esthetic Score were analyzed using Wilcoxon signed-rank tests. CSR was calculated using life table analysis. Other soft-tissue parameters were analyzed using sign tests.

Results

Of 94 enrolled patients (99 implants), 84 (88 implants) attended the 3-year follow-up. After an initial bone loss between implant insertion and 6 months (− 0.92 ± 1.23 mm), bone levels stabilized from 6 months to 3 years (0.13 ± 0.94 mm) with no significant change. The 3-year CSR was 98.9%, and the cumulative success rate was 96.9%. Papilla index scores of 2 or 3 were observed at 88.6% of sites at the 3-year visit compared with 32.8% at implant insertion. Improvements were observed for all other outcomes, including bleeding on probing, esthetics, plaque, and OHIP.

Conclusions

This restorative protocol was associated with high primary stability, patient satisfaction, stable bone levels, and an overall improvement of the soft tissue outcomes over a 3-year period.

Clinical relevance

The presented treatment is a viable option for single-tooth restorations of maxillary anterior teeth and premolars with successful short- to mid-long-term clinical outcomes.

https://ift.tt/2xy6ux5

Assessing temporal-spatial land use simulation effects with CLUE-S and Markov-CA models in Beijing

Abstract

In order to solve the problem of extensive land use in rural residential areas and promote the construction of a new socialist countryside and farmland protection, it is important to graspe the temporal and spatial evolution of rural settlements. In this study, with Beijing as an example, the efficiencies of CLUE-S and Markov-CA models in simulating spatial temporal evolution of rural residential areas are analyzed. With 14 driving factors chosen, the land uses in Beijing in 2000 and 2005 are simulated and predicted using the two models. Grid size of 220 m × 220 m is used. The accuracies and Kappa coefficients of the simulation and prediction results are analyzed and the following conclusions are made. The core part of CLUE-S model is logistic regression, which grants it obvious advantage in capturing the trends of land use changes with more discrete distributions. Meanwhile, Markov-CA model takes neighborhood into consideration, making it relatively more advantageous in simulating and predicting changes of land uses with the character of nearest-neighbor diffusion. However, among various land uses, only urban land use has this character, the correct prediction rates of the CLUE-S model in 2000 and 2005 were 60.99% and 81.35%, respectively, while the accuracy of the Markov-CA model prediction was 51.33% and 73.68%, and it is the main reason that CLUE-S model returns better simulation and prediction results of rural residential areas for both 2000 and 2005 than Markov-CA model.

https://ift.tt/2MzNkw9

Required cefazolin concentration to maximize diagnostic accuracy of the basophil activation test for cefazolin-induced anaphylaxis

Abstract

Purpose

Identifying the causative agent of perioperative anaphylaxis is key to preventing its recurrence. Besides skin testing, the basophil activation test (BAT) is increasingly being accepted as an additional and reliable method. Cefazolin seems to be a major cause of perioperative anaphylaxis. However, few studies have described use of the BAT for cefazolin-induced anaphylaxis. In this study, we aimed to determine the optimum cefazolin concentration required in the BAT for an accurate diagnosis.

Methods

Seven patients who presented with immediate hypersensitivity to cefazolin and 21 control subjects were studied. We conducted skin tests and performed BATs using both CD203c and CD63 as markers of activated basophils. We measured the ratio of activated basophils after stimulation with serial dilutions of cefazolin and investigated the cefazolin concentration that resulted in better sensitivity and specificity.

Results

All patients demonstrated positive reactions to cefazolin, while all control subjects showed negative reactions on skin tests. The net percentage of both CD203c- and CD63-labeled activated basophils was greater when higher concentrations of cefazolin than previously reported were used. In control subjects, however, the number of activated basophils by cefazolin stimulation was negligible regardless of its concentration. In the case of CD203c, the sensitivity was 86% with a cefazolin concentration of 3 mg/ml, while in the case of CD63, the sensitivity was 100% with a cefazolin concentration of 10 mg/ml.

Conclusion

Using a higher concentration of cefazolin than previously reported for the BAT might increase the accuracy of diagnosis of cefazolin-induced anaphylaxis.

https://ift.tt/2NgS12Z

Outcomes after neoadjuvant treatment with gemcitabine and erlotinib followed by gemcitabine–erlotinib and radiotherapy for resectable pancreatic cancer (GEMCAD 10-03 trial)

Abstract

Background

Neoadjuvant therapy (NAT) for pancreatic adenocarcinoma (PDAC) patients has shown promising results in non-randomized trials. This is a multi-institutional phase II trial of NAT in resectable PDAC patients.

Methods

Patients with confirmed resectable PDAC after agreement by two expert radiologists were eligible. Patients received three cycles of GEM (1000 mg/m²/week) plus daily erlotinib (ERL) (100 mg/day). After re-staging, patients without progressive disease underwent 5 weeks of therapy with GEM (300 mg/m²/week), ERL 100 mg/day and concomitant radiotherapy (45 Gy). Efficacy was assessed using tumor regression grade (TRG) and resection margin status. Using a single-arm Simon's design, considering the therapy not useful if R0 < 40% and useful if the R0 > 70% (alpha 5%, beta 10%), 24 patients needed to be recruited. This trial was registered at ClinicalTrials.gov, number NCT01389440.

Results

Twenty-five patients were enrolled. Adverse effects of NAT were mainly mild gastrointestinal disorders. Resectability rate was 76%, with a R0 rate of 63.1% among the resected patients. Median overall survival (OS) and disease-free survival (DFS) were 23.8 (95% CI 11.4–36.2) and 12.8 months (95% CI 8.6–17.1), respectively. R0 resection patients had better median OS, compared with patients with R1 resection or not resected (65.5 months vs. 15.5 months, p = 0.01). N0 rate among the resected patients was 63.1%, and showed a longer median OS (65.5 vs. 15.2 months, p = 0.009).

Conclusion

The results of this study confirm promising oncologic results with NAT for patients with resectable PDAC. Therefore, the present trial supports the development of phase II randomized trials comparing NAT vs. upfront surgery in resectable pancreatic cancer.

https://ift.tt/2xsncO4

Autophagy therapeutics: preclinical basis and initial clinical studies

Abstract

Autophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Rapidly accumulating attention is being paid to the role of autophagy in the development of cancer, which makes autophagy attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that autophagy dysregulation is causal in many cases of cancer, with autophagy acting as tumor suppressors or tumor promoters, and autophagy inhibitor or promoter has shown promise in preclinical studies. The autophagy-targeted therapeutics using chloroquine/hydroxychloroquine have reached clinical development for treating cancer, but these drugs are actually not efficient probably because of a reduced penetration within the tumor. In this review, we first discuss the discoveries related to dual function of autophagy in cancer. Then, we provide an overview of preclinical studies and clinical trials involved in the development of autophagy therapeutics and finally discuss the future of such therapies.

https://ift.tt/2NQnoAQ

Immunostimulatory activity of low-molecular-weight hyaluronan on dendritic cells stimulated with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis

Abstract

Objectives

Periodontitis is a chronic inflammatory disease characterized by tooth-supporting tissue destruction, which is elicited by the host's immune response triggered against periodonto-pathogen bacteria. During periodontal tissue destruction, extracellular matrix components are metabolized and fragmented. Some extracellular matrix component-derived fragments, such as low-molecular-weight hyaluronan (LMW-HA), have potent immunogenic potential, playing a role as damage-associated molecular patterns (DAMPs) during activation of immune cells. Dendritic cells (DCs) play a central role in the host's immune response displayed during periodontitis; thus, this study aimed to analyze whether LMW-HA has an immunostimulatory activity on DCs when stimulated with periodonto-pathogen bacteria.

Materials and methods

LMW-HA-treated and non-treated DCs were stimulated with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis and the mRNA expression for cytokines tumor necrosis factor-α (TNF-alpha), interleukin-1β (IL-1B), interleukin-6 (IL-6), and interleukin-23 (IL-23A) was quantified by RT-qPCR. In addition, transcription factors interferon regulatory factor 4 (IRF4), interferon regulatory factor 8 (IRF8), neurogenic locus notch homolog protein 2 (NOTCH2), and basic leucine zipper ATF-like transcription factor 3 (BATF3), involved in DC activation, were analyzed.

Results

Higher expression levels of TNF-alpha, IL-1B, IL-6, and IL-23A were detected in LMW-HA-treated DCs after bacterial infection, as compared with non-treated DCs. When LMW-HA-treated DCs were infected with A. actinomycetemcomitans, higher levels of IRF4, NOTCH2, and BATF3 were detected compared with non-treated cells; whereas against P. gingivalis infection, increased levels of IRF4 and NOTCH2 were detected.

Conclusion

LMW-HA plays an immunostimulatory role on the immune response triggered by DCs during infection with A. actinomycetemcomitans or P. gingivalis.

Clinical relevance

Detection of extracellular matrix component-derived fragments produced during periodontal tissue destruction, such as LMW-HA, could explain at least partly unsuccessful periodontal treatment and the chronicity of the disease.

https://ift.tt/2OwCokE

The TiO 2 (B) nano-belts with excellent performance prepared via alkaline stirring hydrothermal method and its application to remove 17α-ethynylestradiol

Abstract

In this work, TiO₂ (B) nano-belts were synthesized by hydrothermal method under stirring, and static conditions and preparation conditions were optimized. The prepared materials were characterized by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), photoluminescence spectroscopy (PL), and N₂ adsorption/desorption measurement. The photocatalytic performance was evaluated by removing synthetic estrogen 17α-ethynylestradiol (EE2), which is the most potent endocrine-disrupting chemical. The results show that the TiO₂ nano-belt possesses pure metastable monoclinic TiO₂ (B) and has uniform nano-belt shape with 80~120-nm diameters and 62.904 m² g⁻¹ of specific surface area. Under the best optimal preparation conditions (0.5 g P25, 20 mL 10 mol L⁻¹ NaOH, hydrothermal temperature 180 °C for 18 h under stirring, 400 °C calcination for 2 h), the TiO₂ (B) has better catalytic activity with 100.00% removal rate towards 3 mg L⁻¹ EE2 in 120 min. The removal rates of EE2 over catalyst which was prepared under static condition and P25 are 74.66% and 70.71%, respectively. The photocatalytic degradation rate constant of TiO₂ (B) prepared under stirring condition (0.0379 min⁻¹) is 4.51 times and 8.42 times than those of TiO₂ prepared under static condition (0.0084 min⁻¹) and P25 (0.0045 min⁻¹). The excellent photocatalytic activity is mainly ascribed to longer one-dimensional nano-belt structure and effective suppression of photo-produced electron-hole.

https://ift.tt/2OuDVrs

Non‐atopic Rhinitis at Age 6 is Associated with Subsequent Development of Asthma

Clinical &Experimental Allergy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2QvFo2d

Accumulation, translocation, and assessment of heavy metals in the soil-rice systems near a mine-impacted region

Abstract

Paddy rice is considered as a main source for human exposure to heavy metal contamination due to its efficient accumulation of heavy metals especially when cultivated in contaminated fields. In the current study, rice grains, straws, roots, and rhizosphere paddy soils were collected from Changsha, a non-ferrous mine-impacted area in China. Heavy metals including Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Cd, Ba, and Pb in the samples were determined using ICP-MS. The heavy metal concentrations were found in the ascending order of grain < straw < root < paddy soil except As and Cd. Rice root is a main organ to retain As and Cd through chelation and adsorption. The translocation behaviors of the heavy metals in the soil-rice system were investigated through bioaccumulation factor (BF) and translocation factor (TF). Similar variation tendencies to decrease BF_p-r (translocation from paddy soil to root) and TF_s-g (translocation from straw to grain) associated with TF_r-s (translocation from root to straw) increasing were observed for most of the heavy metals due to heavy metal detoxification and stress tolerance in rice. The potential adverse effects caused by long-term exposure to heavy metals from rice consumption were evaluated via the target hazard quotient. The results indicated potential health risk to human from exposure to Mn, As, and Cd.

https://ift.tt/2D2zJ0F

Blue lesions of the ears: When dermoscopy is not enough!

Australasian Journal of Dermatology, EarlyView.


https://ift.tt/2xqttK3

Benign Paroxysmal Positional Vertigo in Children

Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Db4DnA

A scoring system to predict recurrence in patients with differentiated thyroid cancer

Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NHHUnx

A novel Sudan Black B-based analogue revives lipofuscin as a biomarker for in vivo senescence

https://ift.tt/2D3qNbA

Blue lesions of the ears: When dermoscopy is not enough!

Australasian Journal of Dermatology, EarlyView.


https://ift.tt/2xqttK3

5‐hydroxytryptophan attenuates imiquimod‐induced psoriasiform dermatitis probably through inhibition of IL‐17A production and keratinocyte activation

Experimental Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D2v4vH

Targeting the ICOS/ICOS‐L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease

Allergy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D17S0Q

Weiße Papeln an Stirn, Wangen und retroaurikulär

https://ift.tt/2NlvXo7

Idiopathic granulomatous vulvitis and subsequent oral granulomatosis: a diagnostic and therapeutic challenge

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2NjnvWq

A novel missense mutation of the STS gene in two siblings with X‐linked ichthyosis, complicated by short stature, bone density reduction, epilepsy, and cryptorchidism

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2OB7BTC

Current Aura Without Headache

Abstract

Purpose of Review

This review evaluates and explains our current understanding of a rare subtype of migraine, typical aura without headache, also known as migraine aura without headache or acephalgic migraine.

Recent Findings

Typical aura without headache is a known entity within the spectrum of migraine. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. No clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura. Bilateral greater occipital nerve blocks may be helpful in aborting migraine with prolonged aura. Transcranial magnetic stimulation has shown efficacy in aborting attacks of migraine with aura but has not been specifically tested in isolated aura.

Summary

Typical aura without headache occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura. Typical aura without headache commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment.

https://ift.tt/2Osk63W

Idiopathic granulomatous vulvitis and subsequent oral granulomatosis: a diagnostic and therapeutic challenge

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2NjnvWq

A novel missense mutation of the STS gene in two siblings with X‐linked ichthyosis, complicated by short stature, bone density reduction, epilepsy, and cryptorchidism

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2OB7BTC

Pachydermodactyly: case report including clinical and histopathologic diagnostic pitfalls

Journal of Cutaneous Pathology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2xmE5d7

“AIR LEAK SYNDROME”: An Unusual Presentation of Foreign Body in the Airway

Abstract

Spontaneous onset pneumomediastinum, pneumothorax and subcutaneous emphysema are rare presentations of a foreign body in the airway. The possible mechanism for unexplainable and non traumatic subcutaneous emphysema can be attributed to "Air leak syndrome" following inhalation of foreign body in the airway.

https://ift.tt/2NmqzBe

Role of Proton Pump Inhibitors in Laryngopharyngeal Reflux: Clinical Evaluation in a North Indian Population

Abstract

There has been an escalation of patients presenting with symptoms of Laryngopharyngeal reflux disease (LPRD) in the otorhinolaryngology clinics due to life style and dietary changes. This study was undertaken to evaluate the effect of various proton pump inhibitors in the treatment of LPRD using Reflux symptom index (RSI) and Reflux finding score (RFS). This was a prospective study conducted from June 2016 to February 2017 with a total of 240 patients with symptoms and signs of LPR. The patients were divided into 5 groups. Each group was subjected to particular proton pump inhibitor. There were 124 males 116 females with a mean age 34.3 and rural to urban ratio being 11. After 3 months, RFS and RSI score within each group, improved significantly with Proton pump inhibitor therapy. In our study patients who were treated with omeprazole 20 mg twice daily had the highest improvement in laryngeal symptoms and laryngeal findings. We conclude emphasizing the effectiveness of proton pump inhibitors with incorporation of lifestyle modification in the successful management of LPRD.

https://ift.tt/2OusgZR