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

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

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

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

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

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

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

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

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

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

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

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

Antimicrobial Susceptibility of Pseudomonas aeruginosa to Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Piperacillin-Tazobactam, and Meropenem Stratified by U.S. Census Divisions: Results from the 2017 INFORM Program [Epidemiology and Surveillance]

P. aeruginosa isolates (n = 1,909) were collected from 70 United Sates medical centers and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (MIC_50/90, 2/8 mg/liter) and ceftolozane-tazobactam (MIC_50/90, 0.5/2 mg/liter) were the most active (highest susceptibility rates) compounds after colistin, with national susceptibility rates of 96.9% and 97.5%, respectively. Overall, piperacillin-tazobactam (MIC_50/90, 4/128 mg/liter) and meropenem (MIC_50/90, 0.5/16 mg/liter) were active against 77.5% and 76.0%, respectively. Susceptibility variations across census divisions were documented for many antimicrobials.

https://ift.tt/2NjGIao

Implications of the "EUCAST trailing" phenomenon in C. tropicalis for the in vivo susceptibility in invertebrate and murine models. [Susceptibility]

Candida tropicalis isolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy.

Fluconazole efficacy against two weakly (≤25% growth), two moderately (26-50% growth), one resistant heavily (>70% growth) trailing, and one resistant (100% growth) isolates was investigated in vitro and in vivo (a Galleria mellonella survival model and two non-lethal murine models). CDR1 expression levels and ERG11 sequences were characterised.

Survival in fluconazole-treated G. mellonella was inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment. The CDR1 expression was significantly higher in trailing and resistant compared to wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibited ERG11 wild-type alleles.

Heavily trailing isolates were less responsive to fluconazole in all in vivo models indicating an impact on fluconazole efficacy. CDR1 upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole efficacy against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larvae model may be a reason for concern in selected vulnerable patient populations.

https://ift.tt/2xuF8HQ

Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen [Antiviral Agents]

Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia, but induce hepatitis B surface antigen (HBsAg) loss in a very few patients and do not much affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, Tazarotene exhibited the most potent anti-HBV effect with an IC₅₀ for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected dHepaRG models, but not in HepG2.215 cells, and HBV genotype A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA, RNAs and the activation of HBV promoters. Moreover, RNA-sequence analysis showed that Tazarotene did not induce an interferon response, but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by specific antagonist significantly attenuated the anti-HBV activity of Tazarotene, suggesting Tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of Tazarotene and Entecavir on HBV-DNA levels was observed. Therefore, RAR agonists as represented by Tazarotene were identified as potential novel anti-HBV agents.

https://ift.tt/2NjzT8B

Comparative epidemiology of vancomycin-resistant enterococci colonization in an acute care hospital and its affiliated intermediate- and long-term care facilities in Singapore [Epidemiology and Surveillance]

Vancomycin-resistant enterococci (VRE) is an important cause of nosocomial infections in acute care hospitals (ACHs), intermediate- (ITCFs) and long-term care facilities (LTCFs). This study contemporaneously compared the epidemiology and risk factors for VRE colonization in different care settings in a healthcare network. We conducted a serial cross-sectional study in a 1700-bed ACH and its six closely-affiliated ITCFs and LTCFs in June-July, 2014–2016. Rectal swabs or stool were cultured for VRE. Multivariable logistic regression was used to assess for independent risk factors associated with VRE colonization. Of 5357 participants, 523 (9.8%) were VRE-colonized. VRE prevalence was higher in ACH (14.2%) than ITCFs (7.6%) and LTCFs (0.8%). Common risk factors between ACH and ITCFs included prior VRE carriage; a longer duration of antibiotic therapy; surgery in the preceding 90 days and presence of skin ulcer. Independent risk factors specific to ACH-admitted patients were prior MRSA carriage; a higher number of beds per room; prior proton pump inhibitors use and length of stay >14 days. For ITCFs, length of stay >14 days was inversely associated with VRE colonization. Similarities and differences in risk factors for VRE colonization were observed between healthcare settings. VRE prevention efforts should target the respective high-risk patients.

https://ift.tt/2xmKHbo

Beyond penicillin - rapid desensitization for specific flucloxacillin hypersensitivity [Pharmacology]

Beta-lactam therapy for severe staphylococcal infections is associated with superior outcomes when compared to non-beta-lactam therapy. In patients with immediate hypersensitivity to beta-lactams, desensitization has been widely employed to allow beta-lactam therapy, but published protocols for anti-staphylococcal beta-lactams such as flucloxacillin are lacking. Here, we report a case and the desensitization protocol successfully used for a patient with isolated flucloxacillin immediate hypersensitivity, where a penicillin desensitization protocol would likely have resulted in an adverse drug reaction.

https://ift.tt/2Nog5RS

A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study [Clinical Therapeutics]

High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response. In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival. A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC_0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%), 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12). Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.

https://ift.tt/2xseM9D

Synergistic antimicrobial activity of colistin in combination with rifampin and azithromycin against Escherichia coli producing MCR-1 [Experimental Therapeutics]

The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli that produces colistin-resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501^R, HE1704^R that produces MCR-1, and colistin-susceptible isolate MZ1509^S. Experiments were conducted at a medium inoculum of ~10⁷ CFU/mL over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic thigh-infected mouse model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. By contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in bacterial burden, albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings where a mean decrease of 0.38 to 0.90 log₁₀ CFU and 1.27 to 1.78 log₁₀ CFU was noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.

https://ift.tt/2Nn4LW3

Low in Vitro Antifungal Activity of Tavaborole Against Yeasts and Moulds from Onychomycosis [Susceptibility]

The in vitro activity of tavaborole, a FDA approved antifungal drug, was compared to four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine and fluconazole, the principal choices for the treatment of onychomycosis. Thus it appears that tavaborole is not a candidate for the treatment of onychomycosis due to Candida species, Aspergillus species and dermatophytes.

https://ift.tt/2xsnbtx

Gametocytes from K13-propeller mutant Plasmodium falciparum clinical isolates demonstrate reduced susceptibility to dihydroartemisinin in the male gamete exflagellation inhibition assay [Susceptibility]

Mutations in the kelch-propeller domain (K13-propeller) of Plasmodium falciparum parasites from Southeast Asia are associated with reduced susceptibility to artemisinin. We exposed in vitro-cultured Stage V gametocytes from Cambodian K13-propeller mutant parasites to dihydroartemisinin and evaluated inhibition of male gamete formation in the in vitro exflagellation inhibition assay (EIA). Gametocytes with R539T and C580Y K13-propeller alleles were less susceptible to dihydroartemisinin and had significantly higher 50% inhibitory concentrations (IC₅₀s) compared to gametocytes with wild-type alleles.

https://ift.tt/2Ni6Xhj

Identification and characterization of IncA/C conjugative, blaNDM-1-bearing plasmid in Vibrio alginolyticus of food origin [Letters]

Vibrio alginolyticus is a Gram-negative halophilic and mesophilic bacterium, particularly associated with severe epidemic vibriosis, which causes high mortality for marine animals, including fish, shellfish and shrimp (1)....

https://ift.tt/2xrMBYn

Intrahepatic Administration of Amphotericin B Liposomal (Ambisome(R)) for the Management of a Liver Abscess from Candida albicans in a preterm infant. [Clinical Therapeutics]

Hepatic fungal abscesses are rare in the neonatal period and often constitute a severe complication of the catheterization of the umbilical vessels. Such life-threatening lesions are observed more frequently in preterm than in other newborn infants and the optimal treatment remains uncertain. We present the case of a preterm neonate, who developed an intrahepatic lesion due to parenteral extravasation, successively contaminated by Candida albicans. Despite the maximal pharmacological therapies, the treatment that led to the definitive resolution of the abscess was the placement of a surgical drainage followed by the direct intralesional administration of liposomal amphotericin B (AmBisome), never described in neonates in the literature, which turned out to be a safe and effective approach.

https://ift.tt/2NhyO16

Comparison of the drug-drug interaction potential of daptomycin in combination with rifampin in healthy adult volunteers [Pharmacology]

We evaluated the effect of rifampin co-administration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in clearance (0.53 vs 0.55 L/hr, P = 1.00), volume of distribution (7.0 vs 7.2 L, P = 0.62), or half-life (9.7 vs 9.6 hrs, P = 0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition.

https://ift.tt/2xqSB3E

A randomized single-dose safety, pharmacokinetics, food effect and effect on thorough QT/QTc of Chinfloxacin in healthy Chinese Volunteers [Clinical Therapeutics]

Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single ascending dose study to assess safety and tolerability of chinfloxacin. The single dose pharmacokinetic study, food effect study and a multiple dose pharmacokinetics study was conducted in Part B, Part C and Part D, respectively. Part E was a randomized, placebo- and positive-controlled single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/QTc interval. The results suggest that single and multiple oral administration of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to C_max (T_max) was about 2 h and T_1/2 was 14-16 h. Food slightly affected the drug's rate and extent of absorption, increasing the T_max from 1.60 to 2.59 h and reducing the C_max by 13.6% and AUC by 8.95%, respectively. Chinfloxacin 400 mg had no effect on prolongation of QT/QTc intervals. Although chinfloxacin 600 mg caused mild effect on prolongation of QT/QTc interval, the effect was less pronounced than that of the positive control, moxifloxacin 400 mg. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at ChiCTR.org.cn. Identifier of Part A to Part D: ChiCTR-TRC-10001619; Identifier of the Part E: ChiCTR1800015906.)

https://ift.tt/2Nhm4rs

Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization Through a Split Luciferase Complementation Assay [Antiviral Agents]

The capsid of hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, which is the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report herein a cell-based assay in which the formation of core dimers is indicated by the Split Luciferase Complementation (SLC). Making use of this model, 2 compounds, Arbidol and 20-Deoxyingenol, were identified as core dimerization regulators from a library containing 672 compounds. Arbidol and 20-Deoxyingenol inhibit the HBV DNA replication in vitro by decreasing and increasing the formation of core dimer and capsid, respectively. Our results provided a proof of concept for the cell model to be used to screen new agents targeting the step of core dimer and capsid formation.

https://ift.tt/2xmTiuw

Synthesis, Biological Evaluation and Molecular Modeling Studies of Chiral Chloroquine Analogues as Antimalarial Agents [Experimental Therapeutics]

In a focused exploration, we have designed synthesized and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity [for in vitro IC₅₀= 56.98nM (3D7), 97.76nM (K1); for in vivo (up to at the dose of 12.5 mg/kg); SI = 3510] as a new lead of antimalarial agent. Other compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a and 9c are also showing moderate activity against CQ-sensitive (3D7) strain and superior activity against resistant (K1) strain of P. falciparum. Furthermore, we have carried out docking and 3D-QSAR studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure activity relationships (SAR). Our new findings specified the significance of H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against 3D7 strain indicated the favourable and unfavourable sites of CQ analogues for incorporating steric, hydrophobic and electropositive groups to improve the antimalarial activity.

https://ift.tt/2NiFdct

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

Effective dose of remifentanil for intubation in children

https://ift.tt/2OtC6Lh

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

Adaptive Optics Imaging of Cone Photoreceptors in Retinal Diseases

Muthiah, Manickam (Nick); (2018) Adaptive Optics Imaging of Cone Photoreceptors in Retinal Diseases. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2NLy2cp

Evidence for a subcortical contribution to intracortical facilitation

Wiegel, P; Niemann, N; Rothwell, JC; Leukel, C; (2018) Evidence for a subcortical contribution to intracortical facilitation. European Journal of Neuroscience , 47 (11) pp. 1311-1319. 10.1111/ejn.13934 .

https://ift.tt/2xpcZSA

Improving biodiversity monitoring using satellite remote sensing to provide solutions towards the 2020 conservation targets

Luque, S; Pettorelli, N; Vihervaara, P; Wegmann, M; (2018) Improving biodiversity monitoring using satellite remote sensing to provide solutions towards the 2020 conservation targets. Methods in Ecology and Evolution , 9 (8) pp. 1784-1786. 10.1111/2041-210X.13057 .

https://ift.tt/2NVnt6J

The role of TREM2 in neurodegeneration

Murray, Christina Elizabeth; (2018) The role of TREM2 in neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2xpcEzi

Evidence for phenotypic plasticity but not for compensatory horn growth in male Iberian ibex

Carvalho, J; Eizaguirre, O; Pérez, JM; Mentaberre, G; Lavín, S; Fandos, P; Olmo, JR; ... Serrano, E; + view all Carvalho, J; Eizaguirre, O; Pérez, JM; Mentaberre, G; Lavín, S; Fandos, P; Olmo, JR; Olivé-Boix, X; Torres, RT; Fonseca, C; Pettorelli, N; Serrano, E; - view fewer (2017) Evidence for phenotypic plasticity but not for compensatory horn growth in male Iberian ibex. Mammalian Biology , 87 pp. 101-106. 10.1016/j.mambio.2017.06.003 . Green open access

https://ift.tt/2NKFuV9

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

Connick, P; De Angelis, F; Parker, RA; Plantone, D; Doshi, A; John, N; Stutters, J; ... UK Multiple Sclerosis Society Clinical Trials Network, ; + view all Connick, P; De Angelis, F; Parker, RA; Plantone, D; Doshi, A; John, N; Stutters, J; MacManus, D; Prados Carrasco, F; Barkhof, F; Ourselin, S; Braisher, M; Ross, M; Cranswick, G; Pavitt, SH; Giovannoni, G; Gandini Wheeler-Kingshott, CA; Hawkins, C; Sharrack, B; Bastow, R; Weir, CJ; Stallard, N; Chandran, S; Chataway, J; UK Multiple Sclerosis Society Clinical Trials Network, ; - view fewer (2018) Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open , 8 , Article e021944. 10.1136/bmjopen-2018-021944 . Green open access

https://ift.tt/2xr6xus

Improved potential energy surface and spectral assignments for ammonia in the near-infrared region

Coles, PA; Ovsyannikov, RI; Polyansky, OL; Yurchenko, SN; Tennyson, J; (2018) Improved potential energy surface and spectral assignments for ammonia in the near-infrared region. Journal of Quantitative Spectroscopy and Radiative Transfer , 219 pp. 199-212. 10.1016/j.jqsrt.2018.07.022 . Green open access

https://ift.tt/2NVmVOd

Developing a vaccine against Zika

Hombach, J; Friede, M; Moorphy, V; Costello, A; Kieny, MP; (2016) Developing a vaccine against Zika. BMJ-British Medical Journal , 355 , Article i5923. 10.1136/bmj.i5923 . Green open access

https://ift.tt/2xtBazc

Sex-specific genetic predictors of Alzheimer's disease biomarkers

Deming, Y; Dumitrescu, L; Barnes, LL; Thambisetty, M; Kunkle, B; Gifford, KA; Bush, WS; ... Hohman, TJ; + view all Deming, Y; Dumitrescu, L; Barnes, LL; Thambisetty, M; Kunkle, B; Gifford, KA; Bush, WS; Chibnik, LB; Mukherjee, S; De Jager, PL; Kukull, W; Huentelman, M; Crane, PK; Resnick, SM; Keene, CD; Montine, TJ; Schellenberg, GD; Haines, JL; Zetterberg, H; Blennow, K; Larson, EB; Johnson, SC; Albert, M; Moghekar, A; Del Aguila, JL; Fernandez, MV; Budde, J; Hassenstab, J; Fagan, AM; Riemenschneider, M; Petersen, RC; Minthon, L; Chao, MJ; Van Deerlin, VM; Lee, VM-Y; Shaw, LM; Trojanowski, JQ; Peskind, ER; Li, G; Davis, LK; Sealock, JM; Cox, NJ; Alzheimer's Disease Neuroimaging Initiative (ADNI), ; Alzheimer Disease Genetics Consortium (ADGC), ; Goate, AM; Bennett, DA; Schneider, JA; Jefferson, AL; Cruchaga, C; Hohman, TJ; - view fewer (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathologica 10.1007/s00401-018-1881-4 . (In press).

https://ift.tt/2NR1mxS

Exploring cosmic origins with CORE: The instrument

de Bernardis, P; Ade, PAR; Baselmans, JJA; Battistelli, ES; Benoit, A; Bersanelli, M; Bideaud, A; ... Vittorio, N; + view all de Bernardis, P; Ade, PAR; Baselmans, JJA; Battistelli, ES; Benoit, A; Bersanelli, M; Bideaud, A; Calvo, M; Casas, FJ; Castellano, MG; Catalano, A; Charles, I; Colantoni, I; Columbro, F; Coppolecchia, A; Crook, M; D'Alessandro, G; De Petris, M; Delabrouille, J; Doyle, S; Franceschet, C; Gomez, A; Goupy, J; Hanany, S; Hills, M; Lamagna, L; Macias-Perez, J; Maffei, B; Martin, S; Martinez-Gonzalez, E; Masi, S; McCarthy, D; Mennella, A; Monfardini, A; Noviello, F; Paiella, A; Piacentini, F; Piat, M; Pisano, G; Signorelli, G; Tan, CY; Tartari, A; Trappe, N; Triqueneaux, S; Tucker, C; Vermeulen, G; Young, K; Zannoni, M; Achucarro, A; Allison, R; Arta, E; Ashdown, M; Ballardini, M; Banday, AJ; Banerji, R; Bartlett, J; Bart, N; Basak, S; Bonaldi, A; Bonato, M; Borri, J; Bouchet, F; Boulanger, F; Brinckmann, T; Bucher, M; Burigana, C; Buzzelli, A; Cai, ZY; Carvalho, CS; Challinor, A; Chluba, J; Clesse, S; De Gasperis, G; De Zotti, G; Di Valentino, E; Diego, JM; Errard, J; Feeney, S; Fernandez-Cobos, R; Finelli, F; Forastieri, F; Galli, S; Genova-Santos, R; Gerbino, M; Gonzalez-Nuevo, J; Hagstotz, S; Greenslade, J; Handley, W; Hernandez-Monteagudo, C; Hervias-Caimapo, C; Hivon, E; Kiiveri, K; Kisner, T; Kitching, T; Kunz, M; Kurki-Suonio, H; Lasenby, A; Lattanzi, M; Lesgourgues, J; Lewis, A; Liguori, M; Lindholm, V; Luzzi, G; Martins, CJAP; Matarrese, S; Melchiorri, A; Melin, JB; Molinari, D; Natoli, P; Negrello, M; Notari, A; Paoletti, D; Patanchon, G; Polastri, L; Polenta, G; Po, A; Poulin, V; Quartin, M; Remazeilles, M; Roman, M; Rubino-Martin, JA; Salvati, L; Tomasi, M; Tramonte, D; Trombetti, T; Valiviita, J; Van de Weyjgaert, R; van Tent, B; Vennin, V; Vielva, P; Vittorio, N; - view fewer (2018) Exploring cosmic origins with CORE: The instrument. Journal of Cosmology and Astroparticle Physics , 2018 (4) , Article 015. 10.1088/1475-7516/2018/04/015 .

https://ift.tt/2xqFMpZ

Neurophysiological correlates of bradykinesia in Parkinson’s disease

Bologna, M; Guerra, A; Paparella, G; Giordo, L; Fegatelli, DA; Vestri, AR; Rothwell, JC; Bologna, M; Guerra, A; Paparella, G; Giordo, L; Fegatelli, DA; Vestri, AR; Rothwell, JC; Berardelli, A; - view fewer (2018) Neurophysiological correlates of bradykinesia in Parkinson's disease. Brain , 141 (8) pp. 2432-2444. 10.1093/brain/awy155 .

https://ift.tt/2NUNIu0

Unfinished Work in UK Company Law Reforms - A Normative and European Perspective to Addressing the Gaping Holes in Directors’ Duties

Chiu, H; Barker, R; (2018) Unfinished Work in UK Company Law Reforms - A Normative and European Perspective to Addressing the Gaping Holes in Directors' Duties. European Company Law (In press).

https://ift.tt/2xtASs6

Britannia Waives the Rules

Grubb, M; (2002) Britannia Waives the Rules. New Economy , 9 (3) pp. 139-142. 10.1111/1468-0041.00259 .

https://ift.tt/2NKFnsH

Red flags in epilepsy surgery: Identifying the patients who pay a high cognitive price for an unsuccessful surgical outcome

Baxendale, S; Thompson, P; (2018) Red flags in epilepsy surgery: Identifying the patients who pay a high cognitive price for an unsuccessful surgical outcome. Epilepsy & Behavior , 78 pp. 269-272. 10.1016/j.yebeh.2017.08.003 .

https://ift.tt/2xq7AL5

Dimensions of difficulty in children reported to have an autism spectrum diagnosis and features of extreme/"pathological' demand avoidance

O'Nions, E; Viding, E; Floyd, C; Quinlan, E; Pidgeon, C; Gould, J; Happe, F; (2018) Dimensions of difficulty in children reported to have an autism spectrum diagnosis and features of extreme/"pathological' demand avoidance. Child and Adolescent Mental Health , 23 (3) pp. 220-227. 10.1111/camh.12242 . Green open access

https://ift.tt/2NKF2Gr

Dissociation between Semantic Representations for Motion and Action Verbs: Evidence from Patients with Left Hemisphere Lesions

Taylor, LJ; Evans, C; Greer, J; Senior, C; Coventry, KR; Ietswaart, M; (2017) Dissociation between Semantic Representations for Motion and Action Verbs: Evidence from Patients with Left Hemisphere Lesions. Frontiers in Human Neuroscience , 11 10.3389/fnhum.2017.00035 . Green open access

https://ift.tt/2xqgk41

Phosphoregulation of KCC2 function

Moore, Yvonne Elizabeth Frances; (2018) Phosphoregulation of KCC2 function. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2NNAQ8M

Cyclodextrin-based Formulations for Pulmonary Delivery of Chemotherapeutic Molecules

Binti Mohtar, Noratiqah; (2018) Cyclodextrin-based Formulations for Pulmonary Delivery of Chemotherapeutic Molecules. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2xqFJuj

Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer’s Disease: A Comparison of the Cognitive and Clinical Profiles

Sadiq, D; Whitfield, T; Lee, L; Stevens, T; Costafreda, S; Walker, Z; (2017) Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer's Disease: A Comparison of the Cognitive and Clinical Profiles. Journal of Alzheimer's Disease , 58 (2) pp. 463-470. 10.3233/JAD-161089 . Green open access

https://ift.tt/2NOtQIB

Reframing the governance of automotive automation: insights from UK stakeholder workshops

Cohen, T; Stilgoe, J; Cavoli, C; (2018) Reframing the governance of automotive automation: insights from UK stakeholder workshops. Journal of Responsible Innovation 10.1080/23299460.2018.1495030 . (In press).

https://ift.tt/2xpnPrI

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

Building General Knowledge of Mechanisms in Information Security

Abstract

We show how more general knowledge can be built in information security, by the building of knowledge of mechanism clusters, some of which are multifield. By doing this, we address in a novel way the longstanding philosophical problem of how, if at all, we come to have knowledge that is in any way general, when we seem to be confined to particular experiences. We also address the issue of building knowledge of mechanisms by studying an area that is new to the mechanisms literature: the methods of what we shall call mechanism discovery in information security. This domain offers a fascinating novel constellation of challenges for building more general knowledge. Specifically, the building of stable communicable mechanistic knowledge is impeded by the inherent changeability of software, which is deployed by malicious actors constantly changing how their software attacks, and also by an ineliminable secrecy concerning the details of attacks not just by attackers (black hats), but also by information security defenders (white hats) as they protect their methods from both attackers and commercial competitors. We draw out ideas from the work of the mechanists Darden, Craver, and Glennan to yield an approach to how general knowledge of mechanisms can be painstakingly built. We then use three related examples of active research problems from information security (botnets, computer network attacks, and malware analysis) to develop philosophical thinking about building general knowledge using mechanisms, and also apply this to develop insights for information security. We show that further study would be instructive both for practitioners (who might welcome the help in conceptualizing what they do) and for philosophers (who will find novel insights into building general knowledge of a highly changeable domain that has been neglected within philosophy of science).

https://ift.tt/2D2wwOT

Alcohol and Cancer Risk

A fact sheet that summarizes the evidence linking alcohol consumption to the risk of various cancers. Includes information about factors that affect the risk of alcohol-associated cancers, such as a person's genes and tobacco use.

https://ift.tt/2daKwas

New insights into the electrochemical behaviour of porous carbon electrodes for supercapacitors

Ibrahim Abouelamaiem, D; Mostazo-López, MJ; He, G; Patel, D; Neville, TP; Parkin, IP; Lozano-Castelló, D; ... Brett, DJL; + view all Ibrahim Abouelamaiem, D; Mostazo-López, MJ; He, G; Patel, D; Neville, TP; Parkin, IP; Lozano-Castelló, D; Morallón, E; Cazorla-Amorós, D; Jorge, AB; Wang, R; Ji, S; Titirici, MM; Shearing, PR; Brett, DJL; - view fewer (2018) New insights into the electrochemical behaviour of porous carbon electrodes for supercapacitors. Journal of Energy Storage , 19 pp. 337-347. 10.1016/j.est.2018.08.014 . (In press). Green open access

https://ift.tt/2xibiXX

Review of: A. Sarri, Material Aspects of Letter Writing in the Graeco-Roman World 500 bc – ad 300

Ceccarelli, P; (2019) Review of: A. Sarri, Material Aspects of Letter Writing in the Graeco-Roman World 500 bc – ad 300. Classical Review , 69 (1) (In press).

https://ift.tt/2Oupzr5

Bluebelle study (phase A): a mixed-methods feasibility study to inform an RCT of surgical wound dressing strategies

Rooshenas, L; Bluebelle Study Group, .; Severn Peninsula Audit and Research Collaborative for Surgeons, .; West Midlands Research Collaborative, .; (2016) Bluebelle study (phase A): a mixed-methods feasibility study to inform an RCT of surgical wound dressing strategies. BMJ Open , 6 (9) , Article e012635. 10.1136/bmjopen-2016-012635 . Green open access

https://ift.tt/2MCAQ6N

Comparative Safety of NSAIDs for Gastrointestinal Events in Asia-Pacific Populations: A Multi-Database, International Cohort Study

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Subjective wellbeing of internal migrants in Chinese cities

Liu, Yuqi; (2018) Subjective wellbeing of internal migrants in Chinese cities. Doctoral thesis (Ph.D), UCL (University College London).

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Anat Helman, Israeli National Ideals and Everyday Life in the 1950s. Waltham: Brandeis University Press, 2014. 312 pp.

Berkowitz, M; (2018) Anat Helman, Israeli National Ideals and Everyday Life in the 1950s. Waltham: Brandeis University Press, 2014. 312 pp. [Review]. Studies in Contemporary Jewry: Place in Modern Jewish Culture and Society , 30 pp. 327-329. 10.1093/oso/9780190912628.003.0058 .

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Community structure of copper supply networks in the prehistoric Balkans: An independent evaluation of the archaeological record from the 7th to the 4th millennium BC

Radivojević, M; Grujić, J; (2018) Community structure of copper supply networks in the prehistoric Balkans: An independent evaluation of the archaeological record from the 7th to the 4th millennium BC. Journal of Complex Networks , 6 (1) pp. 106-124. 10.1093/comnet/cnx013 . Green open access

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Ideas of the Rule of Law in Ancient Rome - from Republic to Empire

McKnight, Elizabeth Sarah; (2018) Ideas of the Rule of Law in Ancient Rome - from Republic to Empire. Doctoral thesis (Ph.D), UCL (University College London).

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Community Targets of JWST's Early Release Science Program: Evaluation of WASP-63b

Kilpatrick, BM; Cubillos, PE; Stevenson, KB; Lewis, NK; Wakeford, HR; MacDonald, RJ; Madhusudhan, N; ... Mandell, AM; + view all Kilpatrick, BM; Cubillos, PE; Stevenson, KB; Lewis, NK; Wakeford, HR; MacDonald, RJ; Madhusudhan, N; Blecic, J; Bruno, G; Burrows, A; Deming, D; Heng, K; Line, MR; Morley, C; Parmentier, V; Tucker, GS; Valenti, JA; Waldmann, IP; Bean, JL; Beichman, C; Fraine, J; Krick, JE; Lothringer, JD; Mandell, AM; - view fewer (2018) Community Targets of JWST's Early Release Science Program: Evaluation of WASP-63b. The Astronomical Journal , 156 (3) , Article 103. 10.3847/1538-3881/aacea7 . Green open access

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Exploring cosmic origins with CORE: Mitigation of systematic effects

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Finite-bath corrections to the second law of thermodynamics

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The constitutionality of facially neutral affirmative action in the United States

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Definition and monitoring of neonatal hypoglycaemia: a nationwide survey of NHS England Neonatal Units

Dixon, KC; Ferris, RL; Marikar, D; Chong, M; Mittal, A; Manikam, L; Rose, PJ; (2016) Definition and monitoring of neonatal hypoglycaemia: a nationwide survey of NHS England Neonatal Units. Archives of Disease in Childhood - Fetal & Neonatal Edition , 102 (1) F92-F93. 10.1136/archdischild-2016-311473 .

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Physical Review C , 98 (2) , Article 024908. 10.1103/PhysRevC.98.024908 . Green open access

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