Dural recurrence among esthesioneuroblastoma patients presenting with intracranial extension

Objective

To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation.

Study Design

Retrospective review.

Methods

All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model.

Results

Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6–199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively.

Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had ≥ two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P < 0.0001), with and without intracranial extension and subtotal resection, respectively.

Of six patients treated at recurrence, five (83%) experienced dural-based failure such that, among all 44 patients, 13 (65%) of 20 recurrences involved the dura. After dural recurrence, the median survival time was 42 months (range, 12–125); salvage treatments were effective in rare cases of isolated low-volume recurrence.

Conclusion

Esthesioneuroblastoma patients presenting with intracranial extension are at substantial and unique risk for long-term dural-based relapse.

Level of Evidence

4. Laryngoscope, 2018

http://ift.tt/2BkBunv

Reviewing smokeless tobacco epidemiology, carcinogenesis, and cessation strategy for otolaryngologists

Objectives/Objectives

We aimed to provide an otolaryngologist-targeted summary regarding the epidemiology, carcinogenesis, and cessation strategies for smokeless tobacco usage.

Study Design

Evidence-based literature review.

Methods

We reviewed the current evidence-based literature concerning trends in smokeless tobacco use, associations with neoplastic change, and therapeutic interventions to assist with sustained abstinence. In complement, we present an actual case of laryngeal squamous cell carcinoma in the setting of chronic tobacco-dentifrice usage in a lifelong nonsmoker.

Results

This report provides a synopsis of epidemiological data and evidence-based recommendations for general, pharmaceutical, and behavioral cessation strategies.

Conclusions

Smokeless tobacco use continues to be prevalent among patients seen by otolaryngologists, particularly of various Indian and Southeast Asian descent. The data presented in this article will aid in the identification of at risk patients. The provided recommended cessation strategies will tool otolaryngologists for patient counseling and management, ultimately aimed at improving health outcomes. Laryngoscope, 2018

http://ift.tt/2BOFWvP

Risk factors for complications in cochlear implant surgery

Abstract

Purpose

The objective of this study was to achieve uniform reporting of complications and failures in cochlear implantation, to analyze complications and failures and to identify risk factors for complications in a series of over 1300 cochlear implantations.

Methods

In a retrospective chart review and observational study, data from all cochlear implantations from 1987 to 2015 were entered in a custom-made database. Complications were classified using the contracted form of the Clavien–Dindo system and risk factors were identified by statistical analysis.

Results

A complication rate of 18.4% and a device failure rate of 2.9% were found. There was a higher rate of hematoma in patients with a clotting disorder and when a subtotal petrosectomy was performed, a higher rate of wound infections in patients who were not vaccinated against Streptococcus pneumoniae and a higher rate of meningitis in patients with an inner ear malformation.

Conclusions

The use of a strict definition of a medical complication and device failure—in combination with the Clavien–Dindo classification system—enables uniform and objective registration of adverse events and prevents any tendency to downgrade complications. Complication and failure rates in this series are comparable to those reported in the literature. These results stress the need for pneumococcal vaccination, which may prevent general wound infections, but is especially important for patients with inner ear malformation, who have an increased risk of (postoperative) meningitis.

http://ift.tt/2smwdcg

Middle ear microvascularization: an “in vivo” endoscopic anatomical study

Abstract

Purpose

To describe the in vivo vascularization of middle ear by an endoscopic point of view, particularly focusing on the medial wall of tympanic cavity and incudostapedial region (ISR).

Study design

Case series with surgical videos review and anatomical description.

Methods

48 videos from exclusive endoscopic middle ear surgery performed at the University Hospital of Modena from November 2015 to July 2017 were reviewed. Data about anatomy of vessels, and blood flow direction (BFD) were collected in an appropriate database for further analyses.

Results

48 cases were included in the present study. In 18/48 patients (37,5%), a clearly identifiable inferior tympanic artery (ITA) was present, running just anteriorly to the round window (RW), with a superior BFD (65% of cases) from the hypotympanic region toward the epitympanum. Some promontorial variants were described in 67% of cases and the most common finding was a mucosal vascular network with a multidirectional BFD. On the ISR, an incudostapedial artery (ISA) was detected in 65% of cases with BFD going from the long process of the incus (LPI) toward the pyramidal eminence in the majority of cases.

Conclusion

The vascular anatomy and BFD of the medial wall of the tympanic cavity can be easily studied in transcanal endoscopy. ITA (with a superior BFD in most cases) and ISA (with a main BFD from the incus to the stapes) are the most constant identifiable vessels.

http://ift.tt/2EuugPL

Systemic juvenile xanthogranuloma: a case report and brief review

http://ift.tt/2EhnYng

First report of COL7A1 mutations in two patients with recessive dystrophic epidermolysis bullosa from Peru

http://ift.tt/2C8LFsi

High Serum Cholesterol Is a Novel Risk Factor for Graves' Orbitopathy: Results of a Cross-Sectional Study

Thyroid , Vol. 0, No. 0.


http://ift.tt/2Eft5k2

Macitentan senkt Lungengefäßwiderstand bei CTEPH

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 84-85
DOI: 10.1055/s-0044-101345

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nRXHBK

ARDS – Ein Update – Teil 1: Epidemiologie, Pathophysiologie und Diagnostik

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 102-111
DOI: 10.1055/s-0043-107166

Das akute Lungenversagen (Acute respiratory Distress Syndrome, ARDS) ist inzwischen seit mehr als 50 Jahren als schwerwiegende Komplikation unterschiedlicher Grunderkrankungen gefürchtet [1]. Häufig leiden ARDS-Patienten langfristig unter schwerwiegenden Beeinträchtigungen – auch nach primär erfolgreicher Therapie. Der erste Teil dieses Updates gibt einen aktualisierten Überblick zu Definition, Epidemiologie und Pathophysiologie des ARDS.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nWbx5y

Fehlerhafte Daten in randomisierten Studien: Statistik kann sie aufdecken

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 82-82
DOI: 10.1055/s-0043-123125

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nMyZTC

Schlafmangel – Einfluss auf Kommunikation und Interaktion im Team?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 81-82
DOI: 10.1055/s-0044-101343

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nWD6f7

Senkt die zusätzliche kontinuierliche Infusion von Tranexamsäure Blutverluste?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 82-83
DOI: 10.1055/s-0044-101342

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nOGadQ

Respiratorisches Versagen: Innovationen zur Diagnostik und Therapie

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 126-140
DOI: 10.1055/s-0043-108216

Die akute oder chronische respiratorische Insuffizienz hat eine große Bedeutung sowohl in der präklinischen als auch innerklinischen Versorgung. Sie zählt zu den häufigsten Gründen für stationäre Aufnahmen. Dieser Beitrag fasst aktuelle Entwicklungen in der Diagnostik und Therapie des Krankheitsbildes zusammen. Darüber hinaus gibt er einen Ausblick, wie sich die Behandlung in den kommenden Jahren weiterentwickeln könnte.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nWD5YB

Respiratorisches Versagen: State of the Art – Diagnose und Therapie

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 90-101
DOI: 10.1055/s-0043-107167

Die respiratorische Insuffizienz beschreibt die Unfähigkeit des Körpers, einen adäquaten Gasaustausch aufrechtzuerhalten. Sie stellt – insbesondere, wenn sie akut auftritt – einen lebensbedrohlichen Zustand dar, der umgehend therapiert werden muss. Dieser Artikel zeigt, welche Diagnostik erforderlich ist, um den Patienten schnell und korrekt behandeln zu können, und welche Therapieverfahren zur Verfügung stehen.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nUTigI

Langzeitüberleben nach venovenöser ECMO

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 85-85
DOI: 10.1055/s-0044-101344

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nRXCxW

ARDS – Ein Update – Teil 2: Therapie und Outcome

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 112-125
DOI: 10.1055/s-0043-122136

Das Acute respiratory Distress Syndrome (ARDS) ist nunmehr seit über 50 Jahren als gravierende Komplikation verschiedener Grunderkrankungen bekannt [1]. Trotz intensiver Forschung in all dieser Zeit gibt es hinsichtlich der bestmöglichen Therapie des ARDS auch heute noch viele offene Fragen – insbesondere zur maschinellen Beatmung. Der zweite Teil des Update ARDS gibt einen aktualisierten Überblick zu Therapie und Outcome des ARDS.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nWD5I5

50 Jahre ARD-Forschung und -Therapie: Resümee und Ausblick

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 87-89
DOI: 10.1055/s-0043-124225

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2nPAf8u

Behandlung der Sepsis und des septischen Schocks – die neuen Leitlinien

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 142-148
DOI: 10.1055/s-0043-114639

Die neue Leitlinie der Surviving Sepsis Campaign wurde im Jahr 2016 überarbeitet und im Jahr 2017 veröffentlicht. Darüber hinaus änderte sich durch „Sepsis-3" die Definition der Sepsis im Jahr 2016 grundlegend, von einer Inflammation mit Infektion hin zu einer „lebensbedrohlichen Organ-Dysfunktion, die durch eine fehlregulierte Wirtsreaktion" verursacht wird. Um die große Herausforderung zu bewältigen, die neuen Erkenntnisse zur Sepsisbehandlung mit der neuen Definition zu vereinen, wurden die Leitlinien vollständig neu strukturiert und umfassend überarbeitet. Die Leitlinie diskutiert die sepsisspezifische Behandlung und gibt Empfehlungen für allgemeine intensivmedizinische Maßnahmen. Der Artikel fasst die wichtigsten Empfehlungen zusammen und diskutiert zusätzlich einige entscheidende Änderungen. Dies soll den Leser ermutigen, die neue Leitlinie in den klinischen Alltag zu übernehmen und somit die Prognose der Patienten, die an einer Sepsis oder einem septischem Schock leiden, zu verbessern.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nVqJQr

Nierenersatzverfahren bei akuter Nierenschädigung – Indikation und Durchführung

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 150-157
DOI: 10.1055/s-0043-110038

Die akute Nierenschädigung ist eine häufige Komplikation kritisch kranker Patienten auf Intensivstationen, die mit einer hohen Morbidität und Letalität einhergeht [1]. Sie ist ein unabhängiger Risikofaktor für ein verschlechtertes Outcome kritisch kranker Patienten [2]. Diese Übersichtsarbeit fasst die verfügbare Evidenz für die Indikation und den Einsatz von Nierenersatzverfahren bei akuter Nierenschädigung anhand aktueller Literatur zusammen.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2nQSfiC

Bowman Birk Inhibitors (BBI) in interception of inflammation and malignant transformation of OPMDs

Publication date: Available online 9 February 2018
Source:Oral Oncology
Author(s): Dr. Samapika Routray




http://ift.tt/2C8vj2M

Latent human papillomavirus type 16 infection is widespread in patients with oropharyngeal cancers

Publication date: Available online 9 February 2018
Source:Oral Oncology
Author(s): Rong Wu, Francesca Paolini, Douglas Frank, Dev Kamdar, Gianfranca Curzio, Barbara Pichi, Raul Pellini, Giuseppe Spriano, Vincent R. Bonagura, Aldo Venuti, Bettie M. Steinberg




http://ift.tt/2Eemk5S

Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset

Chronic rhinosinusitis (CRS) is a major disease condition with high morbidity, and may influence lower airway disease status in adults. However, its associations with adult asthma onset and activity have not been examined in detail in a general adult population.

http://ift.tt/2Echxls

Repeatability of nasal allergen challenge results – further validation of the allergic rhinitis clinical investigator collaborative (AR-CIC) protocols

Nasal Allergen Challenge(NAC) models have been used to study allergic rhinitis and new therapies. Symptoms and biological samples can be evaluated at time points following allergen exposure.

http://ift.tt/2CauBSG

Learnings from a pragmatic pilot trial of text messaging for high risk adolescents with asthma

Clinical research with high risk patient populations is complex due to economic burdens, lack of transportation, etc.1, 2; therefore, it is critical to conduct pilot studies prior to entering into a full scale study. Pilot studies can confirm the design and operational processes for a study3 and increase the likelihood of a successful clinical trial by identifying problems that may occur in the methods.4, 5 Thus, we conducted a pilot study to identify issues in a research trial with low-income, publically insured, minority adolescents.

http://ift.tt/2EfgYrc

Rapid oral desensitization protocol to abiraterone acetate

Abiraterone acetate (AA) is a potent selective inhibitor of cytochrome P450 (CYP) 17, a key enzyme involved in testosterone synthesis. Due to this inhibition, the production of androgens by endocrine tissues decreases. Therefore, this oral hormone therapy is used in castration-resistant prostate cancer combined with prednisone/prednisolone, with a significant increase in overall survival. Common side effects of AA include hypertension, hypokalaemia, peripheral oedema and urinary tract infections.

http://ift.tt/2CauJl8

Lack of effect of Grastek® on birch pollen-induced allergic rhinoconjunctivitis in the Environmental Exposure Unit

Grastek® is a standardized sublingual immunotherapy tablet(SLIT-T) approved for the treatment of grass pollen-induced allergic rhinitis(AR) and conjunctivitis. Many grass-allergic patients are also co-sensitized to birch pollen. Whether Grastek® can confer symptomatic benefits for birch pollen-induced AR symptoms is unknown.

http://ift.tt/2EfgTDU

PRAC Seeks New Pregnancy Prevention Measures For Retinoids

The EMA committee calls for updating pregnancy prevention measures and including a warning with retinoid products on the possible risk for neuropsychiatric disorders.
News Alerts

http://ift.tt/2H49QMe

Media Advisory: Free Community Health Screening

The Johns Hopkins University School of Medicine's Brancati Center will provide free community health screenings this Saturday, Feb. 10, at A Family Affair, an event hosted by Living Classrooms. RSVP encouraged: email tiztraining@livingclassrooms.org or call (443) 835-1463 x667 to register.

http://ift.tt/2EfJTeT

Larval Therapy for Chronic Cutaneous Ulcers

Larval debridement has been historically used in the management of chronic ulcers, but does it still have a place in modern wound healing?
Wounds

http://ift.tt/2EcU3c4

A Holistic Care Approach to Malignant Melanoma

In this editorial, the author underscores the need for a multidisciplinary, collaborative approach to treatment of malignant melanoma, uniting dermatologists, oncologists and researchers.
The British Journal of Dermatology

http://ift.tt/2ESaMCD

Seasonal variation in circulating group 2 innate lymphoid cells in mugwort-allergic asthmatics during and outside pollen season

Group 2 innate lymphoid cells (ILC2s) are a newly identified cell population with the potent capability to produce Th2-type cytokines in a non-antigen specific manner. Previous study demonstrated that enhanced...

http://ift.tt/2C9HA6R

Neoplastic Barrett Esophagus: Endoscopic Piecemeal vs. En Bloc Resection

Conditions:   Barrett Esophagus;   Barrett Adenocarcinoma;   Esophagus Neoplasm
Interventions:   Procedure: Endoscopic mucosal resection;   Procedure: Endoscopic submucosal dissection
Sponsor:   Universitätsklinikum Hamburg-Eppendorf
Recruiting

http://ift.tt/2nNSqer

Adjuvant PD-1 Antibody in Locoregionally Advanced Nasopharyngeal Carcinoma

Condition:   Nasopharyngeal Neoplasms
Intervention:   Drug: PD-1 antibody
Sponsor:   Sun Yat-sen University
Not yet recruiting

http://ift.tt/2nVWtF3

Phase II Trial of M7824 in Subjects With HPV Positive Malignancies

Conditions:   Human Papilloma Virus;   Cervical Cancer;   Oropharyngeal Cancer;   Anal Cancer;   Vaginal or Penile Cancer
Intervention:   Drug: M7824
Sponsor:   National Cancer Institute (NCI)
Not yet recruiting

http://ift.tt/2nOnyL4

A Observational Study to Compare Effectiveness and Safety of the Surgeries in Patients With Esophageal Cancer

Condition:   Esophageal Cancer
Intervention:   Procedure: Minimally invasive surgery of Ivor-Lewis
Sponsors:   Chinese PLA General Hospital;   LinkDoc Technology (Beijing) Co. Ltd.
Recruiting

http://ift.tt/2nVWjgV

PSTPIP1 controls immune synapse stability in human T-cells

Publication date: Available online 9 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): W.J.M. Janssen, V. Grobarova, J. Leleux, C.H. Jongeneel, M. van Gijn, J.M. van Montfrans, M. Boes
BackgroundPSTPIP1 is a cytosolic adaptor protein involved with T-cell activation, differentiation, and migration. Upon cognate T-cell contact, PSTPIP1 is recruited to surface-expressed CD2, where it regulates f-actin remodeling. An immune synapse (IS) is thereby rapidly formed, consisting of TCR clusters surrounded by a ring of adhesion molecules including CD2.ObjectiveFrom genetic screening of primary immunodeficiency patients, we identified two mutations in PSTPIP1, R228C and T274M which we further characterized in primary patient T-cells.MethodsF-actin dynamics were assessed in patient and healthy control primary T-cells by use of FACS. HEK293T and Jurkat cells were transfected with R228C, T274M and WT PSTPIP1 in order to visualize f-actin in immune synapse formation. CD2-PSTPIP1 association was quantified through immunoprecipitation assays.ResultsThe patients presented with immunodeficiency without signs of auto-inflammation. The R228C patient had expansion of mostly naive phenotype T-cells and few memory T-cells; the T274M patient had 75% reduction in CD4 T-cells that were predominantly of memory subset.We observed f-actin polymerization defects in both PSTPIP1 patient T-cells, most notably T274M. Capping of CD2-containing membrane microdomains was disrupted. Analysis of IS formation using Jurkat T-cell transfectants revealed a reduction in f-actin accumulation at the IS, again especially in T274M PSTPIP1 cells. Patient T274M T-cells migrated spontaneously at increased speed as assessed in a 3D collagen matrix, while TCR crosslinking induced a significantly diminished calcium flux.ConclusionsWe propose that PSTPIP1 T-cell differentiation defects are caused by defective control of f-actin polymerization. A pre-activated polymerized f-actin status, as seen in PSTPIP1-T274M T-cells, appears particularly damaging. PSTPIP1 controls IS formation and cell adhesion, through its function as orchestrator of the f-actin cytoskeleton.



http://ift.tt/2Bnbesy

Evolution of IgE responses to multiple allergen components throughout childhood

Publication date: Available online 9 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Rebecca Howard, Danielle Belgrave, Panagiotis Papastamoulis, Angela Simpson, Magnus Rattray, Adnan Custovic
BackgroundThere is a paucity of information about longitudinal patterns of IgE responses to allergenic proteins (components) from multiple sources.ObjectiveTo investigate temporal patterns of component-specific IgE responses from infancy to adolescence, and their relationship with allergic diseases.MethodsIn a population-based birth cohort, we measured IgE to 112 components at 6 follow-ups during childhood. We used a Bayesian method to discover cross-sectional sensitization patterns and their longitudinal trajectories, and related these patterns to asthma and rhinitis in adolescence.ResultsWe identified one sensitization cluster at age one, 3 at age three, 4 at ages five and eight, 5 at age 11, and six at age 16 years. "Broad" cluster was the only cluster present at every follow-up, comprising of components from multiple sources. "Dust mite" cluster formed at age three and remained unchanged to adolescence. At age three, a single-component "Grass" cluster emerged, which at age five absorbed additional grass components and Fel d 1 to form the "Grass/cat" cluster. Two new clusters formed at age 11: "Cat" cluster and "PR-10/profilin" (which divided at age 16 into "PR-10" and "Profilin"). The strongest contemporaneous associate of asthma at age 16 years was sensitization to "Dust mite" cluster (OR [95% CI]: 2.6 [1.2-6.1], P<0.05), but the strongest early-life predictor of subsequent asthma was sensitization to "Grass/cat" cluster (3.5 [1.6–7.4], P<0.01).ConclusionsWe describe the architecture of the evolution of IgE responses to multiple allergen components throughout childhood, which may facilitate development of better diagnostic and prognostic biomarkers for allergic diseases.



http://ift.tt/2BNC6mF

Intravenously administered gene therapy for neuronopathic Gaucher disease

Massaro, Giulia; (2018) Intravenously administered gene therapy for neuronopathic Gaucher disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2C96LGG

Thai traditional medicine as a source for cancer prevention: from local concepts to the discovery of potential chemopreventive extracts

Lumlerdkij, N; (2018) Thai traditional medicine as a source for cancer prevention: from local concepts to the discovery of potential chemopreventive extracts. Doctoral thesis (Ph.D), UCL (University College London).

http://ift.tt/2EbnHlQ

Utilizing CryoSat-2 sea ice thickness to initialize a coupled ice-ocean modeling system

Allard, RA; Farrell, SL; Hebert, DA; Johnston, WF; Li, L; Kurtz, NT; Phelps, MW; ... Wallcraft, AJ; + view all Allard, RA; Farrell, SL; Hebert, DA; Johnston, WF; Li, L; Kurtz, NT; Phelps, MW; Posey, PG; Tilling, R; Ridout, A; Wallcraft, AJ; - view fewer (2018) Utilizing CryoSat-2 sea ice thickness to initialize a coupled ice-ocean modeling system. Advances in Space Research 10.1016/j.asr.2017.12.030 . (In press). Green open access

http://ift.tt/2C885tt

Making primary care placements a universal feature of postgraduate medical training

Rashid, A; Manek, N; (2016) Making primary care placements a universal feature of postgraduate medical training. Journal of the Royal Society of Medicine , 109 (12) pp. 461-462. 10.1177/0141076816673758 .

http://ift.tt/2EfOWvw

The use of basic beat box techniques in speech following laryngectomy

Moors, T; Himonides, E; Silva, S; Maraschin, D; (2017) The use of basic beat box techniques in speech following laryngectomy. Presented at: Pevoc12 (PanEuropean Voice Conference: Cherishing Cross-fertilizing worlds), Ghent, Belgium.

http://ift.tt/2C85YGg

Longitudinal trends in vocal development among girl choristers in a UK Cathedral

Howard, D; Welch, G; Himonides, E; (2017) Longitudinal trends in vocal development among girl choristers in a UK Cathedral. Presented at: Pevoc12 (PanEuropean Voice Conference: Cherishing Cross-fertilizing worlds), Ghent, Belgium.

http://ift.tt/2EdCxbA

International trade and tourism in a CO₂-constrained world

Krammer, Philip; (2018) International trade and tourism in a CO₂-constrained world. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2C8v87q

Always Connected = Always Available? The Role of Microboundaries

Cecchinato, M; (2017) Always Connected = Always Available? The Role of Microboundaries. Presented at: Connected Life 2017, Oxford, United Kingdom.

http://ift.tt/2EhMwNa

Institutional governance in the development of Chinese private universities: three cases study from Sichuan province

Liu, Xu; (2018) Institutional governance in the development of Chinese private universities: three cases study from Sichuan province. Doctoral thesis (Ph.D), UCL (University College London).

http://ift.tt/2C7utTW

Adaptive Knowledge Propagation in Web Ontologies

Minervini, P; Tresp, V; D'Amato, C; Fanizzi, N; (2018) Adaptive Knowledge Propagation in Web Ontologies. ACM Transactions on the Web , 12 (1) , Article 2. 10.1145/3105961 .

http://ift.tt/2EeBHvd

A multi-scale exploration of the relationship between spatial network configuration and housing prices using the hedonic price approach. A Greater London case study

Law, Stephen; (2018) A multi-scale exploration of the relationship between spatial network configuration and housing prices using the hedonic price approach. A Greater London case study. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2C8vOcY

Investigating associations between the built environment and physical activity among older people in 20 UK towns.

Hawkesworth, S; Silverwood, RJ; Armstrong, B; Pliakas, T; Nanchalal, K; Jefferis, BJ; Sartini, C; ... Lock, K; + view all Hawkesworth, S; Silverwood, RJ; Armstrong, B; Pliakas, T; Nanchalal, K; Jefferis, BJ; Sartini, C; Amuzu, AA; Wannamethee, SG; Ramsay, SE; Casas, J-P; Morris, RW; Whincup, PH; Lock, K; - view fewer (2018) Investigating associations between the built environment and physical activity among older people in 20 UK towns. J Epidemiol Community Health , 72 (2) pp. 121-131. 10.1136/jech-2017-209440 . Green open access

http://ift.tt/2EhCNX1

A domain based protein structural modelling platform applied in the analysis of alternative splicing

Lam, Su Datt; (2018) A domain based protein structural modelling platform applied in the analysis of alternative splicing. Doctoral thesis (Ph.D), UCL (University College London).

http://ift.tt/2EgDDnb

What are the Career Plans of GP Trainees and Newly Qualified General Practitioners in the UK? A National Online Survey

Mazhar, K; Rashid, A; (2016) What are the Career Plans of GP Trainees and Newly Qualified General Practitioners in the UK? A National Online Survey. Journal of General Practice , 4 (1) , Article 1000216. 10.4172/2329-9126.1000216 . Green open access

http://ift.tt/2C8faub

Lost Homelands Reinvented: Material Culture of the Chinese Diaspora and Their Family in Taiwan

Kuo, Yang-Yi; (2018) Lost Homelands Reinvented: Material Culture of the Chinese Diaspora and Their Family in Taiwan. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2C9qCpj

Could patient-controlled thirst-driven fluid administration lead to more rapid rehydration than clinician-directed fluid management? An early feasibility study

Hughes, F; Ng, SC; Mythen, M; Montgomery, H; (2017) Could patient-controlled thirst-driven fluid administration lead to more rapid rehydration than clinician-directed fluid management? An early feasibility study. British Journal of Anaesthesia , 120 (2) pp. 284-290. 10.1016/j.bja.2017.11.077 .

http://ift.tt/2Ef17cj

Work-Home Boundaries and Communication Technologies

Cecchinato, M; Cox, AL; (2017) Work-Home Boundaries and Communication Technologies. Presented at: ESRC Ways of Being in the Digital Age Conference, Liverpool, United Kingdom.

http://ift.tt/2C8ewgf

The myth of Persephone as a representation of the death drive

Kontou, Charis; (2018) The myth of Persephone as a representation of the death drive. Doctoral thesis (Ph.D), UCL (University College London).

http://ift.tt/2EghOUH

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

Malek, N; Weil, RS; Bresner, C; Lawton, MA; Grosset, KA; Tan, M; Bajaj, N; ... PRoBaND clinical consortium, ; + view all Malek, N; Weil, RS; Bresner, C; Lawton, MA; Grosset, KA; Tan, M; Bajaj, N; Barker, RA; Burn, DJ; Foltynie, T; Hardy, J; Wood, NW; Ben-Shlomo, Y; Williams, NW; Grosset, DG; Morris, HR; PRoBaND clinical consortium, ; - view fewer (2018) Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study. J Neurol Neurosurg Psychiatry 10.1136/jnnp-2017-317348 . (In press). Green open access

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Role of the complement factor H-related protein 5 in renal disease by protein expression and molecular solution structural studies

Kadkhodayi-Kholghi, Nilufar; (2018) Role of the complement factor H-related protein 5 in renal disease by protein expression and molecular solution structural studies. Doctoral thesis (Ph.D), UCL (University College London).

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Current status of surgical incisions used in donors during living related liver transplantation – a nationwide survey in Japan

AbstractBackgroundSmaller surgical incisions have recently been introduced in living donor liver procurement. This study used national data from Japan to clarify the present status of surgical incisions in living donor liver procurement.MethodsA nationwide, questionnaire-based survey related to 3121 donors and recipients was used. Donors were divided into two groups: left lateral segment graft (LLSG) procurement (n=690) and other types (n=2431). Incisions were classified into six types: type I, upper midline and bilateral subcostal; type II, upper midline and right subcostal; type III: upper midline and right subcostal to the right lateral margin of the abdominal rectus muscle; type IV, upper midline without laparoscopy; type V, upper midline with laparoscopy; and type VI, lower abdominal using the full laparoscopic technique. Types I, II, and III were regarded as standard, and types IV, V, and VI as small incisions.ResultsIn LLSGs, blood transfusion and postoperative complication rates were significantly less frequent in the small incision group than in the standard group. In other graft types, there were no significant differences in blood transfusion, postoperative complication, and recipients' graft loss rates. The rates of wound extension during surgery were 2.8% and 2.1% in the small incision group in LLSGs and in other graft types, respectively. A small incision was adopted more frequently and postoperative complications were less common in high-volume centers.ConclusionsVarious incisions have been adopted in living donor liver procurement. Donor safety and graft integrity appear to have been retained for donors receiving small incisions. Background Smaller surgical incisions have recently been introduced in living donor liver procurement. This study used national data from Japan to clarify the present status of surgical incisions in living donor liver procurement. Methods A nationwide, questionnaire-based survey related to 3121 donors and recipients was used. Donors were divided into two groups: left lateral segment graft (LLSG) procurement (n=690) and other types (n=2431). Incisions were classified into six types: type I, upper midline and bilateral subcostal; type II, upper midline and right subcostal; type III: upper midline and right subcostal to the right lateral margin of the abdominal rectus muscle; type IV, upper midline without laparoscopy; type V, upper midline with laparoscopy; and type VI, lower abdominal using the full laparoscopic technique. Types I, II, and III were regarded as standard, and types IV, V, and VI as small incisions. Results In LLSGs, blood transfusion and postoperative complication rates were significantly less frequent in the small incision group than in the standard group. In other graft types, there were no significant differences in blood transfusion, postoperative complication, and recipients' graft loss rates. The rates of wound extension during surgery were 2.8% and 2.1% in the small incision group in LLSGs and in other graft types, respectively. A small incision was adopted more frequently and postoperative complications were less common in high-volume centers. Conclusions Various incisions have been adopted in living donor liver procurement. Donor safety and graft integrity appear to have been retained for donors receiving small incisions. Correspondence: Ken Shirabe, MD, PhD, Department of Hepatobiliary and Pancreatic Surgery, Gunma University, 3-39-22 Showa Machi, Maebashi, Gunma 371-8511, Japan. E-mail: kshirabe@gunma-u.ac.jp Authorship Ken Shirabe • Participated in research design • Participated in the writing of the paper • Participated in the performance of the research • Contributed new reagents or analytic tools • Participated in data analysis Susumu Eguchi • Participated in research design • Participated in the writing of the paper • Participated in the performance of the research • Participated in data analysis Hideaki Okajima • Participated in research design • Participated in the writing of the paper • Participated in the performance of the research Kiyoshi Hasegawa • Participated in research design • Participated in the writing of the paper • Participated in data analysis Shigeru Marubashi • Participated in research design • Participated in the writing of the paper • Participated in the performance of the research • Participated in data analysis Koji Umeshita • Participated in research design • Participated in the writing of the paper Seiji Kawasaki • Participated in research design Katsuhiko Yanaga • Participated in research design Mitsuo Shimada • Participated in research design • Participated in the writing of the paper Toshimi Kaido • Participated in research design • Participated in the writing of the paper Naoki Kawagishi • Participated in research design Akinobu Taketomi • Participated in research design • Participated in data analysis Koichi Mizuta • Participated in research design Norihiro Kokudo • Participated in research design • Participated in the writing of the paper Shinji Uemoto • Participated in research design • Participated in the writing of the paper Yoshihiko Maehara • Participated in research design • Participated in the writing of the paper Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Extracellular vesicles from human liver stem cells reduce injury in an ex vivo normothermic hypoxic rat liver perfusion model

ABSTRACTBackgroundThe gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV).MethodsWe established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused during 4 hours without (control group, n=10) or with HLSC-EV (treated group, n=9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, ALT, LDH). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by TUNEL assay, and tissue HIF-1α and TGF-β1 RNA expression by quantitative RT-PCR.ResultsDuring hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (p=0.018) and LDH (p=0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (p=0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes and EV treatment significantly reduced histological damage (p=0.030), apoptosis (p=0.049), and RNA over-expression of HIF-1α (p

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Establishment and validation of Galleria mellonella as a novel model organism to study Mycobacterium abscessus infection, pathogenesis and treatment. [PublishAheadOfPrint]

Introduction: Treatment of Mycobacterium abscessus infections is extremely challenging due to its intrinsic resistance to most antibiotics, and research of pathogenesis is limited due to a lack of a practical in vivo model of infection.

Objectives: To establish a simple in-vivo model for M. abscessus infection, virulence, and drug testing in G. mellonella larvae.

Methods: We inoculated larvae with M. abscessus, and followed histopathology, CFU count and mortality with and without antibiotic treatment. We also constructed a luminescent, recombinant M. abscesssus, mDB158, and imaged infected larvae using IVIS®.

Results: M. abscessus proliferated and induced granulomatous-like responses in infected larvae leading to larval mortality. The G. mellonella model was further successfully validated by demonstration of the expected favorable antimicrobial effect of treatment with meropenem, and the superiority of combination treatment (meropenem and tigecycline) over single agents. We then used IVIS® imaging of larvae infected with luminescent M. abscessus, allowing live real-time assessment of bacterial load. We used this method to compare the antimicrobial effect of various antibiotics (meropemen, amikacin, linezolid, levofloxacin, etc.) on bacterial proliferation and larval survival. Meropenem and amikacin had the most favorable effect, correlating well with common clinical practice guidelines.

Conclusions: These findings suggest G. mellonella to be an excellent in vivo model for research of M. abscessus infection, pathogenesis and treatment. Luminescent M. abscessus and IVIS® imaging further facilitates this model. Results obtained in this model clearly substantiated common clinical practice, thus validating the model as a predictor of treatment efficacy and outcome.

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Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity [PublishAheadOfPrint]

In substitution for the current Chagas disease treatment with several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, the balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, where a pro-inflammatory microenvironment modulated by IL-10 is shown to be relevant to potentiate anti-Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activity of the anti-T. cruzi K777, Pyronaridine (PYR) and Furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected subjects (NI) and chronic Chagas disease patients (CD). Our results showed low cytotoxicity to PBMC populations, with CC₅₀ = 13.1μM (K777); 9.0μM (PYR) and greater than 20μM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent pro-inflammatory response (TNF-α⁺CD8⁺/CD4⁺, IFN-⁺CD4⁺/CD8⁺ modulated by IL-10 (IL-10⁺CD4⁺T/CD8⁺T) in comparison with PYR (TNF-α⁺CD8⁺, IL-10⁺CD8⁺) and FUR (TNF-α⁺CD8⁺, IL-10⁺CD8⁺). Signature analysis of intracytoplasmic cytokines corroborated with the proinflammatory/modulated (K777) and pro-inflammatory (PYR and FUR) profiles previously found. In conclusion, K777 lead compound may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease.

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Time to Multidrug-Resistant Tuberculosis Treatment Initiation in Association with Treatment Outcomes in Shanghai, China [PublishAheadOfPrint]

In high TB-burden countries like China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate treatment. The purpose of this study was to investigate the time to MDR-TB treatment initiation, and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based, retrospective cohort study collected the demographic and clinical characteristics, and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. Dates of TB and MDR-TB diagnoses, DST performing and treatment initiation were extracted to calculate the time to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatment initiated within 60 days after DST performing (OR 2.56, 95% CI 1.22-5.36) and empiric treatment (OR 2.09, 95% CI 1.01-4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and, improvements should be made in patient management and information linkage to reduce treatment delay.

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Short proline-rich lipopeptide potentiates minocycline and rifampicin against multidrug- and extensively drug-resistant Pseudomonas aeruginosa. [PublishAheadOfPrint]

A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally-existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C16) possess optimal antibacterial activity relative to others with shorter lipid component. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Pseudomonas aeruginosa. Out of sixteen prepared SPRLPs, C12-PRP was found to significantly potentiate the antibiotics minocycline and rifampicin against multidrug- and extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. This non-hemolytic C12-PRP is comprised of a heptapeptide sequence PRPRPRP-NH₂ acylated to dodecanoic acid (C12) at the N-terminus. The adjuvant potency of C12-PRP was apparent by its ability to reduce the minimum inhibitory concentration of minocycline and rifampicin below their interpretative susceptibility breakpoints against MDR/XDR P. aeruginosa. An attempt to optimize C12-PRP through peptidomimetic modification was performed by replacing all L- to D-amino acids. C12-PRP demonstrated pliability to optimization as synergism with minocycline and rifampicin were retained. Moreover, C12-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C12-PRP is a lead adjuvant candidate that warrants further optimization. Discovery of agents that are able to resuscitate activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially P. aeruginosa are of great clinical interest.

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High genetic plasticity in multidrug resistant ST3-IncHI2 plasmids revealed by sequence comparison and phylogenetic analysis [PublishAheadOfPrint]

We report a novel fusion plasmid pP2-3T co-integrating ST3-IncHI2 with IncFII plasmid backbone mediating multidrug resistance and virulence. Phylogenetic analysis and comparative genomic revealed that pP2-3T and other MDR ST3-IncHI2 plasmids clustered together representing a unique IncHI2 lineage that exhibited high conservation in backbones of plasmid, but possessed highly genetic plasticity in variable regions via acquiring numerous ARGs and fusing with other plasmids. Surveillance studies should be taken to monitor multiresistance IncHI2 plasmids among Enterobacteriaceae.

http://ift.tt/2nWtPnc

A Novel Rabbit Spirometry Model of Type E Botulism and its Use for the Evaluation of Post-symptom Antitoxin Efficacy [PublishAheadOfPrint]

Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time post-intoxication regardless of symptoms. This is most likely due to the difficulty to measure early symptoms of botulism in animals. In the current study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as trigger for treatment. Impaired respiration, in the form of reduced minute volume, was detected as early as 18.1±2.9 hours post-intramuscular exposure to 2 rabbit lethal dose fifty (LD₅₀) of BoNT/E, preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Post-symptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosage as well as to delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins in additional serotypes of BoNT as well as that of next generation anti-BoNT drugs.

http://ift.tt/2nLKcnl

Posaconazole MIC distributions for Aspergillus fumigatus SC by four methods: Impact of Cyp51A mutations on estimation of epidemiological cutoff values (ECVs/ECOFFs) [PublishAheadOfPrint]

Estimating epidemiological cutoff endpoints (ECVs/ECOFFS) may be hindered by the overlap of MICs for mutant and non-mutant strains (harboring or not harboring mutations, respectively). Posaconazole MIC distributions for Aspergillus fumigatus SC were collected from 26 laboratories (Australia, Canada, Europe, India, South/North America, Taiwan) and published studies. Distributions that fulfilled CLSI criteria were pooled and ECVs were estimated. The sensitivity of three ECV analytical techniques (ECOFFinder, NRI, derivatization) to the inclusion of MICs for mutants was examined for three susceptibility testing methods (CLSI, EUCAST, and Etest®). The totals of posaconazole MICs for non-mutant (no known cyp51A mutations) and mutant A. fumigatus isolates were: by CLSI, 2,223 and 274; by EUCAST, 556 and 52; by the Etest®, 1,365 and 29 respectively; 381 Sensititre™ YeastOne™ (SYO) MICs with unknown mutational status were also evaluated. We observed an overlap in posaconazole MICs among non-mutant and cyp51A mutants. At the commonly chosen percentage of the modeled wild-type population (97.5%), almost all ECVs remained the same when the MICs for non-mutant and mutant distributions were merged: ECOFFinder ECVs 0.5 μg/ml (CLSI) and 0.25 μg/ml (EUCAST and Etest®); NRI ECVs: 0.5 μg/ml for all three methods. However, the 95% ECOFFinder CLSI ECV for non-mutants was 0.25 μg/ml. The tentative SYO ECOFFinder ECV was 0.06 μg/ml (data from 3/8 laboratories). Derivatization ECVs with or without mutant inclusion were either 0.25 μg/ml (CLSI, EUCAST, Etest) or 0.06 μg/ml (SYO). It appears that ECV analytical techniques may not be vulnerable to overlap between presumptive wild-type and cyp51A mutants when up to 11.6% of the estimated wild-type population includes mutants.

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In vivo transfer and microevolution of avian native IncA/C2 blaNDM-1-carrying plasmid pRH-1238 during a broiler chicken infection study [PublishAheadOfPrint]

The emergence and spread of carbapenemase-producing Enterobacteriaceae (CPE) in wildlife and livestock animals poses an important safety concern for public health. With our in vivo broiler chicken infection study we investigated transfer and experimental microevolution of the bla_NDM-1-carrying IncA/C₂ plasmid (pRH-1238) introduced by avian native Salmonella (S.) Corvallis, without inducing antibiotic selection pressure. We evaluated dependency of the time point of inoculation on donor [S. Corvallis (12-SA01738)] and a plasmid-free Salmonella spp. recipient [S. Paratyphi B (dTa+), 13-SA01617] excretion by quantifying their excretion dynamics. Using S1-PFGE plasmid profiling we gained insight into the variability of native plasmid content among S. Corvallis reisolates as well plasmid acquisition in S. Paratyphi B (dTa+) and enterobacterial gut microflora. Whole genome sequencing enabled us an in-depth insight into microevolution of pRH-1238 plasmid in S. Corvallis and enterobacterial recipient isolates. Our study revealed that the fecal excretion of avian native carbapenemase-producing S. Corvallis is significantly higher and not hampered by S. Paratyphi (dTa+). Acquisition of pRH-1238 in other Enterobacteriaceae and several transfer events of pRH-1238 plasmid to different E. coli sequence types and Klebsiella pneumoniae demonstrate interspecies broad-host range. Regardless of the microevolutionary structural deletions in pRH-1238, the single carbapenem resistance marker, bla_NDM-1, was maintained on pRH-1238 throughout the trial. Furthermore, we showed the importance of the gut E. coli population as vector of pRH-1238. In a potential scenario of NDM-1-producing S. Corvallis introduced into a broiler flock, the pRH-1238 plasmid can persist and spread to a broad-host range even in absence of antibiotic pressure.

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Synergy between pyrvinium pamoate and azoles against Exophiala dermatitidis [PublishAheadOfPrint]

The black yeast Exophiala dermatitidis causes phaeohyphomycosis in both immunocompetent individuals and immunosuppressed patients, resulting in localized cutaneous and subcutaneous infections to more severe systemic forms such as neurotropic infections (1-3)....

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Penetration of cefotaxime into cerebrospinal fluid in neonates and young infants [PublishAheadOfPrint]

Objective: Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study is to evaluate the penetration of cefotaxime into CSF in neonates and young infants.

Methods: Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy and concentrations were quantified by HPLC-MS/MS. The analysis was performed using NONMEM and R software.

Results: Thirty neonates and young infants (PMA range: 25.4-47.4 weeks) were included. A total of 67 plasma and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter, and from 0.39 to 25.38 mg/liter, respectively. The median ratio of CSF to plasma concentrations was 0.28 (range 0.06-0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg TID would reach the pharmacodynamic target (70% fT>MIC) using the standard EUCAST MIC susceptibility breakpoint of 2 mg/liter and 4 mg/liter, respectively.

Conclusion: The penatration of cefotaxime into CSF was evaluted in neonates and young infants using an opportunistic sampling appoarch. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MIC<2 mg/liter. The individual dosage adaptation was required for more resistant bacterial strains such as Staphylococcus aureus.

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Pharmacokinetics and safety of intravenous Murepavadin infusion in healthy adult subjects administered as Single and Multiple ascending doses. [PublishAheadOfPrint]

Murepavadin is the first in class of Outer Membrane Protein Targeting Antibiotics (OMPTA) which is a pathogen specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa. Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A was a double-blind, randomized, placebo-controlled, single ascending dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple ascending dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean for half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 mL/h/kg), and the volume of distribution (415 to 724 mL/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated and adverse events were transient and generally mild and no dose-limiting toxicity was identified.

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Azole resistance of Aspergillus fumigatus isolates from the environment and the clinic in Switzerland [PublishAheadOfPrint]

Aspergillus fumigatus is an ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target (cyp51A). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example TR34/L98H) have been described. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported in several continents. Here we describe for the first time the occurrence of azole-resistant A. fumigatus isolates from environmental origin in Switzerland with cyp51A mutations and show that they can be also recovered from a few patients. While the TR34/L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was only described from clinical isolates. In conclusion, our study demonstrates that azole resistance with environmental signature is present in environments and patients from Swiss origins and that mutations believed as unique to clinical settings are now also observed in the environment.

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Antifungal susceptibility of the Aspergillus viridinutans complex: comparison of two in vitro methods [PublishAheadOfPrint]

Cryptic species of Aspergillus fumigatus, including the Aspergillus viridinutans species complex, are increasingly reported as a cause of invasive aspergillosis. Their identification is clinically relevant as these species frequently have intrinsic resistance to common antifungals. We evaluated susceptibilities of 90 environmental and clinical isolates from the A. viridinutans species complex, identified by DNA sequencing of the calmodulin gene, to seven antifungals (voriconazole, posaconazole, itraconazole, amphotericin B, anidulafungin, micafungin and caspofungin) using the reference European Committee on Antimicrobial Susceptibility testing (EUCAST) method. The majority of species demonstrated elevated MICs of voriconazole (geometric mean, GM: 4.46 mg/l) and itraconazole (GM: 9.85 mg/l), and had variable susceptibility to amphotericin B (GM: 2.5 mg/l). Overall, the MICs of posaconazole and MECs of echinocandins were low. The EUCAST results were compared with the Sensititre YeastOne (YO) panels. Overall, there was 67% agreement (95% confidence interval, CI: 62–72%) between EUCAST and YO panels when read at 48 hours and 82% (95% CI: 78–86%) at 72 hours. There was a significant difference in agreement between antifungals; agreement was high for amphotericin B, voriconazole and posaconazole (70–86% at 48 hours and 88–93% at 72 hours), but was very low for itraconazole (37% at 48 hours and 57% at 72 hours). The agreement was also variable between species with the maximum agreement observed for A. felis isolates (85 and 93% at 48 and 72 hours, respectively). Elevated MICs of voriconazole and itraconazole were cross-correlated but there was no correlation between other azoles tested.

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Optimization of a meropenem plus tobramycin combination dosage regimen against hypermutable and non-hypermutable Pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model [PublishAheadOfPrint]

Objectives: Hypermutable Pseudomonas aeruginosa are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM).

Methods: The PAO1 wild-type strain and its isogenic hypermutable PAOmutS strain (MIC_meropenem 1.0 mg/liter, MIC_tobramycin 0.5 mg/liter, for both) were assessed using 96-h static concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum ~10^8.4 CFU/ml). MBM of SCTK data was performed to predict expected HFIM outcomes. Regimens studied in the HFIM were: meropenem 1 g 8-hourly (0.5h infusion), meropenem 3 g/day continuous infusion, tobramycin 10 mg/kg 24-hourly (1h infusion) and both combinations; meropenem regimens delivered the same total daily dose. Time-courses of total and less-susceptible populations and MICs were determined.

Results: For PAOmutS in the HFIM, all monotherapies resulted in rapid regrowth to >10^8.7 CFU/ml with near complete replacement by less-susceptible bacteria by day 3. Meropenem 8-hourly with tobramycin caused >7-log₁₀ bacterial killing followed by regrowth to >6-log₁₀ CFU/ml by day 5 and high-level resistance (MIC_meropenem 32 mg/liter, MIC_tobramycin 8 mg/liter). Continuous infusion meropenem with tobramycin achieved >8-log₁₀ bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4-log₁₀ over 7-9 days, with both combination regimens achieving near eradication.

Conclusions: A MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

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The Novel Fungal Cyp51 Inhibitor VT-1598 is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis [PublishAheadOfPrint]

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungal-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of CNS coccidioidomycosis caused C. posadasii and C. immitis. Infection was introduced via intracranial inoculation, and therapy began 48 hours post-inoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 hours post-treatment in the fungal burden studies, and on the days the mice succumbed to infection or at the pre-specified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, fungal burden was significantly reduced in the fungal burden studies. Plasma concentrations 48 hours after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week wash-out. Whereas fungal burden remained suppressed after a 2-week wash-out in the C. immitis model, higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.

http://ift.tt/2nVXWey

Prophylactic anti-heparanase activity by PG545 is anti-viral in vitro and protects against Ross River virus disease in mice [PublishAheadOfPrint]

Recently we reported on the efficacy of pentosan polysulfate (PPS), a heparan sulfate mimetic, to reduce the recruitment of inflammatory infiltrates and protect the cartilage matrix from degradation in Ross River virus (RRV) infected PPS--treated mice. Herein, we describe both prophylactic and therapeutic treatment with PG545, a low molecular weight heparan sulfate mimetic, for arthritogenic alphaviral infection. We first assessed anti-viral activity in vitro, through a 50% plaque reduction (IC₅₀) assay. Increasing concentrations of PG545, inhibited plaque formation prior to viral adsorption in viral strains; RRV T48, Barmah forest virus 2193 (BFV 2193), chikungunya East/Central/South African virus (CHIKV ESCA) and CHIKV Asian strain, suggesting a strong anti-viral mode of action. The viral particle--compound dissociation constant (K_D) was then evaluated through isothermal titration calorimetry (ITC). Furthermore, prophylactic RRV-infected PG545-treated mice had reduced viral titres in target organs corresponding to lower clinical scores of limb weakness and immune infiltrate recruitment. At peak disease, PG545-treated RRV-infected mice had lower concentrations of the matrix degrading enzyme heparanase (HPSE) in conjunction with a protective effect on tissue morphology as seen in the histopathology of skeletal muscle. ELISA quantification of cartilage oligomeric matrix protein (COMP) and crosslinked C-telopeptides of type II collagen (CTX-II) and knee histopathology showed increased matrix protein degradation and cartilage erosion in RRV-infected PBS-treated mice in comparison to their PG545-treated RRV infected counterparts. Taken together these findings suggest that PG545 may have a both a direct anti-viral effect on arthritogenic alphaviral infection, as well curtailing RRV-induced inflammatory disease when administered as a prophylaxis.

http://ift.tt/2nO7jxy

Compounds with potential activity against Mycobacterium tuberculosis [PublishAheadOfPrint]

The high acquisition of drug resistance by Mycobacterium tuberculosis necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high throughput screening of compounds against thiol-deficient M. smegmatis strains and subsequent validations with thiol-deficient M. tuberculosis strains, revealed that egtA and mshA mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su), egtB and egtE mutants had increased susceptibility to bacitracin (Ba) and egtA, mshA, and egtB mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the level of thiols and oxidative stress in M. tuberculosis. This study indicates the activity of Aza, Su, Fu and Ba against M. tuberculosis and provide a rationale for further investigations.

http://ift.tt/2nV3OVm

Development of echinocandin resistance in Candida tropicalis following short-term exposure to caspofungin for empiric therapy [PublishAheadOfPrint]

Isolation of two echinocandin-resistant Candida tropicalis strains from endotracheal secretions of a patient, following short-term exposure to caspofungin, is described. Both strains exhibited resistance to echinocandins by Etest and reference broth microdilution, showing a homozygous S645P mutation within hot-spot (HS)-1 region of FKS1 and belonging to a unique multilocus sequence type. Other C. tropicalis isolates collected from the same intensive care unit patients within a 60-day-period were susceptible to echinocandins and contained wild-type FKS1 sequences

http://ift.tt/2nO0eNr

Feasibility of Salvage Selective Neck Dissection after Primary Irradiation of Pharyngeal and Laryngeal Carcinoma

Introduction: The concept of neck dissection (ND) in the management armamentarium of head and neck squamous cell carcinoma has evolved throughout the years. Nowadays, ND becomes more functional. Methodology: A retrospective study of 865 patients was performed at Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital to investigate the feasibility of selective ND (SND). All patients with squamous cell carcinoma of the pharynx and larynx who received primary radiation and underwent salvage ND were included in the study. Result: A total of 29 NDs were analyzed. In 17 neck sides, viable metastases were found (58%), whereas in the other 12 specimens there were no viable metastases. In 16 of the 17 necks (94%), the metastases were located either in level II, III, or IV or in a combination of these 3 levels. Level V was involved in only 1 case (6%). Conclusion: It is well justified to perform a salvage SND (levels II, III, and IV) for pharyngeal and laryngeal carcinoma after primary radiation. In carefully selected cases of supraglottic and oropharyngeal carcinoma, a superselective ND also appears as an efficient option.
ORL 2018;80:10–18

http://ift.tt/2H3OUVg

In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

Ogunlade, O; Connell, JJ; Huang, JL; Zhang, E; Lythgoe, MF; Long, DA; Beard, P; (2017) In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models. American Journal of Physiology - Renal Physiology 10.1152/ajprenal.00337.2017 . (In press). Green open access

http://ift.tt/2BNFxdk

Encounter and its configurational logic: Understanding spatiotemporal co-presence with road network and social media check-in data

Shen, Y; Karimi, K; Law, S; (2017) Encounter and its configurational logic: Understanding spatiotemporal co-presence with road network and social media check-in data. In: Proceedings of the 11th Space Syntax Symposium. (pp. 111.1-111.22). Instituto Superior Técnico, Portugal: Lisbon, Portugal. Green open access

http://ift.tt/2BNFle6

Aging-associated renal disease in mice is fructokinase dependent

Roncal-Jimenez, CA; Ishimoto, T; Lanaspa, MA; Milagres, T; Hernando, AA; Jensen, T; Miyazaki, M; ... Johnson, RJ; + view all Roncal-Jimenez, CA; Ishimoto, T; Lanaspa, MA; Milagres, T; Hernando, AA; Jensen, T; Miyazaki, M; Doke, T; Hayasaki, T; Nakagawa, T; Marumaya, S; Long, DA; Garcia, GE; Kuwabara, M; Sanchez-Lozada, LG; Kang, D-H; Johnson, RJ; - view fewer (2016) Aging-associated renal disease in mice is fructokinase dependent. American Journal of Physiology - Renal Physiology , 311 (4) F722-F730. 10.1152/ajprenal.00306.2016 . Green open access

http://ift.tt/2BNF7Ui

The sum of the parts is greater than the whole: Multi-scalar socio-spatial definitions of identity in Karachi's Muhajir majority areas

Khan, SS; Karimi, K; (2017) The sum of the parts is greater than the whole: Multi-scalar socio-spatial definitions of identity in Karachi's Muhajir majority areas. In: Proceedings of the 11th Space Syntax Symposium. (pp. 147.1-147.13). Instituto Superior Técnico, Portugal: Lisbon, Portugal. Green open access

http://ift.tt/2Bl2Iut

The economic value of spatial network accessibility for UK cities: A comparative analysis using the hedonic price approach

Law, S; Penn, A; Karimi, K; Shen, Y; (2017) The economic value of spatial network accessibility for UK cities: A comparative analysis using the hedonic price approach. In: Proceedings of the 11th Space Syntax Symposium. (pp. 77.1-77.23). Instituto Superior Técnico, Portugal: Lisbon, Portugal. Green open access

http://ift.tt/2Bk3zLJ

Exploring the functional landscape of the fission yeast genome via Hermes transposon mutagenesis

Grech, L; (2018) Exploring the functional landscape of the fission yeast genome via Hermes transposon mutagenesis. Doctoral thesis (Ph.D), UCL (University College London).

http://ift.tt/2BN4RzR

A Humean account of laws and causation

Friend, Toby; (2018) A Humean account of laws and causation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2BQHfdC

Competitiveness and Climate Change Mitigation – Empirical Evidence on the Effects of Material Use and Material Productivity on Competitiveness and Greenhouse Gas Emissions in Europe

Flachenecker, Florian; (2018) Competitiveness and Climate Change Mitigation – Empirical Evidence on the Effects of Material Use and Material Productivity on Competitiveness and Greenhouse Gas Emissions in Europe. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2BhQthY

Candidate Turnover as a Measure of Party Change

Sikk, A; Koeker, P; (2017) Candidate Turnover as a Measure of Party Change. Presented at: APSA Annual Meeting, San Francisco, California.

http://ift.tt/2BPWSCk

Genetic functional studies of low density lipoprotein- cholesterol (LDL-C) associated variants and the genetic spectrum of familial hypercholesterolemia in different ethnic groups

Fairoozy, Roaa Hani; (2018) Genetic functional studies of low density lipoprotein- cholesterol (LDL-C) associated variants and the genetic spectrum of familial hypercholesterolemia in different ethnic groups. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2BjKQ2S

Incorporating homeowners' preferences of heating technologies in the UK TIMES model

Li, P; Keppo, I; Strachan, N; (2018) Incorporating homeowners' preferences of heating technologies in the UK TIMES model. Energy 10.1016/j.energy.2018.01.150 . (In press). Green open access

http://ift.tt/2BNeI8Z

Estimating effectiveness of components of a smartphone app – Drink Less – to reduce excessive alcohol consumption

Garnett, CV; Crane, D; Brown, J; West, R; Michie, S; (2017) Estimating effectiveness of components of a smartphone app – Drink Less – to reduce excessive alcohol consumption. Presented at: INEBRIA Annual Conference, New York, NY, USA. Green open access

http://ift.tt/2Bks4sj

Modelling Real-Time Pricing Demand Response in a Long-Term Whole Energy System Model, UK TIMES

Li, P; Pye, S; (2017) Modelling Real-Time Pricing Demand Response in a Long-Term Whole Energy System Model, UK TIMES. In: (Proceedings) The 40th IAEE International Conference. IAEE (In press).

http://ift.tt/2BQd4n7

Assessing changes within the lumbosacral spinal cord in Multiple System Atrophy with lower urinary tract symptoms: preliminary results of a pilot in vivo MRI study

Liechti, MD; Yiannakas, MC; Toosy, A; Yang, X; Miller, DH; Houlden, H; Wheeler-Kingshott, C; Liechti, MD; Yiannakas, MC; Toosy, A; Yang, X; Miller, DH; Houlden, H; Wheeler-Kingshott, C; Panicker, J; - view fewer (2016) Assessing changes within the lumbosacral spinal cord in Multiple System Atrophy with lower urinary tract symptoms: preliminary results of a pilot in vivo MRI study. Presented at: 5th International Congress on Multiple System Atrophy, Salerno, Italy.

http://ift.tt/2BiN2I0

Mapping the Enlightenment: Intellectual Networks and the Making of Knowledge in the European Periphery

Routsis, V; Goudarouli, E; Patiniotis, M; (2017) Mapping the Enlightenment: Intellectual Networks and the Making of Knowledge in the European Periphery. Presented at: Digital Humanities 2017 Conference, Montreal, Canada.

http://ift.tt/2BNQpaS

The relationship between cortical beta oscillations and motor learning

Espenhahn, Svenja; (2018) The relationship between cortical beta oscillations and motor learning. Doctoral thesis (Ph.D), UCL (University College London). Green open access

http://ift.tt/2BjSIBm

Cellularity of Thymic Epithelial Cells in the Postnatal Mouse [IMMUNE SYSTEM DEVELOPMENT]

The molecular and cellular biology of thymic epithelial cells (TECs) often relies on the analysis of TECs isolated in enzymatically digested single-cell suspensions derived from mouse thymus. Many independent studies have reported that the estimated cellularity of total TECs isolated from one adult mouse is on the order of up to 10⁵. However, these numbers appear extremely small given that the cellularity of total thymocytes exceeds 10⁸ and that TECs play multiple roles in thymocyte development and repertoire formation. In the present study, we aimed to measure the numbers of β5t-expressing cortical TECs and Aire-expressing medullary TECs in postnatal mouse thymus in situ without enzymatic digestion. The numbers of these TECs were manually counted in individual thymic sections and were three-dimensionally summed throughout the entire thymic lobes. The results show that the cellularity of total TECs in one 5-wk-old female mouse exceeds 10⁶, containing ~9 x 10⁵ β5t⁺ cortical TECs and ~1.1 x 10⁶ Aire⁺ medullary TECs. These results suggest that the use of conventional enzymatic digestion methods for the isolation of TECs may have resulted in the underestimation of the cellularity, and possibly the biology, of TECs.

http://ift.tt/2EgYwKN

Multiple Levels of Control Determine How E4bp4/Nfil3 Regulates NK Cell Development [IMMUNE SYSTEM DEVELOPMENT]

The transcription factor E4bp4/Nfil3 has been shown to have a critical role in the development of all innate lymphoid cell types including NK cells. In this study, we show that posttranslational modifications of E4bp4 by either SUMOylation or phosphorylation have profound effects on both E4bp4 function and NK cell development. We examined the activity of E4bp4 mutants lacking posttranslational modifications and found that Notch1 was a novel E4bp4 target gene. We observed that abrogation of Notch signaling impeded NK cell production and the total lack of NK cell development from E4bp4^–/– progenitors was completely rescued by short exposure to Notch peptide ligands. This work reveals both novel mechanisms in NK cell development by a transcriptional network including E4bp4 with Notch, and that E4bp4 is a central hub to process extrinsic stimuli.

http://ift.tt/2EQxWJu

Correction: A Plant-Derived Nucleic Acid Reconciles Type I IFN and a Pyroptotic-like Event in Immunity against Respiratory Viruses [CORRECTIONS]

http://ift.tt/2EfoyxZ

An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells [TUMOR IMMUNOLOGY]

Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8⁺ and CD4⁺ T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8⁺ CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8⁺ CTLs. Further, Eomes and Runx3 were indispensable for dual-costimulated CD4 T cells to mediate antitumor activity in an aggressive melanoma model. Runx3 is also known to be expressed in standard CD4 Th1 cells where it fosters IFN- expression; however, the CD4 T cell lineage commitment factor ThPOK represses transcription of Eomes and other CD8 lineage genes, such as Cd8a. Hence, CD4 T cells can differentiate into Eomes⁺ cytotoxic CD4⁺CD8⁺ double-positive T cells by terminating ThPOK expression. In contrast, dual-costimulated CD4 T cells express Eomes, despite the continued expression of ThPOK and the absence of CD8α, indicating that Eomes is selectively released from ThPOK repression. Finally, although Eomes was induced by CD137 agonist, but not CD134 agonist, administered individually, CD137 agonist failed to induce CD134^–/– CD4 T cells to express Eomes or Runx3, indicating that both costimulatory pathways are required for cytotoxic Th1 programming, even when only CD137 is intentionally engaged with a therapeutic agonist.

http://ift.tt/2EUmGvO

Correction: Virtual Sorting Has a Distinctive Advantage in Identification of Anticorrelated Genes and Further Negative Regulators of Immune Cell Subpopulations [CORRECTIONS]

http://ift.tt/2EQxNFW

Novel Transcriptional Activity and Extensive Allelic Imbalance in the Human MHC Region [SYSTEMS IMMUNOLOGY]

The MHC region encodes HLA genes and is the most complex region in the human genome. The extensively polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein-coding human endogenous retrovirus genes. We revealed allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Among these variants, the genetic variant associated with Behcet's disease in the HLA-B/MICA region, which tags HLA-B*51, is within novel long intergenic noncoding RNA transcripts that are exclusively expressed from the haplotype with the protective but not the disease risk allele. Further, the transcriptome within the MHC region can be defined by 14 distinct coexpression clusters, with evidence of coregulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.

http://ift.tt/2ESRJYR

IRF1 Is a Transcriptional Regulator of ZBP1 Promoting NLRP3 Inflammasome Activation and Cell Death during Influenza Virus Infection [INNATE IMMUNITY AND INFLAMMATION]

Innate immune sensing of influenza A virus (IAV) induces activation of various immune effector mechanisms, including the nucleotide and oligomerization domain, leucine-rich repeat–containing protein family, pyrin domain containing 3 (NLRP3) inflammasome and programmed cell death pathways. Although type I IFNs are identified as key mediators of inflammatory and cell death responses during IAV infection, the involvement of various IFN-regulated effectors in facilitating these responses are less studied. In this study, we demonstrate the role of IFN regulatory factor (IRF)1 in promoting NLRP3 inflammasome activation and cell death during IAV infection. Both inflammasome-dependent responses and induction of apoptosis and necroptosis are reduced in cells lacking IRF1 infected with IAV. The observed reduction in inflammasome activation and cell death in IRF1-deficient cells during IAV infection correlates with reduced levels of Z-DNA binding protein 1 (ZBP1), a key molecule mediating IAV-induced inflammatory and cell death responses. We further demonstrate IRF1 as a transcriptional regulator of ZBP1. Overall, our study identified IRF1 as an upstream regulator of NLRP3 inflammasome and cell death during IAV infection and further highlights the complex and multilayered regulation of key molecules controlling inflammatory response and cell fate decisions during infections.

http://ift.tt/2EgYoLj

Simultaneous Recognition of Allogeneic MHC and Cognate Autoantigen by Autoreactive T Cells in Transplant Rejection [TRANSPLANTATION]

The autoimmune condition is a primary obstacle to inducing tolerance in type 1 diabetes patients receiving allogeneic pancreas transplants. It is unknown how autoreactive T cells that recognize self-MHC molecules contribute to MHC-disparate allograft rejection. In this report, we show the presence and accumulation of dual-reactive, that is autoreactive and alloreactive, T cells in C3H islet allografts that were transplanted into autoimmune diabetic NOD mice. Using high-throughput sequencing, we discovered that T cells prevalent in allografts share identical TCRs with autoreactive T cells present in pancreatic islets. T cells expressing TCRs that are enriched in allograft lesions recognized C3H MHC molecules, and five of six cell lines expressing these TCRs were also reactive to NOD islet cells. These results reveal the presence of autoreactive T cells that mediate cross-reactive alloreactivity, and indicate a requirement for regulating such dual-reactive T cells in tissue replacement therapies given to autoimmune individuals.

http://ift.tt/2EgYnHf

Staphylococcal Superantigens Use LAMA2 as a Coreceptor To Activate T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Canonical Ag-dependent TCR signaling relies on activation of the src-family tyrosine kinase LCK. However, staphylococcal superantigens can trigger TCR signaling by activating an alternative pathway that is independent of LCK and utilizes a Gα11-containing G protein–coupled receptor (GPCR) leading to PLCβ activation. The molecules linking the superantigen to GPCR signaling are unknown. Using the ligand-receptor capture technology LRC-TriCEPS, we identified LAMA2, the α2 subunit of the extracellular matrix protein laminin, as the coreceptor for staphylococcal superantigens. Complementary binding assays (ELISA, pull-downs, and surface plasmon resonance) provided direct evidence of the interaction between staphylococcal enterotoxin E and LAMA2. Through its G4 domain, LAMA2 mediated the LCK-independent T cell activation by these toxins. Such a coreceptor role of LAMA2 involved a GPCR of the calcium-sensing receptor type because the selective antagonist NPS 2143 inhibited superantigen-induced T cell activation in vitro and delayed the effects of toxic shock syndrome in vivo. Collectively, our data identify LAMA2 as a target of antagonists of staphylococcal superantigens to treat toxic shock syndrome.

http://ift.tt/2EgYrXv

IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis [INFECTIOUS DISEASE AND HOST RESPONSE]

T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4⁺ and CD8⁺ T cells leads to arthritis-promoting IFN-, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non–Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor TLR2 was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell–intrinsic expression of TLR2 contributed to IFN- production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. The IL-10–deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.

http://ift.tt/2ESpFEP

Golgi Phosphoprotein 2 Is a Novel Regulator of IL-12 Production and Macrophage Polarization [INNATE IMMUNITY AND INFLAMMATION]

Golgi phosphoprotein 2 (GOLPH2), a widely expressed Golgi type II transmembrane protein, has been implicated in several important physiological and pathological processes, including virus infections, cancer cell proliferation, and metastasis. However, its biological functions and mechanisms, particularly in the immune system, remain highly obscure. In this study, we report the biochemical identification of GOLPH2 from B cell lymphoma culture supernatant and show that the secreted protein could inhibit IL-12 production by dendritic cells (DCs) and IL-12–induced IFN- production by activated T cells. Further molecular analysis revealed that GOLPH2's IL-12–inhibiting activity was mediated through a proximal IL12p35 promoter element involving a previously identified transcriptional repressor named GC-binding protein that is induced during phagocytosis of apoptotic cells by macrophages. We subsequently generated global golph2 knockout mice, which exhibited little developmental abnormality but were more susceptible to LPS-induced endotoxic shock than were wild-type mice with elevated serum IL-12 levels. Furthermore, we found that GOLPH2 played a regulatory role in macrophage polarization toward the M2 type. A comprehensive analysis of gene expression profiles of activated wild-type and GOLPH2-deficient DCs by RNA sequencing uncovered mechanistic insights into the way GOLPH2 potentially modulates DC function during inflammatory insults. Our functional study of GOLPH2 helps advance the scientific understanding of the biological and pathogenic roles of this novel and intriguing molecule with great potential as a diagnostic and prognostic marker as well as a therapeutic target in many acute and chronic inflammatory disorders.

http://ift.tt/2ES14QE

ISG15-Induced IL-10 Is a Novel Anti-Inflammatory Myeloid Axis Disrupted during Active Tuberculosis [INFECTIOUS DISEASE AND HOST RESPONSE]

IFN-stimulated gene 15 (ISG15) deficiency in humans leads to severe IFNopathies and mycobacterial disease, the latter being previously attributed to its extracellular cytokine-like activity. In this study, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to primary human monocytes. A balanced ISG15-induced monocyte/IL-10 versus lymphoid/IFN- expression, correlating with p38 MAPK and PI3K signaling, was found using targeted in vitro and ex vivo systems analysis of human transcriptomic datasets. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL-10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB, suggesting its potential use as a biomarker, awaiting clinical validation. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB.

http://ift.tt/2EQxTxi

IL-1 Signaling Prevents Alveolar Macrophage Depletion during Influenza and Streptococcus pneumoniae Coinfection [INFECTIOUS DISEASE AND HOST RESPONSE]

Influenza and bacterial coinfection is a significant cause of hospitalization and death in humans during influenza epidemics and pandemics. However, the fundamental protective and pathogenic mechanisms involved in this complex virus–host–bacterium interaction remain incompletely understood. In this study, we have developed mild to lethal influenza and Streptococcus pneumoniae coinfection models for comparative analyses of disease pathogenesis. Specifically, wild-type and IL-1R type 1–deficient (Il1r1^–/–) mice were infected with influenza virus and then superchallenged with noninvasive S. pneumoniae serotype 14 (Spn14) or S. pneumoniae serotype 19A (Spn19A). The coinfections were followed by comparative analyses of inflammatory responses and animal protection. We found that resident alveolar macrophages are efficient in the clearance of both pneumococcal serotypes in the absence of influenza infection; in contrast, they are essential for airway control of Spn14 infection but not Spn19A infection. In agreement, TNF-α and neutrophils play a compensatory protective role in secondary bacterial infection associated with Spn19A; however, the essential requirement for alveolar macrophage–mediated clearance significantly enhances the virulence of Spn14 during postinfluenza pneumococcal infection. Furthermore, we show that, although IL-1 signaling is not required for host defense against pneumococcal infection alone, it is essential for sustaining antibacterial immunity during postinfluenza pneumococcal infection, as evidenced by significantly aggravated bacterial burden and animal mortality in Il1r1^–/– mice. Mechanistically, we show that through preventing alveolar macrophage depletion, inflammatory cytokine IL-1 signaling is critically involved in host resistance to influenza and pneumococcal coinfection.

http://ift.tt/2EgYvGJ

Cleavage of TL1A Differentially Regulates Its Effects on Innate and Adaptive Immune Cells [IMMUNE REGULATION]

TNF superfamily cytokines play major roles in the regulation of adaptive and innate immunity. The TNF superfamily cytokine TL1A (TNFSF15), through its cognate receptor DR3 (TNFRSF25), promotes T cell immunity to pathogens and directly costimulates group 2 and 3 innate lymphoid cells. Polymorphisms in the TNFSF15 gene are associated with the risk for various human diseases, including inflammatory bowel disease. Like other cytokines in the TNF superfamily, TL1A is synthesized as a type II transmembrane protein and cleaved from the plasma membrane by metalloproteinases. Membrane cleavage has been shown to alter or abrogate certain activities of other TNF family cytokines; however, the functional capabilities of membrane-bound and soluble forms TL1A are not known. Constitutive expression of TL1A in transgenic mice results in expansion of activated T cells and promotes intestinal hyperplasia and inflammation through stimulation of group 2 innate lymphoid cells. Through the generation of membrane-restricted TL1A-transgenic mice, we demonstrate that membrane TL1A promotes expression of inflammatory cytokines in the lung, dependent upon DR3 expression on T cells. Soluble TL1A alone was unable to produce this phenotype but was still able to induce intestinal type 2 inflammation independently of T cells. These data suggest differential roles for membrane and soluble TL1A on adaptive and innate immune cells and have implications for the consequences of blocking these two forms of TL1A.

http://ift.tt/2EeAIav

IFN Regulatory Factor 3 Balances Th1 and T Follicular Helper Immunity during Nonlethal Blood-Stage Plasmodium Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Differentiation of CD4⁺ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4⁺ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell–intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites.

http://ift.tt/2EgYtyB

Intrathymic Deletion of IL-7 Reveals a Contribution of the Bone Marrow to Thymic Rebound Induced by Androgen Blockade [IMMUNE SYSTEM DEVELOPMENT]

Despite the well-documented effect of castration in thymic regeneration, the singular contribution of the bone marrow (BM) versus the thymus to this process remains unclear. The chief role of IL-7 in pre- and intrathymic stages of T lymphopoiesis led us to investigate the impact of disrupting this cytokine during thymic rebound induced by androgen blockade. We found that castration promoted thymopoiesis in young and aged wild-type mice. In contrast, only young germline IL-7–deficient (Il7^–/–) mice consistently augmented thymopoiesis after castration. The increase in T cell production was accompanied by the expansion of the sparse medullary thymic epithelial cell and the peripheral T cell compartment in young Il7^–/– mice. In contrast to young Il7^–/– and wild-type mice, the poor thymic response of aged Il7^–/– mice after castration was associated with a defect in the expansion of BM hematopoietic progenitors. These findings suggest that BM-derived T cell precursors contribute to thymic rebound driven by androgen blockade. To assess the role of IL-7 within the thymus, we generated mice with conditional deletion of IL-7 (Il7 conditional knockout [cKO]) in thymic epithelial cells. As expected, Il7cKO mice presented a profound defect in T cell development while maintaining an intact BM hematopoietic compartment across life. Unlike Il7^–/– mice, castration promoted the expansion of BM precursors and enhanced thymic activity in Il7cKO mice independently of age. Our findings suggest that the mobilization of BM precursors acts as a prime catalyst of castration-driven thymopoiesis.

http://ift.tt/2EQxV8o

CD40 Mediates Maturation of Thymic Dendritic Cells Driven by Self-Reactive CD4+ Thymocytes and Supports Development of Natural Regulatory T Cells [IMMUNE SYSTEM DEVELOPMENT]

Thymic dendritic cells (tDCs) play an important role in central tolerance by eliminating self-reactive thymocytes or differentiating them to regulatory T (Treg) cells. However, the molecular and cellular mechanisms underlying these functions are not completely understood. We found that mouse tDCs undergo maturation following cognate interaction with self-reactive CD4⁺ thymocytes and that this maturation is dependent on CD40 signaling. Ablation of CD40 expression in tDCs resulted in a significant reduction in the number of Treg cells in association with a significant reduction in the number of mature tDCs. In addition, CD40-deficient DCs failed to fully mature upon cognate interaction with CD4⁺ thymocytes in vitro and failed to differentiate them into Treg cells to a sufficient number. These findings suggest that tDCs mature and potentiate Treg cell development in feedback response to self-reactive CD4⁺ thymocytes.

http://ift.tt/2Ee9vV4

Modulation of the IL-33/IL-13 Axis in Obesity by IL-13R{alpha}2 [IMMUNE REGULATION]

In obesity, IL-13 overcomes insulin resistance by promoting anti-inflammatory macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine. In this study, we show that IL-13Rα2 is markedly elevated in adipose tissues of obese mice. Mice deficient in IL-13Rα2 had high expression of IL-13 response markers in adipose tissue, consistent with increased IL-13 activity at baseline. Moreover, exposure to the type 2 cytokine-inducing alarmin, IL-33, enhanced serum and tissue IL-13 concentrations and elevated tissue eosinophils, macrophages, and type 2 innate lymphoid cells. IL-33 also reduced body weight, fat mass, and fasting blood glucose levels. Strikingly, however, the IL-33–induced protection was greater in IL-13Rα2–deficient mice compared with wild-type littermates, and these changes were largely attenuated in mice lacking IL-13. Although IL-33 administration improved the metabolic profile in the context of a high fat diet, it also resulted in diarrhea and perianal irritation, which was enhanced in the IL-13Rα2–deficient mice. Weight loss in this group was associated with reduced food intake, which was likely related to the gastrointestinal effects. These findings outline both potentially advantageous and deleterious effects of a type 2–skewed immune response under conditions of metabolic stress, and identify IL-13Rα2 as a critical checkpoint in adipose tissues that limits the protective effects of the IL-33/IL-13 axis in obesity.

http://ift.tt/2ESANll

The Effects of Dendritic Cell Hypersensitivity on Persistent Viral Infection [IMMUNE REGULATION]

Caspase-8 (CASP8) is known as an executioner of apoptosis, but more recent studies have shown that it participates in the regulation of necroptosis and innate immunity. In this study, we show that CASP8 negatively regulates retinoic acid–inducible gene I (RIG-I) signaling such that, in its absence, stimulation of the RIG-I pathway in dendritic cells (DCs) produced modestly enhanced activation of IFN regulatory factor 3 with correspondingly greater amounts of proinflammatory cytokines. In addition, mice lacking DC-specific CASP8 (dcCasp8^–/– mice) develop age-dependent symptoms of autoimmune disease characterized by hyperactive DCs and T cells, spleen and liver immunopathology, and the appearance of Th1-polarized CD4⁺ T cells. Such mice infected with chronic lymphocytic choriomeningitis virus, an RNA virus detected by RIG-I, mounted an enhanced lymphocytic choriomeningitis virus–specific immune response as measured by increased proportions of Ag-specific CD4⁺ T cells and multicytokine-producing CD4⁺ and CD8⁺ T cells. These results show that CASP8 subtly modulates DC maturation, which controls the spontaneous appearance of autoimmune T cells while simultaneously attenuating the acquired immune system and its potential to control a persistent viral infection.

http://ift.tt/2EdIeSX

Reply to Safra et al.: Lack of theoretical rationale and selective analysis does not imply no strong evidence [Social Sciences]

Safra et al. (1) contend that lack of control is not the mechanism for our findings (2); instead, distrust is a better candidate because of its greater explanatory power. There are several issues with their conjecture. First, study 1 was aimed at demonstrating the main effect of economic uncertainty on...

http://ift.tt/2GY7sX3

No strong evidence that authoritarian attitudes are driven by a lack of control [Social Sciences]

Kakkar and Sivanathan (1) provide new evidence of the link between economic crises and the preference for dominant leaders and strengthen previous evidence of the influence of economic crises on authoritarianism (2–5). However, the authors' interpretation of why economic uncertainty favors dominant leaders entails two further predictions that are not...

http://ift.tt/2G0DOzp

Modular origins of biological electron transfer chains [Biophysics and Computational Biology]

Oxidoreductases catalyze electron transfer reactions that ultimately provide the energy for life. A limited set of ancestral protein-metal modules are presumably the building blocks that evolved into this diverse protein family. However, the identity of these modules and their path to modern oxidoreductases is unknown. Using a comparative structural analysis...

http://ift.tt/2H1Xl3N

Full molecular trajectories of RNA polymerase at single base-pair resolution [Biophysics and Computational Biology]

In recent years, highly stable optical tweezers systems have enabled the characterization of the dynamics of molecular motors at very high resolution. However, the motion of many motors with angstrom-scale dynamics cannot be consistently resolved due to poor signal-to-noise ratio. Using an acousto-optic deflector to generate a "time-shared" dual-optical trap,...

http://ift.tt/2FYSWNA

High-resolution cryo-EM structures of actin-bound myosin states reveal the mechanism of myosin force sensing [Biophysics and Computational Biology]

Myosins adjust their power outputs in response to mechanical loads in an isoform-dependent manner, resulting in their ability to dynamically adapt to a range of motile challenges. Here, we reveal the structural basis for force-sensing based on near-atomic resolution structures of one rigor and two ADP-bound states of myosin-IB (myo1b)...

http://ift.tt/2H3Y3gS

Correction for Noh et al., ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons [Correction]

COLLOQUIUM Correction for "ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons," by Kyung-Min Noh, Ian Maze, Dan Zhao, Bin Xiang, Wendy Wenderski, Peter W. Lewis, Li Shen, Haitao Li, and C. David Allis, which was first published December 23, 2014; 10.1073/pnas.1411258112 (Proc Natl Acad...

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