Optimal treatment for lumbar spinal stenosis: an update.

Purpose of review: Our review of current literature within the past 12-24 months for the treatment of lumbar spinals stenosis (LSS) serves to update providers on recent advances and comparisons regarding therapy spanning lifestyle modification, pharmacologic therapy, minimally invasive interventions, and surgical interventions. Recent findings: Current literature supporting the inclusion of physical therapy and gabapentin/pregabalin within an initial treatment regimen have been positive. A recent randomized, double-blinded clinical trial of adding calcitonin to epidural steroid injections have shown improvement in pain and function up to 1 year. The minimally invasive lumbar decompression (mild) procedure is showing ongoing beneficial results in pain and function. Spinal cord stimulation (SCS) may have a role for select patients with lumbar spinal stenosis. Finally, the benefits of surgical treatment versus nonsurgical treatment is ultimately inconclusive because of the nature of data collection, inconsistencies with the clinical definition of LSS, and a lack of standardized treatment guidelines. Summary: Our review of current research demonstrates there is a positive role for the current conservative therapies, with favorable results for interventions such as minimally invasive decompression and SCS. Pharmacologic interventions such as systemic prostaglandin analogues and epidural agents such as calcitonin demonstrate early promise, but need to undergo additional safety testing and confirmatory trials. Further long-term research with validated, objective measurements for the aforementioned treatments are needed to draw any definitive conclusions for clinical practice. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2sOtbZZ

Regional blocks carried out during general anesthesia or deep sedation: myths and facts.

Purpose of review: More patients will accept regional blocks if these are performed during sedation or general anesthesia. This review discusses regional anesthesia in sedated or anesthetized patients. Recent findings: As complications of regional blocks are rare, regional anesthesia can be considered aswell-tolerated. Awake patients will notice only a minority of needle-to-nerve contacts, that renders the notion of a 'live monitor' obsolete. Using high-resolution ultrasound, the needle can be advanced to an extraepineural position for injection, thus strictly avoiding needle-to-nerve contact or intraepineural injection of local anesthetic. Rare cases of intoxication manifest more immediately when the patient is awake but some general anesthesia drugs reduce the seizure-inducing potency of local anesthetics, and hemodynamic signs of intoxication are also detectable under general anesthesia, allowing for faster cardiopulmonary resuscitation as the patient is anesthetized already. Summary: With the use of ultrasound guidance in skilled hands, it is a reasonable option to perform neuraxial and peripheral regional blocks in sedated or anesthetized patients. Performing the procedure safely and effectively requires an adequate level of experience with the specific block technique in question. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Clinical Snippets

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Melanin pigmentation and melanoma

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Issue Information

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Early clinical manifestations of Sézary syndrome: A multicenter retrospective cohort study

Classic Sézary syndrome (SS) is defined by erythroderma, generalized lymphadenopathy, and leukemic blood involvement. Clinical observations suggest that SS begins as a nonerythrodermic disease.

http://ift.tt/2vaYNtI

Squamous proliferations on the legs of women: Qualitative examination of histopathology, TP53 sequencing, and implications for diagnosis in a series of 30 cases

Women with multiple squamous cell carcinomas (SCCs) of the legs have a striking clinical phenotype. Numerous tumors can develop in a short period of time.

http://ift.tt/2uclaBR

Treatment outcome in orthognathic surgery─a prospective randomized blinded case-controlled comparison of planning accuracy in computer-assisted two- and three-dimensional planning techniques (part II)

Treatment of dentofacial deformities and severe malocclusions with orthognathic surgery involves thorough preoperative planning. The planning is based upon clinical recordings, x-ray examinations, photographs and dental casts (Moorrees, 1995, Wahl, 2006). It is important, when performing corrections of the malocclusion, to simultaneously optimize the facial appearance in accordance with the neutral head posture (Downs, 1948, Moorrees, 1994).

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Endotype-driven treatment in chronic upper airway diseases

Rhinitis and rhinosinusitis are the two major clinical entities of chronic upper airway disease. Chronic rhinosinusitis (CRS) and allergic rhinitis (AR) affect respectively up to 10 and 30% of the total popula...

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Iodine Contents in Prenatal Vitamins in the United States

Thyroid , Vol. 0, No. 0.


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A 10-Gene Classifier for Indeterminate Thyroid Nodules: Development and Multicenter Accuracy Study

Thyroid , Vol. 0, No. 0.


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Malignant mesenchymal neoplasms of the dermis and subcutis mimicking benign lesions: a case-based review

Abstract

In this short review, malignant mesenchymal neoplasms of the dermis and subcutis mimicking benign lesions and their differential diagnoses are discussed. These include plaque-like dermatofibrosarcoma protuberans, superficial low-grade fibromyxoid sarcoma, low-grade superficial malignant peripheral nerve sheath tumour, epithelioid sarcoma, pseudomyogenic haemangioendothelioma, Kaposi sarcoma mimicking cavernous haemangioma and benign lymphangioendothelioma, and rare forms of angiosarcoma mimicking a benign vascular lesion.

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The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity

Abstract

Epithelial-mesenchymal transition (EMT) has emerged as a possible mechanism of cancer metastasizing, but strong evidence for EMT involvement in human cancer is lacking. Our aim was to compare oral spindle cell carcinoma (SpCC) as an example of EMT with oral conventional squamous cell carcinoma (SCC) with and without nodal metastases to test the hypothesis that EMT contributes to metastasizing in oral SCC. Thirty cases of oral SCC with and without nodal metastasis and 15 cases of SpCC were included. Epithelial (cytokeratin, E-cadherin), mesenchymal (vimentin, N-cadherin), and stem cell markers (ALDH-1, CD44, Nanog, Sox-2) and transcription repressors (Snail, Slug, Twist) were analyzed immunohistochemically. We also analyzed the expression of microRNAs miR-141, miR-200 family, miR-205, and miR-429. SpCC exhibited loss of epithelial markers and expression of mesenchymal markers or coexpression of both up-regulation of transcription repressors and down-regulation of the investigated microRNAs. SCC showed only occasional focal expression of mesenchymal markers at the invasive front. No other differences were observed between SCC with and without nodal metastases except for a higher expression of ALDH-1 in SCC with metastases. Our results suggest that SpCC is an example of true EMT but do not support the hypothesis that EMT is involved in metastasizing of conventional SCC. Regarding oral SCC progression and metastasizing, we have been facing a shift from the initial enthusiasm for the EMT concept towards a more critical approach with "EMT-like" and "partial EMT" concepts. The real question, though, is, is there no EMT at all?

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Rezidivierende Sialadenitis der Gl. parotis beidseitig in der Adoleszenz

Laryngo-Rhino-Otol 2017; 96: 390-393
DOI: 10.1055/s-0043-104772

© Georg Thieme Verlag KG Stuttgart · New York

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Akute Otitis Media: wie lange Antibiotika einsetzen?

Laryngo-Rhino-Otol 2017; 96: 347-348
DOI: 10.1055/s-0043-105201

Hoberman A et al. Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children. N Engl J Med. 2016; 375: 2446–2456 Führt bei Kindern mit akuter Otitis media die Begrenzung der antimikrobiellen Behandlung auf 5 Tage im Vergleich zur Standardtherapie über 10 Tage zum gleichen Ergebnis? Kann durch die gleiche Strategie in darauffolgenden Episoden der Gesamtantibiotikaverbrauch und damit das Auftreten von Resistenzen reduziert werden? Diese Fragen wollten amerikanische Kinderärzte in einer Vergleichsuntersuchung klären.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Chirurgie der inneren Nase

Laryngo-Rhino-Otol 2017; 96: 422-427
DOI: 10.1055/s-0043-104074

© Georg Thieme Verlag KG Stuttgart · New York

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Nasale Obstruktion wie operativ behandeln?

Laryngo-Rhino-Otol 2017; 96: 348-350
DOI: 10.1055/s-0043-105196

Standlee AG et al. Evaluating the Effect of Spreader Grafting on Nasal Obstruction Using the NOSE Scale. Ann Otol Rhinol Laryngol. 2017; 126: 219–223 Die Nasenobstruktion ist das am häufigsten auftretende Symptom bei Erkrankungen von Nase und Nebenhöhlen. Der Therapieerfolg eines operativen Eingriffs lässt sich anhand der Nasal Obstruction Symptom Evaluation (NOSE)-Scale beurteilen. Amerikanische Ärzte bewerteten nun die NOSE-Scores, um Wirksamkeit von Dehnungsimplantaten auf die postoperative nasale Funktion zu bestimmen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Kochleaimplantatversorgung von Kindern und Erwachsenen

Laryngo-Rhino-Otol 2017; 96: 396-419
DOI: 10.1055/s-0043-104067

In Deutschland werden jährlich etwa 4000 Patienten mit einem Kochleaimplantat versorgt. Während noch vor Jahren schwerhörige ältere Menschen mit konventionellen Hörgeräten und progredientem Hörverlust bei unzureichendem Sprachverständnis mit dem Risiko der sozialen Isolation leben mussten, können heute Cochleaimplantate als Folgeglied in der Hörsystemversorgung mit hoffnungsvollen Ergebnissen auch bei im fortgeschrittenen Alter angesehen werden. Auch bei Kindern ergeben sich neue Indikationen, mit besonderen Anforderungen in der Rehabilitation.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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CI: bei Innenohr-Anomalien oft aberranter Facialis-Verlauf

Laryngo-Rhino-Otol 2017; 96: 350-351
DOI: 10.1055/s-0043-105197

Palabiyik FB et al.; Facial nerve anomalies in paediatric cochlear implant candidates: radiological evaluation; J Laryngol Otol (2017); 131: 26–31 Eine Verletzung des N. facialis mit nachfolgender Facialisparese ist eine der möglichen Komplikationen einer Cochlea-Implantation bei Kindern mit sensorineuralem Hörverlust (SNHL). Türkische Radiologen untersuchten jetzt, welche Rolle Facialis-Anomalien in diesem Zusammenhang spielen und inwieweit sie mit Innenohr-Anomalien assoziiert sind.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Zur Bewertung spontaner Atemänderungen bei der Respirations-Olfaktometrie

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-111239

Einleitung Durch Gerüche evozierte Atemänderungen werden zum objektivierenden Nachweis der Intaktheit des Riechsystems im Sinne einer Respirations-Olfaktometrie genutzt. Spontane Atemänderungen lassen sich in der Regel nicht von evozierten unterscheiden. Es müssen deshalb wiederholt Reize mit reinen Riechstoffen randomisiert mit Leerreizen in die Ruheatmung appliziert werden, um mehrheitliche Atemänderungen bei olfaktorischer Reizung darzustellen. Methodik Bei 26 erwachsenen Normosmikern wurden mit Hilfe eines Fluss-Olfaktometers 15 überschwellige H2S- und 15 Neutralluft-Reize (Dauer: 2 s) randomisiert mit einem Interstimulusintervall von mindestens 1 Minute inspirationssynchron appliziert. Vor der Reizung durfte die Ruheatmung nicht sehr streuen (Variationskoeffizient der Dauer der Inspiration und der Exspiration ≤0,1). Eine respiratorische Reaktion im Reizatemzug lag vor, wenn die Dauer der Inspiration (DIN) bzw. der Exspiration (DEX) des Reizatemzuges jenseits der doppelten Standardabweichung dieser Atemparameter vom Mittelwert der fünf vorausgehenden Ruheatemzüge lag. Die Anzahl der Reaktionen wurde auf die Anzahl der Reize und der off-line als regelmäßig ermittelten Ruheatemkomplexe normiert und Reaktionsindizes gebildet. Ergebnisse H2S-Reize evozierten deutlich mehr Atemänderungen als Neutralluftreize. DIN und DEX verringerten sich bei olfaktorischer Reizung häufiger als bei einer Applikation von Neutralluft. Verlängerungen von DIN und DEX waren zwischen den beiden Reizqualitäten nicht different. Schlussfolgerungen Nur die randomisierte nasale Reizung mit einem Riechstoff und einem Leerreiz machen die Respirations-Olfaktometrie aussagefähig.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Kontaktgranulom

Laryngo-Rhino-Otol 2017; 96: 352-353
DOI: 10.1055/s-0043-104066

Erhöhte Stimmbelastung kann zu Kontaktgranulomen führen, wobei Stimmklangveränderungen meist kein Teil der Beschwerden sind. Sollten sie allerdings auftreten, dann ist eine chirurgische Therapie neben der Stimmtherapie indiziert.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Wie ein Tritt in den Hintern zur Verjährung führte

Laryngo-Rhino-Otol 2017; 96: 394-395
DOI: 10.1055/s-0042-118286

© Georg Thieme Verlag KG Stuttgart · New York

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Prävalenz, Risikofaktoren und Diagnostik von Hörstörungen bei Frühgeborenen

Laryngo-Rhino-Otol 2017; 96: 354-360
DOI: 10.1055/s-0043-109512

Einleitung: Die Frühgeburt bringt ein deutlich gesteigertes Risiko der Ausbildung einer konnatalen Hörstörung mit sich. Der postnatalen Kontrolle der Hörfunktion muss daher bei allen Frühgeborenen besondere Aufmerksamkeit zuteil werden. Die vorgestellte Arbeit untersucht, inwieweit die aktuellen wissenschaftlichen Erkenntnisse hinsichtlich Prävalenz, Diagnostik, Therapie und in Bezug auf die Risikofaktoren von Hörstörungen bei Frühgeborenen praktische Anwendung finden. Material und Methoden: Die Behandlungsdaten von 126 im Arbeitsbereich Phoniatrie und Pädaudiologie der HNO-Universitätsklinik Magdeburg in den Jahren 2006–2011 untersuchten und behandelten ehemaligen Frühgeborenen wurden retrospektiv ausgewertet. Die zusätzliche Analyse aller Datensätze der Screeningzentrale (n=67 640) aus diesem Zeitraum ermöglicht Rückschlüsse auf die Gesamtanzahl und Prävalenz von Hörstörungen bei Frühgeborenen in Sachsen-Anhalt. Ergebnisse: Nahezu alle Frühgeborene erhalten, wie Reifgeborene, ein beidseitiges postnatales Hörscreening. Die Datenauswertung zeigt jedoch, dass die praktische Umsetzung im Detail oft nicht den in der G-BA-Richtlinie festgelegten Qualitätszielen entspricht. Bspw. erfolgt je nach Geburtsklinik keine regelhafte Anwendung der bei Frühgeborenen empfohlenen Screeningmethode (AABR) oder der richtliniengemäße Screening-und Therapiezeitpunkt wird nicht eingehalten. Diskussion: Die Evaluation der praktischen Umsetzung des universellen Neugeborenenhörscreenings wurde bereits zum Zeitpunkt der Einführung des Screeningprogrammes durch den G-BA geplant. Im Rahmen dieser Untersuchung sollte der praktischen Versorgung von Risikogruppen wie Frühgeborenen besondere Beobachtung gewidmet werden, um auf Basis der erhobenen Daten das Hörscreening – sowie die anschließende Diagnostik und Therapie-weiter zu vereinheitlichen. Unabhängig von der Geburtsklinik sollte gleichermaßen die Chance auf rechtzeitige Diagnostik und damit auf frühzeitige, prognostisch günstigere Therapie einer konnatalen Hörstörung bestehen. Durch schnelle postnatale Hörgerätversorgung können die Hörbahnreifung stimuliert und so potentiell Entwicklungsprobleme hinsichtlich der Hör-und Sprachentwicklung vermieden werden.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Fragen für die Facharztprüfung

Laryngo-Rhino-Otol 2017; 96: 420-421
DOI: 10.1055/s-0043-110071

© Georg Thieme Verlag KG Stuttgart · New York

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Hirnnervenlähmung nach endonasaler, endoskopischer Nasennebenhöhlenoperation. Fallbericht

Laryngo-Rhino-Otol 2017; 96: 388-389
DOI: 10.1055/s-0043-105796

© Georg Thieme Verlag KG Stuttgart · New York

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Kommentar der Schriftleitung

Laryngo-Rhino-Otol 2017; 96: 345-345
DOI: 10.1055/s-0043-104080

Liebe Leserinnen und Leser,in Referiert + Diskutiert starten wir mit einer wegweisenden Arbeit aus dem New England Journal of Medicine, dass es bei einer Antibiotikatherapie der kindlichen Otitis media acuta wichtig ist auch konsequent über 10 Tage zu behandeln 1; eine Kurzzeittherapie ist dem eindeutig unterlegen. Dann geht es um die Effektivität von Dehnungsimplantaten bei Septorhinoplastiken und dann um radiologische Befundung von Fazialisanomalien bei Innenohranomalien, was auch für CI Implantationen relevant ist, siehe weiter unten 2.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Anesthesia for Kidney and Pancreas Transplantation

Publication date: Available online 10 July 2017
Source:Anesthesiology Clinics
Author(s): Aaron M. Mittel, Gebhard Wagener

Teaser

Kidney transplants are the most common solid organ abdominal transplant and are occasionally performed simultaneously with pancreas transplants in diabetic patients. Preoperative evaluation of potential transplant recipients should focus on the potential for occult cardiovascular disease while also screening for other signs of end-organ dysfunction. Intraoperatively, it is of utmost importance to ensure adequate graft perfusion to limit the risk of postoperative graft dysfunction or rejection. Postoperative care of the kidney or pancreas transplant patient should focus on ensuring normalization of volume status, electrolyte concentrations, and glycemic control.


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Anesthetic Management of Pediatric Liver and Kidney Transplantation

Publication date: Available online 10 July 2017
Source:Anesthesiology Clinics
Author(s): Nicholas R. Wasson, Jeremy D. Deer, Santhanam Suresh

Teaser

Pediatric patients with liver dysfunction and renal failure may exhibit many comorbidities. There are often associated congenital syndromes to be taken into account. Liver and renal transplantation offer a solution and substantial improvement in quality of life. Anesthetic management of pediatric liver and renal transplantation has not been well-described. There are key differences between adults and children undergoing these procedures, and acknowledgment of some key principles provide a solid foundation to optimize perioperative outcomes. This article provides an overview of the perioperative management and considerations in pediatric patients undergoing liver and renal transplantation.


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Anesthesia for Liver Transplantation

Publication date: Available online 10 July 2017
Source:Anesthesiology Clinics
Author(s): Dieter Adelmann, Kate Kronish, Michael A. Ramsay

Teaser

The provision of anesthesia for a liver transplant program requires a dedicated team of anesthesiologists. Liver transplant anesthesiologists must have an understanding of liver physiology and anatomy; the spectrum of clinical disease associated with liver dysfunction; the impact of warm and cold ischemia times, surgical techniques in liver transplantation, the impact of ischemia–reperfusion syndrome; and optimal practices to protect the liver. The team must provide a 24-hour service, be actively involved in the selection committee process, and stay current with advances in the subspecialty.


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Transfusion Medicine and Coagulation Management in Organ Transplantation

Publication date: Available online 10 July 2017
Source:Anesthesiology Clinics
Author(s): Jaswanth Madisetty, Cynthia Wang

Teaser

Organ transplantation recipients present unusual challenges with regard to blood transfusion. Although this patient population requires a larger proportion of blood product resources, liberal transfusion of allogeneic blood products can lead to a plethora of complications. Recent trends suggest that efforts to minimize bleeding, conserve products, and target transfusion to specific deficits and needs are increasingly becoming the standard practice. This must all occur with optimization of graft function and preservation in mind. With newer monitoring modalities and factor concentrates, the approach toward transfusion and bleeding in organ transplantation has rapidly improved in recent years.


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Organ Transplantation: A Systematic Review

Publication date: Available online 10 July 2017
Source:Anesthesiology Clinics
Author(s): Aman Mahajan, Christopher Wray




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Enzymatic Debridement of Chronic Diabetic Foot Ulcers

What benefits might enzymatic debridement with clostridial collagenase ointment provide in the treatment of diabetic foot ulcers?
Wounds

http://ift.tt/2u1JlmT

Fetal Tobacco Smoke Exposure in the Third Trimester of Pregnancy Is Associated with Atopic Eczema/Dermatitis Syndrome in Infancy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2tbubXv

Fetal Tobacco Smoke Exposure in the Third Trimester of Pregnancy Is Associated with Atopic Eczema/Dermatitis Syndrome in Infancy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2sNj6N3

TERT Promoter Mutations Were Not Found in Papillary Thyroid Microcarcinomas That Showed Disease Progression on Active Surveillance

Thyroid , Vol. 0, No. 0.


http://ift.tt/2uOysCo

Juvenile psammomatoid ossifying fibromas of the ethmoid: Natural history in adults

Publication date: Available online 10 July 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): D. Evrard, W. El Bakkouri, M. Hurseau, D. Ayache




http://ift.tt/2t0FIxI

The effects of ozone application on genotoxic damage and wound healing in bisphosphonate-applied human gingival fibroblast cells

Abstract

Objectives

Medication-related osteonecrosis of the jaws (MRONJ) is an extremely therapy-resistant disease involving the jaws especially following bisphosphonate treatment. Bisphosphonates accumulate in bone in concentrations sufficient to be directly toxic to the oral epithelium. Current therapeutic options are inadequate for the prevention and treatment of MRONJ. The aim of this study was to investigate effects of ozone gas plasma therapy on wound healing in bisphosphonate-applied human fibroblasts.

Material and methods

Human primary gingival fibroblasts were cultured. Cytotoxic concentrations (IC50) of bisphosphonates (pamidronate (PAM), alendronate (ALN), and zoledronate (ZOL)) were determined by MTT test. A 60 μg/μl for 30 s of ozone gas plasma application was performed to all experimental culture flasks after drug treatment at 24-h intervals as 3 s/cm². Genotoxic damages were evaluated by comet assay and wound healing was determined by in vitro scratch assay.

Results

PAM, ALN, and ZOL applications caused genotoxic damage on primary human gingival fibroblast DNA. Ozone gas plasma therapy significantly decreased the genotoxic damage (p < 0.05), and this application provided 25, 29, and 27% less genotoxic damage in order of ALN, PAM, and ZOL groups. Ozone gas plasma therapy significantly increased wound healing rates both in postsurgical 24th and 48th hours for all doses of experimental drug groups (p < 0.05).

Conclusion

The ozone gas plasma application decreased genotoxic damage effect of bisphosphonate usage while improved the wound closure rate on human gingival fibroblasts.

Clinical relevance

Ozone gas plasma therapy may be helpful in prevention of gingival healing delay in MRONJ pathogenesis especially when applied simultaneously with surgical intervention.

http://ift.tt/2tF3wWD

T Cell-Mediated Humoral Immune Responses to Type 3 Capsular Polysaccharide of Streptococcus pneumoniae [IMMUNOTHERAPY AND VACCINES]

Most pathogenic bacteria express surface carbohydrates called capsular polysaccharides (CPSs). CPSs are important vaccine targets because they are easily accessible and recognizable by the immune system. However, CPS-specific adaptive humoral immune responses can only be achieved by the covalent conjugation of CPSs with carrier proteins to produce glycoconjugate vaccines. We previously described a mechanism by which a model glycoconjugate vaccine can activate the adaptive immune system and demonstrated that the mammalian CD4⁺ T cell repertoire contains a population of carbohydrate-specific T cells. In this study, we use glycoconjugates of type 3 Streptococcus pneumoniae CPS (Pn3P) to assess whether the carbohydrate-specific adaptive immune response exemplified in our previous study can be applied to the conjugates of this lethal pathogen. In this article, we provide evidence for the functional roles of Pn3P-specific CD4⁺ T cells utilizing mouse immunization schemes that induce Pn3P-specific IgG responses in a carbohydrate-specific T cell–dependent manner.

http://ift.tt/2tavaal

A Nonadjuvanted IgG2a Monoclonal Antibody against Nucleosomes Elicits Potent T Cell-Dependent, Idiotype-Specific IgG1 Responses and Glomerular IgG1/IgG2a Deposits in Normal Mice [IMMUNE REGULATION]

Idiotypes (Ids) are unique epitopes of Ab V regions and can trigger anti-Id immune responses, but immunization with several nonadjuvanted isologous IgG mAbs has induced tolerance to their Ids. We immunized non–lupus-prone mice with 11 allotype "a" of IgG2a (IgG2a^a) and 4 IgG2c nonadjuvanted, isologous mAbs purified from serum-free medium. Of five IgG2a^a mAbs with specificity for nucleosomes, the repeating histone-DNA subunit of chromatin, four elicited an IgG1 anti-mAb response and one mAb was nonimmunogenic. In contrast, none of six IgG2a^a mAbs with unknown specificity triggered anti-mAb responses. The data suggested a link between immunogenicity and specificity for nucleosomes. One anti-nucleosome IgG2a^a mAb, termed 3F7.A10, copurified with self-histones and was a potent immunogen for BALB/c mice. The response against IgG2a^a 3F7.A10 was CD4⁺ Th cell–dependent, dominated by the IgG1 subclass, and Id specific. Ultracentrifugation converted the purified 3F7.A10 mAb into a weak immunogen, suggesting that the mAb had formed immunogenicity-enhancing immune complexes (ICs) with nucleosomal Ags during cell culture. BALB/c mice injected with viable MHC-incompatible 3F7.A10 hybridoma cells grown in serum-free medium mounted strong anti-Id responses. TLR9-deficient mice responded significantly weaker to Id-3F7.A10 than did TLR9-sufficient mice, suggesting that the cognate BCR efficiently internalizes the Id in an IC with nucleosomes. Passive transfer of IgG2a^a 3F7.A10 to BALB/c mice with high titers of IgG1 anti-3F7.A10 led to glomerular deposits of IgG1/IgG2a complexes. The immunogenicity of Id-3F7.A10 raises the possibility that diverse Ids of nucleosome-specific Abs form ICs with nucleosomes released from dying cells and elicit spontaneous formation of anti-Id Abs in vivo.

http://ift.tt/2tayxye

Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3 [IMMUNE REGULATION]

Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the Hox5 gene family, Hoxa5, Hoxb5, and Hoxc5, genes known to be important in lung development within mesenchymal cell populations. We found that Hox5-mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced Gata3 expression, and elevated production of IL-4, IL-5, and IL-13 in Hox5-deficient T cells compared with wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the Gata3 locus and decreased Gata3 and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for Hox5 genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes.

http://ift.tt/2tEkapb

Dimeric Fc{gamma} Receptor Enzyme-Linked Immunosorbent Assay To Study HIV-Specific Antibodies: A New Look into Breadth of Fc{gamma} Receptor Antibodies Induced by the RV144 Vaccine Trial [NOVEL IMMUNOLOGICAL METHODS]

Ab-dependent cellular cytotoxicity (ADCC) responses are of growing interest in the HIV vaccine field but current cell-based assays are usually difficult to reproduce across laboratories. We developed an ELISA and multiplex assay to model the cross-linking of Fc receptors (FcR) by Abs, which is required to initiate an ADCC response. Our FcR dimer ELISA readily detected Abs in samples from two separate cohorts of the partially efficacious Thai RV144 HIV vaccine efficacy trial. The FcR dimer–binding Abs induced by the RV144 regimen correlated well with a functional measure of ADCC as well as IgG subclasses. The high-throughput multiplex assay allowed us to simultaneously measure FcR dimer–binding Abs to 32 different HIV Ags, providing a measure of the breadth of FcR-binding Abs induced by the RV144 trial. FcR-binding Abs specific to V regions 1 and 2 were strongly associated with increased breadth of recognition of different Env proteins, suggesting anti–V regions 1 and 2 Abs may be a marker of ADCC breadth. This FcR dimer provides an important tool for the further analysis and refinement of ADCC-inducing HIV and other antiviral vaccine regimens.

http://ift.tt/2taa9wC

Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin {alpha}4{beta}1-Expressing Immune Cells [NOVEL IMMUNOLOGICAL METHODS]

Positron emission tomography and computed tomography imaging (PET/CT) is an increasingly valuable tool for diagnosing tuberculosis (TB). The glucose analog [¹⁸F]fluoro-2-deoxy-2-d-glucose ([¹⁸F]-FDG) is commonly used in PET/CT that is retained by metabolically active inflammatory cells in granulomas, but lacks specificity for particular cell types. A PET probe that could identify recruitment and differentiation of different cell populations in granulomas would be a useful research tool and could improve TB diagnosis and treatment. We used the Mycobacterium-antigen murine inflammation model and macaques with TB to identify [⁶⁴Cu]-labeled CB-TE1A1P-PEG₄-LLP2A ([⁶⁴Cu]-LLP2A), a high affinity peptidomimetic ligand for very late Ag-4 (VLA-4; also called integrin α4β1) binding cells in granulomas, and compared [⁶⁴Cu]-LLP2A with [¹⁸F]-FDG over the course of infection. We found that [⁶⁴Cu]-LLP2A retention was driven by macrophages and T cells, with less contribution from neutrophils and B cells. In macaques, granulomas had higher [⁶⁴Cu]-LLP2A uptake than uninfected tissues, and immunohistochemical analysis of granulomas with known [⁶⁴Cu]-LLP2A uptake identified significant correlations between LLP2A signal and macrophage and T cell numbers. The same cells coexpressed integrin α4 and β1, further supporting that macrophages and T cells drive [⁶⁴Cu]-LLP2A avidity in granulomas. Over the course of infection, granulomas and thoracic lymph nodes experienced dynamic changes in affinity for both probes, suggesting metabolic changes and cell differentiation or recruitment occurs throughout granuloma development. These results indicate [⁶⁴Cu]-LLP2A is a PET probe for VLA-4, which when used in conjunction with [¹⁸F]-FDG, may be a useful tool for understanding granuloma biology in TB.

http://ift.tt/2tEssxy

Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation [TRANSPLANTATION]

CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tet^low CTLs) and high tetramer binding (CMV tet^high CTLs) in 53/115 CMV IgG⁺ patients stem cell transplanted from CMV IgG⁺ donors. However, the relevance of these coappearing differentially tetramer binding ("dual") CMV-CTLs was unclear. In this study, we investigated the kinetics, properties, and clinical impact of coappearing CMV tet^low and tet^high CTLs after allogeneic SCT. Patients with dual CMV-CTLs had more CMV tet^high than tet^low CTLs. Chimerism analysis of isolated CMV tet^low and tet^high CTLs revealed their exclusive donor origin. CMV tet^low and tet^high CTLs had an identical effector memory CD45RA^–CCR7^– and CD45RA⁺CCR7^– T cell distribution, equal differentiation, senescence, and exhaustion marker expression and were negative for regulatory CD8⁺ T cell markers. Isolated CMV tet^low and tet^high CTLs were equally sensitive to CMV peptides in IFN- release and cytotoxicity assays. However, CMV tet^high CTLs proliferated more in response to low CMV peptide concentrations than tet^low CTLs. TCR repertoire analysis revealed that CMV tet^low and tet^high CTLs use different TCRs. Finally, dual CMV-CTLs were not associated with CMV antigenemia. In conclusion, these data show for the first time, to our knowledge, that both CMV tet^low and tet^high CTLs are functional effector T cells differing by proliferation, numbers in peripheral blood, and probably by their precursors without increasing the CMV reactivation risk after allogeneic SCT.

http://ift.tt/2tanll5

High-Throughput Single-Cell Analysis of B Cell Receptor Usage among Autoantigen-Specific Plasma Cells in Celiac Disease [SYSTEMS IMMUNOLOGY]

Characterization of Ag-specific BCR repertoires is essential for understanding disease mechanisms involving humoral immunity. This is optimally done by interrogation of paired H chain V region (V_H) and L chain V region (V_L) sequences of individual and Ag-specific B cells. By applying single-cell high-throughput sequencing on gut lesion plasma cells (PCs), we have analyzed the transglutaminase 2 (TG2)-specific V_H:V_L autoantibody repertoire of celiac disease (CD) patients. Autoantibodies against TG2 are a hallmark of CD, and anti-TG2 IgA-producing gut PCs accumulate in patients upon gluten ingestion. Altogether, we analyzed paired V_H and V_L sequences of 1482 TG2-specific and 1421 non–TG2-specific gut PCs from 10 CD patients. Among TG2-specific PCs, we observed a striking bias in IGHV and IGKV/IGLV gene usage, as well as pairing preferences with a particular presence of the IGHV5-51:IGKV1-5 pair. Selective and biased V_H:V_L pairing was particularly evident among expanded clones. In general, TG2-specific PCs had lower numbers of mutations both in V_H and V_L genes than in non–TG2-specific PCs. TG2-specific PCs using IGHV5-51 had particularly few mutations. Importantly, V_L segments paired with IGHV5-51 displayed proportionally low mutation numbers, suggesting that the low mutation rate among IGHV5-51 PCs is dictated by the BCR specificity. Finally, we observed selective amino acid changes in V_H and V_L and striking CDR3 length and J segment selection among TG2-specific IGHV5-51:IGKV1-5 pairs. Hence this study reveals features of a disease- and Ag-specific autoantibody repertoire with preferred V_H:V_L usage and pairings, limited mutations, clonal dominance, and selection of particular CDR3 sequences.

http://ift.tt/2tEv3rr

Bacterial and Viral Products Affect Differential Pattern Recognition Receptor Activation of Chicken Thrombocytes Evidenced through RNA Sequencing [SYSTEMS IMMUNOLOGY]

It is now well understood that thrombocytes (nucleated platelets) express TLRs and respond to both bacterial and viral products. Release of proinflammatory molecules can be expected following relatively short exposure times to LPS, lipoteichoic acid (LTA), thymidine homopolymer phosphorothioate oligonucleotide [Poly(dT)], and polyinosinic-polycytidylic acid [Poly(I:C)]. This study reports the varied expressions of genes encoded for components of the TLR, nucleotide binding oligomerization domain–like receptor, and retinoic acid-inducible gene RIG–like receptor signaling pathways in response to the TLR ligands listed above. Highly sensitive RNA-sequencing technologies were used to analyze the complete transcriptome of thrombocytes treated with all four microbial products for a period of 1 h. A total of 14,326 gene transcripts were found in chicken thrombocytes across all ligand exposures. After 1 h of stimulation with ligands, 87, 138, 1013, and 22 genes were upregulated for LTA, LPS, Poly(dT), and Poly(I:C), and 12, 142, 249, and 16 genes were downregulated for LTA, LPS, Poly(dT), and Poly(I:C), respectively, with at least a 1-fold change relative to unexposed thrombocytes. Summarizations of biological processes, protein classes, and biochemical pathways reveal the role of chicken thrombocytes in proinflammatory responses linked to key signaling pathways. TLR, nucleotide binding oligomerization domain–like receptor, and retinoic acid-inducible gene RIG-like receptor pathways were mapped based on the transcriptome results with gene expression for common signal and proinflammatory mediators highlighted. The information reported in this study is useful for defining a limited set of proinflammatory molecules to evaluate in cases of either bacterial or viral disease monitoring.

http://ift.tt/2tatspG

TLR9 Regulates the NF-{kappa}B-NLRP3-IL-1{beta} Pathway Negatively in Salmonella-Induced NKG2D-Mediated Intestinal Inflammation [MUCOSAL IMMUNOLOGY]

TLRs are key sensors for conserved bacterial molecules and play a critical role in host defense against invading pathogens. Although the roles of TLRs in defense against pathogen infection and in maintaining gut immune homeostasis have been studied, the precise functions of different TLRs in response to pathogen infection in the gut remain elusive. The present study investigated the role of TLR signaling in defense against the Gram-negative bacterial pathogen Salmonella typhimurium. The results indicated that TLR9-deficient mice were more susceptible to S. typhimurium infection compared with wild-type and TLR2- or TLR4-deficient mice, as indicated by more severe intestinal damage and the highest bacterial load. TLR9 deficiency in intestinal epithelial cells (IECs) augmented the activation of NF-B and NLRP3 inflammasomes significantly, resulting in increased secretion of IL-1β. IL-1β increased the expression of NKG2D on intestinal intraepithelial lymphocytes and NKG2D ligands on IECs, resulting in higher susceptibility of IECs to cytotoxicity of intestinal intraepithelial lymphocytes and damage to the epithelial barrier. We proposed that TLR9 regulates the NF-B–NLRP3–IL-1β pathway negatively in Salmonella-induced NKG2D-mediated intestinal inflammation and plays a critical role in defense against S. typhimurium infection and in the protection of intestinal integrity.

http://ift.tt/2tEnocp

B-1a Cells Protect Mice from Sepsis: Critical Role of CREB [INNATE IMMUNITY AND INFLAMMATION]

Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell–deficient CD19^–/– mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10–deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis.

http://ift.tt/2ta8neM

Dendritic Cell Sensing of Hydrophobic Di- and Triacylated Lipopeptides Self-Assembled within Synthetic Virus-like Particles [INNATE IMMUNITY AND INFLAMMATION]

Dendritic cells (DCs) play critical roles in developing immune defenses. One important aspect is interaction with pathogen-associated molecular patterns (PAMPs)/danger-associated molecular patterns, including di- and triacylated lipopeptides. Isolated or synthetic lipopeptides are potent vaccine adjuvants, interacting with cell surface TLR2 heterodimers. In contrast, deep embedment within bacteria cell walls would impair lipopeptide interaction with cell surface TLR2, requiring degradation for PAMP recognition. Accordingly, DC processing in the absence of surface TLR2 ligation was defined using synthetic virus-like particles (SVLPs) carrying hydrophobic TLR2 PAMPs within di- and triacylated lipopeptide cores (P2Cys-SVLPs and P3Cys-SVLPs) compared with SVLPs lacking immunomodulatory lipopeptides. DCs rapidly and efficiently internalized SVLPs, which was dominated by slow endocytic processing via macropinocytosis, although some caveolar endocytosis was implicated. This delivered SVLPs primarily into macropinosomes often interacting with EEA-1⁺ early endosomes. Although endoplasmic reticulum association was occasionally noted, association with recycling/sorting structures was not observed. Involvement of LysoTracker⁺ structures slowly increased with time, with SVLPs present in such structures ultimately dominating. Only SVLPs carrying di- and triacylated lipopeptide cores induced DC activation and maturation independently of surface TLR2 ligation. Intracellular recognition of SVLP TLR2 ligands was confirmed by observing SVLPs' association with internal TLR2, which had similar kinetics to SVLP association with LysoTracker. This related to inflammatory cytokine induction by SVLP⁺ DCs, with adaptive immune response activation ex vivo/in vivo. Importantly, particular DCs, not monocytes, recognized intracellular exposure of the TLR2 PAMPs carried by di- and triacylated SVLP cores, which indicates subset-distinct recognition of functional internal TLR2 ligands. Thus, vaccines carrying hydrophobic TLR2 ligands would interact with particular DCs for efficient induction of specific immunity in the absence of additional adjuvant.

http://ift.tt/2tEpicZ

The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis [INNATE IMMUNITY AND INFLAMMATION]

GPBAR1 (TGR5 or M-BAR) is a G protein–coupled receptor for secondary bile acids that is highly expressed in monocytes/macrophages. In this study, we aimed to determine the role of GPBAR1 in mediating leukocyte trafficking in chemically induced models of colitis and investigate the therapeutic potential of BAR501, a small molecule agonist for GPBAR1. These studies demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation. In contrast, GPBAR1 activation by BAR501 reversed intestinal inflammation in the trinitrobenzenesulfonic acid and oxazolone models by reducing the trafficking of Ly6C⁺ monocytes from blood to intestinal mucosa. Exposure to BAR501 shifted intestinal macrophages from a classically activated (CD11b⁺, CCR7⁺, F4/80^–) to an alternatively activated (CD11b⁺, CCR7^–, F4/80⁺) phenotype, reduced the expression of inflammatory genes (TNF-α, IFN-, IL-1β, IL-6, and CCL2 mRNAs), and attenuated the wasting syndrome and severity of colitis (70% reduction in the Colitis Disease Activity Index). The protective effect was lost in Gpbar1^–/– mice. Exposure to BAR501 increased the colonic expression of IL-10 and TGF-β mRNAs and the percentage of CD4⁺/Foxp3⁺ cells. The beneficial effects of BAR501 were lost in Il-10^–/– mice. In a macrophage cell line, regulation of IL-10 by BAR501 was GPBAR1 dependent and was mediated by the recruitment of CREB to its responsive element in the IL-10 promoter. In conclusion, GPBAR1 is expressed in circulating monocytes and colonic macrophages, and its activation promotes a IL-10–dependent shift toward an alternatively activated phenotype. The targeting of GPBAR1 may offer therapeutic options in inflammatory bowel diseases.

http://ift.tt/2tahgoT

IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra^–/–) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra^–/– mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra^–/– mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra^–/– mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5–expressing pathogenic effector Th2 cells and was independent of TCR T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis.

http://ift.tt/2tEkJ2z

Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse [INNATE IMMUNITY AND INFLAMMATION]

C3a exerts multiple biologic functions through activation of its cognate C3a receptor. C3^–/– and C3aR^–/– mice have been instrumental in defining important roles of the C3a/C3aR axis in the regulation of acute and chronic inflammatory diseases, including ischemia/reperfusion injury, allergic asthma, autoimmune nephritis, and rheumatoid arthritis. Surprisingly little is known about C3aR expression and function in immune and stromal cells. To close this gap, we generated a floxed tandem-dye Tomato (tdTomato)–C3aR reporter knock-in mouse, which we used to monitor C3aR expression in cells residing in the lung, airways, lamina propria (LP) of the small intestine, brain, visceral adipose tissue, bone marrow (BM), spleen, and the circulation. We found a strong expression of tdTomato-C3aR in the brain, lung, LP, and visceral adipose tissue, whereas it was minor in the spleen, blood, BM, and the airways. Most macrophage and eosinophil populations were tdTomato-C3aR⁺. Interestingly, most tissue eosinophils and some macrophage populations expressed C3aR intracellularly. BM-derived dendritic cells (DCs), lung-resident cluster of differentiation (CD) 11b⁺ conventional DCs (cDCs) and monocyte-derived DCs, LP CD103⁺, and CD11b⁺ cDCs but not pulmonary CD103⁺ cDCs and splenic DCs were tdTomato-C3aR⁺. Surprisingly, neither BM, blood, lung neutrophils, nor mast cells expressed C3aR. Similarly, all lymphoid-derived cells were tdTomato-C3aR^–, except some LP-derived type 3 innate lymphoid cells. Pulmonary and LP-derived epithelial cells expressed at best minor levels of C3aR. In summary, we provide novel insights into the expression pattern of C3aR in mice. The floxed C3aR knock-in mouse will help to reliably track and conditionally delete C3aR expression in experimental models of inflammation.

http://ift.tt/2tawQAV

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKK{varepsilon} To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection [INNATE IMMUNITY AND INFLAMMATION]

Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however, the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKK to propel type I IFN–mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to influenza A virus infection. In support of this, SPL-deficient cells were defective in mounting an effective IFN response when stimulated by influenza viral RNAs. SPL augmented the activation status of IKK and enhanced the kinase-induced phosphorylation of IRF3 and the synthesis of type I IFNs. However, the S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL's pro-IFN function is independent of S1P. Biochemical analyses revealed that SPL, as well as the mutant form of SPL, interacts with IKK. Importantly, when endogenous IKK was downregulated using a small interfering RNA approach, SPL's anti-influenza viral activity was markedly suppressed. This indicates that IKK is crucial for SPL-mediated inhibition of influenza virus replication. Thus, the results illustrate the functional significance of the SPL–IKK–IFN axis during host innate immunity against viral infection.

http://ift.tt/2tEapHC

ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin Expression and Promote T Lymphocyte Transmigration [INNATE IMMUNITY AND INFLAMMATION]

The recruitment of blood leukocytes across the endothelium to sites of tissue infection is central to inflammation, but also promotes chronic inflammatory diseases. A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane molecular scissor that is implicated in leukocyte transmigration by proteolytically cleaving its endothelial substrates. These include VE-cadherin, a homotypic adhesion molecule that regulates endothelial barrier function, and transmembrane chemokines CX3CL1 and CXCL16, which have receptors on leukocytes. However, a definitive role for endothelial ADAM10 in transmigration of freshly isolated primary leukocytes under flow has not been demonstrated, and the relative importance of distinct ADAM10 substrates is unknown. Emerging evidence suggests that ADAM10 can be regarded as six different molecular scissors with different substrate specificities, depending on which of six TspanC8 tetraspanins it is associated with, but TspanC8s remain unstudied in leukocyte transmigration. In the current study, ADAM10 knockdown on primary HUVECs was found to impair transmigration of freshly isolated human peripheral blood T lymphocytes, but not neutrophils or B lymphocytes, in an in vitro flow assay. This impairment was due to delayed transmigration rather than a complete block, and was overcome in the presence of neutrophils. Transmigration of purified lymphocytes was dependent on ADAM10 regulation of VE-cadherin, but not CX3CL1 and CXCL16. Tspan5 and Tspan17, the two most closely related TspanC8s by sequence, were the only TspanC8s that regulated VE-cadherin expression and were required for lymphocyte transmigration. Therefore endothelial Tspan5- and Tspan17-ADAM10 complexes may regulate inflammation by maintaining normal VE-cadherin expression and promoting T lymphocyte transmigration.

http://ift.tt/2tawN8d

Antibody-Dependent NK Cell Activation Differentially Targets EBV-Infected Cells in Lytic Cycle and Bystander B Lymphocytes Bound to Viral Antigen-Containing Particles [INFECTIOUS DISEASE AND HOST RESPONSE]

NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN- secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV⁺ individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350⁺ particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN- secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350⁺ particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350⁺ particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN- production, potentially favoring the progression of viral infection.

http://ift.tt/2tEQubL

T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections. To elucidate the role of Notch signaling during fungal infections, we infected mice expressing the pan-Notch inhibitor dominant negative mastermind-like within mature T cells with C. neoformans. Inhibition of T cell–restricted Notch signaling increased fungal burdens in the lungs and CNS, diminished pulmonary leukocyte recruitment, and simultaneously impaired Th1 and Th2 responses. Pulmonary leukocyte cultures from T cell Notch-deprived mice produced less IFN-, IL-5, and IL-13 than wild-type cells. This correlated with lower frequencies of IFN-–, IL-5–, and IL-13–producing CD4⁺ T cells, reduced expression of Th1 and Th2 associated transcription factors, Tbet and GATA3, and reduced production of IFN- by CD8⁺ T cells. In contrast, Th17 responses were largely unaffected by Notch signaling. The changes in T cell responses corresponded with impaired macrophage activation and reduced leukocyte accumulation, leading to diminished fungal control. These results identify Notch signaling as a previously unappreciated regulator of Th1 and Th2 immunity and an important element of antifungal defenses against cryptococcal infection and CNS dissemination.

http://ift.tt/2tavdD3

Elimination of Babesia microti Is Dependent on Intraerythrocytic Killing and CD4+ T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Babesiosis is a tick-borne zoonosis caused by protozoans of the genus Babesia, apicomplexan parasites that replicate within erythrocytes. However, unlike related Plasmodium species, the pathogenesis of Babesia infection remains poorly understood. The primary etiological agent of babesiosis in the United States is B. microti. In healthy individuals, tick-transmitted infection with Babesia causes no specific clinical manifestations, with many having no symptoms at all. However, even in asymptomatic people, a Babesia carriage state can be established that can last up to a year or more. Current blood bank screening methods do not identify infected donors, and Babesia parasites survive blood-banking procedures and storage. Thus, Babesia can also be transmitted by infected blood, and it is currently the number one cause of reportable transfusion-transmitted infection in the United States. Despite a significant impact on human health, B. microti remains understudied. In this study, we evaluated the course of Babesia infection in three strains of mice, C57BL/6J, BALB/cJ, and C3H-HeJ, and examined the contribution of multiple immune parameters, including TLRs, B cells, CD4⁺ cells, IFN-, and NO, on the level of parasitemia and parasite clearance during acute babesiosis. We found that B. microti reaches high parasitemia levels during the first week of infection in all three mice strains before resolving spontaneously. Our results indicate that resolution of babesiosis requires CD4 T cells and a novel mechanism of parasite killing within infected erythrocytes.

http://ift.tt/2tEvXnE

Cytoplasmic Form of Carlr lncRNA Facilitates Inflammatory Gene Expression upon NF-{kappa}B Activation [IMMUNE REGULATION]

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of inflammation. To further understand the interaction between inflammatory signaling pathways and lncRNAs, we characterized the function of cardiac and apoptosis-related lncRNA (Carlr), an lncRNA expressed in both mouse and human cells of diverse tissues. Carlr expression is increased following NF-B signaling in macrophages, with concomitant translocation to, and enrichment of, the transcript in the cytoplasm. Knockdown of Carlr results in impaired expression of NF-B pathway genes and influences the interaction between macrophages and intestinal cells in an inflammatory environment. In human celiac disease patient samples, increased levels of the Carlr transcript were detected in the cytoplasm, alongside elevated expression of NF-B pathway genes. These findings suggest that increased Carlr expression and/or cytoplasmic localization is required for efficient NF-B signaling and is associated with the inflamed tissue state observed in human celiac disease.

http://ift.tt/2tazQNz

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection [IMMUNE REGULATION]

The appropriate orchestration of different arms of the immune response is critical during viral infection to promote efficient viral clearance while limiting immunopathology. However, the signals and mechanisms that guide this coordination are not fully understood. IFNs are produced at high levels during viral infection and have convergent signaling through STAT1. We hypothesized that STAT1 signaling during viral infection regulates the balance of innate lymphoid cells (ILC), a diverse class of lymphocytes that are poised to respond to environmental insults including viral infections with the potential for both antiviral or immunopathologic functions. During infection with respiratory syncytial virus (RSV), STAT1-deficient mice had reduced numbers of antiviral IFN-⁺ ILC1 and increased numbers of immunopathologic IL-5⁺ and IL-13⁺ ILC2 and IL-17A⁺ ILC3 compared with RSV-infected wild-type mice. Using bone marrow chimeric mice, we found that both ILC-intrinsic and ILC-extrinsic factors were responsible for this ILC dysregulation during viral infection in STAT1-deficient mice. Regarding ILC-extrinsic mechanisms, we found that STAT1-deficient mice had significantly increased expression of IL-33 and IL-23, cytokines that promote ILC2 and ILC3, respectively, compared with wild-type mice during RSV infection. Moreover, disruption of IL-33 or IL-23 signaling attenuated cytokine-producing ILC2 and ILC3 responses in STAT1-deficient mice during RSV infection. Collectively, these data demonstrate that STAT1 is a key orchestrator of cytokine-producing ILC responses during viral infection via ILC-extrinsic regulation of IL-33 and IL-23.

http://ift.tt/2ta8iI0

T Cell-Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ~1.5 million deaths annually. CD4⁺ T cells and several cytokines, such as the Th1 cytokine IFN-, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C⁺ monocytes. However, after day 21 postinfection, IL-10–expressing T cells were also highly represented. Notably, mice deficient in T cell–derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL-10–competent mice, indicating a major role for T cell–derived IL-10 in TB susceptibility. IL-10–expressing cells were detected among both CD4⁺ and CD8⁺ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN- and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4⁺ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10–induced TB susceptibility.

http://ift.tt/2taqv8w

Antigen Availability and DOCK2-Driven Motility Govern CD4+ T Cell Interactions with Dendritic Cells In Vivo [IMMUNE REGULATION]

Parenchymal migration of naive CD4⁺ T cells in lymph nodes (LNs) is mediated by the Rac activator DOCK2 and PI3K and is widely assumed to facilitate efficient screening of dendritic cells (DCs) presenting peptide-MHCs (pMHCs). Yet how CD4⁺ T cell motility, DC density, and pMHC levels interdependently regulate such interactions has not been comprehensively examined. Using intravital imaging of reactive LNs in DC-immunized mice, we show that pMHC levels determined the occurrence and timing of stable CD4⁺ T cell–DC interactions. Despite the variability in interaction parameters, ensuing CD4⁺ T cell proliferation was comparable over a wide range of pMHC levels. Unexpectedly, decreased intrinsic motility of DOCK2^–/– CD4⁺ T cells did not impair encounters with DCs in dense paracortical networks and, instead, increased interaction stability, whereas PI3K deficiency had no effect on interaction parameters. In contrast, intravital and whole-organ imaging showed that DOCK2-driven T cell motility was required to detach from pMHC^low DCs and to find rare pMHC^high DCs. In sum, our data uncover flexible signal integration by scanning CD4⁺ T cells, suggesting a search strategy evolved to detect low-frequency DCs presenting high cognate pMHC levels.

http://ift.tt/2tEQrg5

Dose-response relationship of a new Timothy grass pollen allergoid in comparison to a 6-grass pollen allergoid

Abstract

Background

Subcutaneous allergen immunotherapy with grass pollen allergoids has been proven to be effective and safe in the treatment of patients with allergic rhinoconjunctivitis. Based on the extensive cross-reactivity among Pooideae species, it has been suggested that grass pollen extracts could be prepared from a single species, rather than from a multiple species mixture.

Objective

To find the optimal dose of a Phleum pratense allergoid preparation and compare its efficacy and safety to a 6-grass pollen allergoid preparation.

Methods

In this double-blind, placebo-controlled study (EudraCT: 2011-000674-58), 3 doses of Phleum pratense allergoid (1800 Therapeutic Units (TU), standard dose 6000 TU, and 18000 TU) were compared with placebo and the marketed 6-grass pollen allergoid (6000 TU). In a preseasonal dosing regimen, 102 patients were randomized to 5 treatment groups and received 9 subcutaneous injections. The primary efficacy endpoint was the change in wheal size (late phase reaction, LPR) in response to the intracutaneous testing (ICT) before and after treatment, comparing the active allergoids to placebo. Secondary outcomes were the change in Total Nasal Symptom Score (TNSS) assessed in the allergen exposure chamber (AEC), the changes in Phleum pratense-serum specific IgG₄, and the incidence of adverse events (AEs).

Results

All 3 doses of the Phleum pratense and the 6-grass pollen allergoid preparations were significantly superior to placebo for the primary outcome, whereas there were no significant differences in the change in TNSS. Compared to the standard dose, the high dose of Phleum pratense did not produce any additional significant benefit, but showed a slight increase in AEs. Yet this increase in AEs was lower than for the 6-grass pollen preparation.

Conclusions & Clinical Relevance

The standard dose of the new Phleum pratense allergoid was comparable to the marketed 6-grass pollen preparation at equal dose for the parameters measured.

This article is protected by copyright. All rights reserved.

http://ift.tt/2uNB0AO

Medikamentöse Neuroprotektion in der Vestibularisschwannomchirurgie

Zusammenfassung

Hintergrund

Eine spezifische medikamentöse perioperative Neuroprotektion ist in der Neurochirurgie ein ungelöstes Problem.

Ziel der Arbeit

Es wird ein Überblick über klinische Studien gegeben, bei denen der Kalziumantagonist Nimodipin und Hydroxyethylstärke (HES) bei der Resektion von Vestibularisschwannomen (VS) eingesetzt wurden. Darüber hinaus wird auf potenzielle neuroprotektive Wirkmechanismen sowie auf die Übertragbarkeit des Konzepts auf andere Eingriffe mit einem Risiko für eine postoperative Nervenfunktionsverschlechterung eingegangen.

Material und Methoden

Sämtliche 10 in der Datenbank PubMed gelisteten klinischen Studien, die den genannten Kriterien entsprechen, wurden ausgewertet.

Ergebnisse

Vier monozentrische Studien mit intraoperativem Beginn der Medikation zeigten einen positiven Effekt für den Funktionserhalt des N. facialis und für den Erhalt der Hörfunktion. In einer Pilotstudie wurde festgestellt, dass die prophylaktische der intraoperativen Gabe überlegen ist. In einer prospektiven multizentrischen Phase-III-Studie zeigten sich keine signifikanten Ergebnisse. Die Funktion des N. facialis war in beiden Gruppen ein Jahr nach der Operation exzellent. Allerdings war die Wahrscheinlichkeit für einen Hörverlust in der Kontrollgruppe doppelt so hoch. Durch eine Kombination der Daten der multizentrischen Studie mit der dazugehörigen Pilotstudie konnte, am ehesten durch eine Erhöhung der Fallzahl, ein signifikanter Therapieeffekt für den Erhalt des Hörvermögens nachgewiesen werden.

Schlussfolgerung

Bei präoperativ erhaltenem Hörvermögen kann die prophylaktische Gabe von Nimodipin empfohlen werden. Der genaue Wirkmechanismus von Nimodipin und Modifikationen der Prophylaxe sollten weiter untersucht werden.

http://ift.tt/2u4IBNL

A Phase 1 Study of OBP-301 in Combination With Radiation Therapy in Patients With Esophageal Cancer

Condition:   Esophageal Cancer
Interventions:   Biological: OBP-301;   Radiation: Radiation
Sponsor:   Oncolys BioPharma Inc
Recruiting - verified July 2017

http://ift.tt/2uNvtKs

Phase 1 Study of CK-301 as a Single Agent in Subjects With Advanced Cancers

Conditions:   Lung Neoplasms;   Carcinoma, Non-Small-Cell Lung;   Carcinoma, Small Cell;   Malignant Mesothelioma, Advanced;   Head and Neck Cancer;   Melanoma;   Merkel Cell Carcinoma;   Renal Cell Carcinoma;   Urothelial Carcinoma;   Classical Hodgkin Lymphoma
Intervention:   Drug: CK-301
Sponsors:   Checkpoint Therapeutics, Inc.;   Novotech (Australia) Pty Limited
Not yet recruiting - verified July 2017

http://ift.tt/2u4YsMl

Apatinib in Treating Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma (NPC)

Condition:   Nasopharyngeal Carcinoma
Intervention:   Drug: Apatinib
Sponsor:   Zhejiang Cancer Hospital
Recruiting - verified July 2017

http://ift.tt/2ueFCTB

GlucoCEST MRI in Oncology

Conditions:   Head and Neck Squamous Cell Carcinoma;   Lymphoma;   Glioma
Interventions:   Other: Glucose infusion;   Diagnostic Test: Magnetic Resonance Imaging (MRI);   Diagnostic Test: FDG PET
Sponsors:   University College, London;   Cancer Research UK
Recruiting - verified July 2017

http://ift.tt/2u4iTJ3

Physical Activities by Technology Help (PATH)

Conditions:   Breast Cancer;   Prostate Cancer;   Lung Cancer;   Colorectal Cancer;   Cervical Cancer;   Oral Cancer
Interventions:   Behavioral: Mycoach Smart Text;   Behavioral: MyCoach on Amazon Alexa
Sponsor:   Johns Hopkins University
Recruiting - verified July 2017

http://ift.tt/2uMS5uD

A Trial of Durvalumab and Tremelimumab in Comibination With SBRT in Patients With Metastatic Cancer

Conditions:   Head and Neck Squamous Cell Carcinoma;   Lung Cancer;   Oesophageal Cancer
Interventions:   Drug: Durvalumab;   Drug: Tremelimumab;   Radiation: SBRT
Sponsor:   Gustave Roussy, Cancer Campus, Grand Paris
Recruiting - verified July 2017

http://ift.tt/2sLAfqA

Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia

Publication date: Available online 10 July 2017
Source:Clinical Immunology
Author(s): Christoph B. Geier, Alexander Piller, Martha M. Eibl, Peter Ciznar, Denisa Ilencikova, Hermann M. Wolf
Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulins levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.



http://ift.tt/2u4OASN

Nasal allergen challenge in clinical practice – A real life study

Publication date: Available online 10 July 2017
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Maciej Kupczyk, Kamila Malewska, Aleksandra Pyziak, Aleksandra Szostakowska, Piotr Kuna
Nasal allergen challenge represents, together with skin tests and specific IgE, one of the basic diagnostic tools used in allergology. The goals of the study were to evaluate types of allergens used, the clinical picture of the challenge, and its safety in our daily clinical practice. In total 136 challenges in 109 patients were analyzed. The study group included 60 women and 49 men, with an average age of 34 years. In 15 patients (13.8% of the study group), apart from allergic rhinitis, bronchial asthma was also diagnosed. Eighty-two patients (75.23%) were challenged with 1, and 27 subjects (24.77%) with 2 allergens. The majority of challenges were performed with house dust mites (58 challenges, 42.6%), followed by Alternaria, mugwort, grasses, birch, hazel, and alder. The clinical picture mimicked the symptoms reported after the natural exposure to the specific allergen. The mean score after the allergen challenge in the group with the positive result was 154.95 points (p<0.05 vs control solution), and in those with negative challenge 36.67 points. Side effects after the challenge, including itchy throat, cough, dyspnea and facial pruritus, were reported by 21 patients. None of side effects was serious or required any medical intervention. Among evaluated factors only female sex (OR 3.59, 95% CI 1.33–9.68, p=0.012), but not diagnosis of asthma, 2 challenges per day or the type of allergen used, was associated with a higher risk of adverse events. In conclusions, nasal allergen challenge represents safe and valuable diagnostic tool in our clinical practice.



http://ift.tt/2u9OXey

High-flow paediatric mandibular arteriovenous malformations: case reports and a review of current management

Publication date: Available online 10 July 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): J. Kaderbhai, O. Breik, A.A. Heggie, A.J. Penington
High-flow vascular malformations in the paediatric population are potentially life-threatening and are challenging to treat. This paper describes the management of three cases of mandibular arteriovenous malformations and reviews the contemporary management options for these serious lesions.



http://ift.tt/2u9vDOa

UVA1 vs. narrowband UVB phototherapy in the treatment of palmoplantar pustulosis: a pilot randomized controlled study

Abstract

UVA1 phototherapy, a new therapeutic approach, has recently been shown good efficacy in the treatment of palmoplantar pustulosis (PPP). The purpose of this study was to compare the efficacy of UVA1 and narrowband UVB (NB-UVB) therapy in the treatment of PPP. Patients with PPP were randomly assigned to either UVA1 or NB-UVB therapy according to a left-right randomization table. Both treatments were performed three times weekly for up to 30 sessions. Clinical evaluation was based on the Palmoplantar Pustular Psoriasis Area and Severity Index (PPPASI) score. Totally 64 patients completed the study. Both UVA1 and NB-UVB therapy showed a statistically significant reduction of PPPASI score compared with the baseline value at the end of the treatment period (P < 0.05). There was a significantly greater mean reduction of PPPASI score in the UVA1 treated group when compared to the NB-UVB treated patients at 30 sessions (6.0 ± 2.4 vs. 4.4 ± 1.4, P < 0.05). No phototoxic reaction or bullous changes were observed in either group. Both NB-UVB and UVA1 phototherapy of PPP resulted in significant improvement. UVA1 phototherapy was more effective than NB-UVB irradiation in the treatment of PPP.

http://ift.tt/2t98KGy

Autoimmune aspects of psoriasis: Heritability and autoantigens

Publication date: Available online 10 July 2017
Source:Autoimmunity Reviews
Author(s): Jörg Christoph Prinz
Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.



http://ift.tt/2udMVKS

International consensus: what else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren’s syndrome)?

Publication date: Available online 11 July 2017
Source:Autoimmunity Reviews
Author(s): Roberto Giacomelli, Antonella Afeltra, Alessia Alunno, Chiara Baldini, Elena Bartoloni-Bocci, Onorina Berardicurti, Francesco Carubbi, Alberto Cauli, Ricard Cervera, Francesco Ciccia, Paola Cipriani, Fabrizio Conti, Salvatore De Vita, Paola Di Benedetto, Andrea Doria, Alexandros A. Drosos, Ennio Giulio Favalli, Saviana Gandolfo, Mariele Gatto, Rosa Daniela Grembiale, Vasiliki Liakouli, Rik Lories, Ennio Lubrano, Claudio Lunardi, Domenico Paolo Emanuele Margiotta, Laura Massaro, Pierluigi Meroni, Antonia Minniti, Luca Navarini, Monica Pendolino, Federico Perosa, Jacques-Olivier Pers, Marcella Prete, Roberta Priori, Francesco Puppo, Luca Quartuccio, Amelia Ruffatti, Piero Ruscitti, Barbara Russo, Piercarlo Sarzi-Puttini, Yehuda Shoenfeld, George A. Somarakis, Francesca Romana Spinelli, Elisa Tinazzi, Giovanni Triolo, Francesco Ursini, Gabriele Valentini, Guido Valesini, Serena Vettori, Claudio Vitali, Athanasios G. Tzioufas
Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified.Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained.This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.



http://ift.tt/2uMjaOF

Subjektive Patientenzufriedenheit nach Nasenseptumplastik

Zusammenfassung

Hintergrund

Die Nasenseptumplastik (SPL) ist eine der häufigsten Operationen in Deutschland. Die SPL stellt somit eine hohe Kostenbelastung für das Gesundheitssystem dar. Es fehlen bislang ausreichende Daten zur postoperativen Patientenzufriedenheit und objektive Indikationskriterien zur Durchführung der Operation.

Ziel der Arbeit

Ziel dieser Studie war es, die postoperative Patientenzufriedenheit und Faktoren zu bestimmen, die den subjektiven Erfolg einer SPL günstig oder ungünstig beeinflussen, um damit präoperativ die Indikationsstellung zu optimieren.

Methoden

Insgesamt wurden 600 Fragebögen versendet, davon konnten die Daten von 238 Patienten (60 w, 178 m), bei denen eine SPL in der Klinik erfolgt war, in die Studie eingeschlossen werden. Die Befragung erfolgte retrospektiv mithilfe validierter Fragebögen (Nose-D, SNOT-20-GAV) sowie einem selbst entworfenem Fragebogen hinsichtlich der subjektiven Zufriedenheit nach SPL. Ferner wurden die klinischen Daten aus der Patientenakte erfasst.

Ergebnisse

Die Follow-up-Dauer der Studie betrug zwischen 2 und 11 Jahren. Als Hauptgrund zur Durchführung einer SPL gaben 89 % (212) der Patienten eine behinderte Nasenatmung an. Mit dem Ergebnis der SPL zufrieden waren 68 % (161). Nochmals zur Operation entschließen würden sich 73 % (172). Die Scores der visuellen Analogskalen für Nasenatmungsbehinderung, Riechen, Sekretfluss, körperliche Leistungsfähigkeit, Privinismus und Kopfschmerzen zeigten sich postoperativ statistisch signifikant verbessert. Auch die Auswertungen von Nose-D und SNOT-20-GAV ergaben eine signifikante Verbesserung der Scores. Patienten mit einer längeren Verweildauer der Septumfolien zeigten sich zufriedener als bei kurzer Liegezeit. Keinen signifikanten Einfluss hatten Voroperationen.

Schlussfolgerungen

Bei korrekter Indikationsstellung stellt die SPL eine Operationsmethode mit hoher Patientenzufriedenheit dar, die mit einer signifikanten Verbesserung der präoperativen Beschwerden einhergeht. Die Hauptbeschwerde der Patienten sollte eine behinderte Nasenatmung sein.

http://ift.tt/2u94vyU

Die Prophylaxe venöser Thromboembolien bei Kopf‑Hals‑Operationen

Zusammenfassung

Hintergrund

Die Anwendung einer perioperativen Thromboseprophylaxe bei Operationen im Kopf-Hals-Bereich folgt in Deutschland keinen einheitlichen Standards. In der aktuellen S3-Leitlinie zur Prophylaxe venöser Thromboembolien wird zu einem restriktiven Einsatz einer medikamentösen Prophylaxe geraten; es finden sich vor dem Hintergrund der geringen Datenlage jedoch kaum spezifische Empfehlungen für die HNO-Heilkunde.

Ziel

Ziel der vorliegenden Arbeit ist es, anhand einer systematischen Literaturrecherche und der aktuellen S3-Leitlinie konkrete Handlungsempfehlungen zu geben.

Material und Methoden

Auf der Basis einer aktuellen systematischen Literaturrecherche und der S3-Leitlinie „Prophylaxe venöser Thromboembolien" werden die vorhandene Evidenz beschrieben und ein klinischer Algorithmus erstellt.

Ergebnisse

Es wurden 8 zusätzliche Kohortenstudien zur Inzidenz thromboembolischer Ereignisse in der HNO-Heilkunde identifiziert. Randomisierte kontrollierte Studien fehlen. In dem vorgelegten Algorithmus wird eine individuelle Evaluation von dispositionellem (Anamnese) und expositionellem (Op.-Dauer) Risiko in je 3 Gruppen empfohlen. Dies ermöglicht eine schnelle präoperative Risikostratifizierung. Bei kurzen Eingriffen mit geringer Gewebstraumatisierung kann dabei auf eine regelhafte medikamentöse Prophylaxe verzichtet werden, wenn keine Risikofaktoren dritten Grades vorliegen (stattgehabte venöse Thromboembolie, bekannte Koagulopathie oder maligne Erkrankung). Die medikamentöse Prophylaxe sollte mit niedermolekularem Heparin durchgeführt werden.

Schlussfolgerung

Die vorhandene Evidenz in Bezug auf die Thromboseprophlyaxe bei Operationen im Kopf-Hals-Bereich ist limitiert, die Frage nach einer Prophylaxe jedoch von hoher klinischer Relevanz. Das vorgelegte Konzept stellt einen konkreten Handlungsvorschlag für operativ tätige HNO-Ärzte und Kliniken dar.

http://ift.tt/2u9dh01

Efficacy and safety of secukinumab in treating moderate to severe plaque psoriasis in two real-world Canadian dermatology clinics: a multicenter retrospective study

Abstract

Secukinumab is an interleukin (IL)-17A antagonist approved in 2015 by health agencies around the world for the treatment of moderate to severe plaque psoriasis in adult patients. Current knowledge of the efficacy and safety of secukinumab is limited to data from phase III randomized controlled trials (RCT). Despite the acceptable safety profile and promising efficacy results, there remains to be a lack of understanding of treatment outcomes in real-world clinical practice.

This article is protected by copyright. All rights reserved.

http://ift.tt/2tIUyWJ

Systemic contact dermatitis induced by roots of Hosta plantaginea

Abstract

In East Asia, herbs are not only used by traditional medical practitioners but also commonly eaten by public. Compositae and Rhus are well-known antigens that can cause allergic contact dermatitis, but the other herbs are not well studied for antigenicity. Hosta plantaginea (also known as 'August lily' or 'Plantain lily') is originated from China and usually grown for ornamental purposes (Fig. 1a~c). In traditional medicine, flowers are used as oral medicines for sore throat or dysuria and sometimes topically applied for burn.

This article is protected by copyright. All rights reserved.

http://ift.tt/2sZURzm

Acute heart failure as a result of granulomatous myocarditis: case report on a patient with metastatic melanoma treated with dabrafenib and trametinib

Abstract

Treatment options for metastatic melanoma have changed substantially in recent years. Targeting immune checkpoints has improved prognosis of melanoma patients. For melanomas harboring BRAF mutations, inhibition of the mitogen-activated protein kinase pathway is a promising therapeutic option. Combined BRAF and MEK inhibition improves progression-free and overall survival.

This article is protected by copyright. All rights reserved.

http://ift.tt/2uMoPEe

Recognizing Syndromic Hidradenitis Suppurativa: a review of the literature

Abstract

Background

Hidradenitis suppurativa (HS) is an inflammatory skin disease causing painful inflammation and suppuration. It may occur in rare syndromes: follicular occlusion, Bazex-Dupré-Christol, Down's, KID, PAPASH, PASS, PASH, and SAPHO syndromes, as well as Dowling-Degos disease. An overview of syndromic HS may inform the search for etiological factors in HS.

Methods

Pubmed, Ovid, and Web of Science were systematically searched using "(hidradenitis OR acne invers*) AND (syndrome OR KID OR PASS OR PAPA OR PASH OR SAPHO OR bazex-dupre OR "dowling degos" OR triad OR tetrad)" and Cochrane Library using "hidradenitis OR acne invers*". A total of 82 articles were included in the final review.

Results

We summarize 134 cases collected from the 82 included articles. The syndromes are discussed, focusing on etiopathogenesis, clinical presentation, and treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2tJ7KLg

Actinic keratoses treated with cold atmospheric plasma

Abstract

Plasma is a partially or fully ionized gaseous state of matter containing chemically active species, such as ions, electrons, photons, reactive oxygen and nitrogen species, and UV light. Cold atmospheric plasma (CAP) can be applied onto vital, heat-sensitive surfaces and is currently used in surgery, endoscopic procedures, and wound care with proven antimicrobial efficacy and the ability to deactivate pathogens, stop bleeding and stimulate cell proliferation ¹². Recent pre-clinical observations suggested an anti-tumoral potential, for example in melanoma, glioma and colorectal carcinoma cells ³⁴.

This article is protected by copyright. All rights reserved.

http://ift.tt/2udwsq5

Dermoscopic and reflectance confocal microscopy features of cutaneous squamous cell carcinoma

Abstract

Background

Squamous cell carcinoma (SCC) of the skin is a highly prevalent neoplasm. The management and the prognosis of this tumor is dependent on its invasiveness and its grade of differentiation.

Objectives

To evaluate whether specific dermoscopic and reflectance confocal microscopy (RCM) criteria can predict the diagnosis of invasive SCC vs in situ SCC and poorly differentiated compared with well- and moderately differentiated SCC.

Methods

Dermoscopic and RCM images of SCCs were retrospectively evaluated for the presence of predefined criteria.

Results

Among 143 SCC, 121 cases had a complete set of images and thus were included in the study set. The head and neck area was the most frequently involved body site (74/121; 61.1%) followed by extremities (36/121, 29.7%) and trunk (11/121, 9.1%). Seventy tumors were in situ (57.8%), while 51 were invasive (42.1%), of these 11 were poorly differentiated (21.5%), 16 were moderately differentiated (31.3%), and 24 were well differentiated (47.0%). Chi-squared analysis demonstrated that invasive SCC were characterized by polymorphic vessels, erosion/ulceration, architectural disarrangement, speckled nucleated cells in the dermis, irregularly dilated vessels and absence of hyperkeratosis. Botton-hole vessels, white structureless areas and dotted or glomerular vessels were significantly associated with in situ lesions. Poorly differentiated SCC were typified by red areas, erosion/ulceration and architectural disarrangement. Well or moderately differentiated SCC were associated with white areas and speckled nucleated cells in the epidermis.

Conclusion

Clinical, dermscopic and RCM images provide useful information that should be integrated in order to achieve the optimal therapeutic management for the patient.

This article is protected by copyright. All rights reserved.

http://ift.tt/2sZBnej

Frequent Loss of Inositol Polyphosphate-5-Phosphatase in Oropharyngeal Squamous Cell Carcinoma

Abstract

There is an incomplete understanding in the pathogenesis of oropharyngeal squamous cell carcinoma (OPSCC) and cancer broadly. It is essential to discover new pathways of normal cell-cycle regulation and oncogenesis. We identified that the loss of inositol polyphosphate-5-phosphatase (INPP5A) may play a role in the development and progression of cutaneous squamous cell carcinoma (SCC).¹ Loss of INPP5A has been previously linked to cancer development and progression.²

This article is protected by copyright. All rights reserved.

http://ift.tt/2tIMk11

Patient-reported signs of dampness at home may be a risk factor for chronic rhinosinusitis: A cross-sectional study

Abstract

Background

An association between dampness at home and respiratory conditions has been convincingly demonstrated in children. Fewer studies have been performed in adults and data are lacking for chronic rhinosinusitis (CRS). With a prevalence of 10.9% in Europe, CRS imposes a significant burden on quality of life, as well as economy.

Objective

Our aim was to study CRS and other respiratory conditions in relation to dampness at home in a representative sample of adults.

Methods

The Swedish GA²LEN questionnaire was answered by 26,577 adults (16-75 y) and included questions on respiratory symptoms, smoking, education and environmental exposure. CRS was defined according to the EP³OS criteria. Dampness was defined as reporting water damage, floor dampness or visible moulds in the home during the last 12 months. The dampness score was ranked from 0-3, counting the number of signs of dampness reported.

Results

Dampness at home was reported by 11.3% and was independently related to respiratory conditions after adjustment for demographic and socio-economic factors and smoking: CRS odds ratio (OR) 1.71; allergic rhinitis OR 1.24; current asthma OR 1.21; wheeze OR 1.37; nocturnal dyspnea OR 1.80; nocturnal coughing OR 1.34 and chronic bronchitis OR 1.64. The risk of CRS and most of the other respiratory conditions was further elevated in subjects reporting multiple signs of dampness.

Conclusions & Clinical Relevance

This study demonstrated an independent association between dampness at home and CRS in adults. The high burden of this and the other respiratory conditions studied is a strong argument in favour of countering indoor dampness by improving building standards.

This article is protected by copyright. All rights reserved.

http://ift.tt/2t8SPZ5

Biofunctionalization of porcine-derived collagen matrix using enamel matrix derivative and platelet-rich fibrin: influence on mature endothelial cell characteristics in vitro

Abstract

Objectives

The present study evaluated the effect of an enamel matrix derivative (EMD) and platelet-rich fibrin (PRF)-modified porcine-derived collagen matrix (PDCM) on human umbilical vein endothelial cells (HUVEC) in vitro.

Materials and methods

PDCM (mucoderm®) was prepared to 6 mm (±0.1 mm) diameter discs. PDCM samples were incubated with either EMD, PRF, or control solutions for 100 min at 4 °C before the experiments. Cell-inducing properties of test materials on HUVEC cells were tested with cell proliferation assays (MTT, PrestoBlue®), a cytotoxicity assay (ToxiLight®), a Boyden chamber migration assay, and a cell attachment assay. Scanning electron microscopy (SEM) imaging was performed to determine the surface and the architecture of the modified matrices.

Results

Cell proliferation was elevated in the EMD and PRF groups compared with control (p each ≤0.046). PRF modification increased HUVEC migration ability by 8-fold compared with both control and EMD groups (p each <0.001). Both treatments significantly promoted the cell attachment of HUVEC to PDCM, as assessed by direct cell counts on the matrices (p each <0.001).

Conclusions

HUVEC cell characteristics were overall improved by EMD- and PRF- modified PDCM. Adsorbed bioactive molecules to the PDCM surface may have contributed to a more preferable environment to surrounding cells.

Clinical relevance

The results may give evidence that PDCM modification with EMD or PRF, respectively, might be a useful approach to improve clinical outcomes, to prevent inflammatory reactions and wound-healing disturbances, and to expand the clinical application area of PDCM.

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Erythema multiforme triggered by imiquimod 5% cream

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Dermoscopy of syringocystadenoma papilliferum

Abstract

Syringocystadenoma papilliferum is a benign adnexal neoplasm frequently seen in association with other adnexal tumours. We report the dermoscopic features of three cases of syringocystadenoma papilliferum developing in naevus sebaceus. Clinically the lesions were characterised by exophytic papillary structures. Dermoscopically, polymorphous vessels were the prevalent feature.

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A rural environment does not protect against asthma or other allergic diseases amongst Mexican children

Publication date: Available online 4 May 2017
Source:Allergologia et Immunopathologia
Author(s): M. Bedolla-Barajas, F. Javier Ramírez-Cervantes, J. Morales-Romero, J. Jesús Pérez-Molina, C. Meza-López, N. Delgado-Figueroa
IntroductionThe commonly held notion that a rural environment decreases the frequency of allergic diseases has proven to be inconsistent amongst children.ObjectiveOur objective was to contrast the prevalence of bronchial asthma (BA), allergic rhinitis (AR), and atopic dermatitis (AD) between children that live in a rural environment and those that live in urban areas.MethodsWe carried out a cross-sectional study amongst children aged six to seven; they were selected through probabilistic, stratified and conglomerated sampling. The prevalence of BA, AR, and AD was identified with the use of the questionnaire provided by The International Study of Asthma and Allergies in Childhood, additionally, we inquired about each child's family history of atopy, their exposure to farm animals, the intake of unpasteurised cow's milk, and the number of siblings related to every child. We used logistic regression and multivariate analysis to determine the correlation between asthma, allergic diseases, and rural environment.ResultsWe included 189/1003 (18.8%) children from a rural environment, and 814/1003 (81.2%) from an urban area. BA and AR were associated to a family history of atopy (OR=2.15, p=0.001; OR=2.58, p=0.002, respectively). BA was more prevalent in males (OR=1.92, p=0.007). Notably, a higher number of siblings seems to protect against AR (OR=0.45, p=0.008). A paternal history of allergies was associated to AD.ConclusionsIn our study, we were unable to find protective factors in a rural environment that might decrease the prevalence of asthma or allergic diseases.



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The protective role of Helicobacter pylori neutrophil-activating protein in childhood asthma

Publication date: Available online 31 May 2017
Source:Allergologia et Immunopathologia
Author(s): A. Karakullukcu, H.B. Tokman, S. Nepesov, M. Demirci, S. Saribas, S. Vehid, R. Caliskan, Z. Taner, H. Cokugras, T. Ziver, S. Demiryas, B. Kocazeybek
BackgroundHelicobacter pylori quantity and HP-NAP gene expression were evaluated in the faeces of healthy and asthmatic children.MethodsH. pylori DNAs and RNAs were isolated from the stool samples of 92 asthmatic children (AC; 3–8 years) and 88 healthy controls (HC). Quantitative PCR was used to determine the quantity of H. pylori and HP-NAP expression relative to the 16S rRNA (reference gene). Gene expression was analysed using the delta delta-Ct method.ResultsH. pylori DNA was detected in the stool samples of 18 (20.4%) of the 88 HC (p<0.0001, OR=0.79) and none of AC. No meaningful statistical differences were found between individuals with positive and negative family histories for asthma in AC and HC (p>0.05). H. pylori quantity was higher in seven of 18 H. pylori-positive samples, but HP-NAP expression levels were low in four of these seven samples. Based on a multivariate logistic regression analysis of these three variables together, only males displayed a significant difference based on gender differences (p<0.02) and it was determined that, based on the OR value of 0.46 and the 95% CI range of 0.241–0.888, male gender was an independent protective factor in asthma.ConclusionsHP-NAP levels vary to the relative concentrations of bacteria in the stationary or late logarithmic phases. Different napA expression levels may be caused by different endogenous napA gene expression or different environmental conditions.



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