Chemically modified peanut extract shows increased safety while maintaining immunogenicity

Abstract

Background

Peanuts are most responsible for food‐induced anaphylaxis in adults in developed countries. An effective and safe immunotherapy is urgently needed. The aim of this study was to investigate the immunogenicity, allergenicity and immunotherapeutic efficacy of a well characterized chemically modified peanut extract (MPE) adsorbed to Al(OH)₃.

Methods

Peanut extract (PE) was modified by reduction and alkylation. Using sera of peanut allergic patients, competitive IgE‐binding assays and mediator release assays were performed. The immunogenicity of MPE was evaluated by measuring activation of human PE‐specific T‐cell lines and the induction of PE‐specific IgG in mice. The safety and efficacy of MPE adsorbed to Al(OH)₃ was tested in two mouse models by measuring allergic manifestations upon peanut challenge in peanut allergic mice.

Results

Compared to PE, the IgE‐binding and capacity to induce allergic symptoms of MPE was lower in all patients. PE and MPE displayed similar immunogenicity in vivo and in vitro. In mice sensitized to PE, the threshold for anaphylaxis (drop in BT) upon subcutaneous challenge with PE was 0.01 mg, while at 0.3 mg MPE no allergic reaction occurred. Anaphylaxis was not observed when PE and MPE were fully adsorbed to Al(OH)₃. Both PE and MPE + Al(OH)₃ showed to be efficacious in a model for immunotherapy.

Conclusion

In our studies an Al(OH)₃ adsorbed MPE showed reduced allergenicity compared to unmodified PE, while the efficacy of immunotherapy is maintained. The preclinical data presented in this study supports further development of modified peanut allergens for IT.

This article is protected by copyright. All rights reserved.

from Allergy and Immunology via a.sfakia on Inoreader https://ift.tt/2RpHSiI

Much ado about Biologicals:Highlights of the Master Class on Biologicals, Prague, 2018

from Allergy and Immunology via a.sfakia on Inoreader https://ift.tt/2KNb3th

Rush desensitization with a single antigen induces subclinical activation of mast cells and protects against bystander challenge in dually sensitized mice

Abstract

Background

Rush desensitization can provide short‐term tolerance to individuals who are allergic to certain medications in instances where other therapeutic interventions are limited. While rush DS is typically successful in preventing adverse type I hypersensitivity reactions, the mechanism of allergic protection remains unknown. Given the rise in prevalence of individuals displaying multiple allergies, understanding the impact of rush DS on "bystander" allergens, or additional allergens to which an individual is sensitized, could help inform clinical recommendations.

Objective

To evaluate the effect of rush DS on bystander sensitization.

Materials and Methods

We used a murine model of rush DS, whereby BALB/c mice were sensitized to ovalbumin (OVA) and desensitized through repeated intraperitoneal injections of OVA. Using a local anaphylaxis assay, we measured ear swelling by Evans blue extravasation following intradermal challenge. In studies to measure the impact on bystander antigens, a modified protocol was used in which mice were dually sensitized to OVA and Keyhole limpet hemocyanin (KLH), and densensitized to either OVA or KLH prior to allergic challenge.

Results

The immunological effects of rush DS were independent of changes in Th1 and Th2 cytokine production and circulating OVA‐IgE levels. Instead, rush DS resulted in subclinical degranulation of mast cells prior to challenge. In our dual sensitization model, rush DS with a single antigen conferred protection against allergic challenge to a secondary antigen. Bystander protection required prior sensitization, as DS with an irrelevant antigen did not impact allergic responsiveness.

Conclusions and Clinical Relevance

We reveal that a key mechanism of rush DS protection against allergic responsiveness may be the subclinical degranulation of mast cells. Therefore, performing rush DS to a single antigen to which one is IgE‐sensitized may be sufficient to desensitize to multiple allergens. Future studies could lead to streamlined protocols of rush DS for patients with multiple allergies.

This article is protected by copyright. All rights reserved.

from Allergy and Immunology via a.sfakia on Inoreader https://ift.tt/2FVch7a

An integrated framework using high‐dimensional mass cytometry and fluorescent flow cytometry identifies discrete B cell subsets in patients with red meat allergy

Abstract

Background

B cells play a critical role in the development and maintenance of food allergy by producing allergen‐specific IgE. Despite the importance of B cells in IgE‐mediated food allergy, the identity of sIgE‐producing human B cells and how IgE is regulated are poorly understood.

Objective

To identify the immunophenotypes of circulating B cells associated with the production of galactose‐alpha‐1,3‐galactose specific IgE production in patients with red meat allergy.

Methods

B cells in PBMC samples obtained from 19 adults with physician‐diagnosed red meat allergy and 20 non‐meat allergic healthy controls were assessed by mass cytometry along with a bioinformatics analysis pipeline to identify discrete B cell phenotypes that associated with serum sIgE. Fluorescent flow cytometry was then applied to sort purify discrete B cell subsets, and B cells were functionally evaluated on an individual cell level for the production of sIgE by ELISPOT.

Results

Discrete B cell phenotypes abundant in meat allergic subjects compared to non‐meat allergic controls were found in peripheral blood that do not share typical characteristics of classical isotype‐switched memory B cells that express high levels of CD27. These B cell subsets shared higher IgD and lower IgM expression levels coupled with CXCR4, CCR6 and CD25 expression. In vitro polyclonal stimulation of purified B cell subsets from meat allergic subjects demonstrated that these subsets were enriched for cells induced to secrete sIgE.

Conclusions and Clinical Relevance

Circulating B cells display increased abundance of discrete B cell subsets in meat allergic subjects. This observation, coupled with the capacity of individual B cell subsets to produce sIgE following activation, implicates these novel B cell phenotypes in promoting IgE in meat allergy.

This article is protected by copyright. All rights reserved.

from Allergy and Immunology via a.sfakia on Inoreader https://ift.tt/2rjkzvf

Effect of Implant‐Supported Mandibular Overdentures versus Reline on Masticatory Performance and Salivary Flow Rates in Very Old Adults ‐ a randomized clinical trial

Abstract

Purpose

To compare the masticatory efficiency (ME), maximum voluntary bite force (MBF), masseter muscle thickness (MMT) and salivary flow rates (SFR) in completely edentulous dependent elders treated either with a conversion of their existing mandibular complete removable dental prostheses (CRDP) into a 2‐implant overdenture (IOD) or a conventional reline of the CRDP.

Material and Methods

Participants were randomly allocated into intervention (IG), and control (CG) group. The IG received two implants in the mandibular canine regions and their CRDPs were transformed into IODs. The CG received a conventional reline of their mandibular CRDPs. Outcomes were recorded at each recall visit (baseline, immediately‐, 3 months‐, 12 months‐ after intervention and, subsequently on an annual basis). Statistical analyses used mixed linear regression models (level of significance: p<0.05).

Results

The IG comprised 16 participants (age=85.0±6.2 years), while the CG comprised 16 (age=84.8±5.4 years), with a mean follow‐up of 2.7± 2.2 years (range 3m to 7y). A significant increase of MBF in the IG (p<0.001) was observed with an overall gain of 80 N (p<0.001) compared with the reline group. There were no significant long‐term changes in SFR, MMT, or ME within/between groups.

Conclusion

Since dependent elders with mandibular IODs present a significant gain in MBF, but no relative increase in SFR, MMT, and ME, it seems that this increased capacity of MBF is not exploited by the elders during their habitual chewing.

This article is protected by copyright. All rights reserved.

from OroFacial via a.sfakia on Inoreader https://ift.tt/2RqHdNO

Eficacia de la imagen precoz con 68Ga-PSMA-I&T para la discriminación de lesiones en los pacientes con cáncer de próstata

Publication date: Available online 1 December 2018

Source: Revista Española de Medicina Nuclear e Imagen Molecular

Author(s): F. Özülker

Resumen

Objetivo

El ⁶⁸Ga-PSMA muestra captación en las lesiones malignas de los pacientes de cáncer de próstata a los 5 min postinyección. Los estudios realizados para comprender el valor de añadir una imagen pélvica precoz al protocolo de imagen de ⁶⁸Ga-PSMA-11 PET/TC muestran resultados contradictorios. En este estudio, planificamos la evaluación de la relevancia de añadir una imagen precoz a ⁶⁸Ga-PSMA-I&T PET/TC en los pacientes con cáncer de próstata.

Materiales y métodos

Reunimos a un total de 35 pacientes con cáncer de próstata, a quienes se les prescribió ⁶⁸Ga-PSMA-I&T PET/TC para reestadificar la enfermedad, debido a sospecha de recidiva tras la terapia definitiva. En primer lugar, se obtuvo una imagen pélvica estática precoz, a un máximo de 300 s tras la inyección del radiotrazador. A los 60 min de la inyección se realizó una PET/TC de cuerpo entero, con un tiempo de emisión de 3 min por posición del lecho. Se compararon las lesiones categorizadas en las imágenes precoces como recidiva local, lesión ósea y metástasis ganglionar con las imágenes tardías en términos de lesiones detectadas y valores SUVmax.

Resultados

La⁶⁸Ga-PSMA-I&T PET/TC fue positiva en 23 de los 35 pacientes (65,7%). Se observó una captación patológica en el lecho prostático, en los ganglios pélvicos y en los huesos en 17 pacientes (48,5%), 12 pacientes (34,2%) y 13 pacientes (37,1%), respectivamente. En un paciente, se detectó una captación incrementada patológica focal en el lecho prostático con un valor SUVmax de 5,8, aunque esta lesión desapareció en las imágenes tardías. Los valores SUVmax medios de las lesiones en el lecho prostático fueron 13,7 ± 12,1 frente a 26,3 ± 23,8 en los estudios a los 5 min y 60 min, respectivamente (p < 0,001). En un paciente, la captación patológica ganglionar en el estudio temprano desapareció en el estudio tardío, mientras que en otro paciente la acumulación de actividad se detectó en un ganglio pélvico en el estudio tardío, pero no se detectó ningún ganglio en el estudio temprano. Los valores SUVmax ganglionares medios fueron 12,1 ± 8,8 frente a 26,3 ± 22,6 en los estudios a los 5 min y 60 min, respectivamente (p < 0,001). Los valores SUVmax medios de las lesiones óseas fueron 11,4 ± 6,9 frente a 15 ± 10,7 en los estudios a los 5 min y 60 min, respectivamente.

Conclusión

Nuestro estudio es el primero en la literatura que evalúa el impacto de añadir una imagen pélvica estática temprana a ⁶⁸Ga-PSMA-I&T, para valorar la tasa de detección de las lesiones. Aunque no se produjo una discordancia marcada entre los 2 conjuntos de imágenes, la adición de una imagen temprana al protocolo de imagen de ⁶⁸Ga-PSMA-I&T podría incrementar la eficacia en la detección de las lesiones pélvicas malignas, lo cual podría reflejar un rápido aclaramiento, con el riesgo de que fuera enmascarado por la actividad del sistema urinario.

Abstract

Objective

⁶⁸Ga-PSMA-uptake shows accumulation in the malignant lesions of prostate cancer patients as early as 5 min p.i. Studies indicate the value of adding an early image of the pelvis to the imaging protocol of ⁶⁸Ga-PSMA-11 PET/CT scan showed contradictory results. In this study we planned to assess the significance of an additional early imaging in ⁶⁸Ga-PSMA-I&T PET/CT imaging in prostate cancer patients.

Materials and methods

A total of 35 prostate cancer patients referred to ⁶⁸Ga-PSMA-I&T PET/CT imaging for restaging of the disease due to suspicion of relapse after definitive therapy were enrolled. First an early static pelvic image was obtained at a maximum of 300 s following injection of the radiotracer. Sixty minutes postinjection a whole-body PET/CT scan was conducted with an emission time of 3 min per bed position. The lesions which were categorized as local recurrence, bone lesion and lymph node metástasis in the early images, were compared with the late images in terms of number of lesions detected and SUVmax values.

Results

⁶⁸Ga-PSMA-I&T PET/CT was positive in 23 of 35 patients (65.7%). A pathological uptake was observed in the prostatic bed site, in the pelvic lymph nodes, and in the bones in 17 patients (48.5%), 12 patients (34.2%), and 13 patients (37.1%), respectively. In one patient, focal pathological increased uptake in the prostatic bed with a SUVmax value of 5.8 was detected but this lesion disappeared in the late images. The average SUVmax values of the lesions in the prostatic bed were 13.7 ± 12.1 versus 26.3 ± 23.8 in the 5 min and 60 min studies respectively (p < 0.001). In one patient, the pathological uptake in the lymph node in the early study cleared in the late study, whereas in another accumulation of activity was detected in a pelvic lymph node in the late study, while there was no lymph node detected in the early study. The average SUVmax values of the lymph nodes were 12.1 ± 8.8 versus 26.3 ± 22.6 in the 5 min and 60 min studies respectively (p < 0.001). The average SUVmax values of the bone lesions were 11.4 ± 6.9 versus 15 ± 10.7 in the 5 min and 60 min studies respectively.

Conclusion

Our study is the first in the literature to evaluate the impact of adding an early static pelvic image to the ⁶⁸Ga-PSMA-I&T scan, in the detection rate of the lesions. Although there was no marked discordance between the 2 sets of images, the addition of an early image to the imaging protocol of ⁶⁸Ga-PSMA-I&T scan would increase the efficacy of detection of malignant lesions in the pelvis, which might show rapid clearance and has the risk of being masked by the urinary system activity.

from Imaging via a.sfakia on Inoreader https://ift.tt/2Rt5hQl

Emergent cervical internal carotid artery angioplasty before endovascular thrombectomy for acute ischemic stroke: a report of clinical and imaging outcome

Publication date: Available online 2 December 2018

Source: Clinical Imaging

Author(s): Abdullah Alrashed, Adam A. Dmytriw, Victor X.Y. Yang

Abstract

A case of tandem occlusion consisting of right internal carotid artery (ICA) origin dissection and middle cerebral artery (MCA) thromoboembolism is reported. A 45 year-old male with right-sided neurological symptoms of emergent large vessel occlusion was treated with same-session angioplasty and mechanical thrombectomy of the respective lesions. The complete neurological recovery and radiological investigations are chronicled herein, and a review of the state of tandem occlusion management is discussed.

from Imaging via a.sfakia on Inoreader https://ift.tt/2E9dxSi

Combined juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia (JPS/HHT) with MRI and endoscopic correlation

Publication date: Available online 2 December 2018

Source: Clinical Imaging

Author(s): Andrew D. Chung, Koenraad J. Mortelé

Abstract

Juvenile polyposis syndrome (JPS) may coexist with hereditary hemorrhagic telangiectasia (HHT) due to implication of the SMAD4 gene in a subset of both diseases. To the best of our knowledge, we present the first case in the radiologic literature on the MRI findings in a patient with this rare combined diagnosis undergoing workup for burden of disease.

Graphical abstract

from Imaging via a.sfakia on Inoreader https://ift.tt/2SrGMDb

The Effect of Motion Correction Interpolation on Quantitative T1 Mapping with MRI

Publication date: Available online 1 December 2018

Source: Medical Image Analysis

Author(s): Amitay Nachmani, Roey Schurr, Leo Joskowicz, Aviv A. Mezer

Abstract

Quantitative magnetic resonance imaging (qMRI) is a technique for mapping the physical properties of the underlying tissue using several MR images with different contrasts. To overcome subject motion between the acquired images, it is necessary to register the images to a common reference frame. A drawback of registration is the use of interpolation and resampling techniques, which can introduce artifacts into the interpolated data. These artifacts could have unfavorable effects on the accuracy of the estimated tissue's physical properties. Here, we quantified the error of interpolation and resampling on T1-weighted images and studied its effects on the mapping of the longitudinal relaxation time (T1) using variable flip angles. We simulated T1-weighted images and calculated the transformation error resulting from interpolation and resampling. We found that the error is a function of the image contrast (i.e., flip angle) and of the translation and rotation of the image. Furthermore, we found that the error in the T1-weighted images has a substantial effect on the T1 estimation, of the order of 10% of the signal in the brain's gray and white matter. Hence, minimizing the registration error can enable more accurate in vivo modeling of brain microstructure.

Graphical Abstract

from Imaging via a.sfakia on Inoreader https://ift.tt/2Eatp7g