Τρίτη, 4 Ιουνίου 2019

It is not necessary to take 10–12 core biopsy samples in men with PSA levels >20 ng/ml. We recommend taking 2, 4, and 6 samples for patients with PSA levels ≥100 ng/ml, 50–99.99 ng/ml, and 20–49.99 ng/ml, respectively.

Prostate cancer incidence and diagnosis in men with PSA levels >20 ng/ml: is it possible to decrease the number of biopsy cores?

Alper Ozorak ORCID Icon, Ali Ersin Zumrutbas, Gungor Bingol, Yusuf Ozlulerden & Sefa Alperen Ozturk

Received 09 Apr 2019, Accepted 14 May 2019, Published online: 01 Jun 2019

Download citation  https://doi.org/10.1080/13685538.2019.1620204  

 

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Abstract

Objectives: To define if less number of cores would be sufficient to diagnose prostate cancer (PCa) in men with PSA levels >20 ng/ml and to reveal the cancer detection rates in this population.



Methods: The data of the men who had 12-core prostate biopsy with a PSA value >20 ng/mg were reviewed. We recorded age, prostate volume, PSA level, and pathology report findings. Patients grouped according to PSA levels and compared for PCa detection rates, and several parameters. We created 16 prostate biopsy scenarios (S1–S16) and applied these to our database to find out the best biopsy protocol to detect PCa.



Results: A total of 336 patients with a mean age of 70.5 (47–91) years were included. Mean PSA level was 190.6 (20–5474) ng/ml. PCa detection rates were 55.3%, 81.0%, and 97.7% in patients with PSA levels 20–49.99, 50–99.99, and ≥100 ng/ml, respectively. PSA level was correlated to clinically more important digital rectal examination findings. We selected 2 cores in S1–S6, 4 cores in S7–S12, and 6 cores in S13–S16. We calculated the sensitivity of each scenario and found that all scenarios in PSA Group 3 had a sensitivity >95%. In Group 2, S8, S10, S13, and S14 and in Group 1, only S14 had sensitivity >95%.



Conclusions: It is not necessary to take 10–12 core biopsy samples in men with PSA levels >20 ng/ml. We recommend taking 2, 4, and 6 samples for patients with PSA levels ≥100 ng/ml, 50–99.99 ng/ml, and 20–49.99 ng/ml, respectively.



Keywords: Biopsy cores, incidence, prostate cancer, prostate biopsy, PSA

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Clinical Nuclear Medicine

Re: Hepatocellular Carcinoma Mimicking Neuroendocrine Tumor Metastasis on 68Ga-DOTATATE PET/CT
No abstract available

Esthesioneuroblastoma on 68Ga DOTANOC PET/CT
Esthesioneuroblastoma is a rare neoplasm arising from the neural crest cells of olfactory epithelium mostly in the nasal vault. We describe the 68Ga DOTANOC PET/CT findings of a 44-year-old woman who was operated for right nasal mass diagnosed as paraganglioma in the past and then develop a mass in the right nasal cavity after 2 years which upon surgery diagnosed to be esthesioneuroblastoma on histopathology. Received for publication January 17, 2019; revision accepted April 22, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Dr Shamim Ahmed Shamim, MD, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail: sashamim2002@yahoo.co.in. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Parathyroid Glands Hyperplasias Mimicking Medullary Thyroid Carcinoma Metastatic Lymph Nodes on 18F-DOPA PET/CT
A pre operatory assessment by neck US, 18F-DOPA and 18F-choline PET/CT was performed in a 43-year-old MEN 2A woman affected by hyperparathyroidism and medullary thyroid carcinoma (MTC). On 18F-DOPA, two thyroid uptakes were analyzed as multifocal MTC and two others in the central neck compartment as MTC metastatic lymph nodes. After surgery, multifocal intra thyroidal MTC and two parathyroid glands hyperplasias were proved without MTC adenopathies. We report a case of rare false positive uptake on 18F-DOPA. In case of several endocrine diseases coexistence as in MEN 2A, 18F-DOPA should be carefully analyzed. Received for publication February 14, 2019; revision accepted April 19, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Marie Terroir, MD, 114 rue Edouard vaillant, 94805 Villejuif, France. E-mail: marie.terroir-cassou-mounat@gustaveroussy.fr. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

18F-Fluorocholine Uptake by a Head and Neck Meningeal Inflammatory Pseudotumor
18F-Fluoro-ethyl-choline (18F-FCH) PET/CT is widely used to study patients affected by prostate cancer. However, 18F-FCH may be taken-up by other neoplastic diseases, infections, and non-infective inflammatory processes. While this behavior may be an opportunity to study different diseases, on the other hand, this condition brings with it the source of error in the evaluation of the images. Here we present the case of a meningeal inflammatory pseudotumor evidenced by 18F-FCH. Received for publication January 15, 2019; revision accepted April 22, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Giordano Savelli, MD, Nuclear Medicine Division, Fondazione Poliambulanza Istituto Ospedaliero, via L. Bissolati, 57, 25124 Brescia, Italy. E-mail: giordano.savelli@poliambulanza.it. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Re: Concordance Between Intracervical and Fundal Injections for Sentinel Node Mapping in Patients With Endometrial Cancer? A Study Using Intracervical Radiotracer and Fundal Blue Dye Injections
No abstract available

Alveolar Sarcoidosis With Intense FDG Uptake, Mimicking Multi-focal Pneumonia and Infiltrative Lung Malignancy
Alveolar sarcoidosis is an uncommon radiologic manifestation of pulmonary sarcoidosis which appears as infiltrative or mass-like opacities mimicking multifocal pneumonia or infiltrative lung malignancies such as multi-focal adenocarcinoma or pulmonary lymphoma. It has correlation with a more acute and symptomatic phase of thoracic sarcoidosis and therefore expected to show a more severely increased metabolic activity on FDG PET. Alveolar sarcoidosis shows a relatively rapid radiological improvement after initiation of corticosteroid therapy. Tissue diagnosis might be needed in some cases to exclude malignancy. Received for publication January 7, 2019; revision accepted April 22, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Kianoush Ansari-Gilani, MD, Radiology Department, University Hospital Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44124. E-mail: kianoush.ansarigilani@uhhospitals.org. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Radionuclide Therapy With 177Lu-PSMA in a Case of Metastatic Adenoid Cystic Carcinoma of the Parotid
In vivo prostate-specific membrane antigen (PSMA) overexpression creates an opportunity for PSMA-directed theranostic approach in adenoid cystic carcinoma of the parotid. Herein, we illustrate a patient with metastatic PSMA-directed theranostic approach in adenoid cystic carcinoma of the parotid who had intense PSMA uptake on metastatic lesions, followed by radionuclide therapy with 177Lu-PSMA. Received for publication March 14, 2019; revision accepted April 20, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Duygu Has Simsek, MD, Department of Nuclear Medicine, Istanbul Faculty of Medicine, Istanbul University, 34093 Fatih/İstanbul, Turkey. E-mail: dr.duyguhas@hotmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

A Comparison of Angiogenesis and Glycolytic Imaging in Patients With Clinical Suspected Locally Advanced Breast Cancer
18F-FDG PET/CT imaging is an important diagnostic tool for accurate staging and assessment of response to neoadjuvant chemotherapy (NACT) in patients with locally advanced breast carcinoma (LABC). However, 18F-FDG being non-specific marker, it also accumulates in inflammatory conditions, leading to false positive results. Angiogenesis, an essential characteristic for tumor development, intrusion and metastasis can be imaged using 68Ga-labeled RGD tripeptide. We here depict a series of clinically staged LABC patients who underwent both 68Ga-DOTA-RGD2 and 18F-FDG PET/CT imaging for staging and illustrate the similarities and significant differences between the two tracers. Received for publication January 14, 2019; revision accepted April 22, 2019. Conflicts of interest and sources of fundings: none declared. Correspondence to: Bhagwant Rai Mittal, Department of Nuclear Medicine and PET, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: brmittal@yahoo.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

99mTc-MIBI Embolus in the Late Phase of a Parathyroid Scan
We report a case of a transient focal MIBI uptake in the late, 90 minutes postinjection phase of a parathyroid scintigraphy in which SPECT/CT imaging proved valuable in delineating the nature of this incidental finding. Received for publication January 8, 2019; revision accepted April 13, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Christos Savvopoulos, MD, PhD, Department of Radiology, Örebro University Hospital, 701 85 Örebro, Sweden. E-mail: christos.savvopoulos@regionorebrolan.se. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

EBV-Associated T-Cell Lymphoproliferative Disorders Demonstrated on FDG PET/CT in a Patient With Hemophagocytic Lymphohistiocytosis
FDG PET/CT was performed in a 20-year-old woman to find the underlying cause of hemophagocytic lymphohistiocytosis. The images revealed hypermetabolic activity in multiple lymph nodes and in the spleen. Lymphoma was suspected. However, the pathology of bone marrow, lymph nodes, and the spleen demonstrated chronic active Epstein-Barr virus–associated T-cell lymphoproliferative disorders. Received for publication April 1, 2019; revision accepted April 23, 2019. Conflicts of interest and sources of funding: J.Y. was supported by Beijing Natural Science Foundation (No. 7192041), National Key Research and Development Plan (No. 2017YFC0114003) and National Natural Science Foundation of China (No. 81771860). None declared to all other authors. Correspondence to: Jigang Yang, MD, PhD, Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China 100050. E-mail: 13681221974@163.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Radiology

Gray Matter Structural Network Disruptions in Survivors of Acute Lymphoblastic Leukemia with Chemotherapy Treatment

Publication date: Available online 4 June 2019

Source: Academic Radiology

Author(s): Longsheng Wang, Liwei Zou, Qi Chen, Lianzi Su, Jiajia Xu, Ru Zhao, Yanqi Shan, Qing Zhang, Zhimin Zhai, Xijun Gong, Hong Zhao, Fangbiao Tao, Suisheng Zheng

Objectives

Neuroimaging studies of acute lymphoblastic leukemia (ALL) during chemotherapy treatment have shown alterations in structure, function, and connectivity in several brain regions, suggesting neurobiological impairment that might influence the large-scale brain network. This study aimed to detect the alterations in the topological organization of structural covariance networks of ALL patients.

Methods

This study included 28 ALL patients undergoing chemotherapy and 20 matched healthy controls. We calculated the gray matter volume of 90 brain regions based on an automated anatomical labeling template and applied graph theoretical analysis to compare the topological parameters of the gray matter structural networks between the two groups.

Results

The results demonstrated that both the ALL and healthy control groups exhibited a small-world topology across the range of densities. Compared to healthy controls, ALL patients had less highly interactive nodes and a reduced degree/betweenness in temporal regions, which may contribute to impaired memory and executive functions in these patients.

Conclusion

These results reveal that ALL patients undergoing chemotherapy treatment may have decreased regional connectivity and reduced efficiency of their structural covariance network. This is the first report of anomalous large-scale gray matter structural networks in ALL patients undergoing chemotherapy treatment and provides new insights regarding the neurobiological mechanisms underlying the chemo-brain network.



Developing an Education Budget for Radiology Vice Chairs and Leaders: An ADVICER Template

Publication date: Available online 3 June 2019

Source: Academic Radiology

Author(s): Nancy R. Fefferman, Sheryl G. Jordan, Priscilla J. Slanetz, Desiree E. Morgan, Leonie L. Gordon, Robert D. Suh, Mark E. Mullins

Rationale and Objectives

The Alliance of Directors and Vice Chairs in Education group identified the need to develop an education budget template as resource for our community. Having a framework and working knowledge of budgetary considerations is crucial to those with general oversight and executive managerial responsibility for departmental educational programs.

Methods

An online survey was sent to all the Alliance of Directors and Vice Chairs in Education members. Survey questions included education funding sources, presence of vice chair of finance, expectation of revenue generation, existing education budget, funding decision-makers, education budget formulation and approval, vice chair of education's role in budget, education budget line items, and income statement review.

Results

The survey response rate was 41/81 (51%). A majority 26/41 (63%) of respondents had an education budget that typically included funding for all medical students, residents, and fellows but only a minority of respondents report they developed 10/22 (45%), approved 6/22 (27%), or regularly reviewed 6/21 (29%) this budget. In sharp contrast was the role of department chairs and administrators, who presumably all participated in this process. To assist in education budget development and review, as well as meet the need to improve participants' financial accounting knowledge as a key tenet of faculty professional development, the authors developed sample budget templates and an income statement primer.

Conclusion

Our survey results suggested the need for an educational budget framework and financial accounting resources for those in radiology education posts, and resources have been provided.



The Resident Travel Dilemma

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Cory M. Pfeifer



The Importance of Learning to Listen

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Richard B. Gunderman



Automated Test-Item Generation System for Retrieval Practice in Radiology Education

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Gowthaman Gunabushanam, Caroline R. Taylor, Mahan Mathur, Jamal Bokhari, Leslie M. Scoutt

Objective

To develop and disseminate an automated item generation (AIG) system for retrieval practice (self-testing) in radiology and to obtain trainee feedback on its educational utility.

Materials and Methods

An AIG software program (Radmatic) that is capable of generating large numbers of distinct multiple-choice self-testing items from a given "item-model" was created. Instead of writing multiple individual self-testing items, an educator creates an "item-model" for one of two distinct item styles: true/false knowledge based items and image-based items. The software program then uses the item model to generate self-testing items upon trainee request. This internet-based system was made available to all radiology residents at our institution in conjunction with our didactic conferences. After obtaining institutional review board approval and informed consent, a written survey was conducted to obtain trainee feedback.

Results

Two faculty members with no computer programming experience were able to create item-models using a standard template. Twenty five of 54 (46%) radiology residents at our institution participated in the study. Twelve of these 25 (48%) study participants reported using the self-testing items regularly, which correlated well with the anonymous website usage statistics. The residents' overall impression and satisfaction with the self-testing items was quite positive, with a score of 7.89 ± 1.91 (mean ± SD) out of 10. Lack of time and email overload were the main reasons provided by residents for not using self-testing items.

Conclusion

AIG enabled self-testing is technically feasible, and is perceived positively by radiology residents as useful to their education.



Patient-Centered and Specialty-Specific Case Work-Up: An Effective Method for Teaching Appropriateness of Imaging to Medical Students

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Mike Sheng, Preya Shah, John M. Choi, Eleanor Gillis, Sharyn I. Katz, Scott A. Simpson, Sean H. Novak, Arun C. Nachiappan

Rationale and Objectives

Our institution has developed a mini-course program within the diagnostic radiology elective curriculum that promotes active learning, using patient cases specifically tailored to students' future specialties. The purpose of this study is to evaluate the effectiveness of this mini-course on medical student knowledge of imaging appropriateness and attitude toward radiologist consultation.

Materials and Methods

During each month-long radiology elective course, students were divided into teams of up to four students based on their specialty interest and assigned recent patient cases with imaging findings relevant to their specialties. The students researched their customized patient cases, integrated pertinent clinical and imaging findings, and presented their findings in a final preceptor-led session. A five-point Likert-type item preprogram and postprogram survey assessing knowledge of imaging appropriateness and attitude toward radiologist consultation was sent to the enrolled medical students.

Results

Out of 36 medical students, 33 (92%) completed the preprogram survey and 31 (86%) completed the postprogram survey. Students reported improved confidence in knowledge of imaging appropriateness, such as indications for intravenous contrast (p < 0.0005) and oral contrast (p < 0.0005). Furthermore, students reported an improved understanding of how to utilize radiologists (p < 0.005) and how to provide pertinent clinical historical information when requesting a radiology exam (p < 0.0005). Students reported that researching the patient's historical and clinical information in conjunction with the radiology images made them more invested in the case.

Conclusion

Assigning customized patient cases to medical students on diagnostic radiology elective, tailored to their future specialties, is an effective and active way to teach imaging appropriateness and to improve attitudes toward radiologist consultation.



Perceptual and Interpretive Error in Diagnostic Radiology—Causes and Potential Solutions

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Andrew J. Degnan, Emily H. Ghobadi, Peter Hardy, Elizabeth Krupinski, Elena P. Scali, Lindsay Stratchko, Adam Ulano, Eric Walker, Ashish P. Wasnik, William F. Auffermann

Interpretation of increasingly complex imaging studies involves multiple intricate tasks requiring visual evaluation, cognitive processing, and decision-making. At each stage of this process, there are opportunities for error due to human factors including perceptual and ergonomic conditions. Investigation into the root causes of interpretive error in radiology first began over a century ago. In more recent work, there has been increasing recognition of the limits of human image perception and other human factors and greater acknowledgement of the role of the radiologist's environment in increasing the risk of error. This article reviews the state of research on perceptual and interpretive error in radiology. This article focuses on avenues for further error examination, and strategies for mitigating these errors are discussed. The relationship between artificial intelligence and interpretive error is also considered.



Forensic Radiology: An Exciting and Developing Field That Needs More Trained Radiologists

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Barry Daly



Forensic Radiology: A Primer

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Summer J. Decker, Maria Braileanu, Courtney Dey, Leon Lenchik, Michael Pickup, Jason Powell, Maria Tucker, Linda Probyn

Rationale and objective: Forensic radiology is a relatively unknown subspecialty which is becoming increasingly more important. The field incorporates antemortem and postmortem imaging for the detection and documentation of various pathologies for medicolegal purposes. Postmortem imaging is increasingly used in conjunction with the traditional autopsy in a process called a "virtual" autopsy. Radiography has been a staple of forensic investigations for over a century, first used in 1896. Advanced imaging techniques such as postmortem computed tomography and postmortem magnetic resonance imaging have only recently gained acceptance in the forensic science community. Postmortem computed tomography and postmortem magnetic resonance imaging methods are now widely used in some parts of the world, while other countries including the United States have been slower to adopt these methods into their daily practice. Advanced forensic imaging is increasingly used in the courts where juries have responded positively to such presentation of forensic data. For these reasons, advanced postmortem imaging is becoming a regular part of forensic investigations. The increase in the use of forensic imaging presents a unique opportunity for radiologists to collaborate with pathologists and law enforcement officials. This paper provides an overview of forensic radiology and identifies potential challenges and opportunities.



A Review of Options for Localization of Axillary Lymph Nodes in the Treatment of Invasive Breast Cancer

Publication date: June 2019

Source: Academic Radiology, Volume 26, Issue 6

Author(s): Ryan W. Woods, Melissa S. Camp, Nicholas J. Durr, Susan C. Harvey

Invasive breast cancer is a common disease, and the most common initial site of metastatic disease are the axillary lymph nodes. As the standard of care shifts towards less invasive surgery in the axilla for patients with invasive breast cancer, techniques have been developed for axillary node localization that allow targeted dissection of specific lymph nodes without requiring full axillary lymph node dissection. Many of these techniques have been adapted from technologies developed for localization of lesions within the breast and include marker clip placement with intraoperative ultrasound, carbon-suspension liquids, localization wires, radioactive seeds, magnetic seeds, radar reflectors, and radiofrequency identification devices.The purpose of this article is to summarize these methods and describe benefits and drawbacks of each method for performing localization of lymph nodes in the axilla.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Molecular Immunology

S100A9 maintains myeloid-derived suppressor cells in chronic sepsis by inducing miR-21 and miR-181b

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Tuqa Alkhateeb, Ajinkya Kumbhare, Isatou Bah, Dima Youssef, Zhi Q. Yao, Charles E. McCall, Mohamed El Gazzar

Abstract

Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPβ synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPβ protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPβ protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b.

Graphical abstract

Graphical abstract for this article



Sequencing of VDJ genes in Lepus americanus confirms a correlation between VHn expression and the leporid species continent of origin

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Ana Pinheiro, Patricia de Sousa-Pereira, Tereza Almeida, Catarina C. Ferreira, Josée-Anne Otis, Melanie R. Boudreau, Jacob L. Seguin, Dennis K. Lanning, Pedro J. Esteves

Abstract

Leporid VH genes used in the generation of their primary antibody repertoire exhibit highly divergent lineages. For the European rabbit (Oryctolagus cuniculus) four VHa lineages have been described, the a1, a2, a3 and a4. Hares (Lepus spp.) and cottontail (Sylvilagus floridanus) express one VHa lineage each, the a2L and the a5, respectively, along with a more ancient lineage, the Lepus spp. sL and S. floridanus sS. Both the European rabbit and the Lepus europaeus use a third lineage, VHn, in a low proportion of their VDJ rearrangements. The VHn genes are a conserved ancestral polymorphism that is being maintained in the leporid genome.Their usage in a low proportion of VDJ rearrangements by both European rabbit and L. europaeus but not S. floridanus has been argued to be a remnant of an ancient European leporid immunologic response to pathogens. To address this hypothesis, in this study we sequenced VDJ rearranged genes for another North American leporid, L. americanus. Our results show that L. americanus expressed these genes less frequently and in a highly modified fashion compared to the European Lepus species. Our results suggest that the American leporid species use a different VH repertoire than the European species which may be related with an immune adaptation to different environmental conditions, such as different pathogenic agents.



Structural and immunological characterization of a new nucleotidyltransferase-like antigen from Paracoccidioides brasiliensis

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Juliana B. Coitinho, Mariana A.F. Costa, Eliza M. Melo, Elis A. Morais, Lorena G.A. de Andrade, Aline M. da Rocha, Mariana T.Q. de Magalhães, Denize C. Favaro, Lucas Bleicher, Enio R.P. Pedroso, Alfredo M. Goes, Ronaldo A.P. Nagem

Abstract

Pb27 antigen is an interesting alternative to immunological diagnosis of Paracoccidioidomycosis (PCM) and has demonstrated to be protective in experimental PCM. Its tertiary structure and possible function remained unknown till now. To study Pb27 at the atomic level, the recombinant protein was expressed in Escherichia coli BL21(DE3), purified, and its three-dimensional structure was solved by X-ray crystallography. Based on this structure, we performed a residue correlation analysis and in silico ligand search assays to address a possible biological function to Pb27. We identified Pb27 as a member of the extensive nucleotidyltransferase superfamily. The protein has an αβαβαβ topology with two domains (N- and C-terminal domains) and adopts a monomeric form as its biological unit in solution. Structural comparisons with similar members of the superfamily clearly indicate Pb27 C-terminal domain is singular and may play an important role in its biological function. Bioinformatics analysis suggested that Pb27 might bind to ATP and CTP. This suggestion is corroborated by the fact that a magnesium cation is coordinated by two aspartic acid residues present at the active site (between N- and C-terminal domains), as evidenced by X-ray diffraction data. Besides, NMR assays (1H-15N HSQC spectra) confirmed the binding of CTP to Pb27, demonstrating for the first time an interaction between a nucleotide and this protein. Moreover, we evaluated the reactivity of sera from patients with Paracoccidioides brasiliensis infection against the recombinant form of Pb27 and showed that it was recognized by sera from infected and treated patients. Predicted B and T cell epitopes were synthesized and further evaluated against sera of PCM patients, providing information of the most reactive peptides in Pb27 primary structure which interact with specific Pb27 antibodies.



Fish-derived low molecular weight components modify bronchial epithelial barrier properties and release of pro-inflammatory cytokines

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Tanja Kalic, Isabella Ellinger, Sandip D. Kamath, Chiara Palladino, Vanessa Mayr, Angelika Tscheppe, Thimo Ruethers, Eva E. Waltl, Verena Niederberger, Nina Lengger, Christian Radauer, Christine Hafner, Andreas L. Lopata, Merima Bublin, Heimo Breiteneder

Abstract

The prevalence of fish allergy among fish-processing workers is higher than in the general population, possibly due to sensitization via inhalation and higher exposure. However, the response of the bronchial epithelium to fish allergens has never been explored. Parvalbumins (PVs) from bony fish are major sensitizers in fish allergy, while cartilaginous fish and their PVs are considered less allergenic. Increasing evidence demonstrates that components other than proteins from the allergen source, such as low molecular weight components smaller than 3 kDa (LMC) from pollen, may act as adjuvants during allergic sensitization.

We investigated the response of bronchial epithelial cells to PVs and to LMC from Atlantic cod, a bony fish, and gummy shark, a cartilaginous fish. Polarized monolayers of the bronchial epithelial cell line 16HBE14o- were stimulated apically with fish PVs and/-or the corresponding fish LMC. Barrier integrity, transport of PVs across the monolayers and release of mediators were monitored.

Intact PVs from both the bony and the cartilaginous fish were rapidly internalized by the cells and transported to the basolateral side of the monolayers. The PVs did not disrupt the epithelial barrier integrity nor did they modify the release of proinflammatory cytokines. In contrast, LMC from both fish species modified the physical and immunological properties of the epithelial barrier and the responses differed between bony and cartilaginous fish. While the barrier integrity was lowered by cod LMC 24 h after cell stimulation, it was increased by up to 2.3-fold by shark LMC. Furthermore, LMC from both fish species increased basolateral and apical release of IL-6 and IL-8, while CCL2 release was increased by cod but not by shark LMC.

In summary, our study demonstrated the rapid transport of PVs across the epithelium which may result in their availability to antigen presenting cells required for allergic sensitization. Moreover, different cell responses to LMC derived from bony versus cartilaginous fish were observed, which may play a role in different allergenic potentials of these two fish classes.



Phagocytosis of live and dead Escherichia coli and Staphylococcus aureus in human whole blood is markedly reduced by combined inhibition of C5aR1 and CD14

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): E.W. Skjeflo, D. Christiansen, A. Landsem, J. Stenvik, T.M. Woodruff, T. Espevik, E.W. Nielsen, T.E. Mollnes

Abstract
Background

Sepsis is a dysregulated host response to infection. The aim of this study was to investigate the effects of complement- and CD14 inhibition on phagocytosis of live and dead Gram-negative and Gram-positive bacteria in human whole blood.

Methods

Lepirudin-anticoagulated blood was incubated with live or dead E. coli or S. aureus at 37 °C for 120 min with or without the C5aR1 antagonist PMX53 and/or anti-CD14. Granulocyte and monocyte phagocytosis were measured by flow cytometry, and five plasma cytokines by multiplex, yielding a total of 28 mediators of inflammation tested for.

Results

16/28 conditions were reduced by PMX53, 7/28 by anti-CD14, and 24/28 by combined PMX53 and CD14 inhibition. The effect of complement inhibition was quantitatively more pronounced, in particular for the responses to S. aureus. The effect of anti-CD14 was modest, except for a marked reduction in INF-β. The responses to live and dead S. aureus were equally inhibited, whereas the responses to live E. coli were inhibited less than those to dead E. coli.

Conclusion

C5aR1 inhibited phagocytosis-induced inflammation by live and dead E. coli and S. aureus. CD14 blockade potentiated the effect of C5aR1 blockade, thus attenuating inflammation.



The role of the light chain in the structure and binding activity of two cattle antibodies that neutralize bovine respiratory syncytial virus

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Jingshan Ren, Joanne E. Nettleship, Gemma Harris, William Mwangi, Nahid Rhaman, Clare Grant, Abhay Kotecha, Elizabeth Fry, Bryan Charleston, David I. Stuart, John Hammond, Raymond J. Owens

Abstract

Cattle antibodies have unusually long CDR3 loops in their heavy chains (HCs), and limited light chain (LC) diversity, raising the question of whether these mask the effect of LC variation on antigen recognition. We have investigated the role of the LC in the structure and activity of two neutralizing cattle antibodies (B4 and B13) that bind the F protein of bovine respiratory syncytial virus (bRSV). Recombinant Fab fragments of B4 and B13 bound bRSV infected cells and showed similar affinities for purified bRSV F protein. Exchanging the LCs between the Fab fragments produced hybrid Fabs: B13* (B13 HC/B4 LC) and B4* (B4 HC/B13 LC). The affinity of B13* to the F protein was found to be two-fold lower than B13 whilst the binding affinity of B4* was reduced at least a hundred-fold compared to B4 such that it no longer bound to bRSV infected cells. Comparison of the structures of B4 and B13 with their LC exchanged counterparts B4* and B13* showed that paratope of the HC variable domain (VH) of B4 was disrupted on pairing with the B13 LC, consistent with the loss of binding activity. By contrast, B13 H3 adopts a similar conformation when paired with either B13 or B4 LCs. These observations confirm the expected key role of the extended H3 loop in antigen-binding by cattle antibodies but also show that the quaternary LC/HC subunit interaction can be crucial for its presentation and thus the LC variable domain (VL) is also important for antigen recognition.

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Graphical abstract for this article



Persistent stimulation with Mycobacterium tuberculosis antigen impairs the proliferation and transcriptional program of hematopoietic cells in bone marrow

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Fei Li, Xun Liu, Hongxia Niu, Wei Lv, Xue Han, Yifan Zhang, Bingdong Zhu

Abstract

Mycobacterium tuberculosis (M. tuberculosis) persistent infection might cause the dysfunction of hematopoiesis. To investigate whether M. tuberculosis persistent antigen stimulation impairs the proliferation and differentiation of hematopoietic stem and progenitor cells characterized as lineage c-Kit+ (LK cells), C57BL/6 mice were primed with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and boosted with a cocktail of M. tuberculosis antigens ESAT6, CFP10 and Mtb10.4-HspX (MH) along with adjuvant N, N′-dimethyl-N, N′-dioctadecylammonium bromide (DDA) plus polyinosinic-polycytidylic acid (Poly I:C) weekly for 12 or 22 weeks. The cytokine production by splenic T cells, proliferation of LK cells and transcriptional events during differentiation of bone marrow (BM) c-Kit+ cells were investigated. Meanwhile, the mice were treated with interleukin 2 (IL-2) and the therapeutic effects were analyzed. We found that antigen specific interferon-γ (IFN-γ) production by splenic CD4+ T cells increased following antigen stimulation for 12 weeks, but it declined after continuous stimulation for 22 weeks. The long-term exposure of mice to M. tuberculosis antigen compromised the proliferation of LK cells. Moreover, the expression of transcription factors in the c-Kit+ cells was adjusted, with up-regulation of IRF8 and Batf2 involved in myeloid differentiation and down-regulation of NOTCH1 and GATA2 participated in T-cell lineage commitment. The concentrations of IFN-γ in BM of the persistent antigen group were higher than that in sham control at the 12th week, while the concentrations of IL-2 in BM of the persistent antigen group were lower compared with the transient antigen stimulation control. Following IL-2 treatment, the concentrations of IL-2 in BM increased while IFN-γ got declined. IL-2 treatment could restore the expression levels of those transcription factors and the proliferating activity of LK cells impaired by persistent antigen stimulation. Our results indicate that M. tuberculosis antigen persistent stimulation decreases the proliferating activity of LK cells, promotes myelopoietic differentiation, and represses lymphopoietic differentiation as a consequence of elevated IFN-γ production. IL-2 supplementation contributes to maintaining the homeostasis of hemopoiesis.

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Identification of unique key genes and miRNAs in latent tuberculosis infection by network analysis

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Yan Lin, Yuwei Zhang, Huiyuan Yu, Ruonan Tian, Guoqing Wang, Fan Li

Abstract

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M.tb). New cases are now mainly caused by the progression of latent tuberculosis infection (LTBI). Thus, methods to diagnose and treat LTBI are urgently needed to prevent the development of active TB in infected individuals and the subsequent spread of the disease. In this study, a systems biology approach was utilized to obtain numerous microarray data sets for mRNAs and microRNAs (miRNAs) expressed in the peripheral blood mononuclear cells (PBMCs) of TB patients and individuals with LTBI. Within these data sets, we identified the differentially expressed mRNAs and miRNAs and further investigated which differentially expressed genes and miRNAs were uniquely expressed during LTBI. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was employed to analyze the functional annotations and pathway classifications of the identified genes. To further understand the unique miRNA-gene regulatory network of LTBI, we constructed a protein–protein interaction (PPI) network for the targeted genes. The PPI network included 39 genes that were differentially and uniquely expressed in PBMCs of individuals with LTBI, and KEGG pathway enrichment analysis showed that these genes were predominantly involved in the PI3K-Akt signaling pathway, which plays an important role in chronic inflammation. DIANA TOOLs-mirPath analysis revealed that the identified miRNAs in the miRNA–gene regulatory network for LTBI were mainly associated with the Hippo signaling pathway, which functions in the development of inflammation. Quantitative real-time PCR verified the up expression of hsa-miR-212-3p and its predicted target gene —MAPK1 which had low expression and was a major component of the PPI network, and MAPK1 expression was correlated with the clinicopathological characteristics of LTBI by receiver operating characteristic (ROC) curve analysis. Therefore, MAPK1 has potential to be a new investigable marker during LTBI, which merits our further study and solution. The unique aberrant miRNA–gene regulatory network and the related PPI network identified in this study provide insight into the molecular mechanisms of the immune response to LTBI, and thus, may aid in the development of a novel treatment strategy.



In silico analysis of transmembrane protein 31 (TMEM31) antigen to design novel multiepitope peptide and DNA cancer vaccines against melanoma

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Ashkan Safavi, Amirhosein Kefayat, Ardavan Abiri, Elham Mahdevar, Amir Hossein Behnia, Fatemeh Ghahremani

Abstract

Multiepitope cancer vaccines are announcing themselves as the future of melanoma treatment. Herein, high immunogenic regions of transmembrane protein 31 (TMEM31) antigen were selected according to cytotoxic T lymphocytes' (CTL) epitopes and major histocompatibility complex (MHC) binding affinity through in silico analyses. The 32–62, 77–105, and 125–165 residues of the TMEM31 were selected as the immunodominant fragments. They were linked together by RVRR and HEYGAEALERAG motifs to improve epitopes separation and presentation. In addition, to activate helper T lymphocytes (HTL), Pan HLA DR-binding epitope (PADRE) peptide sequence and tetanus toxin fragment C (TTFrC) were incorporated into the final construct. Also, the Beta-defensin conserved domain was utilized in the final construct as a novel adjuvant for Toll-like receptor 4/myeloid differentiation factor (TLR4-MD) activation. The CTL epitopes, cleavage sites, post-translational modifications, TAP transport efficiency, and B cells epitopes were predicted for the peptide vaccine. The final construct contained multiple CTL and B cell epitopes. In addition, it showed 93.55% and 99.13% population coverage in the world for HLA I and HLA II, respectively. According to these preliminary results, the multiepitope cancer vaccine can be an appropriate choice for further experimental investigations.



Carbon monoxide releasing molecule-2 protects against particulate matter-induced lung inflammation by inhibiting TLR2 and 4/ROS/NLRP3 inflammasome activation

Publication date: August 2019

Source: Molecular Immunology, Volume 112

Author(s): Chiang-Wen Lee, Miao-Ching Chi, Lee-Fen Hsu, Chuen-Mao Yang, Tsui-Hua Hsu, Chu-Chun Chuang, Wei-Ning Lin, Pei-Ming Chu, I-Ta Lee

Abstract

Exposure to airborne particulate matter (PM) not only causes lung inflammation and chronic respiratory diseases, but also increases the incidence and mortality of cardiopulmonary diseases. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation has been shown to play a critical role in the formation of many chronic disorders. On the other hand, carbon monoxide (CO) has been shown to possess anti-inflammatory and antioxidant effects in many tissues and organs. Here, we investigated the effects and mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that PM induced C-reactive protein (CRP) expression, NLRP3 inflammasome activation, IL-1β secretion, and caspase-1 activation, which were inhibited by pretreatment with CORM-2. In addition, transfection with siRNA of Toll-like receptor 2 (TLR2) or TLR4 and pretreatment with an antioxidant (N-acetyl-cysteine, NAC), the inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or a mitochondria-specific superoxide scavenger (MitoTEMPO) reduced PM-induced inflammatory responses. CORM-2 also inhibited PM-induced NADPH oxidase activity and NADPH oxidase- and mitochondria-derived ROS generation. However, pretreatment with inactivate CORM-2 (iCORM-2) had no effects on PM-induced inflammatory responses. Finally, we showed that CORM-2 inhibited PM-induced CRP, NLRP3 inflammasome, and ASC protein expression in the lung tissues of mice and IL-1β levels in the serum of mice. PM-enhanced leukocyte count in bronchoalveolar lavage fluid in mice was reduced by CORM-2. The results of this study suggested a protective role of CORM-2 in PM-induced lung inflammation by inhibiting the TLR2 and TLR4/ROS-NLRP3 inflammasome-CRP axial.

Graphical abstract

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Evaluating Penicillin Allergies Without Skin Testing : Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.

Allergy Asthma Proc. 2019 Jan 1;40(1):57-61. doi: 10.2500/aap.2019.40.4184.
Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy.
Kuruvilla M1, Shih J1, Patel K1, Scanlon N2.
Author information
1
From the Department of Allergy/Immunology, Emory University, Atlanta, Georgia.
2
Department of Internal Medicine, Emory University, Atlanta, Georgia.
Abstract
Introduction: Ten percent of hospitalized patients report penicillin allergy; however, recent studies indicate that ∼98% of these patients are not acutely hypersensitive. Unconfirmed penicillin allergy poses public health risks, and an evaluation of penicillin allergy labels is recommended to improve antibiotic stewardship. Although the most widely accepted protocol is penicillin skin testing, followed by oral amoxicillin challenge, time constraints and resources may preclude this. Recent literature supports the safety and efficacy of direct oral amoxicillin challenge in individuals at low risk. Methods: We retrospectively evaluated direct oral challenge acceptance and outcomes in eligible adult outpatients with allergy and with a penicillin allergy label over a 6-month period. Direct oral amoxicillin challenge was recommended in patients with a history of benign rash, benign somatic symptoms, or unknown history associated with the last penicillin exposure >12 months ago. Those with severe reactions or reactions within 12 months of evaluation were not challenged. The patients were monitored for 60 minutes after challenge and were discharged with instructions to call in the event of a delayed reaction. Results: There were 50 of 355 adults (14%) with a penicillin allergy label seen by a single allergist; of these patients, 38 (76%) met our criteria for a direct oral challenge. The index penicillin associated reactions were mostly remote, and 44 subjects (88%) reported reactions >10 years earlier. Four patients (8%) were de-labeled based on history alone. Twenty subjects (40%) consented to challenge in the clinic, and none developed immediate, or to our knowledge, delayed hypersensitivity reactions. Three of 20 patients (15%) developed self-limited subjective symptoms that were not deemed to constitute true immunoglobulin E mediated hypersensitivity. A total of 24 patients (48%) had the penicillin allergy label removed from their medical record. Conclusion: This study added to the accumulating body of evidence that supports the safety and efficacy of direct provocative challenge without preliminary skin testing to exclude penicillin allergy in individuals at low risk. Larger prospective studies are necessary to confirm these observations.

PMID: 30582497 DOI: 10.2500/aap.2019.40.4184

Evaluating Penicillin Allergies Without Skin Testing

Abstract

Purpose of Review

An unconfirmed penicillin allergy is known to confer significant risk to patients. Only a small minority of patients labeled with penicillin allergy will be confirmed to be hypersensitive with the current reference standard test, an oral amoxicillin therapeutic dose challenge. Skin testing has been recommended prior to oral challenges to reduce the risk of severe acute challenge reactions. The rate of severe acute anaphylactic reactions with oral amoxicillin is currently extremely low. Unfortunately, penicillin skin testing, as commonly performed, has a high rate of false positive results.

Recent Findings

Encouraging skin testing in all individuals with an unconfirmed penicillin allergy, prior to a confirmatory oral challenge, would be technically difficult, make testing all individuals with an unconfirmed penicillin allergy very unlikely, and ultimately increase the risk to patients because of suboptimal antibiotic use. Most patients, who are appropriate candidates for a direct oral amoxicillin challenge, to confirm current penicillin tolerance, can be safely identified by their clinical histories. Higher risk individuals, those with a history of anaphylaxis or other acute onset potentially IgE-mediated reaction such as hives within 6 h of the first dose of the last course of a penicillin, may benefit from properly performed puncture and intradermal skin testing, using commercially available penicilloyl-polylysine, prior to an oral challenge, if skin test negative.

Summary

Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.


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HomeSearch ResultsStudy Record Detail Save this study
Amoxicillin Challenge for Penicillin Allergy Diagnosis (Pen-VIE)
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03757052
Recruitment Status  : Recruiting
First Posted  : November 28, 2018
Last Update Posted  : March 14, 2019
See Contacts and Locations
Sponsor:
CHU de Quebec-Universite Laval
Information provided by (Responsible Party):
CHU de Quebec-Universite Laval

Study Details Tabular ViewNo Results PostedDisclaimerHow to Read a Study Record
Study Description
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Brief Summary:
False diagnosis of penicillin allergy are frequently reported, and have been proven detrimental to patients. Current guidelines for the assessment of drug allergies recommend that penicillin allergy be evaluated first with prick and intradermal skin tests, and then completed with a graded oral challenge, spread over at least two doses. However, it has been shown that these skin tests, in addition to consuming resources and time, are of limited, or even doubtful validity, given the poor predictive values that have been reported in the modern penicillins era. It now seems unreasonable to continue their use without addressing other, more efficient diagnostic stategies. Several groups have now demonstrated the safety, validity, and efficiency of a direct, two-step amoxicillin oral challenge (starting with 10% of the standard therapeutic dose, followed by 90 % of the dose), without prior skin tests, first for any type of reaction in the pediatric population, then for any non-immediate reaction in the adult population. The objective of this study is to demonstrate the safety, efficiency, and validity of direct, two-step graded oral challenge with amoxicillin for the evaluation of any reported penicillin allergy in the adult population, excluding high-risk patients (documented anaphylaxis to a penicillin in the last 5 years). Skin tests will first be performed according to the protocol currently in use at the CHUL, then consented patients will proceed with the graded oral challenge still according to the protocol currently in use at the CHUL, but regardless of the skin tests results. The results of the two tests will be compared to determine the safety, efficiency and validity of proceeding directly to the graded oral challenge.

Condition or disease Intervention/treatment Phase
Penicillin Allergy
Diagnostic Test: Penicillin Skin Testing
Not Applicable

Study Design
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Study Type  : Interventional  (Clinical Trial)
Estimated Enrollment  : 1000 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Safety, Validity and Efficiency of a Direct Graded Oral Challenge With Amoxicillin for the Evaluation of Penicillin Allergy in Adults
Actual Study Start Date  : November 20, 2018
Estimated Primary Completion Date  : April 2020
Estimated Study Completion Date  : June 2020
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Allergy
Drug Information available for: Penicillins Amoxicillin Amoxicillin sodium
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Skin testing and Graded Oral Challenge
Penicillin skin testing as described in the intervention section, followed by amoxicillin graded oral challenge as described in the intervention section
Diagnostic Test: Penicillin Skin Testing
Skin test protocol: prick skin tests (penicilloyl-polylysine 0.000012 mol/0.05 mL, penicillin G 10,000 U/mL, penoate 10,000 U/mL, ampicillin 100 mg/mL, amoxicillin 71 mg/mL, histamine/positive control, diluent/negative control), then intradermal skin tests (penicilloyl-polylysine 0.000012 mol/0.05 mL, penicillin G 10,000 U/mL, penoate 10,000 U/mL, ampicillin 1 mg/mL, diluent/negative control), administered as an intradermal injection of a standardized volume of 0.02 mL. Graded oral challenge with amoxicillin : a first dose of 50 mg of amoxicillin; 20-minute observation period; in the absence of any objective symptom of an allergic reaction, a second dose of amoxicillin of 450 mg; final observation period of 60 minutes, under nurse and medical supervision.
Other Name: Amoxicillin Graded Oral Challenge



Outcome Measures
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Primary Outcome Measures  :
Type 1 Hypersensitivity Reaction [ Time Frame: 60 minutes ]
The primary outcome is the occurrence of immediate hypersensitivity symptoms, occuring during the test period, which is up to 60 minutes after the last dose of amoxicillin.


Secondary Outcome Measures  :
Skin Tests Results [ Time Frame: 60 minutes ]
Concordance of Skin Tests Results with Oral Challenge Results

Severity of immediate hypersensitivity symptoms [ Time Frame: 60 minutes ]
Mild, moderate and severe

Delayed hypersensitivity symptoms [ Time Frame: 14 days ]
Occurrence of delayed hypersensitivity symptoms


Eligibility Criteria
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Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
Inclusion Criteria:

Being 18 years of age or older at the time of the test
Being referred by a health professional for the evaluation of any allergic reaction to a penicillin, including natural penicillins, anti-staphylococcal penicillins, aminopenicillins, penicillins combined with a beta-lactamase inhibitor, and carboxypenicillins ; or an antibiotic of the beta-lactam family, whose assessment requires testing for penicillins, according to the treating allergist
Exclusion Criteria:

Pregnancy
Poorly controlled asthma, chronic lung disease or heart disease
Failure to stop beta-blockers prior to the test
Occurrence of the reaction in the 4 weeks preceding the test (possibility of false negatives)
History of severe delayed hypersensitivity reaction, reaction requiring hospitalization of more than 24 hours, or bullous, pustular, exfoliative or mucosal reaction (excluding angioedema)
Recent anaphylaxis (<5 years), defined as concomitant involvement of at least two systems (respiratory, digestive, mucocutaneous or cardiovascular) within one hour of administration of the drug
Contacts and Locations
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Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03757052


Contacts
Contact: Jean-Philippe Drolet, MD FRCPC 418-525-4444 jean-philippe.drolet@chudequebec.ca
Contact: Gaston De Serres, MD PhD 418-525-4444 Gaston.DeSerres@inspq.qc.ca

Locations
Canada, Quebec
CHU de Quebec Recruiting
Quebec city, Quebec, Canada
Contact: Jean-Philippe Drolet, MD        
Sponsors and Collaborators
CHU de Quebec-Universite Laval
Investigators
Principal Investigator: Jean-Philippe Drolet, MD FRCPC CHU de Quebec-Universite Laval
More Information
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Responsible Party: CHU de Quebec-Universite Laval
ClinicalTrials.gov Identifier: NCT03757052     History of Changes
Other Study ID Numbers: 2019-4379
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Hypersensitivity
Drug Hypersensitivity
Immune System Diseases
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Amoxicillin
Penicillins
Anti-Bacterial Agents
Anti-Infective Agents


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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Allergy and Asthma

Vitamin D and Otitis Media

Abstract

Purpose of Review

To examine the relationship between vitamin D and otitis media.

Recent Findings

Vitamin D deficiency has been associated with several respiratory diseases, including otitis media. Vitamin D supplementation may reduce the risk of otitis media. This relationship may be explained by vitamin D supporting the immune system by upregulating antimicrobial peptides which are effective against otopathogens and biofilm formation, supporting a less inflammatory immune response, or promoting beneficial commensal bacteria.

Summary

This review will explore risk factors of both otitis media and vitamin D deficiency, the evidence of vitamin D being beneficial for various forms of otitis media, and possible mechanisms of action.



Role of Obesity in Otorhinolaryngologic Diseases

Abstract

Purpose of Review

Obesity is a major public health problem associated with various diseases. Improving obesity control and achieving greater patient satisfaction are critical unmet needs. Various otorhinolaryngologic diseases can have negative effects on quality of life or actual health status depending on their type. Over the past decade, the relationship between obesity and otorhinolaryngologic conditions has been investigated. The purpose of this review was to discuss the relationship between obesity and otorhinolaryngological diseases.

Recent Findings

This is a narrative review on the current state of incidence, effects, and associated mechanisms between obesity and otorhinolaryngologic diseases. In various otologic diseases, otitis media (OM) and hearing loss (HL) are associated with obesity. In rhinologic parts, chronic rhinosinusitis (CRS) and obstructive sleep apnea (OSA) were significantly associated with obesity. Most of these diseases are reported to have higher susceptibility and severity as body mass index (BMI) increases. However, the incidence of head and neck cancer (HNC) was inversely associated with obesity, especially central adiposity. The relevance of obesity in laryngopharyngeal reflux disease (LPR) and allergic rhinitis (AR) has yet to be clarified, and this remains controversial.

Summary

This review provides a comprehensive overview of the current state of incidence, effects, and associated mechanisms between obesity and otorhinolaryngologic diseases. Various otorhinolaryngological diseases are related to obesity. As obesity can be a negative risk factor in these otorhinolaryngologic diseases, early diagnosis and treatment of these diseases in obese patients will be critical.



Idiopathic, Refractory Sweet's Syndrome Associated with Common Variable Immunodeficiency: a Case Report and Literature Review

Abstract

Purpose of Review

Sweet's syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients.

Recent Findings

Few case reports exist regarding the co-occurrence of Sweet's syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet's associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet's syndrome.

Summary

Sweet's syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.



The Role of KIT Mutations in Anaphylaxis

Abstract

Purpose of Review

Gain of function KIT mutations are detected in clonal mast cell diseases, namely mastocytosis and monoclonal mast cell activation syndrome. Timely diagnosis and treatment of these disorders are crucial because of their association with severe and life-threatening anaphylaxis. KIT mutations also have implications for targeted therapies of mast cell disorders. This review article strives to serve as an overview of the role of clonal mast cell disorders in anaphylaxis while elucidating current and future therapies.

Recent Findings

Clonal mast cell disease has been increasingly diagnosed in patients with severe hymenoptera allergy and those with recurrent unexplained anaphylaxis. The current state of knowledge of the epidemiology, pathophysiology, diagnosis, and treatment of mastocytosis with a particular focus on anaphylaxis and its triggers which are described in this context. Novel and forthcoming treatments are discussed including the relevance of KIT mutation status.

Summary

This review provides an overview of the role of KIT mutations in mastocytosis and anaphylaxis, and highlights emerging therapies for mastocytosis, targeting these mutations.



GRADE-ing the Benefit/Risk Equation in Food Immunotherapy

Abstract

Purpose of Review

We reviewed the existing evidence base to desensitisation for food allergy, applying the Grading of Recommendations, Assessment, Development and Evaluation approach to discuss whether desensitisation is likely to become part of routine treatment for patients with food allergy.

Recent Findings

Desensitisation for food allergy to peanut, egg and cow's milk is efficacious, but whether such interventions are cost-effective is less clear, due to the issues over a sustained desensitisation effect and the increase in allergic reactions occurring in patients on treatment. Few studies have assessed the change in health-related quality of life associated with treatment, and most have not considered discordance between parent-reported changes in health-related quality of life (HRQL) outcomes compared to those of the patients themselves; none to date have controlled for the improvement in HRQL occurring after initial challenge which will confound outcomes.

Summary

The lack of longer-term safety and cost-effectiveness data, as well as an absence of current consensus in the reporting of patient-relevant outcomes, must be addressed in order to be able to recommend the introduction of desensitisation as a routine treatment in healthcare systems.



Th9 Cells in Allergic Disease

Abstract

Purposes of Review

Th9 cells are recognized as a novel subset of effector T helper cells that preferentially produce IL-9. Here, we provide a current update on the reports related to the function of Th9 cells in allergic inflammatory diseases.

Recent Findings

The effector Th9 cells differentiating from naïve T helper cells have recently been identified. Because of accumulating findings of Th9 cells in many inflammatory diseases, including allergic diseases, diverse functions of Th9 cells in regulating immune responses have been suggested. Related reports indicate multiple sources of IL-9 besides Th9 cells and their association with the pathogenesis of allergic rhinitis, asthma, atopic dermatitis, contact dermatitis, and food allergy. More recently, elements of the epigenetic landscape involving in the regulation of IL-9 by Th9 cells have been identified to be the potential target for allergic inflammation.

Summary

This review provides the most recent information about Th9 cells and their contribution in airway allergic disease, skin, and food allergy.



Evaluating Penicillin Allergies Without Skin Testing

Abstract

Purpose of Review

An unconfirmed penicillin allergy is known to confer significant risk to patients. Only a small minority of patients labeled with penicillin allergy will be confirmed to be hypersensitive with the current reference standard test, an oral amoxicillin therapeutic dose challenge. Skin testing has been recommended prior to oral challenges to reduce the risk of severe acute challenge reactions. The rate of severe acute anaphylactic reactions with oral amoxicillin is currently extremely low. Unfortunately, penicillin skin testing, as commonly performed, has a high rate of false positive results.

Recent Findings

Encouraging skin testing in all individuals with an unconfirmed penicillin allergy, prior to a confirmatory oral challenge, would be technically difficult, make testing all individuals with an unconfirmed penicillin allergy very unlikely, and ultimately increase the risk to patients because of suboptimal antibiotic use. Most patients, who are appropriate candidates for a direct oral amoxicillin challenge, to confirm current penicillin tolerance, can be safely identified by their clinical histories. Higher risk individuals, those with a history of anaphylaxis or other acute onset potentially IgE-mediated reaction such as hives within 6 h of the first dose of the last course of a penicillin, may benefit from properly performed puncture and intradermal skin testing, using commercially available penicilloyl-polylysine, prior to an oral challenge, if skin test negative.

Summary

Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.



Contributions of Innate Lymphoid Cells in Chronic Rhinosinusitis

Abstract

Purpose of Review

To review innate lymphoid cells (ILCs) and their role in chronic rhinosinusitis (CRS).

Recent Findings

The immune system consists of the innate and adaptive response. Until the recognition of ILCs, chronic inflammatory diseases were characterized by cytokines linked only to T helper cells. However, these immune responses are now described more broadly to include contributions from both the innate and adaptive immunity. In CRS, focus had been on ILC2s in CRS with nasal polyps. These studies also highlight the importance of epithelial cell–derived cytokines in coordinating these responses. In addition to indirect crosstalk via cytokines, ILCs and T helper cells can utilize the OX40/OX40 ligand and major histocompatibility complex class II pathways to directly interact and coordinate responses.

Summary

In addition to T helper cells, ILCs contribute to the inflammatory response associated with CRS. The understanding of these cells along with pathways that activate and perpetuate these cells leads to new potential therapeutic targets for CRS treatment.



Exosomes in Allergic Airway Diseases

Abstract

Purpose of Review

This review will cover what is known regarding exosomes and allergy, and furthermore discuss novel mechanism of exosome-mediated immune modulation and metabolic regulation via the transfer of mitochondria.

Recent Findings

Exosomes are nano-sized extracellular vesicles (EVs) derived from the endosome that play a direct role in governing physiological and pathological conditions by transferring bioactive cargo such as proteins, enzymes, nucleic acids (miRNA, mRNA, DNA), and metabolites. Recent evidence suggest that exosomes may signal in autocrine but, most importantly, in paracrine and endocrine manner, being taken up by neighboring cells or carried to distant sites. Exosomes also mediate immunogenic responses, such as antigen presentation and inflammation. In asthma and allergy, exosomes facilitate cross-talk between immune and epithelial cells, and drive site-specific inflammation through the generation of pro-inflammatory mediators like leukotrienes. Recent studies suggest that myeloid cell-generated exosomes transfer mitochondria to lymphocytes.

Summary

Exosomes are nano-sized mediators of the immune system which can modulate responses through antigen presentation, and the transfer of pro- and anti-inflammatory mediators. In addition to conventional mechanisms of immune modulation, exosomes may act as a novel courier of functional mitochondria that is capable of modulating the recipient cells bioenergetics, resulting in altered cellular responses. The transfer of mitochondria and modulation of bioenergetics may result in immune activation or dampening depending on the context.



Microbial Adjuncts for Food Allergen Immunotherapy

Abstract

Purpose of Review

Food allergen immunotherapy may benefit from adjunct therapies to enhance safety and efficacy. We review preclinical studies investigating the effects of probiotics and other microbial-based interventions on oral tolerance, describe the human clinical trial evidence thus far for microbial adjuncts, and discuss steps for translating research findings in this area to clinical therapy.

Recent Findings

Murine studies support that microbial-based interventions confer protection against sensitization and may augment treatment efficacy for food allergy. Microbial adjunct therapies can promote regulatory T cells and modulate Th1 vs. Th2 responses. There is a wide array of novel modalities utilizing microbial components. Ongoing efforts are focused on translating preclinical data into potential treatments.

Summary

Probiotics, prebiotics, and microbial components have all been examined as microbial adjunct therapies in murine models of food allergy. The effects of probiotics appear to be strain-specific. Prebiotics and bacterial components are innovative modalities to modulate oral tolerance. Better characterization of dysbiosis in human cohorts with food allergy, deeper mechanistic understanding of microbial adjunct therapies, safety evaluation, and careful clinical trial design will be crucial for the development of microbial adjuncts for food allergen immunotherapy. Microbial adjunct therapies have the potential to enhance the efficacy, safety, and durability of food allergen immunotherapy.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

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