Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra ?-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion

Real-life assessment of chronic rhinosinusitis patients using mobile technology : The mySinusitisCoach project by EUFOREA

Background Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient-reported outcomes by mobile technology offers the possibility to better understand real-life burden of CRS. Methods This study reports on the cross-sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria. Results The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well-controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell. Conclusion Real-life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient-reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real-life monitoring, supporting the evolution of care towards precision medicine.Peer reviewe

Rhinosinusitis in children

The definition of rhinosinusitis (RS) in children is based here on category IV reports. The diagnosis of RS is mainly made on clinical grounds helped by endoscopic investigation. Indications for additional investigation and radiological examination are outlined. Medical treatment with antibiotics is advised when bacterial infections and complications are present. There is insufficient evidence for the use of antibiotics for uncomplicated common colds in children. The strength of evidence for recommendations is mainly A-based, unless otherwise specified. There is a paucity of studies (with a rather low numbers of participants) in children. The absolute and relative indications for surgical intervention are outlined. Decisional algorithms are presented for acute and chronic rhinosinusitis in children.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Meccanismi vascolari nella vestibolopatia periferica acuta unilaterale: Una revisione sistematica

Acute unilateral peripheral vestibulopathy (AUPVP) is a frequent cause of vestibular loss. Several aetiologies have been proposed, but the exact mechanism remains unknown. The aim of this study is a systematic analysis of the literature evaluating the vascular aetiology of AUPVP. A systematic literature search was performed in PubMed, Cochrane Library and Embase, including articles published from January 1st, 2010 to November 30th, 2020. Two reviewers independently selected articles investigating a link between AUPVP and vascular disease. The following information was extracted: year of publication, country, level of evidence, assessed vascular risk factors and number of patients. A total of 450 articles was obtained. Eleven articles were retained with 100% agreement between the two reviewers. In a pooled population of 805 patients, the main results were the higher neutrophil to lymphocyte ratio and higher prevalence of vascular risk factors among AUPVP patients. A meta-analysis was not performed because the studies were too heterogeneous in terms of methodology. Indirect arguments for vascular mechanisms in AUPVP were found. These findings indicate that larger prospective well-controlled studies are needed to clarify the vascular aetiology of AUPVP.La vestibolopatia periferica unilaterale acuta (AUPVP) è causa frequente di perdita della funzione vestibolare. Sono state proposte diverse eziologie, ma il meccanismo esatto rimane sconosciuto. Lo scopo di questo studio è condurre un’analisi sistematica della letteratura per valutare l’eziologia vascolare dell’AUPVP. Una ricerca sistematica della letteratura è stata eseguita mediante PubMed, Cochrane Library ed Embase, includendo articoli pubblicati dal 1 gennaio 2010 al 30 novembre 2020. Due revisori hanno selezionato in modo indipendente articoli che studiano un collegamento tra AUPVP e malattie vascolari. Sono state estratte le seguenti informazioni: anno di pubblicazione, paese, livello di evidenza, fattori di rischio vascolare valutati e numero di pazienti. In totale sono stati identificati 450 articoli. Tra questi sono stati considerati gli undici su cui vi era completo accordo fra i due revisori. In una popolazione aggregata di 805 pazienti, i risultati principali sono stati il più alto rapporto tra neutrofili e linfociti e la maggiore prevalenza di fattori di rischio vascolare tra i pazienti con AUPVP. Non è stata eseguita una meta-analisi perché gli studi erano troppo eterogenei per quanto riguarda la metodologia. Sono stati trovati argomenti indiretti per i meccanismi vascolari in AUPVP. Questi risultati indicano che sono necessari studi prospettici più ampi e ben controllati per chiarire l’eziologia vascolare in AUPVP

Pathophysiological and clinical aspects of chronic rhinosinusitis : current concepts

Adult chronic rhinosinusitis (CRS) is a chronic inflammation of the mucosa of the nose and paranasal sinuses. According to the latest EPOS guidelines CRS should be regarded as primary or secondary with distinction between diffuse and localized disease. Further pathophysiologic research identified different inflammatory patterns leading to the term “endotyping of CRS.” The primary focus of endotyping is to define a dominant inflammatory type allowing for better orientation of therapy. The current approach proposes the differentiation between type 2 (eosinophilic) and non-type 2 inflammatory responses. In this review pathophysiological concepts of CRS will be discussed, focusing on the different inflammatory endotypes of T cells with special attention to the eosinophilic type 2 inflammatory response. The contribution of innate and adaptive immune system responses is presented. The possibility of endotyping based on sinonasal secretions sampling is brought to attention because it is indicative of corticosteroid responsiveness and available to most ENT surgeons. Furthermore, the clinical aspects of the three distinct phenotypes are analyzed in view of their characteristics, the related endoscopic findings, typical radiological imaging, histopathology findings, their relation toward allergy and obvious therapeutical implications. This overview will enable clinicians to relate pathophysiological patterns with clinical observations by explaining the different inflammatory mechanisms, hence providing a better understanding of therapy

Proposal for Structured Histopathology of Nasal Secretions for Endotyping Chronic Rhinosinusitis: An Exploratory Study

Background: The EPOS guidelines promote cellular analysis as a primary goal in endotyping chronic rhinosinusitis (CRS). Current analysis is mainly based on biopsy or operative tissue collection, whereas the use of sinonasal secretions for inflammatory endotyping is not advocated in clinical practice. Early endotyping is crucial though, especially regarding the increasing evidence of patient-tailored therapy. We aimed to investigate the diagnostic value and reproducibility of sinonasal secretions sampling. Methods: First, preoperative secretion analysis of 53 Caucasian CRS patients was compared to subsequent operative tissue analysis. Second, secretion analysis at two different time points was compared for 10 postoperative Caucasian CRS patients with type 2 (T2) inflammation and 10 control participants. Secretions were collected by both endoscopic aspiration and nasal blown secretions in all participants. Results: The sensitivity to detect T2 inflammation was higher in nasal aspiration samples (85%) compared to nasal blow secretions (32%). A specificity of 100% for both techniques was obtained. A 90% reproducibility for T2 eosinophil detection was found by sampling at different time points regardless of the technique. Of the T2 patients, 60% showed no T2 inflammatory pattern more than one year after endoscopic sinus surgery. Conclusions: Nasal secretion sampling, especially aspiration of nasal secretions, is useful in the detection of T2 inflammation in CRS pathology. We proposed a structured histopathology analysis to be useful in daily clinical practice, which includes Congo red staining sensitive for eosinophilic cells and free eosinophil granules. Analysis of nasal secretions enables endotyping in an early stage, allowing more directed therapy

The importance of local eosinophilia in the surgical outcome of chronic rhinosinusitis : a 3-year prospective observational study

Background: Patients with chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP) benefit from endoscopic sinus surgery (ESS), with an estimated success rate of 80%. At present, the influence on clinical outcome after ESS of eosinophils, eosinophilic mucin (EM), and fungal hyphae (FH) in secretions remains unclear. By delineating CRS groups and subgroups based on the finding of eosinophils, EM, and FH, differences in recurrence after ESS were investigated. Methods: A prospective monocenter study including 221 CRS patients who were unresponsive to medical treatment and underwent ESS was performed. All tissue and sinonasal secretions were microscopically examined for the presence of eosinophils, EM, and FH. Patients were followed for 3 years after surgery. Recurrence was defined according to the European position paper on rhinosinusitis and nasal polyps. Results: In total, 96 CRSwNP and 125 CRSsNP patients were included. Tissue eosinophils were found in 78% of CRSwNP patients compared with 42% in CRSsNP patients. EM was observed in 52% of the CRSwNP group versus 20% of the CRSsNP group. Furthermore, secretion analysis revealed FH in 7% of CRS. Recurrence in the total group was 22% over 3 years. CRSwNP patients with tissue eosinophilic involvement showed a recurrence rate of 48%, and those with additional EM showed recurrence in 56%. Conclusion: The presence of eosinophils in tissue or airway secretions greatly increases the risk of recurrent disease in CRSwNP patients. The finding of tissue eosinophilia and EM provides valuable information regarding the increased likelihood of CRS recurrence after ESS, whereas the finding of FH does not

Surgery in nasal polyp patients : outcome after a minimum observation of 10 years

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) often requires surgery, but recurrence even after surgery is common. Recurrence rates largely vary in literature and asthma seems to be a comorbid factor. Objective In this study, we aim to estimate disease recurrence during a long-term follow-up, together with the investigation of possible predicting and/or influencing parameters. Methods Out of 196 patients operated for CRSwNP between 01/2000 and 01/2006, 133 patients had a follow-up of at least 10 years and could be included. The inflammatory profile at surgery was determined on nasal tissue and sinonasal secretions, and included analysis of eosinophils, eosinophilic-rich mucus (ERM) typically containing Charcot-Leyden crystals (CLC), and fungal hyphae (FH). During follow-up, recurrence, received treatments and comorbidities were collected. Results Out of the 133 included patients, local eosinophilia was present in 81% and ERM in 60%. Recurrence during follow-up was observed in 62%, and was associated with local eosinophilia and ERM (both p < 0.001). Asthma was present in 28% at inclusion, and 17% developed asthma after surgery during follow-up. The presence of asthma, at inclusion as well as developed during follow-up, was significantly associated with recurrence of CRSwNP (p = 0.001 for group comparison). Conclusion Recurrence after CRSwNP surgery is common when a long-term follow-up is taken into account. ERM detected in sinonasal secretions at surgery seems to be a predictive factor for recurrence and need for revision surgery. Asthma is a frequently found comorbid factor in CRSwNP, develops even at higher age despite surgical treatment for CRSwNP, and is also associated with a higher recurrence rate. Sustained medical care after surgery is mandatory