Olfactory Neuron Prokineticin-2 as a Potential Target in Parkinson's Disease.

OBJECTIVE: The objective of this study was to outline the dynamics of prokineticin-2 pathway in relation to clinical-pathological features of Parkinson's disease by examining olfactory neurons of patients. METHODS: Thirty-eight patients (26 de novo, newly diagnosed) and 31 sex/age-matched healthy controls underwent noninvasive mucosa brushing for olfactory neurons collection, and standard clinical assessment. Gene expression levels of prokineticin-2, prokineticin-2 receptors type 1 and 2, and prokineticin-2-long peptide were measured in olfactory neurons by real-time polymerase chain reaction (PCR); moreover, the prokineticin-2 protein and α-synuclein species (total and oligomeric) were quantified by immunofluorescence staining. RESULTS: Prokineticin-2 expression was significantly increased in Parkinson's disease. De novo patients had higher prokineticin-2 levels, directly correlated with Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III motor score. In addition, oligomeric α-synuclein was higher in Parkinson's disease and directly correlated with prokineticin-2 protein levels. Total α-synuclein did not differ between patients and controls. INTERPRETATION: Prokineticin-2 is a chemokine showing neuroprotective effects in experimental models of Parkinson's disease, but translational proof of its role in patients is still lacking. Here, we used olfactory neurons as the ideal tissue to analyze molecular stages of neurodegeneration in vivo, providing unprecedented evidence that the prokineticin-2 pathway is activated in patients with Parkinson's disease. Specifically, prokineticin-2 expression in olfactory neurons was higher at early disease stages, proportional to motor severity, and associated with oligomeric α-synuclein accumulation. These data, consistently with preclinical findings, support prokineticin-2 as a candidate target in Parkinson's disease, and validate reliability of olfactory neurons to reflect pathological changes of the disease. ANN NEUROL 2023;93:196-204.

Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction.

Persistent olfactory dysfunction (OD) is one of the most complaining and worrying complications of long COVID-19 because of the potential long-term neurological consequences. While causes of OD in the acute phases of the SARS-CoV-2 infection have been figured out, reasons for persistent OD are still unclear. Here we investigated the activity of two inflammatory pathways tightly linked with olfaction pathophysiology, namely Substance P (SP) and Prokineticin-2 (PK2), directly within the olfactory neurons (ONs) of patients to understand mechanisms of persistent post-COVID-19 OD. ONs were collected by non-invasive brushing from ten patients with persistent post-COVID-19 OD and ten healthy controls. Gene expression levels of SP, Neurokinin receptor 1, Interleukin-1ß (IL-1ß), PK2, PK2 receptors type 1 and 2, and Prokineticin-2-long peptide were measured in ONs by Real Time-PCR in both the groups, and correlated with residual olfaction. Immunofluorescence staining was also performed to quantify SP and PK2 proteins. OD patients, compared to controls, exhibited increased levels of both SP and PK2 in ONs, the latter proportional to residual olfaction. This work provided unprecedented, preliminary evidence that both SP and PK2 pathways may have a role in persistent post-COVID-19 OD. Namely, if the sustained activation of SP, lasting months after infection's resolution, might foster chronic inflammation and contribute to hyposmia, the PK2 expression could instead support the smell recovery.

Nasal Allergy and Otitis Media: A real correlation?

OBJECTIVES: The correlation between middle ear pathology and nasal allergy has been debated for almost 30 years. This study aimed to evaluate the relationship between otitis media with effusion (OME) and persistent allergic rhinitis symptoms versus intermittent rhinitis in children. METHODS: The study included 100 atopic children (52 boys, 48 girls) aged 5-9 years with otological symptoms who were patients of the University of Siena Hospital, Italy. Ear, nose and throat evaluations, tympanometry, skin prick tests (SPTs), mucociliary transport time (MCTt) and Eustachian tube function tests were performed. RESULTS: The SPTs revealed 50 children sensitised to Dermatophagoides pteronyssinus, 34 to grass pollen and 16 to Parietaria. Of all patients, mild symptoms were intermittent in 19 children and persistent in 18; moderate/severe symptoms were intermittent in 22 and persistent in 41. Tubal dysfunction was present in 25 children, whereas middle ear effusion was present in 45 children undergoing myringotomy. The MCTt was slower in the persistent group (21 ± 2 mins) versus the intermittent group (16 ± 2 mins) with a significant difference (P <0.01). Mean eosinophil cationic protein (ECP) values in the middle ear effusions of children who had undergone myringotomy were 251 ± 175.2 µg/L, and mean ECP blood values were 25.5 ± 16.3 µg/L, with significant differences (P < 0.001). CONCLUSION: There was a significant association between OME, delayed MCTt, ECP values in middle ear effusion and persistent symptoms of allergic rhinitis. These results suggest a direct involvement of the middle ear mucosa as a target organ in persistent forms.

Inactivation of human salivary glutathione transferase P1-1 by hypothiocyanite: a post-translational control system in search of a role.

Glutathione transferases (GSTs) are a superfamily of detoxifying enzymes over-expressed in tumor tissues and tentatively proposed as biomarkers for localizing and monitoring injury of specific tissues. Only scarce and contradictory reports exist about the presence and the level of these enzymes in human saliva. This study shows that GSTP1-1 is the most abundant salivary GST isoenzyme, mainly coming from salivary glands. Surprisingly, its activity is completely obscured by the presence of a strong oxidizing agent in saliva that causes a fast and complete, but reversible, inactivation. Although salivary α-defensins are also able to inhibit the enzyme causing a peculiar half-site inactivation, a number of approaches (mass spectrometry, site directed mutagenesis, chromatographic and spectrophotometric data) indicated that hypothiocyanite is the main salivary inhibitor of GSTP1-1. Cys47 and Cys101, the most reactive sulfhydryls of GSTP1-1, are mainly involved in a redox interaction which leads to the formation of an intra-chain disulfide bridge. A reactivation procedure has been optimized and used to quantify GSTP1-1 in saliva of 30 healthy subjects with results of 42±4 mU/mg-protein. The present study represents a first indication that salivary GSTP1-1 may have a different and hitherto unknown function. In addition it fulfills the basis for future investigations finalized to check the salivary GSTP1-1 as a diagnostic biomarker for diseases.

Clinical guideline on adenotonsillectomy: the Italian experience.

Five years after publishing the document on 'The clinical and organizational appropriateness of tonsillectomy and adenoidectomy' in 2003, a multidisciplinary group of experts came together again to update this document and to publish a guideline with grading of evidences and recommendations. Major revisions of the previous document were addressed to: (1) the diagnosis and indications for adenotonsillectomy in presence of OSAS in children, (2) the analysis of advantages of new surgical techniques in terms of effectiveness, costs or the risk of postsurgery bleeding and recurrences, and (3) the efficacy of perioperative management in reducing the incidence and duration of post-operative events. In fact, in the last years, a relevant number of evidence became available on the above-mentioned items making the need for a continuing updating of guidelines tangible. As a premise to the guideline, it is stressed how the previous document impact was prominent: the decrease of total number of tonsillectomy in Italy was evident and accompanied by a decrease of variations in the regional rates. Besides the document contributed to strengthen the multidisciplinary collaboration, especially between pediatricians and otorhinolaryngologists, and to divulge the Evidence-Based Medicine culture.