Increase in the Level of Proinflammatory Cytokine HMGB1 in Nasal Fluids of Patients With Rhinitis and its Sequestration by Glycyrrhizin Induces Eosinophil Cell Death

OBJECTIVES: The nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis. METHODS: HMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments. RESULTS: We report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1-binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes. CONCLUSION: Collectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa.

Thyroid dysfunction in thalassaemic patients: ferritin as a prognostic marker and combined iron chelators as an ideal therapy.

OBJECTIVE: Endocrine complications characterised patients with ß thalassaemia (ßT). In particular, thyroid dysfunction occurs frequently in ßT major, but its long-term natural history is poorly understood. DESIGN: A total of 72 ßT patients were followed for 8 years. The incidence of thyreopathies, defined as the primary study endpoint, was assessed. The aim of this study was to analyse the prognostic role of ferritin for thyreopathies in patients with major and intermedia ßT. The power of different iron chelators to treat iron overload and to prevent or reverse thyreopathies was also assessed. METHODS: Patients were treated with chelators with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying thyroid dysfunction in thalassaemic patients. Kaplan-Meier curves were generated to assess incidence of thyreopathy. Adjusted risk estimates for thyreopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: PATIENTS WITH THYROID DYSFUNCTION WERE CHARACTERISED BY HIGHER FERRITIN WHEN COMPARED WITH PATIENTS WITHOUT THYREOPATHIES (1500 (8722336) VS 513 (370698) G/L; P0.0001). PATIENTS WITH FERRITIN VALUES ABOVE 1800G/L EXPERIENCED A SIGNIFICANTLY FASTER EVOLUTION TO ENDPOINT (LOG-RANK ((2)): 7.7; P=0.005). Ferritin predicted high risk of thyroid dysfunction independently of confounding factors (hazard ratio: 1.20; P<0.0001). The intensification of chelation therapy led to an amelioration of thyroid function. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to thyroid dysfunction. Intensive chelation therapy allows the prevention and reversibility of thyroid complications.

Gynecomastia disclosing diagnosis of Leydig cell tumour in a man with thalassemia, secondary hypogonadism and testis microlithiasis.

Aim of this paper is to report about a 35-year old man suffering from beta-Thalassemia major and longstanding untreated hypogonadotropic hypogonadism, who was referred because of a recent onset and painful bilateral gynecomastia, with no palpable testicular masses. Due to the finding of a solid mass at left testis ultrasonography, monolateral testicular exeresis was performed and histology revealed a Leydig Cell Tumour and testicular microlithiasis. Post-surgical restoration of testosterone/estradiol ratio under testosterone therapy was followed by a very rapid reduction of gynecomastia. Our report confirms the usefulness of scrotal ultrasonography for finding an occult testicular tumour in a patient with painful and recent onset bilateral gynecomastia and underlines: a) the important role of testosterone/estradiol ratio in the pathophysiology of gynecomastia; b) the questionable significance of testicular microlithiasis as marker of testis tumours; c) the possible association between beta-Thalassemia and tumoral pathologies.