Understanding the mechanism of binding between Gab2 and the C terminal SH3 domain from Grb2

Gab2 is a large disordered protein that regulates several cellular signalling pathways and is overexpressed in different forms of cancer. Because of its disordered nature, a detailed characterization of the mechanisms of recognition between Gab2 and its physiological partners is particularly difficult. Here we provide a detailed kinetic characterization of the binding reaction between Gab2 and the C-terminal SH3 domain of the growth factor receptor-bound protein 2 (Grb2). We demonstrate that Gab2 folds upon binding following an induced fit type mechanism, whereby recognition is characterized by the formation of an intermediate, in which Gab2 is primarily disordered. In this scenario, folding of Gab2 into the bound conformation occurs only after binding. However, an alanine scanning of the proline residues of Gab2 suggests that the intermediate contains some degree of native-like structure, which might play a role for the recognition event to take place. The results, which represent a fundamental step forward in the understanding of this functional proteinprotein interaction, are discussed on the light of previous structural works on these proteins

Anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of vestibular migraine: A prospective observational cohort study

Background: Vestibular migraine is considered the most common cause of recurrent vertigo for which specific treatments are missing. Monoclonal antibodies against calcitonin gene-related peptide,, are effective in preventing migraine. Since CGRP is also detected in human cochlear and vestibular organs it may also play a role in vestibular physiology. Methods: This is a prospective observational cohort study, aiming at evaluating the efficacy of erenumab, fremanezumab or galcanezumab for the treatment of fifty vestibular migraine patients. We assessed mean monthly days with headache and dizziness/vestibular symptoms, pain intensity and migraine-related clinical burden occurring for 18 months. Results: Response to treatment was excellent as 45 (90%) patients had at least a 50% reduction in vertigo frequency, 43 (86%) had at least a 50% reduction in headache frequency, and 40 (80%) a MIDAS reduction of at least 50%. Overall, 39 (78%) patients had a concomitant reduction of all three parameters. Mean monthly days with dizziness/vestibular symptoms showed an overall significant decrease from a mean of 10.3 ± 1.9 at baseline to 0.8 ± 0.3 days, difference 9.5 (CI 95% 3.6, 15.4; p < 0.001) after twelve months. Conclusion: We show that anti-CGRP mAbs may be effective in the treatment of Vestibular Migraine. Their use should be encouraged early in the disease course to allow for a better symptom control and quality of life improvement

Life-Threatening Cardiac Manifestations of Pheochromocytoma

Pheochromocytoma is a catecholamine-secreting tumor of the adrenal glands, usually with benign manifestations, whose typical clinical presentation includes the triad of headache, palpitations and diaphoresis. However, a wide range of signs and symptoms may be present. In the cardiovascular system, the most common signs are labile hypertension and sinus tachycardia. Systolic heart failure and ST-segment deviations mimicking myocardial infarction have also been reported, as well as QT interval prolongation and, rarely, ventricular tachycardia. We describe a challenging diagnosis of pheochromocytoma with many cardiovascular manifestations, which could have been missed due to the absence of typical symptoms

Usefulness of Ultrasound Imaging in Detecting Psoriatic Arthritis of Fingers and Toes in Patients with Psoriasis

Background. Given that clinical evaluation may underestimate the joint damage and that early treatment can slow down psoriatic arthritis (PsA) progression, screening psoriasis patients with imaging tools that can depict early PsA changes would entail clear benefits. Objective. To compare the ability of X-ray and ultrasound (US) examination in detecting morphological abnormalities consistent with early PsA in patients with psoriasis, using rheumatological evaluation as the gold standard for diagnosis. Methods. Patients with chronic plaque psoriasis and no previous PsA diagnosis attending our outpatient dermatology clinic and reporting finger/toe joint and/or tendon pain underwent X-ray and US evaluation; they were subsequently referred to a rheumatologist for clinical examination and review of imaging findings. Results. Abnormal US and/or X-ray findings involving at least one finger and/or toe (joints and/or tendons) were seen in 36/52 patients: 11 had one or more X-ray abnormalities, including erosion, joint space narrowing, new bone formation, periarticular soft tissue swelling, and periarticular osteoporosis; 36 had suspicious changes on US. Conclusion. US proved valuable in detecting joint and/or tendon abnormalities in the fingers and toes of patients with suspicious changes. The dermatologist should consider US to obtain an accurate assessment of suspicious findings

"All-in-one mesh" hernioplasty: A new procedure for primary inguinal hernia open repair.

Summary: Background: We propose a new open mesh hernia repair procedure for the treatment of inguinal hernias in adults aiming to improve patients' comfort and to reduce the incidence of chronic neuralgia. Methods: From September 2012 to August 2015, 250 consecutive patients were treated with "all in-one" mesh hernioplasty procedure in our Institution. According to the devised technique, a new smaller prosthesis was placed on the floor of the inguinal canal in order to strengthen all areas of weakness from which hernias may originate. The mesh was enveloped by a fibro-cremasteric sheath avoiding contact with neural structures. Follow-up was carried out at 3, 6, 12, 18 and 24 months for evaluation of postoperative pain using Visual Analogue Scale score, need of medication, patients' comfort and short or long-term complications. Results: All patients were discharged within 24 h from surgery. Slight pain was reported by the majority of patients and 47.6% of them did not require pain medication at home. After the 1st postoperative week 96.8% reported no pain and no other symptoms. No relevant limitation of normal activities was reported. There has been no postoperative neuralgia. One recurrence was observed. Conclusions: This new hernioplasty technique respects the anatomy of the inguinal canal, uses a smaller mesh, and seems to avoid neuralgia with maximum comfort for the patients. Keywords: Inguinal hernioplasty, Tension free hernia repair, Hernioplasty technique, Mesh for groin hernia, Neuralgia post-hernioplast

Rapid Quantification of SARS-Cov-2 Spike Protein Enhanced with a Machine Learning Technique Integrated in a Smart and Portable Immunosensor

An IoT-WiFi smart and portable electrochemical immunosensor for the quantification of SARS-CoV-2 spike protein integrated with machine learning features was developed. The immunoenzymatic sensor is based on the immobilization of monoclonal antibodies directed to SARS-CoV-2 S1 subunit on Screen-Printed Electrodes functionalized with gold nanoparticles, the analytical protocol involving a single-step sample incubation. Immunosensor performance was assessed by validation carried out in viral transfer medium, which is commonly used for de-sorption of nasopharyngeal swabs. Remarkable specificity of the response was demonstrated by testing H1N1 Hemagglutinin from swine-origin influenza A virus and Spike Protein S1 from Middle East respiratory syndrome coronavirus. Machine learning was successfully used for data processing and analysis: different support vector machine classifiers were evaluated proving that algorithms affect the classifier accuracy. The test accuracy of the best classification model in terms of true positive/true negative sample classification was 97.3%. In addition, ML algorithm can be easily integrated into the developed cloud-based portable Wi-Fi device. Finally, the immunosensor was successfully tested using a third generation replicating incompetent lentiviral vector pseudotyped with SARS-CoV-2 spike glycoprotein, thus proving the applicability of the immunosensor to whole virus detection

Pustular psoriasis with a focus on generalized pustular psoriasis: classification and diagnostic criteria. An Italian expert consensus

Generalized pustular psoriasis (GPP) is a severe and life-threatening systemic disease associated with significant morbidity and mortality. Recent progress has been made in understanding the pathogenetic pathways involved in GPP and an intricate interaction between innate and adaptive immune mechanisms has been suggested. Despite formal consensus guidelines on pustular psoriasis currently available in the literature, the definitions and classifications of GPP used across studies were inconsistent. Consequently, there are no unified criteria that can be universally adopted for precise diagnosis, classification and effective treatment of GPP patients with new targeted drugs. The aim of this review was to col- lect all the main evidence on available diagnostic criteria for GPP and to establish recommendations in order to promote a better stratification and therapeutic management of this severe and heterogeneous disease. (Cite this article as: Costanzo A, Bardazzi F, De Simone C, Fabbrocini G, Foti C, Marzano AV, et al. Pustular psoriasis with a focus on generalized pustular psoriasis: classification and diagnostic criteria. An Italian expert consensus. Ital J Dermatol Venereol 2022;157:489-96. DOI: 10.23736/ S2784-8671.22.07415-1

Gatekeeper Improves Voluntary Contractility in Patients With Fecal Incontinence

Background. Gatekeeper (GK) has shown to be safe and effective in patients with fecal incontinence (FI). We aimed to understand its mechanism of action by comparing pre- and post-implant change in the external anal sphincter (EAS) contractility. Methods. Study of EAS contractility was conducted in 16 FI females (median age = 69 years) before and after implant of 6 GK prostheses. Muscle tension (Tm), expressed in millinewtons per centimeter squared, mN(cm2) 121, was calculated using the equation Tm = P(ri)(tm) 121, where P is the average maximum squeeze pressure and ri and tm the inner radius and thickness of the EAS, respectively. The effect of a predefined set of covariates on Tm was tested by restricted maximum likelihood models. Results. Compared with baseline, despite unchanged tm (2.7 [2.5-2.8] vs 2.5 [2.2-2.8] mm; P =.31 mm), a significant increase in P (median = 45.8 [26.5-75.8] vs 60.4 [43.1-88.1] mm Hg; P =.017), and ri (12.4 [11.5-13.4] vs 18.7 [17.3-19.6] mm; P &lt;.001) resulted in an increase in Tm (233.2 [123.8-303.2] vs 490.8 [286.9-562.4] mN(cm2) 121; P &lt;.001) at 12 months after GK implant. Twelve-month follow-up improvements were also observed on Cleveland Clinic FI score (8-point median decrease; P =.0001), St Marks FI score (10-point median decrease; P &lt;.0001), and American Medical Systems score (39-point median decrease; P &lt;.0001). Restricted maximum likelihood models showed that years of onset of FI was negatively associated with change in Tm (P =.048). Conclusions. GK-related EAS compression positively influences muscle contractility by increasing ri, with consequent increase in Tm (length-tension relationship). Further studies are needed to confirm the long-term effectiveness of GK