Assessing the Prevalence of Male Obesity-Associated Gonadal Dysfunction in Severe Obesity: A Focus on the Impact of Bariatric Surgery and Surgical Approaches

Purpose: Obesity is an important risk factor for secondary hypogonadism in men. Several studies evaluated the impact of bariatric surgery on gonadal function in men, proving an improvement in testosterone levels, without yet a global consensus on the impact of different surgical approaches. Objectives of the study are: to estimate the prevalence of obesity-associated gonadal dysfunction among men with severe obesity; to evaluate the response to bariatric surgery in terms of resolution of this condition, distinguishing between restrictive and restrictive-malabsorptive surgery. Methods: We conducted a retrospective evaluation of 413 males with severe obesity (BMI 44.7 ± 8.3 kg/m2). A subgroup of them (61.7%) underwent bariatric surgery. Anthropometric assessment (weight, BMI, waist and hip circumference), metabolic (glyco-lipidic asset and urate) and hormonal (morning gonadotropin and total testosterone) assessments were carried out at baseline and 3–6 months post-surgery. Results: Using a TT threshold of 2.64 ng/ml, 256 out of 413 (62%) patients were categorized as having biochemical hypogonadism. At multivariate analysis, the only parameter significantly associated with biochemical hypogonadism, was BMI value (p = 0.001). At 3–6 months after surgery, during the acute weight loss phase, only 20.1% of patients still had biochemical hypogonadism. At multivariate analysis, which included age, presurgical BMI, pre-surgical TT, surgical approach and %EWL, presurgical TT levels (p = 0.0004), %EWL (p = 0.04), and mixed restrictive-malabsorptive surgery (p = 0.01), were independently associated with the recovery of gonadal function. Conclusions: The results of this study underscore the potential reversibility of obesity-associated gonadal dysfunction through bariatric surgery, highlighting the importance of considering surgical approach. Graphical Abstract: (Figure presented.) © The Author(s) 2024

Pulmonary arterial hypertension and interstitial lung fibrosis in systemic sclerosis: One-stop shop assessment with cardiac and chest ultrasound

Background: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are common complications of systemic sclerosis (SSc). Echocardiography evaluates PAH, and chest sonography detects even mild ILC as ultrasound lung comets (ULC), i.e. multiple comet-tails fanning out from the lung surface and originating from subpleural interlobular septa thickened by fibrosis. Aim: to assess ILD and PAH by integrated cardiac and chest ultrasound in SSc. Materials and methods: We enrolled 30 consecutive SSc patients (age=54?13 years, 23 females) in the Rheumatology Clinic of Pisa University. In all, we assessed Systolic Pulmonary Arterial Pressure (SPAP), from maximal velocity of tricuspid regurgitation flow, and ULC score with chest sonography (summing the number of ULC from each scanning space of anterior and posterior right and left chest, from second to fifth intercostal space). All patients underwent plasma assay for anti-topoisomerase antibodies (anti-Scl70), associated with development of pulmonary fibrosis. Twenty-eight patients also underwent High Resolution Computed Tomography, HRCT (from 0=no fibrosis to 3=honey combing). Results: ULC number - but not SPAP - was correlated to HRCT fibrosis and presence SSc-70 antibodies (see figure). ULC number was similar in localized or diffuse forms (16?20 vs. 21?19, p=ns) and was unrelated to SPAP (r=0.216, p=ns). Conclusions: Cardiac and chest sonography assessment of SPAP and ULC allow a complete, simple, radiation-free characterization of vascular and interstitial lung involvement in SSc - all in one setting and with the same instrument, same transducer and the same sonographer. In particular, ULC number, but not SPAP, is associated with HRCT evidence of lung fibrosis and presence of Scl-70 antibodies

Ultrasound lung comets in systemic sclerosis: a chest sonography hallmark of pulmonary interstitial fibrosis

Objective. To assess the correlation between ultrasound lung comets (ULCs, a recently described echographic sign of interstitial lung fibrosis) and the current undisputed gold-standard high-resolution CT (HRCT) to detect pulmonary fibrosis in patients with SSc. Methods. We enrolled 33 consecutive SSc patients (mean age 5413 years, 30 females) in the Rheumatology Clinic of the University of Pisa. We assessed ULCs and chest HRCT within 1 week independently in all the patients. ULC score was obtained by summing the number of lung comets on the anterior and posterior chest. Pulmonary fibrosis was quantified by HRCT with a previously described 30-point Warrick score. Results. Presence of ULCs (defined as a total number more than 10) was observed in 17 (51%) SSc patients. Mean ULC score was 3750, higher in the diffuse than in the limited form (7366 vs 2135; P<0.05). A significant positive linear correlation was found between ULCs and Warrick scores (r?0.72; P<0.001). Conclusions. ULCs are often found in SSc, are more frequent in the diffuse than the limited form and are reasonably well correlated with HRCT-derived assessment of lung fibrosis. They represent a simple, bedside, radiation-free hallmark of pulmonary fibrosis of potential diagnostic and prognostic value

Characterization of antibody response in asymptomatic and symptomatic SARS-CoV-2 infection

SARS-CoV-2 pandemic is causing high morbidity and mortality burden worldwide with unprecedented strain on health care systems. To investigate the time course of the antibody response in relation to the outcome we performed a study in hospitalized COVID-19 patients. As comparison we also investigated the time course of the antibody response in SARS-CoV-2 asymptomatic subjects. Study results show that patients produce a strong antibody response to SARS-CoV-2 with high correlation between different viral antigens (spike protein and nucleoprotein) and among antibody classes (IgA, IgG, and IgM and neutralizing antibodies). The antibody peak is reached by 3 weeks from hospital admission followed by a sharp decrease. No difference was observed in any parameter of the antibody classes, including neutralizing antibodies, between subjects who recovered or with fatal outcome. Only few asymptomatic subjects developed antibodies at detectable levels

Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter

PI3Ks (phosphoinositide 3-kinases) are signalling molecules and drug targets with important biological functions, yet the regulation of PI3K gene expression is poorly understood. Key PI3Ks are the class IA PI3Ks that consist of a catalytic subunit (p110α, p110β and p110δ) in complex with a p85 regulatory subunit. Whereas p110α and p110β are ubiquitously expressed, high levels of p110δ are mainly found in white blood cells, with most non-leucocytes expressing low levels of p110δ. In the present paper we report that TNFα (tumour necrosis factor α) stimulation induces p110δ expression in human ECs (endothelial cells) and synovial fibroblasts, but not in leucocytes, through transcription start sites located in a novel promoter region in the p110δ gene (PIK3CD). This promoter is used in all cell types, including solid tumour cell lines that express p110δ, and is activated by TNFα in ECs and synovial fibroblasts. We further present a detailed biochemical and bioinformatic characterization of p110δ gene regulation, demonstrating that PIK3CD has distinct promoters, some of which can be dynamically activated by pro-inflammatory mediators. This is the first molecular identification of a PI3K promoter under the control of acute extracellular stimulation

Angiogenic gene expression and vascular density are reflected in ultrasonographic features of synovitis in early Rheumatoid Arthritis: an observational study.

INTRODUCTION: Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Ultrasound (US) provides an indirect method of assessing synovial blood flow and has been shown to correlate with clinical disease activity in patients with Rheumatoid Arthritis. This study examines the relationship of US determined synovitis with synovial vascularity, angiogenic/lymphangiogenic factors and cellular mediators of inflammation in a cohort of patients with early Rheumatoid Arthritis (RA) patients prior to therapeutic intervention with disease modifying therapy or corticosteroids. METHODS: An ultrasound guided synovial biopsy of the supra-patella pouch was performed in 12 patients with early RA prior to treatment. Clinical, US and biochemical assessments were undertaken prior to the procedure. Ultrasound images and histological samples were obtained from the supra-patella pouch. Histological samples were stained for Factor VIII and a-SMA (a-smooth muscle actin). Using digital imaging analysis a vascular area score was recorded. QT-PCR (quantitative-PCR) of samples provided quantification of angiogenic and lymphangiogenic gene expression and immunohistochemistry stained tissue was scored for macrophage, T cell and B cell infiltration using an existing semi-quantitative score. RESULTS: Power Doppler showed a good correlation with histological vascular area (Spearman r--0.73) and angiogenic factors such as vascular endothelial growth factor-A (VEGF-A), Angiopoietin 2 and Tie-2. In addition, lymphangiogenic factors such as VEGF-C and VEGF-R3 correlated well with US assessment of synovitis. A significant correlation was also found between power Doppler and synovial thickness, pro-inflammatory cytokines and sub-lining macrophage infiltrate. Within the supra-patella pouch there was no significant difference in US findings, gene expression or inflammatory cell infiltrate between any regions of synovium biopsied. CONCLUSION: Ultrasound assessment of synovial tissue faithfully reflects synovial vascularity. Both grey scale and power Doppler synovitis in early RA patients correlate with a pro-angiogenic and lymphangiogenic gene expression profile. In early RA both grey scale and power Doppler synovitis are associated with a pro-inflammatory cellular and cytokine profile providing considerable validity in its use as an objective assessment of synovial inflammation in clinical practice

Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination

Background. The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees. Methods. Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant. Results. In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant. Conclusions. Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD

Cerebrospinal Fluid Pressure-Related Features in Chronic Headache: A Prospective Study and Potential Diagnostic Implications

Objective: To identify the pressure-related features of isolated cerebrospinal fluid hypertension (ICH) in order to differentiate headache sufferers with ICH from those with primary headache disorder.Methods: In this prospective study, patients with refractory chronic headaches and suspected of having cerebrospinal fluid-pressure elevation without papilledema or sixth nerve palsy, together with controls, underwent 1-h lumbar cerebrospinal fluid pressure monitoring via a spinal puncture needle.Results: We recruited 148 consecutive headache patients and 16 controls. Lumbar cerebrospinal fluid pressure monitoring showed high pressure and abnormal pressure pulsations in 93 (63 %) patients with headache: 37 of these patients with the most abnormal pressure parameters (opening pressure above 250 mm H2O, mean pressure 301 mm H2O, mean peak pressure 398 mm H2O, and severe abnormal pressure pulsations) had the most severe headaches and associated symptoms (nocturnal headache, postural headache, transient visual obscuration); 56 patients with the less abnormal pressure parameters (opening pressure between 200 and 250 mm H2O, mean pressure 228 mm H2O, mean peak pressure 316 mm H2O, and abnormal pressure pulsations) had less severe headaches and associated symptoms.Conclusions: Nocturnal and postural headache, and abnormal pressure pulsations are the more common pressure-related features of ICH in patients with chronic headache. Abnormal pressure pulsations may be considered a marker of ICH in chronic headache

Different biological and prognostic breast cancer populations identified by FDG-PET in sentinel node-positive patients: Results and clinical implications after eight-years follow-up

Abstract Background Sentinel node (SN) biopsy is the standard method to evaluate axillary node involvement in breast cancer (BC). Positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (FDG-PET) provides a non-invasive tool to evaluate regional nodes in BC in a metabolic-dependent, biomolecular-related way. In 1999, we initiated a prospective non-randomized study to compare these two methods and to test the hypothesis that FDG-PET results reflect biomolecular characteristics of the primary tumor, thereby yielding valuable prognostic information. Patients and methods A total of 145 cT1N0 BC patients, aged 24–70 years, underwent FDG-PET and lymphoscintigraphy before surgery. SN biopsy was followed in all cases by complete axillary dissection. Pathologic evaluation in tissue sections for involvement of the SN and other non-SN nodes served as the basis of the comparison between FDG-PET imaging and SN biopsy. Results FDG-PET and SN biopsy sensitivity was 72.6% and 88.7%, respectively, and negative predictive values were 80.5% and 92.2%, respectively. A subgroup of more aggressive tumors (ER-GIII, Her2+) was found mainly in the FDG-PET true-positive (FDG-PET+) patients, whereas LuminalA, Mib1 low-rate BCs were significantly undetected ( p = 0.009) in FDG-PET false-negative (FDG-PET−) patients. Kaplan–Meier survival estimates after a median follow-up of more than 8 years showed significantly worse overall survival for FDG-PET+ patients in node-positive (N+) patients ( p = 0.035) as compared to N+/FDG-PET− patients, which overlapped with survival curves of N− and FDG-PET+ or − patients. Conclusions Our findings suggest that FDG-PET results reflect intrinsic biologic features of primary BC tumors and have prognostic value with respect to nodal metastases. FDG-PET false negative cases appear to identify less aggressive indolent metastases. The possibility to identify a subgroup of N+ BC patients with an outcome comparable with N− BC patients could reduce the surgical and adjuvant therapeutic intervention

Low-dose Oral Imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide. A phase II pilot study

none16noFraticelli P, Gabrielli B; Pomponio, G; Valentini, G; Bosello, S; Riboldi, P; Gerosa, M; Faggioli, P; Giacomelli, R; Del Papa, N; Gerli, R; Lunardi, C; Bombardieri, S; Malorni, W; Corvetta, A; Moroncini, G; Gabrielli, A.Fraticelli P, Gabrielli B; Pomponio, G; Valentini, G; Bosello, S; Riboldi, P; Gerosa, M; Faggioli, P; Giacomelli, R; Del Papa, N; Gerli, R; Lunardi, C; Bombardieri, S; Malorni, W; Corvetta, A; Moroncini, Gianluca; Gabrielli, Armand