Enrichment of intestinal Lactobacillus by enhanced secretory IgA coating alters glucose homeostasis in P2rx7 −/− mice

The secretory immunoglobulin A (SIgA) in mammalian gut protects the organism from infections and contributes to host physiology by shaping microbiota composition. The mechanisms regulating the adaptive SIgA response towards gut microbes are poorly defined. Deletion of P2rx7, encoding for the ATP-gated ionotropic P2X7 receptor, leads to T follicular helper (Tfh) cells expansion in the Peyer\u2019s patches (PPs) of the small intestine, enhanced germinal centre (GC) reaction and IgA secretion; the resulting alterations of the gut microbiota in turn affects host metabolism. Here, we define gut microbiota modifications that correlate with deregulated SIgA secretion and metabolic alterations in P2rx7 12/ 12 mice. In particular, Lactobacillus shows enhanced SIgA coating in P2rx7 12/ 12 with respect to wild-type (WT) mice. The abundance of SIgA-coated lactobacilli positively correlates with Tfh cells number and body weight, suggesting Lactobacillus-specific SIgA response conditions host metabolism. Accordingly, oral administration of intestinal Lactobacillus isolates from P2rx7 12/ 12 mice to WT animals results in altered glucose homeostasis and fat deposition. Thus, enhanced SIgA production by P2X7 insufficiency promotes Lactobacillus colonization that interferes with systemic metabolic homeostasis. These data indicate that P2X7 receptor-mediated regulation of commensals coating by SIgA is important in tuning the selection of bacterial taxa, which condition host metabolism

Pirfenidone in idiopathic pulmonary fibrosis: real-life experience in the referral centre of Siena

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and has a median survival after diagnosis of 2–5 years. Pirfenidone is the first approved antifibrotic drug for the treatment of IPF. Here we report the functional progress, side effects and survival data of a population of patients with IPF, diagnosed at our centre and treated with pirfenidone. Methods: We enrolled 91 patients with IPF (71 males) treated with pirfenidone. Clinical, survival and functional details were collected retrospectively at start of therapy and after 12, 24, 36 and 48 months of treatment. Lung function tests at least 12 months before starting therapy were available for 40 patients and were entered in the database, as well as side effects. Results: During the observation period (922 ± 529 days), 27 patients died, 5 patients underwent lung transplant and 10 patients interrupted therapy due to adverse events or IPF progression. The median survival was 1606 days. There was a significant reduction in disease progression rate, as measured by trend of forced vital capacity, after 1 year of therapy with respect to before treatment (p = 0.0085). Forced vital capacity reduction rate was progressively higher in the subsequent years of treatment. Treatment-related side effects were reported in 25 patients and were predominantly mild. Overall, four patients discontinued therapy due to severe photosensitivity. Conclusions: Our findings confirm the efficacy of pirfenidone in reducing functional progression of IPF and its excellent safety profile in a real-life setting. This study, designed on a long-term follow up, contributes to the growing evidence on safety, tolerability and efficacy of pirfenidone in IPF. The reviews of this paper are available via the supplemental material section

T follicular helper cells promote a beneficial gut ecosystem for host metabolic homeostasis by sensing microbiota-derived extracellular ATP

The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer’s patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis. The results of this study indicate that Tfh cells play a role in host-microbiota mutualism beyond protecting the intestinal mucosa by induction of affinity-matured IgA and suggest that extracellular ATP constitutes an inter-kingdom signaling molecule important for selecting a beneficial microbial community for the host via P2X7-mediated regulation of B cell help

Cryogenic Characterization of FBK RGB-HD SiPMs

We report on the cryogenic characterization of Red Green Blue - High Density (RGB-HD) SiPMs developed at Fondazione Bruno Kessler (FBK) as part of the DarkSide program of dark matter searches with liquid argon time projection chambers. A dedicated setup was used to measure the primary dark noise, the correlated noise, and the gain of the SiPMs at varying temperatures. A custom-made data acquisition system and analysis software were used to precisely characterize these parameters. We demonstrate that FBK RGB-HD SiPMs with low quenching resistance (RGB-HD-LR$_q$) can be operated from 40 K to 300 K with gains in the range $10^5$ to $10^6$ and noise rates on the order of a few Hz/mm$^2$

Pleuroparenchymal fibroelastosis (PPFE) associated with giant cell arteritis: A coincidence or a novel phenotype?

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by the fibrotic thickening of subpleural and parenchymal areas of the upper lobes. It may be both idiopathic or secondary to infections, interstitial lung diseases and/or drug exposure. Often PPFE patients report recurrent lower respiratory tract infections, suggesting that repeated inflammatory alterations induced by pulmonary infections may contribute to the development/progression of PPFE. Here, we report for the first time the case of a patient affected by Giant cell Arteritis with histologically proven PPFE. The lung involvement in GCA is rare and interstitial lung diseases are usually reported as an uncommon clinical manifestation of GCA. Our patient is probably the first case presenting PPFE associated with GCA and we wonder if this is a real associative disease or a coincidence perhaps, secondary to drug effects

IVF Lite: a smart IVF programme based on mild ovarian stimulation for good prognosis patients

Research question: The IVF Lite programme is based on mild ovarian stimulation including up to three fresh/frozen embryo transfers within 12 months. Is it effective and safe in good prognosis patients? Design: Single-centre prospective study on infertile patients at their first IVF attempt (female age ≤38 years, anti-Müllerian hormone concentrations >1.5 ng/ml and/or FSH ≤10 mIU/ml). Induction of multiple follicular growth was based on a fixed protocol consisting of clomiphene citrate (100 mg/day) from day 3 to 7 of the menstrual cycle and 150 IU of recombinant FSH on days 5, 7 and 9. In case of low follicular recruitment (fewer than four follicles), the cycle was cancelled. The IVF Lite programme was considered complete after a live birth delivery or up to three embryo transfers within 12 months. The primary outcome was the cumulative live birth rate (cLBR) per couples that completed the programme. Results: A total of 369 patients completed the IVF Lite programme, with 239 live births; 132 patients delivered after one embryo transfer (35.8%), 70 after a second embryo transfer (cLBR 54.7%), and 37 after a third attempt (cLBR 64.8%). No cases of ovarian hyperstimulation syndrome or clinical complications occurred. Spontaneous dropout rate from the programme was 4.5%. The cLBR per intention to treat was 46.8%. Conclusions: The IVF Lite programme proved to be effective and safe in good prognosis patients with a good response to clomiphene citrate stimulation. It was well tolerated and implied low gonadotrophin consumption. Two-thirds of the patients achieved a live birth at the completion of the programme