SRC FAMILY KINASE MEMBERS MEDIATE TYPE I INTERFERON PRODUCTION BY PLASMACYTOID DENDRITIC CELLS

Plasmacytoid dendritic cells (pDCs) are the most powerful type I interferon (IFN-I) producing cells, playing important roles in defense against pathogens, tumor immune-surveillance and autoimmune diseases. Therefore, understanding pDC regulatory pathways to ultimately manipulate them holds great promise for immune-based therapeutics to attenuate several human illnesses. Here we investigated the role of Src Family Kinases (SFKs), a family of non-receptor tyrosine kinases, in pDC response to toll like receptor (TLR) stimulation. We observed for the first time that pDCs from either Fyn or Lyn deficient mice exhibited impaired IFN-I and pro-inflammatory cytokine production after TLR7 and TLR9 stimulation, whereas no difference was observed in conventional DCs. Consistently, treatment with either a pan-SFK inhibitor or a selective dual BCR-ABL/LYN inhibitor (i.e. Bafetinib) profoundly ablated TLR-induced IFN-I production in both a human pDC cell line (CAL-1) and in primary pDCs from human peripheral blood. Furthermore, genetic ablation of LYN by CRISPR/Cas9 in CAL-1 cells resulted in diminished TLR responses. Mechanistically, we showed that the inhibition of SFK activity by Bafetinib reduced the TLR-induced activation of IKK\u3b1/\u3b2, ERK1/2, P38 and IRF7, key elements downstream pDC TLR signaling, as well as those of MTOR and BCAP, an adaptor protein that bridges PI3K and TLR pathways. Taken together, our data indicate that SFKs, particularly LYN, promote pDC IFN-I and pro-inflammatory cytokine production and suggest that SFK inhibitory drugs, such as Bafetinib, could be considered for attenuating pDC response in autoimmune diseases

Anthropometric parameters in relation to glycaemic status and lipid profile in a multi-ethnic sample in Italy.

OBJECTIVE: To examine the health status of ethnic minorities in Italy. Furthermore, we aimed to assess the association between anthropometric and blood parameters connected with health status. DESIGN: A cross-sectional study. Anthropometric data were collected by direct measurements and blood glucose, total cholesterol and TAG were analysed. SETTING: Bologna, northern Italy. SUBJECTS: A multi-ethnic sample of adult immigrants and Roma. RESULTS: Significant correlations between anthropometric and blood parameters were found. Among the ethnic groups, Roma males had the highest values of glucose, total cholesterol and TAG. In the females the situation was more balanced among ethnic groups. CONCLUSIONS: The data from this survey indicate that poor health status is a very common problem among ethnic groups living in Italy, especially the Roma. The use of anthropometric parameters as rapid indicators of health status in screenings of a large number of subjects could be an effective and cheap method to provide preliminary indications on individuals or ethnic groups at greater risk of poor health

Incidence of mesothelioma in Lombardy, Italy: exposure to asbestos, time patterns and future projections

Objectives In Italy, asbestos has been extensively used from 1945 to 1992. We evaluated the impact of exposure to asbestos on occurrence of malignant mesothelioma (MM) in the Lombardy Region, Northwest Italy, the most populated and industrialised Italian region. Methods From the Lombardy Mesothelioma Registry, we selected all incident cases of MM diagnosed between 2000 and 2012. We described sources of exposure to asbestos and examined time trends of MM rates. Using Poisson age-cohort models, we derived projections of burden of MM in the Lombardy population for the period 2013-2029. Results In 2000-2012, we recorded 4442 cases of MM (2850 men, 1592 women). Occupational exposure to asbestos was more frequent in men (73.6%) than in women (38.2%). Non-occupational exposure was found for 13.6% of women and 3.6% of men. The average number of cases of MM per year was still increasing (+3.6% in men, +3.3% in women). Incidence rates were still increasing in individuals aged 65+ years and declining in younger people. A maximum of 417 cases of MM (267 men, 150 women) are expected in 2019. We forecast there will be 6832 more cases (4397 in men, 2435 in women) in the period 2013-2029, for a total of 11274 cases of MM (7247 in men, 4027 in women) in 30years. Conclusions This study documented a high burden of MM in both genders in the Lombardy Region, reflecting extensive occupational (mainly in men) and non-occupational (mainly in women) exposure to asbestos in the past. Incidence rates are still increasing; a downturn in occurrence of MM is expected to occur after 2019

Cementless ceramic-on-ceramic total hip replacement in children and adolescents

Background: total hip replacement (THR) is a rare surgical option in children and adolescents with disabling hip diseases. The aim of this study is to report results from a retrospective cohort of patients aged 18 years or less who underwent cementless Ceramic-on-Ceramic (CoC) THR at a single institution, investigating clinical and radiographic outcomes, survival rates, and reasons for revision of the implants. Materials and methods: we queried the Registry of Prosthetic Orthopedic Implants (RIPO) to identify all children and adolescents undergoing THR between 2000 and 2019 at a single Institution. Inclusion criteria were patients undergoing cementless CoC THR, aged less than 18 years at surgery, followed for at least 2 years. Sixty-eight patients (74 hips) matched all the inclusion criteria and were enrolled in the study. We assessed the clinical and radiographic outcomes, the rate of complications, the survival rate, and reasons for revision of the implants. Results: The mean follow-up was 6.6 ± 4.4 years (range 2–20). The most frequent reason for THR was post-traumatic or chemotherapy-induced avascular necrosis (38%). The overall survival rate of the cohort was 97.6% (95% CI: 84.9–99.7%) at 5 years of follow-up, 94.4% (95% CI: 79.8–98.6%) at 10 years and 15 years of follow-up. Two THR in two patients (2.7%) required revision. With the numbers available, Cox regression analysis could not detect any significant interaction between preoperative or intraoperative variables and implant survivorship (p-value 0.242 to 0.989).” The average HOOS was 85 ± 14.3 (range 30.6–100). Overall, 23 patients (48%) reported excellent HOOS scores (>90 points), 21 patients (44%) reported acceptable HOOS scores (60–90 points) while 4 patients (8%) reported poor outcomes (<60 points). Twenty-one patients (43%) were regularly involved into moderate-to high-intensity sport activities (UCLA ≥ 6). Conclusions: Cementless CoC THR is a successful procedure in children and teenagers, having demonstrated high implant survivorship and low rates of complications and failure. A meticulous preoperative planning and implant selection is mandatory, to avoid implant malposition, which is the main reason of failure and revision in these cases. Further studies are needed to assess the impact of the THR on the psychosocial wellbeing of teenagers, as well as risks and benefits and cost-effectiveness in comparison to the hip preserving surgical procedures

IL-27R signalling mediates early viral containment and impacts innate and adaptive immunity after chronic lymphocytic choriomeningitis virus infection

Chronic viral infections represent a major challenge to host's immune response and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin 27 (IL-27), in the control of chronic infection. We found that IL-27R signalling promoted control of LCMV Cl13 as early as day 1 and 5 after infection and that il27p28 transcripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells. In particular, plasmacytoid DCs (pDCs), the most potent type-1-interferon (IFN-I) producing cells, significantly increased il27p28 in a TLR7 dependent fashion. Notably, mice deficient in IL-27 specific receptor (R), WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic LCMV infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared cell-extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11b+ DCs and myeloid cells, may explain the compromised IFN-I elevation that we observed early after LCMV Cl13 infection in IL-27R-deficient mice. Together these data highlight the critical role of IL-27 in enabling optimal anti-viral immunity early and late after infection with a systemic persistent virus and suggest that a previously unrecognized positive feedback-loop mediated by IL-27 in pDCs might be involved in this process

Next Generation Driver for Attosecond and Laser-plasma Physics

The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 10(20)W/cm(2) with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-field-driven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources