Regulatory T (Treg) cells, driven by the Foxp3 transcription factor, are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3gfp reporter mouse, ...which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in vitro function are not markedly altered in Foxp3gfp NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGF-β-induced Treg cell development was reduced. Foxp3gfp was unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.
► Foxp3gfp is a hypomorph that causes accelerated autoimmune diabetes in NOD mice ► Foxp3gfp causes nTreg cell insufficiency and impaired iTreg cell development ► Foxp3gfp has defective interaction with Tip60, HDAC7, and Eos ► Foxp3gfp causes altered Foxp3-dependent transcription and epigenetic modification
Congenital cytomegalovirus infection is considered the main cause of infantile non-genetic neurosensory hearing loss. Although this correlation was described more than 50 years ago, the natural ...history of internal ear involvement has not yet been fully defined. Hearing loss is the most frequent sequela and is seen in a variable percentage up to 30%; the hearing threshold is characterised by fluctuations or progressive deterioration. The purpose of this study was to evaluate the prevalence of hearing loss in cases of congenital CMV infection from Modena county, starting from the database of the microbiology and virology reference laboratory. All children undergoing urine testing for suspected CMV infection or viral DNA testing on Guthrie Card in the period between January 2004 and December 2014 were enrolled in the study. Family paediatricians were contacted and asked about clinical information on the possible presence at birth or subsequent occurrence of hearing loss, excluding cases where this was not possible. The results showed an annual prevalence of congenital cytomegalovirus infection among suspected cases that was stable over time despite the progressive increase in subjects tested. The prevalence of hearing loss was in line with the literature, whereas in long-term follow-up cases of moderate, medium-to-severe hearing loss with late onset were not detected. The introduction of newborn hearing screening in the county has allowed early diagnosis of hearing loss at birth as non-TEOAE-born births underwent a urine virus test. Moreover, despite all the limitations of the study, we can conclude that European epidemiological studies are needed to better define the relationship between congenital CMV infection and internal ear disease as the impact of environmental and genetic factors is still not entirely clarified.
The experimental set-up of the RIB in-flight facility EXOTIC Pierroutsakou, D.; Boiano, A.; Boiano, C. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
10/2016, Volume:
834
Journal Article
Peer reviewed
Open access
We describe the experimental set-up of the Radioactive Ion Beam (RIB) in-flight facility EXOTIC consisting of: (a) two position-sensitive Parallel Plate Avalanche Counters (PPACs), dedicated to the ...event-by-event tracking of the produced RIBs and to time of flight measurements and (b) the new high-granularity compact telescope array EXPADES (EXotic PArticle DEtection System), designed for nuclear physics and nuclear astrophysics experiments employing low-energy light RIBs. EXPADES consists of eight ΔE–Eres telescopes arranged in a cylindrical configuration around the target. Each telescope is made up of two Double Sided Silicon Strip Detectors (DSSSDs) with a thickness of 40/60μm and 300μm for the ΔE and Eres layer, respectively. Additionally, eight ionization chambers were constructed to be used as an alternative ΔE stage or, in conjunction with the entire DSSSD array, to build up more complex triple telescopes. New low-noise multi-channel charge-sensitive preamplifiers and spectroscopy amplifiers, associated with constant fraction discriminators, peak-and-hold and Time to Amplitude Converter circuits were developed for the electronic readout of the ΔE stage. Application Specific Integrated Circuit-based electronics was employed for the treatment of the Eres signals. An 8-channel, 12-bit multi-sampling 50MHz Analog to Digital Converter, a Trigger Supervisor Board for handling the trigger signals of the whole experimental set-up and an ad hoc data acquisition system were also developed. The performance of the PPACs, EXPADES and of the associated electronics was obtained offline with standard α calibration sources and in-beam by measuring the scattering process for the systems 17O+58Ni and 17O+208Pb at incident energies around their respective Coulomb barriers and, successively, during the first experimental runs with the RIBs of the EXOTIC facility.
Pharyngocutaneous fistula (PCF) is the most common complication following total laryngectomy and the most difficult to manage. It often causes increased morbidity, delays starting adjuvant therapy, ...prolongs hospitalisation, increases treatment costs and reduces the quality of life (QoL). The objective of this study is to analyse the predisposing factors and the most important nutritional parameters related to the development of PCF in patients undergoing total laryngectomy and to suggest medical alternatives that might improve results. We performed a retrospective study of 69 patients who underwent either primary or salvage total laryngectomy in our department between January 2008 and January 2012. Risk factors for fistula formation were analysed including tumour characteristics (histology, grading, AJCC stage), treatment (primary or salvage surgery, extent of resection, flap reconstruction, preoperative radiotherapy), comorbidity and nutritional status (preoperative haemoglobin, albumin and prealbumin levels and their changes during hospitalisation). Twenty-four patients developed a PCF (overall incidence 34.8%). Fistula formation was significantly higher in patients with diabetes, preoperative malnutrition (identified from low preoperative albumin and prealbumin levels). After specific nutritional evaluation and support, no patient developed a PCF. Risk factors for PCF formation are extensively treated in the literature but identification of high-risk patients is still controversial. Our study demonstrates that nutritional status of the patient, assessed by preoperative albumin, is also an important risk factor for PCF formation in addition to classical factors. Maintenance of a normal perioperative nutritional status can be helpful to avoid this complication.
•We realized a detection array for Exotic Radioactive Ion Beams.•High granularity (32×32 pixels 2×2mm wide for 8 telescopes).•High solid angle (8 telescopes 64×64mm wide in a cylindrical ...configuration covering up to 2.6sr).•We tested each component of the array by both alpha particles and in-beam environment.•We measured the angular distribution for 17O elastic scattering on a 58Ni target.
The EXPADES (EXotic PArticle DEtection System) detector array consists of 16 Double Side Silicon Strip Detectors (DSSSD) with active areas of 64×64mm2, arranged in 8 ΔE (40/50μm)–E (300μm) telescopes. All detector faces are segmented into 32×2-mm wide strips, ensuring a 2×2mm2 pixel configuration. Eight ionization chambers can be alternatively used as ΔE stages or, if needed, as an additional third layer for more complex triple telescopes. The signals from silicon ΔE layers and from ionization chambers are read by standard electronics, while innovative 32-channel ASIC chips are employed for the readout of the E stages. The results of off-line tests with alpha sources and from the first in-beam experiment with a 17O beam are presented.
Background and purpose: Sporadic amyotrophic lateral sclerosis (sALS) is a disease with a focal clinical onset and contiguous spread. We examined patterns of disease spread following symptoms onset ...in sALS and whether the pattern of spread predicted survival.
Methods: Review of medical records (2003–2009) at London Ontario and Buenos Aires clinic cohorts retrieved 318 patients with sporadic sALS. According to patient self‐report, we determined eight spread patterns: rostro‐caudal, caudo‐rostral, crossed, circular, superior interposed, middle interposed, inferior interposed and isolated. The variables studied were as follows: age, gender, sALS phenotypes, time from onset to diagnosis and time and direction of the spreading to the first region. Survival from symptoms onset was analysed by Kaplan–Meier, Tarone‐Ware and Cox proportional hazards methods.
Results: The direction of first spread was horizontal in 33%, rostral to caudal in 32% and caudal to rostral in 21%, whereas spread to remote regions was observed in 14% of patients. Survival curves and 3‐ and 5‐year survival rates favoured patients with an isolated and caudo‐rostral pattern of spread compared to patients progressing to distant regions without involvement in the intervening region, or ‘superior and inferior interposed patterns’ (Tarone‐Ware P = 0.001, χ2 = 0.002 and χ2 = 0.006, respectively). Factors affecting survival were gender, time to diagnosis, flail arm phenotype and age at diagnosis.
Conclusions: We have provided evidence that not all spread in ALS is contiguous and that the nature of symptom progression influences survival. Patients with sALS with ‘interposed patterns’ had a worse prognosis, whereas patients with caudo‐rostral pattern fared better than the rest.
Aim: Neutrophil migration in the intestine depends on chemotaxis of neutrophils to CXC chemokines produced by epithelial cells. The goal of this project was to determine if acute induction of a CXC ...chemokine gradient originating from intestinal epithelial cells is sufficient to induce neutrophil influx into intact intestinal tissue. Methods and results: The authors developed a double transgenic mouse model with doxycycline induced human IL-8 expression restricted to intestinal epithelial cells. Doxycycline treatment of double transgenic mice for three days resulted in a 50-fold increase in the caecal IL-8 concentration and influx of neutrophils into the lamina propria. Although neutrophils entered the paracellular space between epithelial cells, complete transepithelial migration was not observed. Doxycycline treatment also increased the water content of the caecal and colonic stool, indicating dysfunctional water transport. However, the transmural electrical resistance was not decreased. Neutrophils recruited to the intestinal epithelium did not show evidence of degranulation and the epithelium remained intact as judged by histology. Conclusions: This conditional transgenic model of chemokine expression provides evidence that acute induction of IL-8 in the intestinal epithelium is sufficient to trigger neutrophil recruitment to the lamina propria, but additional activation signals are needed for full activation and degranulation of neutrophils, mucosal injury, and complete transepithelial migration.
This paper describes the entrance detector of the magnetic spectrometer PRISMA recently installed at Legnaro. The detector is based on rectangular (
80
×
100
mm
2
) Micro-Channel Plates (MCP). It ...provides a fast time signal and its position-sensitive anode allows to extract the
X
and
Y
information. It exploits an electrostatic field for the acceleration of secondary electrons from a thin Carbon foil (
≃
20
μ
g
/
cm
2
) onto the MCP assembly. The electrons are guided by a parallel magnetic field. Good performances were obtained in the laboratory tests. The detector is presently installed at the entrance of PRISMA and gives resolutions
⩽
400
ps
in time, and 1
mm in both
X
and
Y
-axes, with efficiency
≃
100
%
, in typical experiments with heavy-ion beams.
Foxp3+ regulatory T cells (Tregs ) contribute significantly to the maintenance of peripheral tolerance, but they ultimately fail in autoimmune diseases. The events that lead to Treg failure in ...controlling autoreactive effector T cells (Teffs ) during autoimmunity are not completely understood. In this review, we discuss possible mechanisms for this subversion as they relate to type 1 diabetes (T1D) and multiple sclerosis (MS). Recent studies emphasize firstly, the role of inflammatory cytokines, such as IL-6, in inhibiting or subverting Treg function; secondly, the issue of Treg plasticity; thirdly, the possible resistance of autoimmune T cells to Treg -mediated control; and fourthly, Treg -associated inhibitory cytokines TGFβ, IL-10 and IL-35 in facilitating Treg suppressive activity and promoting Treg generation. These recent advances place a large emphasis on the local tissue specific inflammatory environment as it relates to Treg function and disease development.
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