ABSTRACT
In the present study, we show that SARS-CoV-2 can infect palatine tonsils, adenoids, and secretions in children without symptoms of COVID-19, with no history of recent upper airway ...infection. We studied 48 children undergoing tonsillectomy due to snoring/OSA or recurrent tonsillitis between October 2020 and September 2021. Nasal cytobrushes, nasal washes, and tonsillar tissue fragments obtained at surgery were tested by RT-qPCR, immunohistochemistry (IHC), flow cytometry, and neutralization assay. We detected the presence of SARS-CoV-2 in at least one specimen tested in 27% of patients. IHC revealed the presence of the viral nucleoprotein in epithelial surface and in lymphoid cells in both extrafollicular and follicular regions, in adenoids and palatine tonsils. Also, IHC for the SARS-CoV-2 non-structural protein NSP-16 indicated the presence of viral replication in 53.8% of the SARS-CoV-2-infected tissues. Flow cytometry showed that CD20
+
B lymphocytes were the most infected phenotypes, followed by CD4+ lymphocytes and CD123 dendritic cells, CD8+ T lymphocytes, and CD14+ macrophages. Additionally, IF indicated that infected tonsillar tissues had increased expression of ACE2 and TMPRSS2. NGS sequencing demonstrated the presence of different SARS-CoV-2 variants in tonsils from different tissues. SARS-CoV-2 antigen detection was not restricted to tonsils but was also detected in nasal cells from the olfactory region. Palatine tonsils and adenoids are sites of prolonged RNA presence by SARS-CoV-2 in children, even without COVID-19 symptoms.
IMPORTANCE
This study shows that SRS-CoV-2 of different lineages can infect tonsils and adenoids in one quarter of children undergoing tonsillectomy. These findings bring advancement to the area of SARS-CoV-2 pathogenesis, by showing that tonsils may be sites of prolonged infection, even without evidence of recent COVID-19 symptoms. SARS-CoV-2 infection of B and T lymphocytes, macrophages, and dendritic cells may interfere with the mounting of immune responses in these secondary lymphoid organs. Moreover, the shedding of SARS-CoV-2 RNA in respiratory secretions from silently infected children raises concern about possible diagnostic confusion in the presence of symptoms of acute respiratory infections caused by other etiologies.
This study shows that SRS-CoV-2 of different lineages can infect tonsils and adenoids in one quarter of children undergoing tonsillectomy. These findings bring advancement to the area of SARS-CoV-2 pathogenesis, by showing that tonsils may be sites of prolonged infection, even without evidence of recent COVID-19 symptoms. SARS-CoV-2 infection of B and T lymphocytes, macrophages, and dendritic cells may interfere with the mounting of immune responses in these secondary lymphoid organs. Moreover, the shedding of SARS-CoV-2 RNA in respiratory secretions from silently infected children raises concern about possible diagnostic confusion in the presence of symptoms of acute respiratory infections caused by other etiologies.
Body composition parameters and immunonutritional indexes provide useful information on the nutritional and inflammatory status of patients. We sought to investigate whether they predict the ...postoperative outcome in patients with pancreatic cancer (PC) who received neoadjuvant therapy (NAT) and then pancreaticoduodenectomy.
Data from locally advanced PC patients who underwent NAT followed by pancreaticoduodenectomy between January 2012 and December 2019 in four high-volume institutions were collected retrospectively. Only patients with two available CT scans (before and after NAT) and immunonutritional indexes (before surgery) available were included. Body composition was assessed and immunonutritional indexes collected were: VAT, SAT, SMI, SMA, PLR, NLR, LMR, and PNI. The postoperative outcomes evaluated were overall morbidity (any complication occurring), major complications (Clavien-Dindo ≥ 3), and length of stay.
One hundred twenty-one patients met the inclusion criteria and constituted the study population. The median age at the diagnosis was 64 years (IQR16), and the median BMI was 24 kg/m
(IQR 4.1). The median time between the two CT-scan examined was 188 days (IQR 48). Skeletal muscle index (SMI) decreased after NAT, with a median delta of -7.8 cm
/m
(
< 0.05). Major complications occurred more frequently in patients with a lower pre-NAT SMI (
= 0.035) and in those who gained in subcutaneous adipose tissue (SAT) compartment during NAT (
= 0.043). Patients with a gain in SMI experienced fewer major postoperative complications (
= 0.002). The presence of Low muscle mass after NAT was associated with a longer hospital stay Beta 5.1, 95%CI (1.5, 8.7),
= 0.006. An increase in SMI from 35 to 40 cm
/m
was a protective factor with respect to overall postoperative complications OR 0.43, 95% (CI 0.21, 0.86),
< 0.001. None of the immunonutritional indexes investigated predicted the postoperative outcome.
Body composition changes during NAT are associated with surgical outcome in PC patients who receive pancreaticoduodenectomy after NAT. An increase in SMI during NAT should be favored to ameliorate the postoperative outcome. Immunonutritional indexes did not show to be capable of predicting the surgical outcome.
Abstract
The Toll-like receptors (TLRs), 2, 4 and 9 are important to immunity against Trypanosoma cruzi, etiologic agent of Chagas disease. Intracellular receptors, including NLRP3 and AIM2, ...associate to ASC forming a complex that active caspase-1, called inflammasome. This complex is required for cleavage of the active forms of the IL-1β and IL-18. Recently, we show that ASC inflammasome is necessary to control T. cruzi infection, however the receptors that participate in this signalizing are not complete clear. Here, we investigated the participation of NLRP3 and AIM2 in the immune response against T. cruzi. First, we found high IL-1β production and caspase-1 activation in BMMs from WT mice, but not from NLRP3-/- and AIM2-/- mice. To understand the role of the inflammasome pathway during T. cruzi infection, WT, caspase-1-/-, ASC-/-, AIM2-/- and NLRP3-/- mice were infected with Y strain of T.cruzi. Our results showed that ASC-/- and caspase-1-/- mice presented higher mortality, whereas WT, AIM3-/- and NLRP3-/- are resistant to infection, suggesting more than one NLR is necessary to confer resistance for T. cruzi infection. In addition, caspase-1-/-, ASC-/-, AIM2-/- and NLRP3 BMMs presented higher parasitism and reduced amount of Nitric oxide (NO) production. Together, these results suggest that AIM2 and NLRP3 via ASC inflammasome participate of the infection against T. cruzi. Financial Support: FAPESP
Abstract
The fungus Paracoccidioides brasiliensis (Pb), causative agent of chronic systemic mycosis endemic in rural areas of Latin America, is sensed by the TLR-2, 4 and dectin-1 receptors. However, ...during this infection, the upstream pathways responsible for the cytokines production by macrophages as IL-1β and IL-18 are completely unknown. In Nlrp3-/- macrophages (BMMs), although amounts of IL-1β were reduced, it is still detectable when compared with uninfected macrophages, suggesting that there are additional receptors required for caspase-1 activation and IL-1β production. Then, we evaluate if Nlrc4 could induce IL-1β production and caspase-1 activation in vitro. Strikingly, we observed higher IL-1β release and caspase-1 activation in Nlrc4-/- BMMs than WT cells. To characterize the role of Nlrc4 during experimental infection, WT and Nlrc4-/- mice were infected intravenously with 1x10^6 yeasts forms of Pb18 and fungal burdens in the lung were analyzed at day 15 and 30 post infection. Whereas at 15 dpi WT and Nlrc4-/- mice had similar fungal counts in the lung tissue, at 30 dpi the lung homogenates from Nlrc4-/- mice contained lower numbers of Pb colony-forming units. Moreover, we showed that the reduction in number of viable yeasts was followed by compact and well defined granulomas formation. Taken together, these results suggest that Nlrc4 mediates efficient granulomatous organization and host resistance to P. brasiliensis infection. Financial support: FAPESP, CNPq, CAPES
Abstract
Recognition of L. pneumophila flagellin by Naip5-Nlrc4 inflammasome is required for innate immune restriction of the infection in restrictive mice background. Therefore, regardless to the ...mice background, flaA- mutant bacteria can be used to screen for important components of the immune system that account for growth restriction. flaA- bacteria were used to systematically infect mice and macrophages deficient for: 1) molecules important for effectors mechanisms of immune response (IFNγ, IL-6, 10, 12, 17, 18, 23, MIP-1α and TNFRp55); 2) cells of immune response (CD4KO-MHCII-/-, CD8KO-β2m-/-, BKO and neutrophils-anti-LY6G); 3) transmembrane innate immune receptors (CCR2, CCR4, Fas/Fas-L, ST2-, TLRs-); and 4) intracellular signaling molecules (PI3k, MyD88, Nod1, Nod2 and Rip2). Our data shows that mechanisms related with innate immune response, but not adaptive response are important for bacterial growth restriction in vivo and in vitro. Activation of these responses are critical for bacterial growth restriction and resolution of pulmonary infection in a murine model of Legionnaires’ disease.
To provide an overview of the drug profile of the orally active, selective endothelin A receptor antagonist ambrisentan, and its efficacy and safety in the treatment of patients with pulmonary ...arterial hypertension (PAH).
Medical literature on the use of ambrisentan in PAH was identified using MEDLINE and EMBASE. Additional references were identified from the reference lists of published articles and from the authors' own bibliographies.
Significant improvements in exercise capacity were observed with approved dosages of ambrisentan (5 or 10 mg once daily) in the AMB-220 dose-ranging study and the pivotal ARIES-1 and ARIES-2 trials, with sustained effects up to 2 years observed in ARIES-E. Improvements in cardiopulmonary hemodynamic variables were reported in AMB-220 and ARIES-E (subset analysis). Ambrisentan had little or no effect on hepatic transporters in in vitro studies and displayed a low risk of potential drug-drug interactions, including those with other PAH therapies. Results from the VOLT post-marketing program confirmed the safety profile of ambrisentan observed in the ARIES studies, including the low incidence of liver function test abnormalities. Peripheral edema and anemia were common side effects of endothelin receptor antagonist therapies, including ambrisentan. In the recently completed AMBITION study (ClinicalTrials.gov Identifier: NCT01178073), upfront initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (primary endpoint) by 50% compared with the pooled monotherapy groups.
The long-term efficacy and safety profile of ambrisentan in patients with PAH is supported by data from a comprehensive clinical trial program and real-life, post-marketing observations.
Purposes of this study are to evaluate the main changes that have occurred in the Italian MILS activity in the last decade in terms of indications, approaches and outcomes as reported in the national ...registry and to provide specific details on the main areas of development of MILS. Data from patients undergoing minimally invasive liver resections at centers included in the I Go MILS Registry from its start-up (November 2014) to March 2023 were analyzed for the purposes of this study. The registry is intention-to-treat and prospective. Global recruitment trends stratified by indication to surgery and type of approach were analysed. 7413 MILS procedures were performed across all centers (median number of procedures per center: 63). Years (2020–2023) displayed a significantly higher proportion of treated patients diagnosed with hepatocellular carcinoma (HCC) (38.2% vs. 28.9% and 33.9%,
p
< 0.001) and cholangiocarcinoma (6.7% vs. 6.5% and 4.2%,
p
< 0.001) compared to the preceding triennial periods. Additionally, technical complexity demonstrated an increased prominence in Years (2019–2023) with a significantly higher percentage of grade III cases compared to the earlier periods (39.3% vs. 21.7% and 25.6%,
p
< 0.001). Annual case trends focusing on laparoscopic and robotic techniques demonstrated a steadily increase in the use of these techniques for complex case mix of indications. Overall, attitude and attention to MILS approach has evolved, so that currently indications to hepatic mini-invasiveness have expanded and surgical technique has been refined: Areas mainly involved in increasing growth trends are hepatocellular carcinoma, possible applications of MILS in transplant setting, intrahepatic cholangiocarcinoma and robotic approach.
As part of Cell’s 40th anniversary celebration, we are spotlighting 40 principal investigators under the age of 40, and we asked each of them to describe their biggest personal challenges while ...working in science. See the full profiles of all our “40 under 40” scientists and their responses to this and other questions at http://www.cell.com/40/under40.
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