COVID-19 has spread to most countries in the world. However, there are differences in the rate of infection in different countries. Specifically, high incidence was reported in specific areas in ...China (Wuhan) and Italy (Lombardy). These differences may be related to different Human Leucocyte Antigen (HLA) patterns in various geographic areas. We suggest HLA spreading between Italy and China is related to the travels of Marco Polo through the Silk Road as a potential historic explanation to COVID-19 spreading. Keywords: COVID-19, infection rate, HLA, Marco Polo, silk road
Background
Studies of anti‐SARS‐CoV‐2 humoral and adaptive response in COVID‐19 non‐vaccinated pediatric convalescents are controversial and further evidence from the pediatric population are needed.
...Objectives
To elucidate SARS‐CoV‐2 humoral and memory B‐ and T‐cells responses in pediatric convalescents as compared with the adult.
Methods
Blood samples were obtained from 80 non‐vaccinated, IgG‐positive, COVID‐19 convalescents (age 8.0–61.0 years), 4.0 months from onset. Frequency of responders and magnitudes of SARS‐COV‐2 IgG, memory B‐cells (MBC) and IFNg‐ and IL2‐secreting memory T‐cells (MTC) in response to immuno‐dominant peptide pools in pediatric, young adults and middle‐aged adults with onset age 8–18 years (N = 20), 19–39 years (N = 30) and 40–61 years (N = 30), respectively, were analyzed. SARS‐CoV‐2 IgG were detected by ELISA (Euroimmun, Germany). MBC, IFNg‐, IL2‐ and IFNg+IL2‐secreting MTC (IFNg‐MTC, IL2‐MTC and IFNg+IL2‐MTC) were detected using FluoroSpot (Mabtech, Sweden).
Results
MBC level was lower in pediatric as compared with the middle‐aged adults (median 12.75 interquartile range IQR 4.27–33.7 and 32.0 IQR 6.0–124.2, respectively, p = .003). MBC level in young adults was lower than in middle‐aged adults (median 18.5 IQR 1.7–43.8 and 32.0 IQR 6.0–124.2, respectively, p = .006). The level of IL2‐MTC was lower in the pediatric group as compared with middle aged‐adults (median 2.1 IQR 0–16.9 and 28.6 IQR 11–49.6, respectively, p < .03) and in young adults lower than in middle‐aged adults (median 1.45 IQR 0–18.6 and 28.6 IQR 11–49.6, respectively, p = .02). In addition, the level of IFNg‐MTC was lower in pediatric as compared with young adults (median 4.25 IQR 0.0–15.0 and 20.9 IQR 0–75.2, respectively, p = .05). The level of IgG was comparable between pediatric and both young and middle‐aged adult groups (4.82 ± 2.95, 3.70 ± 2.65 and 4.9 ± 2.94, respectively, p > .34).
Conclusion
Non‐vaccinated COVID‐19 pediatric convalescents have lower adaptive immune responses than adults sustaining the recommendation for vaccination of the pediatric population.
During the coronavirus disease-2019 (COVID-19) pandemic outbreak our blood bank developed protocols to guarantee accurate blood components to COVID-19 patients.
To provide convalescent whole blood ...donor screening strategies for patients recovering from COVID-19.
We recruited COVID-19 recovering patients who met our defined inclusion criteria for whole blood donation. All blood units were screened for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA by real time reverse transcription polymerase chain reaction (RT-PCR) and SARS-COV-2 immunoglobulin G (IgG) antibodies against the S1 domain.
We screened 180 blood units from patients recovering from COVID-19. All results were negative for SARS-CoV-2 RNA and 87.2% were positive for SARS-COV-2 IgG antibodies in the plasma.
Blood component units from recovering COVID-19 patients are safe. Plasma units with positive IgG antibodies could serve as an efficient passive immunization for COVID-19 patients. Moreover, in the face of increased transfusion demand for treatment of anemia and coagulation dysfunction in critical ill COVID-19 patients, red blood cells units and random platelets units from convalescent donors can be safely transfused.
•Immune responses were measured in untreated MS patients or treated with teriflunomide or alemtuzumab, following COVID-19 vaccination.•RBD specific memory B-cells were detected only in 30%-44% of ...patients with positive anti-SARS-CoV-2 IgG.•Only 41%-55% of MS patients demonstrated memory T-cells secreting IFN-g and/or IL-2 or both in response to SARS-CoV-2 peptides.•Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients.
The impact of disease-modifying therapies on the efficacy to mount appropriate immune responses to COVID-19 vaccination in patients with multiple sclerosis (MS) is currently under investigation.
To characterize long-term humoral and cellular immunity in mRNA-COVID-19 MS vaccinees treated with teriflunomide or alemtuzumab.
We prospectively measured SARS-COV-2 IgG, memory B-cells specific for SARS-CoV-2 RBD, and memory T-cells secreting IFN-γ and/or IL-2, in MS patients vaccinated with BNT162b2-COVID-19 vaccine before, 1, 3 and 6 months after the second vaccine dose, and 3–6 months following vaccine booster.
Patients were either untreated (N = 31, 21 females), under treatment with teriflunomide (N = 30, 23 females, median treatment duration 3.7 years, range 1.5–7.0 years), or under treatment with alemtuzumab (N = 12, 9 females, median time from last dosing 15.9 months, range 1.8–28.7 months). None of the patients had clinical SARS-CoV-2 or immune evidence for prior infection. Spike IgG titers were similar between untreated, teriflunomide and alemtuzumab treated MS patients both at 1 month (median 1320.7, 25–75 IQR 850.9–3152.8 vs. median 901.7, 25–75 IQR 618.5–1495.8, vs. median 1291.9, 25–75 IQR 590.8–2950.9, BAU/ml, respectively), at 3 months (median 1388.8, 25–75 1064.6–2347.6 vs. median 1164.3 25–75 IQR 726.4–1399.6, vs. median 837.2, 25–75 IQR 739.4–1868.5 BAU/ml, respectively), and at 6 months (median 437.0, 25–75 206.1–1161.3 vs. median 494.3, 25–75 IQR 214.6–716.5, vs. median 176.3, 25–75 IQR 72.3–328.8 BAU/ml, respectively) after the second vaccine dose. Specific SARS-CoV-2 memory B cells were detected in 41.9%, 40.0% and 41.7% of subjects at 1 month, in 32.3%, 43.3% and 25% at 3 months, and in 32.3%, 40.0%, 33.3% at 6 months following vaccination in untreated, teriflunomide treated and alemtuzumab treated MS patients, respectively. Specific SARS-CoV-2 memory T cells were found in 48.4%, 46.7% and 41.7 at 1 month, in 41.9%, 56.7% and 41.7% at 3 months, and in 38.7%, 50.0%, and 41.7% at 6 months, of untreated, teriflunomide-treated and alemtuzumab –treated MS patients, respectively. Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients.
MS patients treated with teriflunomide or alemtuzumab achieved effective humoral and cellular immune responses up to 6 months following second COVID-19 vaccination. Immune responses were reinforced following the third vaccine booster.
Multiple sclerosis (MS) is an autoimmune disease where T-cells activated against myelin antigens are involved in myelin destruction. Yet, healthy subjects also harbor T-cells responsive to myelin ...antigens, suggesting that MS patient-derived autoimmune T-cells might bear functional differences from T-cells derived from healthy individuals. We addressed this issue by analyzing gene expression patterns of myelin oligodendrocytic glycoprotein (MOG) responsive T-cell lines generated from MS patients and healthy subjects. We identified 150 transcripts that were differentially expressed between MS patients and healthy controls. The most informative 43 genes exhibited > 1.5-fold change in expression level. Eighteen genes were upregulated including BCL2, lifeguard, IGFBP3 and VEGF. Twenty five genes were down-regulated, including apoptotic activators like TNF and heat shock protein genes. This gene expression pattern was unique to MOG specific T-cell lines and was not expressed in T-cell lines reactive to tetanus toxin (TTX). Our results indicate that activation in MS that promotes T-cell survival and expansion, has its own state and that the unique gene expression pattern that characterize autoreactive T-cells in MS represent a constellation of factors in which the chronicity, timing and accumulation of damage make the difference between health and disease.
A unique property of the photodynamic signal transduction inhibitor hypericin is functionality in the dark. We show in tumor cells that hypericin targets the heat shock protein (Hsp) 90 chaperone but ...not Hsp70 (Hsc70) to enhanced ubiquitinylation. As a consequence Hsp90 chaperone functionality is abrogated and the client proteins, mutant p53, Cdk4, Raf-1, and Plk, are displaced from complexes with Hsp90, destabilized, and degraded via a proteasome-independent pathway. Decline in Raf-1 prevents downstream activation of extracellular signal-regulated kinase 1/2 kinases, the Ras/Raf pathway is inhibited, and tumor cell proliferation is arrested. The cells exhibit multiple aberrations including retardation at G(2)-M, increased cell volume, and multinucleation, all of which are hallmarks of mitotic cell death. The studies demonstrate that ubiquitinylation of Hsp90 inactivates the chaperone, destabilizes the plethora of client proteins, and creates deficiencies in multiple unrelated cellular functions. This combination constitutes a mechanism by which hypericin generates mitotic cell death in cancer cells.
Failure of conventional therapies to alleviate glioblastoma (GBM) fosters search for novel therapeutic strategies. These include epigenetic modulators as histone deacetylase inhibitors (HDACi), which ...relax abnormally compact tumor cell chromatin organization, enabling cells to overcome blockage in differentiation. However, in clinical settings, HDACi efficacy is confined to subsets of hematologic malignancies. We reasoned that molecules targeting multiple epigenetic mechanisms may exhibit superior anti-cancer activities. We focused on the redox perylene-quinone Hypericin (HYP) and showed that HYP targets Hsp90 for polyubiquitination, degradation and inactivation. Hsp90 is implicated in mediating inheritable epigenetic modifications transferable to progeny. We therefore examined if HYP can induce epigenetic alterations in GBM cells and show here that HYP indeed, targets multiple mechanisms in human glioblastoma tumor cell lines via unique manners. These elicit major epigenetic signature changes in key developmentally regulated genes. HYP induces neuroglial tumor cell differentiation modulating the cytoarchitecture, neuroglial differentiation antigen expression and causes exit from cell proliferation cycles. Such activities characterize HDACi however HYP is not an HDAC inhibitor. Instead, HYP effectively down-regulates expression of Class-I HDACs, creating marked deficiencies in HDACs cellular contents, leading to histones H3 and H4 hyperacetylation. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3K27 is also suppressed. The resulting histone hyperacetylation and diminished H3K27-trimethylation relax chromatin structure, activating gene transcription including differentiation-promoting genes. DNMT profiles are also modulated increasing global DNA methylation. HYP induces unique epigenetic down-regulations of HDACs, EZH2 and DNMTs, remodeling chromatin structure and culminating in tumor cell differentiation. These modulations generate clinically significant anti-GBM effects obtained in a clinical trial performed in patients with recurrent, progressive disease. Despite this advanced disease stage, patients responded to HYP, displaying stable disease and partial responses; patients on compassionate therapy survived for up to 34 months. Hypericin may constitute a novel anti-glioblastoma therapeutic paradigm.
Pediatric cardiopulmonary bypass involves the creation of a large obligatory priming reservoir. Packed red blood cells are an essential part of the cardiopulmonary bypass priming solution in ...children. The storage media in packed red blood cells might cause significant acid-base, glucose, and electrolyte imbalances, which have been associated with severe complications. The purpose of the present study was to evaluate the metabolic effects of fresh (< or =5 days) versus old (>5 days) stored packed red blood cells added to the priming solutions of pediatric patients undergoing cardiac surgery.
Blood samples were drawn from cardiopulmonary bypass priming of 30 consecutive pediatric patients undergoing cardiac surgery. Patients were divided into 2 groups. Fresh (< or =5 days old) stored packed red blood cells were added to the priming solution in group 1, and old (>5 days old) stored packed red blood cells were added to the priming solution in group 2. In each group blood samples were drawn from the packed red blood cells on arrival to the operating room and from the priming solution immediately after packed red blood cells were added and after 20 minutes of prime circulation. Samples were also collected at the beginning of cardiopulmonary bypass and after 30 minutes. The last sample was collected on arrival to the pediatric intensive care unit. The levels of potassium, glucose, and lactate and the acid-base balance were analyzed in each sample.
There was a linear increase in potassium levels in packed red blood cell samples with increasing packed red blood cell age, ranging from 5.4 to 18.4 mEq/L. Significant differences in the concentrations of potassium, glucose, and lactate and the acid-base balance were found when comparing old and fresh packed red blood cells in samples taken during the packed red blood cell and early prime time. Those differences resolved after 20 minutes of reconstitution of the priming solution. The age of the packed red blood cells had no effect on the samples taken during bypass and those taken in the pediatric intensive care unit.
The significantly higher concentration of potassium and lactate and lower pH in old stored packed red blood cells has a minimal effect on the final constitution of priming solution before and during cardiopulmonary bypass in children undergoing corrective cardiac surgery.
The identification of antinuclear antibodies (ANA) is an essential step in the diagnosis of different autoimmune diseases. The gold standard method for their detection is immunofluorescence assay. ...However, this is a subjective and laborious method, thus a need for simplified objective methods has aroused. In the current work, we evaluated such automated method, the LIAISON
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(DiaSorin, Italy) for the detection of ANA. A total of 242 sera were analyzed including 67 from healthy subjects, 107 from primary biliary cirrhosis (PBC) patients, 20 from scleroderma patients and 48 from patients with Sjögren’s syndrome. All sera were analyzed using the automated chemiluminescent immunoassays, LIAISON
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for the presence of ANA (kit No. 310300). Positive samples were further analyzed for the presence of antidouble-stranded DNA (dsDNA) and autoantibodies to 6 extractable nuclear antigens (ENA) of the LIAISON
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(kits No. 310330 and 310331). Negative samples were further analyzed by Blueblot ANA assay (D-TEK, Belgium) or BlueDot Liver (D-TEK, Belgium) as appropriate. The LIAISON
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specificity for ANA screening was 97 %. ANA positivity was determined in 80 % of all patients. The sensitivity was 95.5 % in scleroderma, 83 % in PBC and 72.9 % in Sjogren’s syndrome. ENA was positive in all ANA-positive scleroderma and Sjögren’s sera and in 27 % of ANA-positive PBC sera. Among scleroderma or Sjögren patients that were ANA negative, 4 samples were positive for anti-SSA and 2 for RNP-68 utilizing Blueblot assays. M2 protein was found in 1 out of the ANA-negative PBC patients. The LIAISON
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ANA screen is specific and sensitive for the evaluation of ANA in patients with primary biliary cirrhosis, scleroderma and Sjögren’s syndrome.
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