Radiation Syndrome Research Articles

Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b+ cell-dependent mechanism

BackgroundStromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes–macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2.MethodsMice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses.ResultsUsing flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b+Ly6C+CCR2+ population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80+CX3CR1+ macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C−MCHII+CX3CR1+ population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b+ being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b+ treatment impaired F4/80+CX3CR1+macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival.ConclusionsThese data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS.

Influence of Peptide Bioregulators on Indicators of Hemostasis in Blood of Irradiated Experimental Animals at Low Altitude Conditions

In modern biology and medicine, much attention is paid to the study of the hemostasis regulation of some cell populations by substances of a peptide nature. They have the ability to regulate the functional and proliferative activity of cells and ensure communication in normal and pathological conditions. Research data showed that significant violations of the hemostatic system also occur with radiation damage to the body. One of the first radiation responses involves the coagulation cascade's activation, which leads to the breakdown of fibrinogen and the formation of fibrin clots. The potential threat of this is quite evident due to the existence of uranium mining tailings in several regions of the Kyrgyz Republic. Considering that significant disturbances of the hemostatic system occur during radiation damage to the body, and effective means are clearly not enough, the study of the effect of bioregulatory peptides in these conditions is of great importance. In the study, we carried out the total X-ray irradiation of laboratory animals on the X-ray therapeutic apparatus RUM-17. Peptide bioregulators peptide-1 and peptide-2 were administered intramuscularly to irradiated animals. Throughout the research, we used methods characterizing all links of hemostasis: vascular-platelet hemostasis, coagulation hemostasis, and fibrinolysis. The study has shown that the use of the peptide bioregulators in the background of acute radiation pathology leads to a decrease in the intensity of the chronic course of post-radiation thrombo hemorrhagic syndrome, contributing to an increase in the content of antithrombin III in the blood and modulating the versatile effects of endogenous heparin, which undoubtedly have a beneficial effect on the pathogenesis of radiation sickness.

Comorbidity burden assessed by the charlson comorbidity index and its influence on prognosis of patients with pulmonary embolism

Abstract Background Pulmonary embolism (PE) is an acute cardiovascular syndrome and can be associated with high morbidity and mortality. Short-term outcomes of PE are closely related to right ventricular dysfunction (RVD) and the patient’s haemodynamic status as well as age and comorbidity profile. According to the current ESC guidelines for management of acute PE patients, initial risk stratification is based on clinical symptoms and signs, whereby haemodynamic instability indicates a high-risk status with substantial increase of the risk for early death. However, the vast majority of PE patients are haemodynamically stable at presentation; they require further risk stratification with clinical, imaging, and laboratory indicators of PE severity as well as the patient’s comorbidity profile and other aggravating conditions. The pulmonary embolism severity index (PESI) and the simplified pulmonary embolism severity index (sPESI) are implemented for risk stratification in the ESC guidelines. However, other tools may be more suitable for characterizing the comorbidity profile of PE patients. One established approach to evaluate the comorbidity profile is the Charlson Comorbidity Index. Purpose The objective of the present study is to investigate the impact of the comorbid profile on prognosis of patients with acute PE in a large nationwide inpatient sample. Methods We used the German nationwide inpatient sample to analyse the Charlson Comorbidity Index score of all hospitalised patients with PE in Germany 2005-2020 (source: RDC of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005-2020, own calculations). The patients were categorized in the very-low severity (Charlson Comorbidity Index 0 points, mild severity (Charlson Comorbidity Index 1-2 points), moderate severity (Charlson Comorbidity Index 3-4 points) and severe severity (Charlson Comorbidity Index >4 points) and severity classes were compared. Results Overall, 1,373,145 hospitalizations of patients with acute PE (53.0% females, 55.9% aged ≥70years) were recorded in Germany between 2005 and 2020; they were stratified by the Charlson Comorbidity Index class. Among these, 100,156 (7.3%) were categorized as very-low, 221,545; (16.1%) as mild, 394,965 (28.8%) as moderate, and 656,479 (47.8%) as patients with a severe comorbidity burden. In-hospital case-fatality increased with the current Charlson Comorbidity Index class: 3.6% in very-low, 6.5% in mild, 12.1% in moderate and 22.1% in the severe Charlson Comorbidity Index class (P<0.001). The Charlson Comorbidity Index class was associated with increased in-hospital case-fatality (OR 2.014 [95%CI 2.000-2.027], P<0.001). Conclusion The results of our study may help to better understand and measure the association between an aggravated comorbidity profile and increased in-hospital case-fatality in patients with acute PE.

Effect of The Rs-10 Radioprotector on Protein-Steroid Interaction in Irradiated Animals with Biphasic Adrenocortical Response to Irradiation

The article is devoted to the influence of RS-10 radioprotector on the protein-steroid interaction in irradiated animals. Introduction. Increasing threats to the radiation safety of the population is now causing the need for comprehensive studies of the anti-beam properties of chemical radioprotectors. The aim of the study is to study the effect of the RS-10 radioprotector on protein-steroid interaction in irradiated guinea pigs with biphasic adrenocortical response to irradiation. Study methods: experiments were conducted on 146 guinea pigs weighing 300-350 g, which were exposed to total ƴ radiation at a dose of 3.5 Gy and 4.5 Gy at a dose rate of 5.76 Gy/min, which caused them radiation disease of II and III severity. Experimental animals were injected intraperitoneally with RS-10 (chitosan bitartrate) 15 minutes before irradiation. Control animals were administered an equal volume of saline. The total plasma content of 11-oxycorticosteroids (11-OKS) was determined by the fluorometric method of Guillemin et al. in the author's modification. The binding capacity of corticosteroid binding globulin (CSG) was determined by gel filtration of De Moor at al. in the author's modification. Conclusions. Prophylactic administration of RS-10 to irradiated animals with a two-phase adreno-cortical reaction to radiation causes a later onset of secondary hypercorticism in the midst of radiation sickness in animals. Prophylactic administration of RS-10 before irradiation reduces the level of free hormone and leads to a decrease in hypercorticism, increasing the reserve capabilities of the binding ability of the CSG at the height of radiation sickness. A leading role in the mechanism of reducing affected hypercorticism under protective conditions has a lesser degree of impairment of the binding capacity of the CSG, rather than a change in the total level of 11-OKS in the blood.

Novel adsorbent derived from sludge of paper industry for removal of cesium ion in water

Metal ion contamination has been a public concern due to its negative impact on human health and the environment. Cesium (Cs), a harmful metal ion, can cause cell damage; acute radiation syndrome includes nausea, vomiting, diarrhea, bleeding, and, in extreme cases, death. As a result, removing cesium ion from water is critical. This research aims to examine the capacity of a novel adsorbent derived from paper industry solid waste to remove cesium ion from water. The adsorption process was carried out with some variables including adsorbent dose, solution of pH, contact time, initial Cs concentration, and adsorbent form. According to characterization data, paper industry sludge contains elements such as SiO2 (28.1%), CaO (21.8%), Al2O3 (16.1%), and Fe2O3 (12%), among others. The surface area of the adsorbent is 100 m2/g and a diameter of 3.8 nm. Following equilibrium, the current study discovered that the developed adsorbent has the highest cesium removal, up to 79% for 10 mg/L of Cs initial. The novel adsorbent has high adsorption removal and may be a promising adsorbent material for metal ion removal in water.

A Spatial Analysis Model for Proactive Assessment on Radioactive Isotopes in Environment

— In general, no one can escape from radiation. Radiation exists in various forms as minerals in earth and water, cosmic rays in space, radioactive energy in human body, man-made effects as in the form of industrial waste, result of nuclear weapon test, nuclear reactor and medical procedures. The people those who are living closer to the environment where radioactive emission is found to be high, would have a high risk of getting significant health aliments like skin burns and radiation sickness. Moreover people who receive constant exposure to lower level of radiation will susceptible to have cancer and cardio vascular diseases in their life time. The primary motive of the proposed work is to evaluate the concentration of the radioactivity substances, tracking the impact through present and futuristic patterns using deep learning techniques.

The increase in core body temperature in response to exertional-heat stress can predict exercise-induced gastrointestinal syndrome

ABSTRACT Utilizing metadata from existing exertional and exertional-heat stress studies, the study aimed to determine if the exercise-associated increase in core body temperature can predict the change in exercise-induced gastrointestinal syndrome (EIGS) biomarkers and exercise-associated gastrointestinal symptoms (Ex-GIS). Endurance-trained individuals completed 2 h of running exercise in temperate (21.2-30.0°C) to hot (35.0-37.2°C) ambient conditions (n = 132 trials). Blood samples were collected pre- and post-exercise to determine the change in gastrointestinal integrity biomarkers and systemic inflammatory cytokines. Physiological and thermoregulatory strain variables were assessed every 10–15 min during exercise. The strength of the linear relationship between maximal (M-Tre) and change (Δ Tre) in rectal temperature and EIGS variables was determined via Spearman’s rank correlation coefficients. While the strength of prediction was determined via simple and multiple linear regression analyses dependent on screened EIGS and Ex-GIS confounding factors. Significant positive correlations between Tre maximum (M-Tre) and change (Δ Tre) with I-FABP (rs = 0.434, p < 0.001; and rs = 0.305, p < 0.001; respectively), sCD14 (rs = 0.358, p < 0.001; and rs = 0.362, p < 0.001), systemic inflammatory response profile (SIR-Profile) (p < 0.001), and total Ex-GIS (p < 0.05) were observed. M-Tre and Δ Tre significantly predicted (adjusted R2) magnitude of change in I-FABP (R2(2,123)=0.164, p < 0.001; and R2(2,119)=0.058, p = 0.011; respectively), sCD14 (R2(2,81)=0.249, p < 0.001; and R2(2,77)=0.214, p < 0.001), SIR-Profile (p < 0.001), and total Ex-GIS (p < 0.05). Strong to weak correlations were observed between M-Tre and Δ Tre with plasma concentrations of I-FABP, sCD14, SIR-Profile, and Ex-GIS in response to exercise. M-Tre and Δ Tre can predict the magnitude of these EIGS variables and Ex-GIS in response to exercise.

Cardiac Involvement Due to COVID-19: Insights from Imaging and Histopathology

Lingering cardiac symptoms are increasingly recognised complications of severe acute respiratory syndrome coronavirus 2 infection, now referred to as post-acute cardiovascular sequelae of COVID-19 (PASC). In the acute phase, cardiac injury is driven by cytokine release and stems from ischaemic and thrombotic complications, resulting in myocardial necrosis. Patients with pre-existing cardiac conditions are particularly vulnerable. Myocarditis due to a direct viral infection is rare. Chronic symptoms relate to either worsening of pre-existing heart disease (PASC – cardiovascular disease) or delayed chronic inflammatory condition due to heterogenous immune dysregulation (PASC – cardiovascular syndrome), the latter affecting a broad segment of previously well people. Both PASC presentations are associated with increased cardiovascular risk, long-term disability and reduced quality of life. The recognition and management of PASC in clinical settings remains a considerable challenge. Sensitive diagnostic methods are needed to detect subtler inflammatory changes that underlie the persistent symptoms in PASC – cardiovascular syndrome, alongside considerable clinical experience in inflammatory cardiac conditions.

Nano-Architecture of Persistent Focal DNA Damage Regions in the Minipig Epidermis Weeks after Acute γ-Irradiation.

Exposure to high acute doses of ionizing radiation (IR) can induce cutaneous radiation syndrome. Weeks after such radiation insults, keratinocyte nuclei of the epidermis exhibit persisting genomic lesions that present as focal accumulations of DNA double-strand break (DSB) damage marker proteins. Knowledge about the nanostructure of these genomic lesions is scarce. Here, we compared the chromatin nano-architecture with respect to DNA damage response (DDR) factors in persistent genomic DNA damage regions and healthy chromatin in epidermis sections of two minipigs 28 days after lumbar irradiation with ~50 Gy γ-rays, using single-molecule localization microscopy (SMLM) combined with geometric and topological mathematical analyses. SMLM analysis of fluorochrome-stained paraffin sections revealed, within keratinocyte nuclei with perisitent DNA damage, the nano-arrangements of pATM, 53BP1 and Mre11 DDR proteins in γ-H2AX-positive focal chromatin areas (termed macro-foci). It was found that persistent macro-foci contained on average ~70% of 53BP1, ~23% of MRE11 and ~25% of pATM single molecule signals of a nucleus. MRE11 and pATM fluorescent tags were organized in focal nanoclusters peaking at about 40 nm diameter, while 53BP1 tags formed nanoclusters that made up super-foci of about 300 nm in size. Relative to undamaged nuclear chromatin, the enrichment of DDR protein signal tags in γ-H2AX macro-foci was on average 8.7-fold (±3) for 53BP1, 3.4-fold (±1.3) for MRE11 and 3.6-fold (±1.8) for pATM. The persistent macro-foci of minipig epidermis displayed a ~2-fold enrichment of DDR proteins, relative to DSB foci of lymphoblastoid control cells 30 min after 0.5 Gy X-ray exposure. A lasting accumulation of damage signaling and sensing molecules such as pATM and 53BP1, as well as the DSB end-processing protein MRE11 in the persistent macro-foci suggests the presence of diverse DNA damages which pose an insurmountable problem for DSB repair.

PERINATAL ASPECTS OF MEDICAL CARE WITH COVID-19

Purpose. To determine perinatal aspects of medical care for COVID-19. Materials and methods. 200 patients with confirmed SARS-CoV-2 hospitalized at the Kiev City Center for Reproductive and Perinatal Medicine were comprehensively examined: group 1 - 50 pregnant women with severe Covid-19 and group 2 - 150 pregnant women with moderate severity of the disease. Research results. Severe Covid-19 disease is observed in 12.2% of pregnant women, critical condition - in 7.5% of patients. Severe disease directly or indirectly determined a significantly higher incidence of pregnancy complications. First of all, this is placental insufficiency in the vast majority of patients (72.0%), which was manifested by fetal growth retardation and distress (in 32.0% and 48.0%). Half of the women experience oligohydramnios (50.0%), 38.0% have a threat of premature birth, and a third (30.0%) have premature birth. 44.0% of children are born in a state of asphyxia, 36.0% of children have manifestations of respiratory failure, and 16.0% have bilateral pneumonia. High incidence of neurological disorders (56.0%), gastrointestinal (50.0%), hypoglycemic (34.0%) and hemorrhagic (32.0%) syndromes. Testing of newborns for COVID-19 was positive in 6.0% of cases. 22.0% of children required intensive care unit care. Perinatal mortality was 0.4%. Conclusions. The identified high frequency of perinatal disorders in women with COVID-19 indicates the need for careful care for this category of pregnant women and their newborns, constant monitoring of vital functions, follow-up observation, and the development of clear algorithms for the actions of medical personnel depending on the patients’ condition.

SAT473 First Case Of Diffuse Thyroid Lipomatosis With Amyloid Deposits Presenting With Hyperthyroidism

Abstract Disclosure: A.M. Gonzalez Gil: None. M.A. Ruiz Santillan: None. H. Quadri: None. B.K. Force: None. R. Gaba: None. Background: Diffuse thyroid lipomatosis (DTL) is an exceedingly rare entity of unknown etiology which can be associated with amyloidosis. It generally presents with euthyroidism but very few cases with hyperthyroidism have been reported. Clinical Case: A 64-year-old woman from Pakistan with a several-year history of a non-tender goiter presented to the emergency department with an upper respiratory and gastrointestinal viral syndrome in the context of several weeks of progressively worsening fatigue. She also reported unintentional weight loss over several years. She denied other hyperthyroid or compressive symptoms. Her exam was notable for resting sinus tachycardia and an approximately 100 gm painless goiter. Laboratory evaluation was notable for a markedly elevated creatinine with nephrotic range proteinuria. She was declared to have end stage renal disease (ESRD) and hemodialysis was initiated. She was also found to have a suppressed TSH (&amp;lt;0.01 uIU/mL, NR=0.45-5.33) and elevated FT4 (2.17 ng/dl, NR=0.64-1.42). Total T3 was low (42 ng/dl, NR=87-178), which was attributed to hypoalbuminemia and altered peripheral thyroid hormone metabolism with underlying ESRD. Further evaluation revealed elevated ESR, CRP and thyroglobulin levels (625.9 ng/mL, NR=1.5-38.5), while thyroid stimulating immunoglobulin, thyroid receptor antibodies and thyroid peroxidase antibodies were undetectable. A thyroid ultrasound revealed an enlarged fatty thyroid consistent with DTL. A radioactive iodine uptake scan revealed normal 24-hour uptake (14.1%, NR=7-32%) in a slightly heterogeneous thyroid with no aberrant functioning thyroid tissue. She was started on atenolol, with significant improvement in her tachycardia, but her FT4 continued to increase. Methimazole was initiated. Dose uptitration and administration after dialysis resulted in near-normalization of FT4 levels. She subsequently underwent renal and thyroid biopsies, both of which showed apple green birefringence under polarized light with Congo Red stain, indicating amyloidosis. Core thyroid biopsy additionally showed benign adipose tissue with entrapped thyroid follicles, confirming concomitant DTL. Although other authors have found thyroid amyloid deposits in DTL, and yet others have reported hyperthyroidism in DTL without amyloidosis, this is the first reported case of hyperthyroidism in a patient with DTL with amyloid deposits. Interestingly, chronic hypoxia in amyloid goiters has been hypothesized to cause fibroblast-to-adipocyte metaplasia leading to DTL. We speculate that excess thyroid hormone release could also be mediated by follicular cells’ response to hypoxia induced by amyloid and fatty infiltration of the thyroid. Conclusion: To the best of our knowledge, this is the first reported case of diffuse thyroid lipomatosis with amyloid deposits to be associated with concurrent hyperthyroidism. Presentation Date: Saturday, June 17, 2023

FRI352 Diabetes Insipidus With Hypokalemia In A 30 Week Pregnant Female

Abstract Disclosure: C.B. Stanfield: None. In this case, we will discuss a 29 year old G4P0121 African American female at 30 weeks gestation presented to women’s urgent care for nausea, vomiting and diarrhea after starting magnesium supplementation for incidentally diagnosed hypokalemia around 4 weeks prior. Vitals were significant for a BP of 133/60 and HR 110. Laboratory studies were significant for potassium of 3 mmol/L, sodium 155 mmol/L, magnesium 2.2mmol/L, AST 104, ALT 62 and UA with 2+ proteinuria. Patient admitted to the OBGYN service for preeclampsia with severe features. Patient was noted to have over 16L UOP over the first 24 hours of admission; 4.5L intake. Further labs obtained showed hemoglobin A1C of 4.9, serum osmolality of 308 mOsm/kg, urine osmolality 77 mOsm/kg and urine specific gravity 1.002. DDAVP was given with urine osmolality increasing from 77 to 137 mmol/L. Working differential diagnoses included gestational diabetes insipidus (DI), central DI or nephrogenic DI due to hypokalemia. Co-peptin assay was drawn; is a send out at our institution. Of note, the patient had no known history of brain injury, surgery, radiation or Sheehan Syndrome. However her previous pregnancies had been complicated by hypokalemia, hypertension and pre-eclampsia with emergent cesarean-section. She subsequently underwent emergency cesarean-section on hospital day 2 for non-reassuring fetal activity with delivery of viable 1230g male. After delivery, the patients hypokalemia resolved. Post-op, DDAVP for 3 days was continued per hospital DI protocol with appropriate response. Co-peptin resulted at 22.3, excluding central DI as a diagnosis. On time of discharge, patient had gone without DDAVP for &amp;gt;48 hours with intact thirst mechanism. Given improvement/resolution of DI and persistently low urine osmolality even after DDAVP administration prior to delivery, the DI was believed to be gestational with a component of nephrogenic DI as well due to hypokalemia. Gestational DI occurs due to increased placental vasopressinase which degrades the antidiuretic hormone (ADH). It is associated with pre-eclampsia, acute fatty liver of pregnancy and HELLP syndrome. DDAVP is a modified synthetic analog of endogenous ADH and is resistant to breakdown by placental vasopressinase and can be used to treat gestational DI. Definitive management is achieved with delivery of the fetus and can last up to six weeks after delivery. Presentation: Friday, June 16, 2023

First person – Jeanne Rakotopare

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models &amp; Mechanisms, helping researchers promote themselves alongside their papers. Jeanne Rakotopare is first author on ‘ A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities’, published in DMM. Jeanne is a PhD student in the lab of Franck Toledo at Institut Curie, Paris, France, investigating the impact of p53 deregulation in bone marrow syndromes and cancer.

Anti-ceramide Single-Chain Variable Fragment Mitigates Gastrointestinal-Acute Radiation Syndrome and Improves Marrow Reconstitution, Rendering Near-Normal 90-Day Autopsies.

After September 11, 2001, nuclearthreat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5+stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality. For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GI-ARS lethal dose for this mouse strain. Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy+BMT+scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these findings, mice receiving 15 Gy+BMT+scFv exhibit prolonged survival. At day 90, before sacrifice, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined. Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies.

Evaluating transport conditions of conventional, widely used EDTA blood tubes for gene expression analysis in comparison to expensive, specialized PAXgene tubes in preparedness for radiological and nuclear events

Purpose Gene expression (GE) analysis of a radio-sensitive gene set (FDXR, DDB2, WNT3, POU2AF1) has been introduced in the last decade as an early and high-throughput prediction tool of later developing acute hematologic radiation syndrome (H-ARS) severity. The use of special tubes for RNA extraction from peripheral whole blood (PAXgene) represent an established standard in GE studies, although uncommonly used in clinics and not immediately available in the quantities needed in radiological/nuclear (R/N) incidents. On the other hand, EDTA blood tubes are widely utilized in clinical practice. Material and Methods Using blood samples from eleven healthy donors, we investigated GE changes associated with delayed processing of EDTA tubes up to 4 h at room temperature (RT) after venipuncture (simulating delays caused by daily clinical routine), followed by a subsequent transport time of 24 h at RT, 4 °C, and −20 °C. Differential gene expression (DGE) of the target genes was further examined after X-irradiation with 0 Gy and 4 Gy under optimal transport conditions. Results No significant changes in DGE were observed when storing EDTA whole blood samples up to 4 h at RT and subsequently kept at 4 °C for 24 h which is in line with expected DGE. However, other storage conditions, such as −20 °C or RT, decreased RNA quality and/or (significantly) caused changes in DGE exceeding the known methodological variance of the qRT-PCR. Conclusion Our data indicate that the use of EDTA whole blood tubes for GE-based H-ARS severity prediction is comparable to the quality of PAXgene tubes, when processed ≤ 4 h after venipuncture and the sample is transported within 24 hours at 4 °C.

B-251 Nmr Lipoproteins Help to Reveal Subphenotypes of Phenoreversion from sars-cov-2 Infection

Abstract Background It is estimated that 10% of patients that suffered from severe acute SARS-CoV-2 infection experience symptoms beyond 3 months post-disease onset. Long COVID is a multisystemic condition that comprises more than 200 symptoms. Common new-onset medical conditions include cardiovascular, type-2 diabetes and chronic fatigue syndrome. Whilst progress has been made in characterising the mechanisms underlying long COVID, supported by similarities with other viral infections, available diagnostics are still insufficient. Molecular phenotyping is an established systems medicine tool that provides an integrative profile of an individual’s biological status that results from the cooperative genomic, transcriptomic and proteomic response to environmental stimuli. It exploits spectroscopic platforms based on nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) to generate precise information on a plethora of molecules that can be modelled to explain specific physiological and pathological conditions. Methods A well characterised longitudinal cohort with &amp;gt;200 SARS-CoV-2 positive individuals was collected in Cambridge Hospitals (2020, Wuhan strain). Each individual was classified according to the severity of its respiratory symptoms ranging from A (asymptomatic) to E (external ventilation). For each sample, cellular and immunological parameters, NMR lipoproteins, amino acid, tryptophan and lipidomics assays were measured. Functional PCA models captured latent dynamics in individual trajectories for C-reactive protein, an established marker of inflammation, and metabolic parameters found to be associated with it. Based on these trends, patient heterogeneity was explored using Gaussian mixture modelling and the resulting stratification was used to train personalised predictors of disease outcome using the first time point after onset as input. The addition of a penalty function during training ensured a parsimonious selection of parameters. Patients were asked to complete surveys months (2–6) after infection. Abundance and co-occurrence of symptoms was assessed using latent factor analysis. Results Linear mixed model regression revealed strong associations between C-reactive protein abundance and molecular parameters. Quinolinic acid, VLDL triglycerides and phospholipids, VLDL and IDL cholesterol and glycoprotein related GlycA are positively correlated, while tryptophan, taurine, indole-3-acetic acid, HDL cholesterol, and phospholipids and the supramolecular phospholipid composite (SPC) peak are strongly anti-correlated. Those findings are congruent with prior work on cohorts from Western Australia and Spain. In both cases, strong lipoprotein signatures were observed; GlycA is increased during acute phase, while SPC and HDL subfraction 4 are strongly depleted. The analysis of individual trajectories measured by CRP and associated parameters revealed 3 groups, mildly affected, good recovery and poor prospect. Patients from the last category showed profoundly altered metabolic profiles even weeks after onset, and a higher co-occurrence of neurological related symptoms. Furthermore, disease outcome scores were predicted for each patient in the early stage of infection. The training of these predictors also distilled a panel of most relevant parameters for that purpose. NMR lipoproteins featured excellent predictive capabilities. Conclusion Broad phenotyping, combined with multi-view multivariate analysis, allowed for robust stratification of COVID-19 patients and accurate personalised prediction of disease outcome. It also confirms the critical role played by lipoprotein metabolism in the immune response that is successfully captured by NMR-base lipoprotein parameters.

Exercise-Induced Gastrointestinal Symptoms in Endurance Sports: A Review of Pathophysiology, Symptoms, and Nutritional Management

Strenuous exercise can be associated with “Exercise Induced Gastrointestinal Syndrome” (Ex-GIS), a clinical condition characterized by a series of gastrointestinal (GI) disturbances that may impact the physical and psychological performance of athletes. The pathophysiology comprises multi-factorial interactions between the GI tract and the circulatory, immune, enteric, and central nervous systems. There is considerable evidence for increases in the indices of intestinal damage, permeability, and endotoxemia associated with impaired gastric emptying, slowing of small intestinal transit, and malabsorption of nutrients. Heat stress and racing mode seem to exacerbate these GI disturbances. GI symptomatology that derives from strenuous exercise is similar to that of IBS and other GI functional disorders defined in the Rome IV Criteria. To manage Ex-GIS, the exercise modality, state of dehydration, environmental temperature, concomitant therapies, and self-managed diet should be evaluated, and if risk elements are present, an attempt should be made to modify them. Multiple strategies can be successively adopted to manage Ex-GIS. Nutritional and behavioral interventions appear to be the principal ones to avoid symptoms during the exercise. The aim of this review will be to explore the pathophysiology, clinical aspect, and current literature on behavioral and nutritional strategies to manage Ex-GIS, regarding a gluten-free diet and low-fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP) diet.

PEGylated thrombopoietin mimetic, JNJ‑26366821 a novel prophylactic radiation countermeasure for acute radiation injury

Thrombopoietin (TPO) is the primary regulator of platelet generation and a stimulator of multilineage hematopoietic recovery following exposure to total body irradiation (TBI). JNJ‑26366821, a novel PEGylated TPO mimetic peptide, stimulates platelet production without developing neutralizing antibodies or causing any adverse effects. Administration of a single dose of JNJ‑26366821 demonstrated its efficacy as a prophylactic countermeasure in various mouse strains (males CD2F1, C3H/HeN, and male and female C57BL/6J) exposed to Co-60 gamma TBI. A dose dependent survival efficacy of JNJ‑26366821 (− 24 h) was identified in male CD2F1 mice exposed to a supralethal dose of radiation. A single dose of JNJ‑26366821 administered 24, 12, or 2 h pre-radiation resulted in 100% survival from a lethal dose of TBI with a dose reduction factor of 1.36. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pre-treated with JNJ‑26366821. The drug also increased bone marrow cellularity and megakaryocytes, accelerated multi-lineage hematopoietic recovery, and alleviated radiation-induced soluble markers of bone marrow aplasia and endothelial damage. These results indicate that JNJ‑26366821 is a promising prophylactic radiation countermeasure for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.

Therapeutic mechanism of Liangxue-Guyuan-Yishen decoction on intestinal stem cells and tight junction proteins in gastrointestinal acute radiation syndrome rats.

On the basis of the previous research, the Traditional Chinese Medicine theory was used to improve the drug composition for gastrointestinal acute radiation syndrome (GI-ARS). The purpose of this study was to study the therapeutic mechanism of Liangxue-Guyuan-Yishen decoction (LGYD) on GI-ARS and to provide a new scheme for the treatment of radiation injury. Here, we investigated the effects of LGYD on intestinal stem cells (ISCs) in a GI-ARS rat model. Rat health and survival and the protective efficacy of LGYD on the intestines were analyzed. The active principles in LGYD were detected using liquid chromatography-mass spectrometry (LC-MS). ISC proliferation, intestinal epithelial tight junction (TJ) protein expression and regulatory pathways were explored using immunohistochemistry, western blotting (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Involvement of the WNT and MEK/ERK pathways in intestinal recovery was screened using network pharmacology analysis and validated by WB and RT-qPCR. LGYD administration significantly improved health and survival in GI-ARS rats. Pathological analysis showed that LGYD ameliorated radiation-induced intestinal injury and significantly promoted LGR5+ stem cell regeneration in the intestinal crypts, upregulated TJ protein, and accelerated crypt reconstruction in the irradiated rats. LC-MS revealed ≥13 constituents that might contribute to LGYD's protective effects. Collectively, LGYD can promote crypt cell proliferation and ISCs after radiation damage, the above effect may be related to WNT and MEK/ERK pathway.

Gastrointestinal Symptoms in Pediatric Patients with Anxiety Disorders and Their Relationship to Selective Serotonin Reuptake Inhibitor Treatment or Placebo.

Gastrointestinal symptoms are commonly reported as adverse effects of selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacologic treatment for pediatric anxiety disorders; however, the temporal course of these symptoms during treatment, although believed to be transient, has never been prospectively evaluated. Additionally, rates of gastrointestinal symptoms and functional gastrointestinal syndromes in anxious youth are poorly understood. We examined gastrointestinal symptoms in youth with anxiety disorders during a double-blind, placebo-controlled trial of escitalopram (n = 51). Then, in a separate sample of prospectively treated children and adolescents with generalized, social and/or separation anxiety disorders (n = 56), we examined the frequency of gastrointestinal symptoms based on the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS) and ROME III criteria and the association of these symptoms with clinical and demographic characteristics using logistic regression. The frequency/severity of abdominal pain, diarrhea, bloating constipation or total gastrointestinal symptoms did not differ between patients receiving placebo (n = 25) or escitalopram (n = 26). However, escitalopram-treated youth had transient changes in nausea/vomiting and total upper gastrointestinal symptoms during the first two weeks of treatment. ROME III criteria for functional gastrointestinal syndromes were present in 12/56 patients (21.4%). QPGS-related functional gastrointestinal syndromes and symptoms were unrelated to treatment, treatment type, or clinical or demographic variables. Gastrointestinal symptoms are common in youth with anxiety and SSRIs produce transient-rather than sustained-gastrointestinal symptoms. Assessing gastrointestinal symptoms prior to pharmacotherapy and discussing factors that increase (or decrease) the likelihood of transient SSRI-related symptoms in youth may decrease patient uncertainty related to side effects and decrease medication-related anxiety.