scholarly journals Biodosimetry of Low Dose Ionizing Radiation Using DNA Repair Foci in Human Lymphocytes

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 58 ◽  
Author(s):  
Lukáš Jakl ◽  
Eva Marková ◽  
Lucia Koláriková ◽  
Igor Belyaev
Keyword(s):  
Dna Repair ◽  
Ionizing Radiation ◽  
Low Dose ◽  
Time Window ◽  
Human Lymphocytes ◽  
High Dose ◽  
Low Doses ◽  
Significant Difference ◽  
Kinetics Of ◽  
Higher Doses

Purpose: Ionizing radiation induced foci (IRIF) known also as DNA repair foci represent most sensitive endpoint for assessing DNA double strand breaks (DSB). IRIF are usually visualized and enumerated with the aid of fluorescence microscopy using antibodies to γH2AX and 53BP1. This study analyzed effect of low dose ionizing radiation on residual IRIF in human lymphocytes to the aim of potential biodosimetry and possible extrapolation of high-dose γH2AX/53BP1 effects to low doses and compared kinetics of DSB and IRIF. We also analyzed whether DNaseI, which is used for reducing of clumps, affects the IRIF level. Materials and Methods: The cryopreserved human lymphocytes from umbilical cord blood (UCB) were thawed with/without DNaseI, γ-irradiated at doses of 0, 5, 10, and 50 cGy and γH2AX/53BP1 foci were analyzed 30 min, 2 h, and 22 h post-irradiation using appropriate antibodies. We also analyzed kinetics of DSB using PFGE. Results: No significant difference was observed between data obtained by γH2AX foci evaluation in cells that were irradiated by low doses and data obtained by extrapolation from higher doses. Residual 53BP1 foci induced by low doses significantly outreached the data extrapolated from irradiation by higher doses. 53BP1 foci induced by low dose-radiation remain longer at DSB loci than foci induced by higher doses. There was no significant effect of DNaseI on DNA repair foci. Conclusions: Primary γH2AX, 53BP1 foci and their co-localization represent valuable markers for biodosimetry of low doses, but their usefulness is limited by short time window. Residual γH2AX and 53BP1 foci are more useful markers for biodosimetry in vitro. Effects of low doses can be extrapolated from high dose using γH2AX residual foci while γH2AX/53BP1 foci are valuable markers for evaluation of initial DSB induced by ionizing radiation. Residual IRIF induced by low doses persist longer time than those induced by higher doses.

Intrawound Low-dose Vancomycin (250 mg) Powder has Lower Risk of Wound Dehiscence than Higher Doses in Spine Surgeries

2021 ◽  
pp. 46
Author(s):  
Ahmed Sonbol
Keyword(s):  
Surgical Site Infection ◽  
Low Dose ◽  
Wound Dehiscence ◽  
High Dose ◽  
Site Infection ◽  
Systemic Complications ◽  
Significant Difference ◽  
Vancomycin Powder ◽  
Vancomycin Group ◽  
Higher Doses

Introduction: Surgical site infection post spinal surgery is a known complication which can be serious and may require aggressive intervention. Intrawound vancomycin powder application is an evolving method to prevent such complication. Although it has very low systemic complications, wound dehiscence with negative culture is reported in the literature. The aim of this study was to find the risk of wound dehiscence with low-dose intrawound vancomycin in comparison to 1 gr and its effectiveness in prevention of surgical site infection. Methodology: A chart review of all patients who underwent posterior thoracic, lumbar or sacral spine surgeries from December 2009 to September 2016 in a single center was done. Patients were categorized into three groups. First, patients who did not receive any intrawound vancomycin; second, patients who received high-dose vancomycin (1 gr); and third, patients who received low-dose vancomycin (250 mg). Additionally, patients’ demographic information, clinical data, and surgical variables were collected. Primary outcome was the presence of wound dehiscence or surgical site infection. Result: In total, 391 patients were included in this study, of which 56 (14.3%) received high-dose intrawound vancomycin, 126 (32.2%) received low dose, and 209 (53.5%) did not receive any. The overall incidence of wound dehiscence was 6.14% (24 out of 391 patients). Wound dehiscence was statistically and significantly higher (p = 0.039) in the high-dose vancomycin group in comparison to the patients who received low dose. The overall incidence of postoperative infection was 2.05% (eight patients). There was no statistically significant difference between the groups. Conclusion: The use of intrawound low-dose vancomycin (250 mg) has less wound dehiscence in comparison with other higher standard doses. Further trials are needed to evaluate the effectiveness of this dose in preventing postoperative infections.

Exposure to Low Doses of Ionizing Radiation: Is the Linear No-Threshold Model Valid?

2014 ◽  
Author(s):  
Luca Giannoni ◽  
Marino Mazzini
Keyword(s):  
Risk Assessment ◽  
Ionizing Radiation ◽  
Low Dose ◽  
Threshold Dose ◽  
High Dose ◽  
Low Doses ◽  
Repair Capacity ◽  
Nobel Lecture ◽  
Starting Point ◽  
Lnt Model

The risk assessment for population’s exposures to low doses and low dose-rates of ionizing radiation is still subject to clear uncertainties. The issue has outstanding societal importance in relation to radiologic occupational safety, medical applications of radiation, effects of the natural background radioactivity and the future of nuclear power, due to its particular influence on the public acceptance of this form of energy. This review article analyzes, in a critical, historical and bibliographical manner, the worldwide accepted hypothesis of linearity without a threshold dose (LNT model). As well known, it rejects, from its first proposal in 1946 by American geneticist and Nobel laureate Hermann J. Muller, the concept of zero-risk for exposures to any dose level of ionizing radiation. The starting point is the dose-effects relationship provided by this model and related risk’s excess graphic curve. The biological and physical motivations for the linearity assumption are argued and challenged by the explanation of human body’s natural defense mechanisms and its repair capacity of the radiation damage. Furthermore, the historical and political truthfulness of the LNT model is also contested by the review of a recent investigation by Prof. Edward Calabrese, regarding the lack of scientific sources behind Muller’s Nobel Prize Lecture. Calabrese’s inquiry demonstrates that Muller, at the moment of his declaration on LNT model’s validity, had experimental proofs contradicting his conclusions about the unacceptability of a threshold dose. This finding is of historical importance since Muller’s Nobel Lecture is a turning point in the acceptance of the linearity model in risk assessment by the major regulatory agencies till today. Finally, the results of many epidemiological and statistical studies are shown specifically. They give further evidences concerning the inapplicability of the LNT model and its overestimation of the risk for various cases of exposures to low doses of ionizing radiation in different fields. By that, hormesis model is also discussed, with its assumption of possible benefits for the organism following low dose exposures: a dose-response model characterized by low-dose stimulation and high-dose inhibition, which has been frequently observed in the aforementioned studies. The argumentations and the experimental evidences provided here challenge the validity of the LNT model. We contest the fact that its establishment is principally based on a cautionary philosophy on nuclear public safety, rather than on actual scientific comprehension of the phenomenon. As such, it implies an exaggerated conception of the radiological hazard. In particular, this article calls attention to the need for a deeper understanding of the biological impact of low doses of ionizing radiation and the development of further specific and exhaustive researches.

scholarly journals Evaluation of Calyculin A Effect on γH2AX/53BP1 Focus Formation and Apoptosis in Human Umbilical Cord Blood Lymphocytes

2021 ◽  
Vol 22 (11) ◽  
pp. 5470
Author(s):  
Lucián Zastko ◽  
Anna Račková ◽  
Petra Petrovičová ◽  
Matúš Durdík ◽  
Jakub Míšek ◽  
...  
Keyword(s):  
Dna Repair ◽  
Low Dose ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Low Doses ◽  
Calyculin A ◽  
Focus Formation ◽  
Radiation Induced ◽  
Kinetics Of ◽  
Cord Blood Lymphocytes

Dephosphorylation inhibitor calyculin A (cal A) has been reported to inhibit the disappearance of radiation-induced γH2AX DNA repair foci in human lymphocytes. However, other studies reported no change in the kinetics of γH2AX focus induction and loss in irradiated cells. While apoptosis might interplay with the kinetics of focus formation, it was not followed in irradiated cells along with DNA repair foci. Thus, to validate plausible explanations for significant variability in outputs of these studies, we evaluated the effect of cal A (1 and 10 nM) on γH2AX/53BP1 DNA repair foci and apoptosis in irradiated (1, 5, 10, and 100 cGy) human umbilical cord blood lymphocytes (UCBL) using automated fluorescence microscopy and annexin V-FITC/propidium iodide assay/γH2AX pan-staining, respectively. No effect of cal A on γH2AX and colocalized γH2AX/53BP1 foci induced by low doses (≤10 cGy) of γ-rays was observed. Moreover, 10 nM cal A treatment decreased the number of all types of DNA repair foci induced by 100 cGy irradiation. 10 nM cal A treatment induced apoptosis already at 2 h of treatment, independently from the delivered dose. Apoptosis was also detected in UCBL treated with lower cal A concentration, 1 nM, at longer cell incubation, 20 and 44 h. Our data suggest that apoptosis triggered by cal A in UCBL may underlie the failure of cal A to maintain radiation-induced γH2AX foci. All DSB molecular markers used in this study responded linearly to low-dose irradiation. Therefore, their combination may represent a strong biodosimetry tool for estimation of radiation response to low doses. Assessment of colocalized γH2AX/53BP1 improved the threshold of low dose detection.

scholarly journals SUBCHRONIC TOXICITY TEST OF COMBINATION ETHANOL EXTRACT OF DETAM 1 SOYBEAN (GLYCINE MAX L. MERR) AND JATI BELANDA (GUAZUMA ULMIFOLIA LAMK) TOWARD FUNCTION, WEIGHT, AND HISTOPATHOLOGICAL OF WISTAR RAT LIVER

2016 ◽  
Vol 9 (5) ◽  
pp. 197
Author(s):  
Meilinah Hidayat ◽  
Sijani Prahastuti ◽  
Estherolita Dewi ◽  
Dewi Safitri ◽  
Siti Farah Rahmawati ◽  
...  
Keyword(s):  
Liver Function ◽  
Toxicity Test ◽  
Low Dose ◽  
Ethanol Extract ◽  
Good Effect ◽  
Control Group ◽  
High Dose ◽  
Subchronic Toxicity ◽  
Treatment Groups ◽  
Significant Difference

ABSTRACTObjective: As an antiobesity therapy, combination extracts of Detam 1 soybean and Jati Belanda will be consumed for a long time; therefore, theirtoxicities to the liver need to be investigated. To determine the effect of subchronic toxicity test of combination of ethanol extract of Detam 1 soybean(EEDS) and ethanol extract of Jati Belanda (EEJB) on liver function with parameters: Alanine transaminase (ALT), macroscopic, and histopathologicalof liver.Methods: This study was conducted on 120 Wistar rats (60 males and 60 females), 90 days (treatment group) and 120 days (satellite group). Ratswere divided into six treatment groups (3 test materials, 1 control, and 2 satellites); each group included 10 males and 10 females.Results: ALT levels of treatment groups (low dose, medium, and high), both males and females were lower than the control group (p<0.05). Thetreatment groups demonstrated a good effects effect on liver function. Liver weight of all groups showed no significant difference compared with thecontrol group (p>0.05). Results of histopathological score interpretation of male and female liver rats of low dose groups were not disturbed; middledose groups were slightly disturbed and high dose groups were damaged. Satellite high doses of male groups were disrupted, while female groupswere not.Conclusion: The combination of EEDS and EEJB has a good effect on liver function, did not lead to change organ weight and at low doses did not causerenal histopathology damage in rats after 90 days administration.Keywords: Combination of soybean Jati Belanda, Toxicity subchronic test, Function, Weight, Histopathology, Liver.

scholarly journals Effectiveness of Valganciclovir 900mg Versus 450mg for Cytomegalovirus Prophylaxis in Renal Transplantation: A Systematic Review and Meta-Analysis

2017 ◽  
Vol 20 ◽  
pp. 168 ◽  
Author(s):  
Wang Xin ◽  
Yang Hui ◽  
Zhang Xiaodong ◽  
Cui Xiangli ◽  
Wang Shihui ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Acute Rejection ◽  
Low Dose ◽  
Opportunistic Infections ◽  
Meta Analysis ◽  
High Dose ◽  
Renal Transplant Recipients ◽  
Significant Difference ◽  
Allograft Loss ◽  
Cmv Disease

Objectives: Valganciclovir 900 mg/day is approved for cytomegalovirus (CMV) prophylaxis, but 450 mg/day is seems also effective. We systematically reviewed the efficacy and safety of low-dose versus high-dose valganciclovir prophylaxis in renal transplantation recipients. Methods: An electronic search was conducted up to November 29, 2016. The primary outcomes were incidences of CMV, CMV disease, mortality and opportunistic infection. The second outcomes were acute rejection, allograft loss, adverse drug reaction (ADR). Results: 7 cohort studies, all with high quality involving (1431 patients) were included. There was no significant difference of the incidence of following CMV disease (1271 patients, odds ratio [OR] 0.74, 95% confidence interval [CI], 0.38-1.43, p=0.36), acute rejection (1343 patients, OR 0.77, 95%CI 0.53-1.14, p=0.19), allograft loss (1271 patients, OR 0.64, 95%CI 0.31-1.35, p=0.24), mortality (1271 patients, OR 0.55, 95%CI 0.20-1.47, p=0.23) and opportunistic infections (OI) (985 patients, OR 0.76, 95%CI 0.52-1.10, p=0.14) between the low-dose and the high-dose valganciclovir  prophylaxis. And no significant difference was observed for premature valganciclovir discontinuation (1010 patients, OR 0.81, 95%CI 0.52-1.25, p=0.33) and the incidence of leukopenia (1082 patients, OR 0.65, 95%CI 0.34-1.22, p=0.18) between the two regimens. Conclusion: 450 mg and 900 mg doses of valganciclovir are equipotent for CMV universal prophylaxis. CMV 450 mg prophylaxis should be used for renal transplant recipients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals The effect of azathioprine (Imuran) on the kinetics of monocytes and macrophages during the normal steady state and an acute inflammatory reaction

Blood ◽  
1975 ◽  
Vol 46 (1) ◽  
pp. 51-64 ◽  
Author(s):  
AE Gassmann ◽  
R van Furth
Keyword(s):  
Inflammatory Reaction ◽  
Peripheral Blood ◽  
Low Dose ◽  
Peritoneal Macrophages ◽  
High Dose ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Azathioprine Treatment ◽  
Monocytes And Macrophages ◽  
Kinetics Of

Abstract The effect of azathioprine on the kinetics of peripheral blood monocytes and peritoneal macrophages was studied in normal mice and in mice in which an inflammatory reaction was provoked. Two dosage levels were used: a high dose of 200mg/kg which is the maximum tolerated daily dose in mice, and low dose of 3 mg/kg which is about equivalent to a nontoxic, immunosuppressive, anti-inflammatory dose in man. The number of peripheral blood monocytes decreases gradually during azathioprine treatment of normal mice, the extent and duration being dependent on the dose and duration of administered over a period of 9 days gives an almost complete reduction, and a low dose (3 mg/kg) given for the same period results in a reduction of about 50%. This effect seems to be reversible, because when treatment is stopped the number of monocytes starts to increase 24–48 hr later. The number of peritoneal macrophages is only affected when a high dose (200 mg/kg) is given over a long period; a low dose has virtually no effect. In mice in which an inflammatory reaction was prevoked in the peritoneal cavity, the normally occurring increase in the numbers of both peripheral blood monocytes and peritoneal macrophages was suppressed, the extent being dependent on the dose of azathioprine administered. Labeling studies with 3H-thymidine indicated that the reduction of peripheral blood monocytes and peritoneal macrophages in the inflammatory exudate is due to a diminished monocyte production.

scholarly journals A clinical comparison of high dose and low dose of Suxamethonium

2014 ◽  
Vol 9 (2) ◽  
pp. 1-8
Author(s):  
RK Yadav ◽  
PC Majhi ◽  
D Tiwari
Keyword(s):  
Intraocular Pressure ◽  
Dose Group ◽  
Low Dose ◽  
Cardiovascular Responses ◽  
High Dose ◽  
Clinical Effects ◽  
Duration Of Action ◽  
Group I ◽  
Significant Difference ◽  
Group Ii

Background: Suxamethonium having its rapid onset and short duration of action makes this drug unique amongst the neuromuscular blocking drugs described so far. However, use of suxamethonium is associated with a large number of undesirable side effects. Objective: To evaluate clinical effects of high and low dose of suxamethonium and to determine whether lower dose of suxamethonium can be used for any beneficial effects in terms of its various adverse effects e.g. cardiovascular responses, post-operative muscle pains and intraocular pressure. Methods: A total of 100 patients were included in this prospective study. All these patients on preoperative clinical evaluation were assessed to have adequate airway. All the patients were divided in two groups, low dose group (group I) and High dose group (group II) with 50 patients in each at random. A standard anesthetic technique was adhered to all the patients and following parameters were observed on comparative basis: a. Fasciculation and post operative myalgia. b. Cardiovascular effects, c. Intraocular pressure. Observation: The incidence of post Suxamethonium pain was significantly greater in group II. Increase in heart rate from baseline was significant in both groups. There was no significant difference between the two groups in the diastolic pressure but rise in systolic blood pressure was significant at all assessment times in both groups. This rise from control was statistically significant. Conclusion: Suxamethonium can be used in lower doses (0.5 mg/kg) in elective cases without airway compromise. It gives benefits of reduced muscle pains, cardiovascular responses and intraocular hypertension. Journal of College of Medical Sciences-Nepal, 2013, Vol-9, No-2, 1-8 DOI: http://dx.doi.org/10.3126/jcmsn.v9i2.9677

scholarly journals Rapid Recovery and Short Duration Anesthesia after Low Dose Ketamine and High Dose Dexmedetomidine in Rhesus Macaques (Macaca mulatta)

2021 ◽  
Author(s):  
Kristin E Killoran ◽  
Courtney A Walsh ◽  
Jennifer L Asher ◽  
Molly B Tarleton ◽  
Steven R Wilson
Keyword(s):  
Macaca Mulatta ◽  
Recovery Time ◽  
Low Dose ◽  
Rhesus Macaques ◽  
High Dose ◽  
Selective Agonist ◽  
Female Rhesus ◽  
Recovery From Anesthesia ◽  
Higher Doses ◽  
Female Rhesus Macaques

Anesthesia in rhesus macaques is required for many procedures. Although ketamine is the backbone of most anestheticprotocols, tolerance to the drug can develop, resulting in the need for higher doses to provide sufficient restraint. Combination with other drugs, such as α-agonists, can be ketamine-sparing, providing for sufficient restraint at lower ketamine doses. In addition, because α-agonists are reversible, recovery from anesthesia has the potential to be much shorter. We hypothesized that use of a low dose of ketamine with a high dose of dexmedetomidine, an α2 receptor selective agonist, in male and female rhesus macaques less than 15 y of age would provide adequate anesthesia for short procedures and that recovery would be faster than in macaques given a higher dose of ketamine (10 mg/kg) alone. We found that the combination, in conjunction with atipamezole for reversal, provided smooth induction of anesthesia and significantly shorter recovery time than did ketamine alone, with no significant effects of sex. The combination of low dose ketamine and high dose dexmedetomidine also provided a 30-min window of anesthesia with analgesia sufficient for mild to moderately painful procedures.

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