71 research outputs found
Administration of ON 01210.Na after exposure to ionizing radiation protects bone marrow cells by attenuating DNA damage response
<p>Abstract</p> <p>Background</p> <p>Ionizing radiation-induced hematopoietic injury could occur either due to accidental exposure or due to diagnostic and therapeutic interventions. Currently there is no approved drug to mitigate radiation toxicity in hematopoietic cells. This study investigates the potential of ON 01210.Na, a chlorobenzylsulfone derivative, in ameliorating radiation-induced hematopoietic toxicity when administered after exposure to radiation. We also investigate the molecular mechanisms underlying this activity.</p> <p>Methods</p> <p>Male C3H/HeN mice (n = 5 mice per group; 6-8 weeks old) were exposed to a sub-lethal dose (5 Gy) of γ radiation using a <sup>137</sup>Cs source at a dose rate of 0.77 Gy/min. Two doses of ON 01210.Na (500 mg/kg body weight) were administered subcutaneously at 24 h and 36 h after radiation exposure. Mitigation of hematopoietic toxicity by ON 01210.Na was investigated by peripheral white blood cell (WBC) and platelet counts at 3, 7, 21, and 28 d after radiation exposure. Granulocyte macrophage colony forming unit (GM-CFU) assay was done using isolated bone marrow cells, and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) was performed on bone marrow sections at 7 d post-exposure. The DNA damage response pathway involving ataxia telangiectasia mutated (ATM) and p53 was investigated by Western blot in bone marrow cells at 7 d post-exposure.</p> <p>Results</p> <p>Compared to the vehicle, ON 01210.Na treated mice showed accelerated recovery of peripheral WBC and platelet counts. Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts. The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice. Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice. Furthermore, the Bcl2:Bax ratio was higher in the drug treated mice than the vehicle treated groups.</p> <p>Conclusions</p> <p>ON 01210.Na treatment significantly mitigated the hematopoietic toxicity induced by a sub-lethal radiation dose. Mechanistically, attenuation of ATM-p53 mediated DNA damage response by ON 01210.Na is contributing to the mitigation of radiation-induced hematopoietic toxicity.</p
Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia
International audienceABSTRACT: BACKGROUND: The development of polymerase chain reaction (PCR)-based methods for the detection of known mutations has facilitated detecting specific red blood cell (RBC) enzyme deficiencies. We carried out a study on glucose-6-phosphate dehydrogenase (G6PD) deficient subjects in Jeddah to evaluate the molecular characteristics of this enzyme deficiency and the frequency of nucleotide1311 and IVS-XI-93 polymorphisms in the glucose-6-phosphate dehydrogenase gene. RESULTS: A total of 1584 unrelated Saudis (984 neonates and 600 adults) were screened for glucose-6-phosphate dehydrogenase deficiency. The prevalence of glucose-6-phosphate dehydrogenase deficiency was 6.9% (n=110). G6PD Mediterranean mutation was observed in 98 (89.1%) cases, G6PD Aures in 11 (10.0%) cases, and G6PD Chatham in 1 (0.9%) case. None of the samples showed G6PD A mutation. Samples from 29 deficient subjects (25 males and 4 females) were examined for polymorphism. The association of two polymorphisms of exon/intron 11 (c.1311T/IVS XI 93C) was observed in 14 (42.4%) of 33 chromosomes studied. This association was found in 9 (31.0%) carriers of G6PD Mediterranean and in 4 (13.8%) carriers of G6PD Aures. CONCLUSIONS: The majority of mutations were G6PD Mediterranean, followed by G6PD Aures and <1% G6PD Chatham. We conclude that 1311T is a frequent polymorphism in subjects with G6PD Mediterranean and Aures variants in Jeddah
Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria
<p>Abstract</p> <p>Background</p> <p>There are limited data on the evolution of the leukocyte and platelet counts in malaria patients.</p> <p>Methods</p> <p>In a clinical trial of chloroquine vs. chloroquine plus doxycycline vs. doxycycline alone against <it>Plasmodium vivax </it>(n = 64) or <it>Plasmodium falciparum </it>(n = 98) malaria, the total white cell (WCC) and platelet (PLT) counts were measured on Days 0, 3, 7 and 28 in 57 indigenous Papuans with life long malaria exposure and 105 non Papuan immigrants from other parts of Indonesia with limited malaria exposure.</p> <p>Results</p> <p>The mean Day 0 WCC (n = 152) was 6.492 (range 2.1–13.4) × 10<sup>9</sup>/L and was significantly lower in the Papuans compared to the non Papuans: 5.77 × 10<sup>9</sup>/L vs. 6.86 × 10<sup>9</sup>/L, difference = -1.09 [(95% CI -0.42 to -1.79 × 10<sup>9</sup>/L), P = 0.0018]. 14 (9.2%) and 9 (5.9%) patients had leukopaenia (<4.0 × 10<sup>9</sup>/L) and leukocytosis (>10.0 × 10<sup>9</sup>/L), respectively. By Day 28, the mean WCC increased significantly (P = 0.0003) from 6.37 to 7.47 × 10<sup>9</sup>/L (73 paired values) and was similar between the two groups. Ethnicity was the only WCC explanatory factor and only on Day 0.</p> <p>The mean Day 0 platelet count (n = 151) was 113.0 (range 8.0–313.0) × 10<sup>9</sup>/L and rose significantly to 186.308 × 10<sup>9</sup>/L by Day 28 (P < 0.0001). There was a corresponding fall in patient proportions with thrombocytopaenia (<150 × 10<sup>9</sup>/L): 119/151 (78.81%) vs. 16/73 (21.92%, P < 0.00001). Papuan and non Papuan mean platelet counts were similar at all time points. Only malaria species on Day 0 was a significant platelet count explanatory factor. The mean D0 platelet counts were significantly lower (P = 0.025) in vivax (102.022 × 10<sup>9</sup>/L) vs. falciparum (122.125 × 10<sup>9</sup>/L) patients.</p> <p>Conclusion</p> <p>Changes in leukocytes and platelets were consistent with other malaria studies. The Papuan non Papuan difference in the mean Day 0 WCC was small but might be related to the difference in malaria exposure.</p
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Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990-2021: findings from the Global Burden of Disease Study 2021
Background
Anaemia is a major health problem worldwide. Global estimates of anaemia burden are crucial for developing appropriate interventions to meet current international targets for disease mitigation. We describe the prevalence, years lived with disability, and trends of anaemia and its underlying causes in 204 countries and territories.
Methods
We estimated population-level distributions of haemoglobin concentration by age and sex for each location from 1990 to 2021. We then calculated anaemia burden by severity and associated years lived with disability (YLDs). With data on prevalence of the causes of anaemia and associated cause-specific shifts in haemoglobin concentrations, we modelled the proportion of anaemia attributed to 37 underlying causes for all locations, years, and demographics in the Global Burden of Disease Study 2021.
Findings
In 2021, the global prevalence of anaemia across all ages was 24·3% (95% uncertainty interval [UI] 23·9–24·7), corresponding to 1·92 billion (1·89–1·95) prevalent cases, compared with a prevalence of 28·2% (27·8–28·5) and 1·50 billion (1·48–1·52) prevalent cases in 1990. Large variations were observed in anaemia burden by age, sex, and geography, with children younger than 5 years, women, and countries in sub-Saharan Africa and south Asia being particularly affected. Anaemia caused 52·0 million (35·1–75·1) YLDs in 2021, and the YLD rate due to anaemia declined with increasing Socio-demographic Index. The most common causes of anaemia YLDs in 2021 were dietary iron deficiency (cause-specific anaemia YLD rate per 100 000 population: 422·4 [95% UI 286·1–612·9]), haemoglobinopathies and haemolytic anaemias (89·0 [58·2–123·7]), and other neglected tropical diseases (36·3 [24·4–52·8]), collectively accounting for 84·7% (84·1–85·2) of anaemia YLDs.
Interpretation
Anaemia remains a substantial global health challenge, with persistent disparities according to age, sex, and geography. Estimates of cause-specific anaemia burden can be used to design locally relevant health interventions aimed at improving anaemia management and prevention.
Funding
Bill & Melinda Gates Foundation
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Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021
Background
Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020.
Methods
We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990–2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data.
Findings
We estimated 9·40 million (95% uncertainty interval [UI] 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5–14 years, 6·29% (5·05 to 7·70) in those aged 15–49 years, 5·72% (4·02 to 7·39) in those aged 50–69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5–14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15–49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50–69 years, and a 3·29% (–5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis for 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (–713 to 2180) fewer deaths.
Interpretation
Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups
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