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Current Opinion in Clinical Nutrition... Jul 2020Genome instability has long been implicated as a primary causal factor in cancer and diseases of aging. The genome is constantly under attack from extrinsic and... (Review)
Review
PURPOSE OF REVIEW
Genome instability has long been implicated as a primary causal factor in cancer and diseases of aging. The genome is constantly under attack from extrinsic and intrinsic damaging agents. Uracil misincorporation in DNA and its repair is an intrinsic factor resulting in genomic instability and DNA mutations. Additionally, the presence of uracil in DNA can modify gene expression by interfering with promoter binding and transcription inhibition or upregulation of apoptotic proteins. In immune cells, uracil in DNA drives beneficial genomic diversity for antigen-driven immunity. This review addresses diseases that are linked to uracil accumulation in DNA, its causes, consequences, and the associated biomarkers of risk factors.
RECENT FINDINGS
Elevated genomic uracil is associated with megaloblastic anemia, neural tube defects, and retroviral immunity. Current evidence supporting causal mechanisms and nutritional interventions that rescue impaired pathways associated with uracil accumulation in DNA are summarized in this review.
SUMMARY
Nutritional deficiencies in B vitamins can cause uracil misincorporation into DNA leading to genome instability and associated diseases. Nutritional approaches to preventing uracil accumulation in DNA show some promise to address its associated diseases, but additional randomized controlled trials are needed.
Topics: DNA; DNA Repair; Deoxyuracil Nucleotides; Genetic Markers; Genomic Instability; Humans; Nutritional Physiological Phenomena; Risk Factors; Uracil; Vitamin B Deficiency
PubMed: 32398439
DOI: 10.1097/MCO.0000000000000660 -
Nature Communications Jul 2023Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are...
Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a group of blood cancers characterised by cytopenias, dysplasia of hematopoietic cells and blast expansion. Examination of peripheral blood slides (PBS) in MDS often reveals changes such as abnormal granulocyte lobulation or granularity and altered red blood cell (RBC) morphology; however, some of these features are shared with conditions such as haematinic deficiency anemias. Definitive diagnosis of MDS requires expert cytomorphology analysis of bone marrow smears and complementary information such as blood counts, karyotype and molecular genetics testing. Here, we present Haemorasis, a computational method that detects and characterizes white blood cells (WBC) and RBC in PBS. Applied to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia, and iron deficiency anemia), Haemorasis detected over half a million WBC and millions of RBC and characterized their morphology. These large sets of cell morphologies can be used in diagnosis and disease subtyping, while identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS. Additionally, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. By integrating cytomorphological features using machine learning, Haemorasis was able to distinguish SF3B1-mutant MDS from other MDS using cytomorphology and blood counts alone, with high predictive performance. We validate our findings externally, showing that they generalize to other centers and scanners. Collectively, our work reveals the potential for the large-scale incorporation of automated cytomorphology into routine diagnostic workflows.
Topics: Humans; Myelodysplastic Syndromes; Anemia; Anemia, Megaloblastic; Blood Cells; Neutrophils
PubMed: 37474506
DOI: 10.1038/s41467-023-39676-y -
Frontiers in Genetics 2022Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites.... (Review)
Review
Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites ( 40 known), 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (mmunodeficiency entromeric instability and acial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.
PubMed: 36468036
DOI: 10.3389/fgene.2022.985975 -
Discovery Medicine Sep 2017Pernicious anemia (PA) is an autoimmune disease of multifactorial etiologies characterized by autoimmune chronic atrophic gastritis, cobalamin deficiency (CD) due to... (Review)
Review
Pernicious anemia (PA) is an autoimmune disease of multifactorial etiologies characterized by autoimmune chronic atrophic gastritis, cobalamin deficiency (CD) due to defective absorption of dietary cobalamin from the terminal ileum, and by the presence of intrinsic factor and parietal cell antibodies. PA is a very common cause of CD-related anemia worldwide. Despite advances in the understanding molecular biology and pathophysiology of PA, the diagnosis of PA remains challenging in many circumstances for many clinicians because of its diverse clinical manifestations and the limitations of currently available diagnostic tools. Diagnostic dilemmas could occur when patients with PA present with spuriously normal or high cobalamin levels, normocytic or microcytic anemia, non-anemic macrocytosis, autoimmune hemolytic anemia, pseudo-thrombotic microangiopathy, hyperhomocysteinemia-associated thromboembolism, pseudoleu-kemia, bone marrow failure, bone marrow ring sideroblasts, and neurologic manifestations without anemia or macrocytosis. Herein, we provide an overview of the challenging clinical presentations of PA, diagnostic approach, and management.
Topics: Anemia, Pernicious; Animals; Autoantibodies; Autoimmune Diseases; Gastritis, Atrophic; Humans; Vitamin B 12 Deficiency
PubMed: 28972879
DOI: No ID Found -
Indian Journal of Pathology &... 2023β-thalassemia trait is usually diagnosed by raised hemoglobin A (HbA). The presence of megaloblastic anemia can cause an increase in HbA and create a diagnostic...
CONTEXT
β-thalassemia trait is usually diagnosed by raised hemoglobin A (HbA). The presence of megaloblastic anemia can cause an increase in HbA and create a diagnostic dilemma. Here, we have analyzed the effect of vitamin B12 and folic acid supplementation on HbA and diagnosis of β-thalassemia trait in cases of megaloblastic anemia with raised HbA.
MATERIALS AND METHODS
Cases of megaloblastic anemia with raised HbA on high-performance liquid chromatography (HPLC) were supplemented with vitamin B12 and folic acid. Post-treatment evaluation was done after 2 months. Cases showing adequate hematological response were subjected to statistical analysis. Based on post-treatment HbA value, the cases were diagnosed as normal, borderline raised HbA, or β-thalassemia trait. Pre- and post-treatment values of red cell parameters and HbA were analyzed.
RESULTS
There was a significant decrease in HbA value after vitamin B12 and folic acid supplementation. The diagnosis was changed in 70.97% of the cases after treatment. The chance of inconclusive diagnosis was decreased from more than 50% to less than 10%. Pre-treatment mean corpuscular volume (MCV) and HbA% showed a significant difference between the thalassemic and normal groups.
CONCLUSIONS
Megaloblastic anemia can lead to false-positive diagnosis of β-thalassemia trait on HPLC. Repeat HPLC should be done after adequate supplementation of vitamin B12 and folic acid in cases of megaloblastic anemia with raised HbA. Red cell parameters are not helpful to suspect β-thalassemia trait in presence of megaloblastic anemia. However, HbA% on HPLC can be a useful parameter to suspect or exclude β-thalassemia trait in cases of megaloblastic anemia.
Topics: Humans; beta-Thalassemia; Hemoglobin A2; Anemia, Megaloblastic; Vitamin B 12; Folic Acid
PubMed: 37077076
DOI: 10.4103/ijpm.ijpm_233_21 -
Experimental & Molecular Medicine Feb 2019Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is... (Review)
Review
Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5-15 μmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 μmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed.
Topics: Alleles; Animals; Cystathionine beta-Synthase; Disease Susceptibility; Folic Acid; Genetic Predisposition to Disease; Homocysteine; Humans; Hydrogen Sulfide; Hyperhomocysteinemia; Metabolic Networks and Pathways; Neoplasms; Polymorphism, Genetic; Risk Factors; Sulfur; Thromboembolism
PubMed: 30804341
DOI: 10.1038/s12276-019-0216-4 -
Bioengineered Dec 2021Megaloblastic anemia (MA) patients often exhibit hemolysis, but it is not clear whether there are other hemolytic mechanisms in addition to intramedullary hemolysis. We...
Megaloblastic anemia (MA) patients often exhibit hemolysis, but it is not clear whether there are other hemolytic mechanisms in addition to intramedullary hemolysis. We retrospectively analyzed the clinical characteristics of 124 MA patients, measured erythrocyte physical parameters in two patients with hemolysis and one healthy volunteer by atomic force microscopy, and measured 18F-FDG uptake in one MA patient with hemolysis. In multivariate analysis, hemolysis was associated with mean corpuscular volume (MCV) and indirect bilirubin. A receiver operating characteristic curve analysis, with sensitivity of 83.1% and specificity of 68.7%, suggested that the MCV cutoff value that predicts hemolysis is 116.4 fL. Hb was negatively correlated with MCV in the hemolysis group (r = -0.317, P = 0.007) but not in the nonhemolysis group. The erythrocyte peak-valley value, average cell surface roughness and surface area in the MA patients with hemolysis were significantly lower than those in controls (P < 0.05). 18F-FDG uptake by the liver and spleen was diffuse and increased in MA patients undergoing hemolysis. MA combined with extramedullary hemolysis could be caused by macrophages removing mechanically damaged erythrocytes and the retention of erythrocytes with decreased deformability when blood circulates through narrow spaces in the liver and spleen.
Topics: Aged; Anemia, Megaloblastic; Erythrocyte Indices; Erythrocytes; Female; Hemolysis; Humans; Liver; Male; Middle Aged; Spleen
PubMed: 34542005
DOI: 10.1080/21655979.2021.1952366 -
Romanian Journal of Internal Medicine =... Mar 2017The association between obesity and different types of anemia remained uncertain. The present study aimed to assess the relation between obesity parameters and the...
BACKGROUND
The association between obesity and different types of anemia remained uncertain. The present study aimed to assess the relation between obesity parameters and the occurrence of iron deficiency anemia and also megaloblastic anemia among Iranian population.
METHODS AND MATERIALS
This cross-sectional study was performed on 1252 patients with morbid obesity that randomly selected from all patients referred to Clinic of obesity at Rasoul-e-Akram Hospital in 2014. The morbid obesity was defined according to the guideline as body mass index (BMI) equal to or higher than 40 kg/m2. Various laboratory parameters including serum levels of hemoglobin, iron, ferritin, folic acid, and vitamin B12 were assessed using the standard laboratory techniques.
RESULTS
BMI was adversely associated with serum vitamin B12, but not associated with other hematologic parameters. The overall prevalence of iron deficiency anemia was 9.8%. The prevalence of iron deficiency anemia was independent to patients' age and also to body mass index. The prevalence of vitamin B12 deficiency was totally 20.9%. According to the multivariable logistic regression model, no association was revealed between BMI and the occurrence of iron deficiency anemia adjusting gender and age. A similar regression model showed that higher BMI could predict occurrence of vitamin B12 deficiency in morbid obese patients.
CONCLUSION
Although iron deficiency is a common finding among obese patients, vitamin B12 deficiency is more frequent so about one-fifth of these patients suffer vitamin B12 deficiency. In fact, the exacerbation of obesity can result in exacerbation of vitamin B12 deficiency.
Topics: Adolescent; Adult; Aged; Anemia, Iron-Deficiency; Anemia, Megaloblastic; Biomarkers; Body Mass Index; Child; Cross-Sectional Studies; Female; Ferritins; Folic Acid; Hemoglobins; Hospitals, University; Humans; Iran; Iron; Male; Middle Aged; Obesity, Morbid; Prevalence; Vitamin B 12; Vitamin B Complex
PubMed: 27648630
DOI: 10.1515/rjim-2016-0046 -
Cureus Nov 2021Epilepsy is a disorder that causes unprovoked seizures regularly. It affects between 1% and 3% of the population. After the first seizure, the chances of having another... (Review)
Review
Epilepsy is a disorder that causes unprovoked seizures regularly. It affects between 1% and 3% of the population. After the first seizure, the chances of having another one are almost 40%-52%. The etiology of febrile seizures in children with sickle cell disease is still unknown. In some groups, iron deficiency anemia has been linked to an increased risk of seizures. Although the reason and process are uncertain, some people believe that taking iron supplements can help prevent seizures. This literature covers haptene, non-haptene immune-related hemolysis, and oxidative processes activated by anti-seizure medications (ASMs). In epileptic patients, ASMs can cause anemia. Folic acid can be given to carbamazepine-treated anemic patients. There is growing evidence that it improves hemoglobin and leukocytes in individuals who take it. Therefore, one of the most efficient strategies to avoid future seizures is to take ASMs daily to maintain an even level of anticonvulsant in the body. To prevent further seizures, lifestyle changes are essential. Further studies and clinical trials are warranted to prove a clear association between epilepsy and hematologic disease, which will improve quality of life in the future.
PubMed: 34909297
DOI: 10.7759/cureus.19334