The diagnosis of iron deficiency anemia is typically straightforward, especially when classic biochemical and hematological changes are present in a subject at risk. It can be challenging in the presence of diseases or when it is due to inherited defects of iron metabolism. The identification of iron deficiency prior to anemia development is also difficult. New hematological parameters such as reticulocyte Hb content have expanded the classic ones such as MCV, MCH and MCHC. A variety of hematology analyzers now provide novel parameters to assess cellular hypochromia and microcytosis in both reticulocytes and mature red blood cells. The repertoire of biochemical markers has also been expanded, with iron, transferrin and ferritin being supplemented by circulating transferrin receptor and hepcidin. Molecular identification of functional variants of key iron metabolism determinants has provided explanations for the heritability of some iron metabolism biomarkers. Genetic defects in some of these molecules are responsible for hereditary microcytic anemias, also called atypical microcytic anemias. In this review, we examine the most significant hematological and biochemical markers for iron metabolism, as well as relevant genetic polymorphisms and defects affecting iron handling.
Sickle cell trait (AS) confers partial protection against lethal malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.
BACKGROUND Rhabdomyosarcoma (RMS) represents a diverse category of myogenic malignancies with marked differences in molecular alterations and histology. This study examines the question if RMS predisposition due to germline TP53 mutations correlates with certain RMS histologies. METHODS The histology of RMS tumors diagnosed in 8 consecutive children with TP53 germline mutations was reviewed retrospectively. In addition, germline TP53 mutation analysis was performed in 7 children with anaplastic RMS (anRMS) and previously unknown TP53 status. RESULTS RMS tumors diagnosed in 11 TP53 germline mutation carriers all exhibited nonalveolar, anaplastic histology as evidenced by the presence of enlarged hyperchromatic nuclei with or without atypical mitotic figures. Anaplastic RMS was the first malignant diagnosis for all TP53 germline mutation carriers in this cohort, and median age at diagnosis was 40 months (mean, 40 months ± 15 months; range, 19-67 months). The overall frequency of TP53 germline mutations was 73% (11 of 15 children) in pediatric patients with anRMS. The frequency of TP53 germline mutations in children with anRMS was 100% (5 of 5 children) for those with a family cancer history consistent with Li-Fraumeni syndrome (LFS), and 80% (4 of 5 children) for those without an LFS cancer phenotype. CONCLUSIONS Individuals harboring germline TP53 mutations are predisposed to develop anRMS at a young age. If future studies in larger anRMS cohorts confirm the findings of this study, the current Chompret criteria for LFS should be extended to include children with anRMS irrespective of family history.
A 21 year old male student presented in 1980 as an Olympic athlete with a 12 year history of jaundice, pallor, and darkened urine induced by the atraumatic exercise of swimming (1). Physical examination at that time was remarkable only for moderate scleral icterus without hepatosplenomegaly. Hematological examination revealed moderate macrocytosis (MCV 102 fL) without anemia (Hct 50%, Hb 17 g/dL, 9% reticulocytes). The peripheral blood smear showed occasional target cells. Red cell osmotic fragility was decreased. Red cell Na content was increased and K content was decreased, with reduced total monovalent ion content. Passive red cell permeability of both Na and K were increased. A supervised 2.5 hr swimming workout increased free plasma Hb from <5 to 45 mg/dL and decreased serum haptoglobin from 25 to 6 mg/dL. The post-exercise urine sediment was remarkable for hemosiderin-laden tubular epithelial cells, without frank hemoglobinuria. The circulating 15 day erythrocyte half-life measured after 6 days without exercise was further shortened to 12 days after resumption of twice-per-day swimming workouts for 1 week. The patient’s red cells were hypersensitive to in vitro shear stress applied by cone-plate viscometer.
Background Rhabdomyosarcoma survivors have an increased risk of developing second malignant neoplasms (SMN); this risk is traditionally attributed to the effects of multidisciplinary management required for cure. However, the impact of constitutional predisposition has not been properly analyzed. Methods We analyzed the risk of SMN among 1,151 children diagnosed with rhabdomyosarcoma and reported to the Surveillance, Epidemiology, and End Results registries (SEER‐9) from 1973 to 2010. Standardized incidence ratios (SIR) and corresponding 95% confidence intervals (CI) were calculated using SEERStat 8.1.2. Results Children with pleomorphic and embryonal rhabdomyosarcoma had an increased risk of developing a SMN (SIR = 15.77, 95%CI 1.91–56.96 and SIR = 5.6, 95%CI 3.32–8.85, respectively). The risk was age‐dependent; the highest was among children <2 years (SIR = 13.38, 95%CI 4.34–31.22) and the lowest was in children >10 years (SIR = 3.35, 95%CI 1.53–6.35). The risk for the youngest patients was higher for those with embryonal rhabdomyosarcoma (SIR = 14.72, 95%CI 4.01–37.70) compared to other histiotypes. Additionally, the risk of SMN was independent of the use of radiation to the primary (SIR = 6.50, 95%CI 3.97–10.03 and SIR = 4.57, 95%CI 2.09–8.68, for children receiving and not receiving radiation, respectively). The pattern of SMN observed was consistent with the Li‐Fraumeni spectrum. Conclusions Children with rhabdomyosarcoma are at high risk of developing SMN. This risk is higher for a subgroup of young children with pleomorphic and embryonal histologies, and is independent of the use of radiation. This suggests that a subgroup of children with pleomorphic and embryonal rhabdomyosarcoma may have a constitutional cancer predisposition. Pediatr Blood Cancer 2015; 9999:1–6 © 2015 Wiley Periodicals, Inc.
Polymerization of HbS and cell sickling are the prime pathophysiological events in sickle cell disease (SCD). Over the last 30 years, a substantial understanding at the molecular level has been acquired on how a single amino acid change in the structure of the beta chain of hemoglobin leads to the explosive growth of the HbS polymer and the associated changes in red cell morphology. O2 tension and intracellular HbS concentration are the primary molecular drivers of this process, and are obvious targets for developing new therapies. However, polymerization and sickling are driving a complex network of associated cellular changes inside and outside of the erythrocyte, which become essential components of the inflammatory vasculopathy and result in a large range of potential acute and chronic organ damages. In these areas, a multitude of new targets for therapeutic developments have emerged, with several ongoing or planned new therapeutic interventions. This review outlines the key points of SCD pathophysiology as they relate to the development of new therapies, both at the pre-clinical and clinical levels.
On January 12, 2010, Haiti experienced one of the worst disasters in human history, a magnitude 7.0 earthquake, resulting in the deaths of approximately 222,000 Haitians and grievous injury to hundreds of thousands more. International agencies, academic institutions, nongovernmental organizations, and associations responded by sending thousands of medical professionals, including nurses, doctors, medics, and physical therapists, to support the underresourced Haitian health system. The volunteers who came to provide medical care to disaster victims worked tirelessly under extremely challenging conditions, but in many cases they had no previous work experience in resource-limited settings, minimal training in tropical disease, and no knowledge of the historical background that contributed to the catastrophe. Often, this lack of preparedness hindered their ability to care adequately for their patients. The authors of this perspective argue that the academic medicine community must prepare medical trainees not only to treat the illnesses of patients in resource-limited settings but also to fight the injustice that fosters disease and allows such catastrophes to unfold. The authors advocate purposeful attention to building global health curricula; providing adequate time, funding, and opportunity to work in resource-limited international settings; and ensuring sufficient supervision for trainees to work safely. They also call for an interdisciplinary approach to global health that both affirms health care as a fundamental human right and explores the historical, economic, and political causes of inequitable health care.
Key Points P falciparum growth is not inhibited in either cord or heterozygote hereditary persistence of fetal hemoglobin erythrocytes. P falciparum growth in fetal hemoglobin erythrocytes is oxygen independent.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.