SciCombinator

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Concept: Hemoglobin

141

Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo.

Concepts: Hemoglobin, Pregnancy, Childbirth, Embryo, Fetus, Liver, Placenta, Gestational age

137

There has been no evidence for the necessity of endoscopy in asymptomatic young men with iron deficiency anemia (IDA). To determine whether endoscopy should be recommended in asymptomatic young men with IDA, we compared the prevalence of gastrointestinal (GI) lesions between young men (< 50 years) with IDA and those without IDA.

Concepts: Hemoglobin, Iron, Hematology, Iron deficiency anemia, Transferrin, Human iron metabolism, Iron deficiency, Serum iron

113

Individuals with colorectal cancer (CRC) have a tendency to intestinal bleeding which may result in mild to severe iron deficiency anemia, but for many colon cancer patients hematological abnormalities are subtle. The fecal occult blood test (FOBT) is used as a pre-screening test whereby those with a positive FOBT are referred to colonscopy. We sought to determine if information contained in the complete blood count (CBC) report coud be processed automatically and used to predict the presence of occult colorectal cancer (CRC) in the setting of a large health services plan. Using the health records of the Maccabi Health Services (MHS) we reviewed CBC reports for 112,584 study subjects of whom 133 were diagnosed with CRC in 2008 and analysed these with the MeScore tool. The odds ratio for being diagnosed with CRC in 2008 was calculated with regards to the MeScore, using cutoff levels of 97% and 99% percentiles. For individuals in the highest one percentile, the odds ratio for CRC was 21.8 (95% CI 13.8 to 34.2). For the majority of the individuals with cancer, CRC was not suspected at the time of the blood draw. Frequent use of anticoagulants, the presence of other gastrointestinal pathologies and non-GI malignancies were assocaitged with false positive MeScores. The MeScore can help identify individuals in the population who would benefit most from CRC screening, including those with no clinical signs or symptoms of CRC.

Concepts: Hemoglobin, Cancer, Colorectal cancer, Anemia, Hematology, Ulcerative colitis, Hematocrit, Fecal occult blood

92

It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero.

Concepts: Hemoglobin, Childbirth, Brain, Fetus, Neuroscience, Magnetic resonance imaging, Electroencephalography, Patent ductus arteriosus

82

Background Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia. Methods In this randomized, double-blind trial, we assigned 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to receive either darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure. Results The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin alfa group and 565 of 1142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P=0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P=0.01). Cancer-related adverse events were similar in the two study groups. Conclusions Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Our findings do not support the use of darbepoetin alfa in these patients. (Funded by Amgen; RED-HF ClinicalTrials.gov number, NCT00358215 .).

Concepts: Hemoglobin, Clinical trial, Red blood cell, Heart failure, Anemia, Clinical research, Darbepoetin alfa, Amgen

64

Tea interferes with iron absorption and can lead to iron deficiency anemia when consumed in large quantities. The rechallenge effect of green tea on anemia in a middle-aged man emphasizes the potential causal role of this beverage. Lifestyle and dietary habits are important diagnostic considerations in diseases of this type.

Concepts: Hemoglobin, Death, Iron, Iron deficiency anemia, Transferrin, Human iron metabolism

56

The teleost fishes represent over half of all extant vertebrates; they occupy nearly every body of water and in doing so, occupy a diverse array of environmental conditions. We propose that their success is related to a unique oxygen (O2) transport system involving their extremely pH-sensitive haemoglobin (Hb). A reduction in pH reduces both Hb-O2 affinity (Bohr effect) and carrying capacity (Root effect). This, combined with a large arterial-venous pH change (ΔpHa-v) relative to other vertebrates, may greatly enhance tissue oxygen delivery in teleosts (e.g., rainbow trout) during stress, beyond that in mammals (e.g., human). We generated oxygen equilibrium curves (OECs) at five different CO2 tensions for rainbow trout and determined that, when Hb-O2 saturation is 50% or greater, the change in oxygen partial pressure (ΔPO2) associated with ΔpHa-v can exceed that of the mammalian Bohr effect by at least 3-fold, but as much as 21-fold. Using known ΔpHa-v and assuming a constant arterial-venous PO2 difference (Pa-vO2), Root effect Hbs can enhance O2 release to the tissues by 73.5% in trout; whereas, the Bohr effect alone is responsible for enhancing O2 release by only 1.3% in humans. Disequilibrium states are likely operational in teleosts in vivo, and therefore the ΔpHa-v, and thus enhancement of O2 delivery, could be even larger. Modeling with known Pa-vO2 in fish during exercise and hypoxia indicates that O2 release from the Hb and therefore potentially tissue O2 delivery may double during exercise and triple during some levels of hypoxia. These characteristics may be central to performance of athletic fish species such as salmonids, but may indicate that general tissue oxygen delivery may have been the incipient function of Root effect Hbs in fish, a trait strongly associated with the adaptive radiation of teleosts.

Concepts: Hemoglobin, Oxygen, Carbon dioxide, Salmon, Salmonidae, Actinopterygii, Partial pressure, Niels Bohr

50

Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodiumfalciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection.

Concepts: Immune system, Hemoglobin, Malaria, Plasmodium falciparum, Red blood cell, Iron deficiency anemia, Sickle-cell disease, Transferrin

39

Background Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia. Methods In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. Results At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β0/β0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. Conclusions Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).

Concepts: DNA, Hemoglobin, Protein, Gene, Genetics, Allele, Amino acid, Integral

39

Mutations in hemoglobin can cause a wide range of phenotypic outcomes, including anemia due to protein instability and red cell lysis. Uncovering the biochemical basis for these phenotypes can provide new insights into hemoglobin structure and function as well as identify new therapeutic opportunities. We report here a new hemoglobin α chain variant in a female patient with mild anemia, whose father also carries the trait and is from the Turkish city of Kirklareli. Both the patient and her father had a His58(E7)→Leu mutation in α1. Surprisingly, the patient’s father is not anemic, but he is a smoker with high levels of HbCO (~16%). In order to understand these phenotypes, we examined recombinant human Hb (rHb) Kirklareli containing the α H58L replacement. Mutant α subunits containing Leu58(E7) autooxidize ~8 times and lose hemin ~200 times more rapidly than native α subunits, causing the oxygenated form of rHb Kirklareli to denature very rapidly under physiological conditions. The crystal structure of rHb Kirklareli shows that the α H58L replacement creates a completely apolar active site, which prevents electrostatic stabilization of bound O2, promotes autooxidation, and enhances hemin dissociation by inhibiting water coordination to the Fe(III) atom. At the same time, the mutant α subunit has an ~80,000 fold higher affinity for CO than O2, causing it to rapidly take up and retain carbon monoxide, which prevents denaturation both in vitro and in vivo and explains the phenotypic differences between the father, who is a smoker, and his daughter.

Concepts: Hemoglobin, Oxygen, Gene, Carbon dioxide, Phenotype, Hemolysis, In vitro, Carbon monoxide