Blood Cell Turnover Research Articles

Use of breath carbon monoxide measurements to assess erythrocyte survival in subjects with chronic diseases

Anemia is very common in patients with chronic diseases. To determine the role of increased red blood cell (RBC) turnover in such subjects, we estimated RBC survival in three groups of chronically ill patients using a simple technique in which RBC life span is estimated via measurements of breath carbon monoxide concentration. The study groups consisted of subjects with: (1) osteoarthritis, (2) rheumatoid arthritis, and (3) anemia who were hospitalized for treatment of a variety of chronic illnesses. None of the anemic subjects had evidence of hemorrhage, a deficiency state, or a marrow abnormality to account for their reduced hemoglobin concentration. Subjects with osteoarthritis had a mean RBC life span (127 +/- 25 days) that did not differ significantly from normal (122 +/- 23 days). In contrast, RBC life span was significantly reduced (P < 0.001) in both the rheumatoid arthritis subjects (90 +/- 15 days) and the anemic, hospitalized patients (87 +/- 33 days). The hemoglobin concentration of the rheumatoid patients was near normal (13.5 +/- 1.5 g/dl), indicating that the marrow was compensating for the reduced RBC life span, whereas no such compensation was apparent in the anemic, chronically ill subjects. We conclude that a modest (approximately 25%) reduction in RBC life span commonly occurs in patients with chronic disease, and this reduction becomes clinically relevant in subjects whose marrow cannot respond with increased RBC output.

Pharmacokinetics, Pharmacodynamics and Anti-Tumor Efficacy of PR-171, a Novel Inhibitor of the 20S Proteasome.

Clinical studies using the boronic acid-based proteasome inhibitor bortezomib (VelcadeTM) have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin's Lymphoma. Despite encouraging clinical response rates with this drug, significant toxicities, including neutropenia, thrombocytopenia and peripheral neuropathy have restricted the intensity of bortezomib dosing. PR-171 is a novel peptide epoxyketone inhibitor that selectively and irreversibly inhibits the chymotryptic subunit of the 20S proteasome. We have characterized the pharmacokinetics, pharmacodynamics and anti-tumor efficacy of PR-171 in rodents and non-human primates. PR-171 is rapidly cleared from the plasma compartment following intravenous bolus administration, with a terminal half-life in rats and monkeys of 15 and 7.2 min, respectively. Despite this rapid clearance, PR-171 administration results in a prolonged dose-dependent inhibition of the 20S proteasome in all tissues examined with the exception of brain. Single doses of PR-171 that are tolerated in mice, rats and monkeys result in greater than 90% inhibition of proteasome activity in blood and many tissues. Recovery of proteasome activity following exposure to PR-171 is dependent upon synthesis of new proteasome subunits and occurs with a t1/2 of ~ 24 hr in nucleated cells. Recovery of proteasome activity in erythrocytes is dependent upon red blood cell turnover and occurs more slowly in animals. The safety of PR-171 has been assessed in rodents using multiple dosing schedules including weekly, biweekly, daily and BID administration. In rats, daily administration of PR-171 at doses that resulted in >80% inhibition of proteasome activity in whole blood and selected tissues were well tolerated. Recovery of proteasome activity following repeated daily administrations was unchanged from that seen after a single dose. PR-171 was also well tolerated when administered daily to monkeys at equivalent doses on a body surface area comparison. A transient thrombocytopenia was noted in both rats and monkeys but neutrophil and lymphocyte counts were not decreased in response to PR-171 administration. PR-171 induced a significant anti-tumor response in beige-nu-xid (BNX) triple immunodeficient mice bearing established HS-Sultan Burkitt's lymphoma tumors and in Balb/c mice challenged with A20 lymphoma cells. We have also demonstrated anti-tumor activity of PR-171 in several mouse models of solid tumors including syngeneic and human tumor xenograft models of colorectal cancer. These studies demonstrate the tolerability, anti-tumor activity and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies utilizing dose intensive schedules.

Serum Erythropoietin and Aging: A Longitudinal Analysis

To determine the changes in serum erythropoietin with age in patients with and without anemia and to assess the importance of certain comorbidities on changes in erythropoietin level and the development of anemia. Clinical history, hematological parameters, and serum erythropoietin levels were examined at 1- to 2-year intervals for 8 to 30 years. Baltimore Longitudinal Study on Aging (BLSA), National Institute on Aging. One hundred forty-three BLSA participants. Complete blood count and serum chemistries were performed at the time of each visit, and archived serum samples were used for erythropoietin level. Although all subjects were healthy and without anemia at the time of initial evaluation, some developed chronic illness-most notably hypertension and diabetes mellitus. Erythropoietin levels rose significantly for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes mellitus or hypertension. During the subsequent years, subjects who developed anemia but did not have hypertension or diabetes mellitus had the greatest slope in erythropoietin rise over time, whereas those with hypertension or diabetes mellitus and anemia had the lowest erythropoietin slope. The increase in serum erythropoietin with aging may be compensation for subclinical blood loss, increased red blood cell turnover, or increased erythropoietin resistance of red cell precursors. It is suspected that, with very advanced age, or in those with compromised renal function (e.g., diabetes mellitus or hypertension), the compensatory mechanism becomes inadequate and anemia results.

Obesity, cigarette smoking, and telomere length in women

Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.

Hb Buffalo [α89(FG1)His→Gln (α1)], Observed Solely and in the Presence of an Hb S [β6(A3)Glu→Val] Heterozygosity

The hemoglobin (Hb) pattern of a 32‐year‐old Somali male living in The Netherlands, during routine diabetes mellitus monitoring, showed two more peaks in addition to the characteristic heterozygous Hb A/S pattern. A major peak of 15% faster than Hb A, and a minor one of 10.8%, overlapping Hb A2 and the glycated Hb S1c fraction were present. The patient was not anemic or microcytic but had a low haptoglobin level, possibly indicating a slightly elevated red blood cell (RBC) turnover. Hb S was confirmed by a sickle test and at the DNA level. The DNA sequence of the α1 gene revealed a C→G transversion at position 89, changing the local positively charged histidine to a neutral glutamine. This mutant has been previously described in a Yemenite woman and two apparently unrelated Somali males. Our case is the first showing Hb Buffalo in combination with Hb S and a G6PD deficiency, and is again observed in a Somali. No functional abnormalities associated with mutations at this amino acid residue are reported in the literature. Also, in this case no sign of any hematological abnormalities that could not be explained by the Hb S heterozygosity G6PD deficiency was found. The abnormal α chain is expressed at the expected rate and without thalassemic effect or instability. The mutated α chain seems to associate with a slight preference to the βA (15%) rather than with the βS counterpart. The sum of both Hb ABuffalo and Hb SBuffalo results in about 19–20% of total Hb. This figure is in agreement with a stable mutant of the α1 gene.

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Growth Deficits in Children with Sickle Cell Disease

Background Growth deficits are common in children with sickle cell disease. Few prospective studies are available and the pathophysiologic basis for the impaired growth is not clearly understood. Our objectives were to collect data on anthropomorphic measurements of children with sickle cell disease prospectively followed for 1 year and to correlate them with hematologic data. Methods One hundred children <8 years of age (73 with homozygous SS sickle cell anemia [HbSS] and 27 with hemoglobinopathy SC [HbSC]) were included. Standardized Z scores of weight for age (waz), height for age (haz), and weight for height (whz) were compared to the National Center for Health Statistics (NCHS) reference population. Results At study entry, the means (standard deviation [SD]) of waz, haz, and whz were −0.69 (1.06), −0.65 (1.11), and −0.32 (1.00), respectively. After 1 year of study, children with HbSS presented a significant decrease in waz ( p = 0.01) and whz ( p = 0.02); the decrease in haz was not statistically significant ( p = 0.48). The effect was similar for children older or younger than 24 months of age. The decrease in waz and whz was significant for boys but not for girls. After 1 year of follow-up, lower mean waz scores were observed among patients with lower hemoglobin concentration and higher reticulocyte count ( p = 0.03 and p = 0.08). Hemoglobin concentration was higher in girls. The anthropomorphic measurements did not deteriorate significantly in children with HbSC. Conclusions Growth deficits may be demonstrable in children with HbSS, even during a short period of observation. Fast red blood cell turnover may be partially responsible for the observed effect.

Cystic Fibrosis-Related Diabetes and Abnormal Glucose Tolerance: Overview and Medical Nutrition Therapy

Cystic fibrosis (CF) is an autosomal recessively inherited defect in the cystic fibrosis transmembrane receptor, a cell membrane chloride channel. The deficiency or absence of the channel results in thick, sticky secretions in many organs, including lung, liver, gastrointestinal tract, and pancreas. Eighty-five percent of CF patients have exocrine pancreatic insufficiency. The obstructive nature of the tenacious mucus predisposes to infection, particularly in the respiratory tract.1 CF was once considered a disease of childhood. However, with improvements in medical care during the past few decades, patients with CF are now living well into their third, fourth, or fifth decade of life and have a median life expectancy of 32.2 years.2 As survival has increased, CF-related diabetes (CFRD) has become the leading co-morbidity in this patient population,3–5 occurring in ∼13% of all patients with CF.2 This figure is widely believed to be an underestimate because of the lack of routine screening for diabetes in the CF population.6 CFRD is most commonly diagnosed in patients who are between 18 and 21 years of age.4,7 The 1998 CFRD Consensus Committee identified four glucose tolerance categories for clinical management and research purposes (Table 1).8 The four categories are based on a standard glucose tolerance test: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), CFRD without fasting hyperglycemia (FH), and CFRD with FH. There are important differences in medical nutrition therapy (MNT) for the various categories of glucose intolerance and other circumstances in patients with CFRD. Glycated hemoglobin (A1C) is not useful for diagnosing CFRD because increased red blood cell turnover in CF patients may falsely lower A1C levels. However, it can be useful in monitoring overall blood glucose control in established CFRD patients.8 The American Diabetes Association (ADA) classifies CFRD under …

Accelerated Red Blood Cell Turnover Can Invalidate the Use of Hemoglobin A1c as a Diagnostic Test for Cystic Fibrosis Related Diabetes

Accelerated Red Blood Cell Turnover Can Invalidate the Use of Hemoglobin A1c as a Diagnostic Test for Cystic Fibrosis Related Diabetes

Altitude training at 2690m does not increase total Haemoglobin mass or sea level V̇O 2max in world champion track cyclists

Haemoglobin mass (Hb mass), maximum oxygen consumption (VO2max), simulated 4000 m individual pursuit cycling performance (IP4000), and haematological markers of red blood cell (RBC) turnover were measured in 8 male cyclists before and after (A) 31 d of altitude training at 2690 m. The dependent variables were measured serially after altitude on d A3-4, A8-9 and A20-21. There was no significant change in Hb mass over the course of the study and VO2max at d A9 was significantly lower than the baseline value (79.3 +/- 0.7 versus 81.4 +/- 0.6 ml x kg(-1) x min(-1), respectively). No increase in Hb mass or VO2max was probably due to initial values being close to the natural physiological limit with little scope for further change. When the IP4000 was analysed as a function of the best score on any of the three test days after altitude training there was a 4% improvement that was not reflected in a corresponding change in VO2max or Hb mass. RBC creatine concentration was significantly reduced after altitude training, suggesting a decrease in the average age of the RBC population. However, measurement of reticulocyte number and serum concentrations of erythropoietin, haptoglobin and bilirubin before and after altitude provided no evidence of increased RBC turnover. The data suggest that for these elite cyclists any benefit of altitude training was not from changes in VO2max or Hb mass, although this does not exclude the possibility of improved anaerobic capacity.

Epoxybutene–Hemoglobin Adducts in Rats and Mice: Dose Response for Formation and Persistence During and Following Long-Term Low-Level Exposure to Butadiene

Measurement of specific adducts to hemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in humans. The purpose of this study was to investigate the dose response for adduct formation and persistence in rats and mice during long-term low-level exposure to butadiene by inhalation. Adducts of 3,4-epoxy-1-butene, the primary metabolite of butadiene, with N-terminal valine in hemoglobin were determined in male B6C3F1 mice and male Sprague–Dawley rats following exposure to 0, 2, 10, or 100 ppm of 1,3-butadiene, 6 h/day, 5 days/week for 1, 2, 3, or 4 weeks. Blood samples were collected from groups of five mice and three rats at the end of each week during the 4 weeks of exposure and weekly for 3 weeks following the end of the 4-week exposure period. The increase and decrease, respectively, of the adduct levels during and following the end of the 4-week exposure followed closelythe theoretical curve for adduct accumulation and removalfor rats and mice, thereby demonstrating that the adductsare chemically stablein vivoand that the elimination followsthe turnover of the red blood cells. The adduct level increased linearly with butadiene exposure concentration in the mice, whereas a deviation from linearity was observed in the rats. For example, after exposure to 100 ppm butadiene, the epoxybutene–hemoglobin adduct levels were about four times higher in mice than in rats; at lower concentrations of butadiene, the species difference was less pronounced. Blood concentrations of epoxybutene, estimated from hemoglobin adduct levels, were in general agreement with reported concentrations in mice and rats exposed by inhalation to 62.5 ppm. These studies show that adducts of epoxybutene with N-terminal valine in hemoglobin can be used to predict blood concentration of epoxybutene in experimental animals.

Hormonal, immunological, and hematological responses to intensified training in elite swimmers.

The purpose of this study was to compare the responses of selected hormonal, immunological, and hematological variables in athletes showing symptoms of overreaching with these variables in well-trained athletes during intensified training. Training volume was progressively increased over 4 wk in 24 elite swimmers (8 male, 16 female); symptoms of overreaching were identified in eight swimmers based on decrements in swim performance, persistent high ratings of fatigue, and comments in log books indicating poor adaptation to the increased training. Urinary excretion of norepinephrine was significantly lower (P < 0.05, post hoc analysis) in overreached (OR) compared with well-trained (WT) swimmers throughout the 4 wk. There were no significant differences between OR and WT swimmers for other variables including: concentrations of plasma norepinephrine, cortisol, and testosterone, and the testosterone/cortisol ratio; peripheral blood leukocyte and differential counts, neutrophil/lymphocyte ratio, and CD4/CD8 cell ratio; serum ferritin and blood hemoglobin concentrations, erythrocyte number, hematocrit, and mean red cell volume (MCV). MCV increased significantly over the 4 wk in both groups, suggesting increased red blood cell turnover. These data show that, of the 16 hormonal, immunological, and hematological variables measured, urinary norepinephrine excretion appears to be the only one to distinguish OR from WT swimmers during short-term intensified training. Low urinary norepinephrine excretion was observed 2 to 4 wk before the appearance of symptoms of overreaching, suggesting the possibility that neuroendocrine changes may precede, and possibly contribute to, development of the overreaching/overtraining syndromes.

Exercise, training and red blood cell turnover.

Endurance training can lead to what has been termed 'sports anaemia'. Although under normal conditions, red blood cells (RBCs) have a lifespan of about 120 days, the rate of aging may increase during intensive training. However, RBC deficiency is rare in athletes, and sports anaemia is probably due to an expanded plasma volume. Cycling, running and swimming have been shown to cause RBC damage. While most investigators measure indices of haemolysis (for example, plasma haemoglobin or haptoglobin), RBC removal is normally an extravascular process that does not involve haemolysis. Attention is now turning to cellular indices (such as antioxidant depletion, or protein or lipid damage) that may be more indicative of exercise-induced damage. RBCs are vulnerable to oxidative damage because of their continuous exposure to oxygen and their high concentrations of polyunsaturated fatty acids and haem iron. As oxidative stress may be proportional to oxygen uptake, it is not surprising that antioxidants in muscle, liver and RBCs can be depleted during exercise. Oxidative damage to RBCs can also perturb ionic homeostasis and facilitate cellular dehydration. These changes impair RBC deformability which can, in turn, impede the passage of RBCs through the microcirculation. This may lead to hypoxia in working muscle during single episodes of exercise and possibly an increased rate of RBC destruction with long term exercise. Providing RBC destruction does not exceed the rate of RBC production, no detrimental effect to athletic performance should occur. An increased rate of RBC turnover may be advantageous because young cells are more efficient in transporting oxygen. Because most techniques examine the RBC population as a whole, more sophisticated methods which analyse cells individually are required to determine the mechanisms involved in exercise-induced damage of RBCs.

Anemia induced by ingestion of excess zinc in chicks: importance of red blood cell turnover?

Three studies were conducted to determine whether ingestion of excess zinc induces anemia, at least partially, by increasing red blood cell fragility directly or through changes in copper-zinc—dependent superoxide dismutase (Cu-Zn-SOD). Chicks from the cross New Hampshire × Single Comb White Leghorn were fed adequate (0.72–0.76 μmol Zn/g diet) or high (22.60–25.17 μmol Zn/g diet) levels of zinc and adequate (0.11–0.14 μmol Cu/g diet) or high (3.13–3.45 μmol Cu/g diet) levels of copper. To assess whether excess zinc could induce a hemolytic anemia, we monitored red blood cell (RBC) Cu-Zn-SOD, RBC fragility in vitro, and erythrocyte t 1 2 in vivo. Cu-Zn-SOD activity was depressed among chicks fed excess zinc and the ingestion of extra copper restored Cu-Zn-SOD activities to the levels of the control chicks. However, lysis of erythrocytes in diluted saline (0.35% NaCl) was lower when chicks were fed high levels of zinc and the ingestion of extra copper further decreased lysis. With these counteracting influences, the lifespan of erythrocytes was not affected by any of the treatments in one study and was greater in chicks fed both high zinc and copper in another study. These data indicate that the anemia induced by excess zinc is not a hemolytic anemia.

The fall of zinc protoporphyrin levels in workers treated for chronic lead intoxication.

A temporal fall of zinc protoporphyrin (ZPP) levels in whole blood was observed in 51 patients with occupational chronic lead intoxication who were removed from exposure, treated with intravenous calcium disodium edetate (EDTA), and followed for periods up to 2,273 days. ZPP levels fell, with a mean half-life of 68 days, to a mean baseline level of 36 micrograms/dl of whole blood. The baseline ZPP level was positively associated with the length of exposure (p less than .01) and the blood lead half-life (p less than .001). The amount of EDTA received had no apparent effect on ZPP levels. These data suggest that the fall of ZPP levels is largely a function of red blood cell turnover. The baseline ZPP level appears to be a useful biologic index of the biologically active pool of lead for at least two years after removal from exposure.

Zinc content of red and white blood cells in aboriginal children.

Studies were carried out on erythrocyte, granulocyte and lymphocyte zinc content of aboriginal children at the La Grange settlement in the north-west area of the Kimberley. Forty-eight children, 34 boys and 14 girls between 6 and 13 years were studied. Only the boys were investigated for white blood cell (WBC) zinc. Twenty-five Caucasian children volunteered to give blood for control studies. Two approaches were made concerning zinc analyses, atomic absorption spectroscopy and proton induced x-ray emission. It was found that lymphocyte, granulocyte and erythrocyte zinc content were significantly reduced in aboriginal boys aged 6 to 13 years. Since the turnover of white blood cells is relatively fast, it follows that the zinc content of these cells may be a true index of current zinc status confirming previous observations.

Subcellular distribution of hepatic copper, zinc and iron and serum ceruloplasmin in rats intoxicated by oral pyrrolizidine (Senecio) alkaloids.

Pair-fed rats were given diets containing 250 ppm added Cu with or without 5% Senecio jacobaea (SJ), a poisonous plant containing the highly toxic pyrrolizidine alkaloids (PA). Levels of Cu, Zn and Fe were determined in whole liver, kidney, spleen, serum and subcellular fractions of liver. Serum ceruloplasmin and hematocrit values were also obtained. At 5 wk, a 7.5-fold increase in liver Cu was observed for the SJ-treated rats when compared with controls (P<.01). Percentage distribution of total Cu was greater in the nuclei and debris fraction (P<.001) and reduced in the lysosomal and cytosolic fractions (P<.05) as a response to PA intoxication caused by SJ. Liver Zn was decreased (P<.05) as a result of SJ consumption; however, alterations in distribution of Zn among the fractions were not significant. The SJ caused an increase in liver Fe levels (P<.01) with the cytosol fraction showing the only significant increase. Ingestion of SJ also caused increased spleen weight (P<.001), spleen Cu level (P<.05), kidney weight (P<.01) and kidney Cu level (P<.01). Mean hematocrit was not different (P>.05), between treatments, but more variation was observed as a result of SJ consumption. Consumption of SJ also resulted in elevated activity of serum ceruloplasmin (P<.01) and serum Cu (P<.05). Higher levels of Cu in the nuclei and debris suggest impairment or saturation of normal subcellular excretory mechanisms and may involve a lysosomal defect. The increased hepatic Fe, hematocrit changes and spleen swelling suggest increased red blood cell turnover. The increased ceruloplasmin levels could be in response to increased erythropoiesis and the demand for Fe mobilization.

Changes in red cell membrane fatty acids in patients receiving total parenteral nutrition supplemented with a safflower oil emulsion.

Previous studies in patients suffering from essential fatty acid deficiency (EFAD) have shown erythrocyte membrane fatty acids to change in parallel with those seen in plasma. A study was conducted to determine if this same relationship existed in patients that were not diagnosed as having EFAD. Three subjects maintained on parenteral nutrition were given 500 milliliters of a safflower oil emulsion twice weekly for 14 days. Plasma and red blood cell membrane fatty acids were determined before and after the study period. The red blood cell membrane fatty acids did not appear to follow the changes seen in the plasma. Changes that did occur in the erythrocyte membrane fatty acid composition were inconsistent between patients. The incorporation of plasma fatty acids into erythrocyte membranes may occur at a different rate for patients with EFAD compared to those without EFAD due to an increased red blood cell turnover associated with EFAD.

Hydrocortisone regulation of thymidine kinase in thymus involution and hematopoietic tissues

Thymus involution, initiated by hydrocortisone treatment, was accompanied by a 90% decrease of thymidine kinase activity per g tissue. The concentration of six other enzymes remained essentially unchanged and that of two increased significantly, indicating that hydrocortisone has a selective effect on the enzymic composition of this organ. Hydrocortisone also decreased the level of thymidine kinase in two erythropoietic organs, fetal liver and neonatal spleen. These results indicate a close connection between thymidine kinase and the effect of glucocorticoids on organs involved in blood cell turnover. The effect of hydrocortisone on thymidine kinase levels does not necessarily coincide with that on cellularity. In spleen of 3–4-day-old rats the hormone did not alter the number of nuclei per g. In fetal liver an injection of hydrocortisone can cause maximal loss of thymidine kinase before there is any detectable loss in the number of hematopoietic cells. These results suggest that intracellular changes in enzyme concentrations precede alterations in cytocomposition.

Immunohemolytic Anemia During Therapy With Methyldopa

Immunohemolytic anemia secondary to methyldopa therapy occurred in an adult. Folate deficiency was also present because of rapid red blood cell turnover induced by the hemolysis. The globulin responsible for the positive direct and indirect Coomb's tests was of the warmacting IgG variety, with specificity for the Rh locus. The degree of hemolysis decreased and the hematocrit reading increased when methyldopa therapy was discontinued and prednisone and folate sodium were given. The Coomb's tests remained positive nine months after treatment was begun.