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Concept: Hemoglobin

240

Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.

Concepts: Hemoglobin, Chronic kidney disease, Kidney, Erythropoietin, Red blood cell, Anemia, Transferrin, Ferritin

192

While intermittent hypoxic training (IHT) has been reported to evoke cellular responses via hypoxia inducible factors (HIFs) but without substantial performance benefits in endurance athletes, we hypothesized that repeated sprint training in hypoxia could enhance repeated sprint ability (RSA) performed in normoxia via improved glycolysis and O(2) utilization. 40 trained subjects completed 8 cycling repeated sprint sessions in hypoxia (RSH, 3000 m) or normoxia (RSN, 485 m). Before (Pre-) and after (Post-) training, muscular levels of selected mRNAs were analyzed from resting muscle biopsies and RSA tested until exhaustion (10-s sprint, work-to-rest ratio 1∶2) with muscle perfusion assessed by near-infrared spectroscopy. From Pre- to Post-, the average power output of all sprints in RSA was increased (p<0.01) to the same extent (6% vs 7%, NS) in RSH and in RSN but the number of sprints to exhaustion was increased in RSH (9.4±4.8 vs. 13.0±6.2 sprints, p<0.01) but not in RSN (9.3±4.2 vs. 8.9±3.5). mRNA concentrations of HIF-1α (+55%), carbonic anhydrase III (+35%) and monocarboxylate transporter-4 (+20%) were augmented (p<0.05) whereas mitochondrial transcription factor A (-40%), peroxisome proliferator-activated receptor gamma coactivator 1α (-23%) and monocarboxylate transporter-1 (-36%) were decreased (p<0.01) in RSH only. Besides, the changes in total hemoglobin variations (Δ[tHb]) during sprints throughout RSA test increased to a greater extent (p<0.01) in RSH. Our findings show larger improvement in repeated sprint performance in RSH than in RSN with significant molecular adaptations and larger blood perfusion variations in active muscles.

Concepts: Hemoglobin, Oxygen, Carbon dioxide, Peroxisome proliferator-activated receptor, Red blood cell, Muscle, Muscular system, Carbonic anhydrase

189

Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hb(mass)) and maximal oxygen uptake ([Formula: see text] O(2 max)). PURPOSE: This study defined the time course of changes in Hb(mass), [Formula: see text] O(2 max) as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field. METHODS: 19 trained men received rHuEpo injections of 50 IU•kg(-1) body mass every two days for 4 weeks. Hb(mass) was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. [Formula: see text] O(2 max) and 3,000 m time trial performance were measured pre, post administration and at the end of the study. RESULTS: Relative to baseline, running performance significantly improved by ∼6% after administration (10∶30±1∶07 min:sec vs. 11∶08±1∶15 min:sec, p<0.001) and remained significantly enhanced by ∼3% 4 weeks after administration (10∶46±1∶13 min:sec, p<0.001), while [Formula: see text] O(2 max) was also significantly increased post administration (60.7±5.8 mL•min(-1)•kg(-1) vs. 56.0±6.2 mL•min(-1)•kg(-1), p<0.001) and remained significantly increased 4 weeks after rHuEpo (58.0±5.6 mL•min(-1)•kg(-1), p = 0.021). Hb(mass) was significantly increased at the end of administration compared to baseline (15.2±1.5 g•kg(-1) vs. 12.7±1.2 g•kg(-1), p<0.001). The rate of decrease in Hb(mass) toward baseline values post rHuEpo was similar to that of the increase during administration (-0.53 g•kg(-1)•wk(-1), 95% confidence interval (CI) (-0.68, -0.38) vs. 0.54 g•kg(-1•)wk(-1), CI (0.46, 0.63)) but Hb(mass) was still significantly elevated 4 weeks after administration compared to baseline (13.7±1.1 g•kg(-1), p<0.001). CONCLUSION: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated [Formula: see text] O(2 max) and Hb(mass).

Concepts: Better, Hemoglobin, Oxygen, Erythropoietin, Improve, Carbon monoxide, VO2 max, Knitting

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Background Intravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluated effectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients. Patients and methods Of 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 received FCM at the oncologist’s discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least one follow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion. Results The median total iron dose was 1000 mg per patient (interquartile range 600-1500 mg). The median Hb increase was comparable in patients receiving FCM alone (1.4 g/dl [0.2-2.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl [0.7-2.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml benefited from FCM treatment (stable Hb ≥11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation benefited from FCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events. Conclusions The substantial Hb increase and stabilisation at 11-12 g/dl in FCM-treated patients suggest a role for i.v. iron alone in anaemia correction in cancer patients.

Concepts: Hemoglobin, Oncology, Iron, Interquartile range, Anemia, Iron deficiency anemia, Transferrin, Ferritin

169

BACKGROUND: Allostery is one of the most powerful and common ways of regulation of protein activity. However,for most allosteric proteins identified to date the mechanistic details of allosteric modulation are notyet well understood. Uncovering common mechanistic patterns underlying allostery would allow notonly a better academic understanding of the phenomena, but it would also streamline the design ofnovel therapeutic solutions. This relatively unexplored therapeutic potential and the putativeadvantages of allosteric drugs over classical active-site inhibitors fuel the attention allosteric-drugresearch is receiving at present. A first step to harness the regulatory potential and versatility ofallosteric sites, in the context of drug-discovery and design, would be to detect or predict theirpresence and location. In this article, we describe a simple computational approach, based on theeffect allosteric ligands exert on protein flexibility upon binding, to predict the existence and positionof allosteric sites on a given protein structure. RESULTS: By querying the literature and a recently available database of allosteric sites, we gathered 213allosteric proteins with structural information that we further filtered into a non-redundant set of 91proteins. We performed normal-mode analysis and observed significant changes in protein flexibilityupon allosteric-ligand binding in 70% of the cases. These results agree with the current view thatallosteric mechanisms are in many cases governed by changes in protein dynamics caused by ligandbinding. Furthermore, we implemented an approach that achieves 65% positive predictive value inidentifying allosteric sites within the set of predicted cavities of a protein (stricter parameters set,0.22 sensitivity), by combining the current analysis on dynamics with previous results on structuralconservation of allosteric sites. We also analyzed four biological examples in detail, revealing thatthis simple coarse-grained methodology is able to capture the effects triggered by allosteric ligandsalready described in the literature. CONCLUSIONS: We introduce a simple computational approach to predict the presence and position of allosteric sitesin a protein based on the analysis of changes in protein normal modes upon the binding of acoarse-grained ligand at predicted cavities. Its performance has been demonstrated using a newlycurated non-redundant set of 91 proteins with reported allosteric properties. The software developedin this work is available upon request from the authors.

Concepts: Enzyme kinetics, Hemoglobin, Allosteric regulation, Proteins, Scientific method, Protein, Protein structure

168

Rhesus-positive and rhesus-negative persons differ in the presence-absence of highly immunogenic RhD protein on the erythrocyte membrane. This protein is a component of NH(3) or CO(2) pump whose physiological role is unknown. Several recent studies have shown that RhD positivity protects against effects of latent toxoplasmosis on motor performance and personality. It is not known, however, whether the RhD phenotype modifies exclusively the response of the body to toxoplasmosis or whether it also influences effects of other factors.

Concepts: Hemoglobin, Psychology, Cell nucleus, Blood, Cell membrane, Raymond Cattell

167

BACKGROUND Iron deficiency and iron deficiency anaemia are frequent problems in both the primary and the specialist health services. It is important to detect iron deficiency and to determine the causal relationship because iron deficiency may be secondary to a serious disease. The diagnosis of iron deficiency is largely based on biochemical and haematological laboratory findings, but there is no standardisation or consensus on the interpretation of these findings.METHOD Non-systematic search in the PubMed database with a discretionary selection of articles, based on the authors' knowledge of the field.RESULTS Ferritin measurement is the most important analysis in the study of iron deficiency, but there is no consensus on the diagnostic cut-off. It is usual in Norway today to use a ferritin level of < 12 - 20 μg/L, but at this low level the sensitivity for detecting iron deficiency is very low. A number of studies show that if the diagnostic cut-off is increased to the order of 30 μg/L the sensitivity is significantly higher for only a small reduction in specificity.INTERPRETATION When studying iron deficiency as a cause of anaemia, the diagnostic cut-off for detecting deficiency should be higher than that used today. The ferritin level increases with inflammation and ought in practice to be considered in conjunction with the CRP level. The level of transferrin receptor in plasma increases with iron deficiency without being influenced by inflammation and is therefore a good supplement to ferritin measurement. Measurement of iron, transferrin and transferrin saturation provides little information additional to that provided by ferritin in iron deficiency studies.

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

166

Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology has not been characterized when repeated blood loss occurs. Hepcidin was measured in plasma samples obtained from 114 first-time/reactivated (no blood donations in prior 2 years) female donors and 34 frequent (≥3 red blood cell donations in prior 12 months) male donors as they were phlebotomized ≥4 or more times over 18-24 months. Hepcidin was compared to ferritin and hemoglobin using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin declined with increasing frequency of donation in the first-time/reactivated females. Hepcidin and ferritin correlated well with each other (Spearman correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (≤45.7 ng/ml) or decreasing hepcidin and low ferritin (≤26 ng/ml), and was essentially zero for other subjects including those with high (>45.7 ng/ml) or increasing hepcidin and low ferritin (≤26 ng/ml) (p<0.001). Hepcidin rapidly changes in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of low ferritin suggests that plasma hepcidin may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone.

Concepts: Hemoglobin, Blood, Red blood cell, Spearman's rank correlation coefficient, Liver, Anemia, Hematology, Iron deficiency anemia

151

We sought to evaluate the feasibility and efficacy of hybrid transapical closure of paravalvar mitral leaks using a new Occlutech PLD occluder in patients with heart failure and/or haemolytic anaemia.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology

114

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