Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response

Background

Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.

Design and Methods

Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.

Results

Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.

Conclusions

The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number {"type":"clinical-trial","attrs":{"text":"NCT00350662","term_id":"NCT00350662"}}NCT00350662.     

Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis

Background

We recently assigned a new fibrinolytic function to cell-derived microparticles in vitro. In this study we explored the relevance of this novel property of microparticles to the in vivo situation.

Design and Methods

Circulating microparticles were isolated from the plasma of patients with thrombotic thrombocytopenic purpura or cardiovascular disease and from healthy subjects. Microparticles were also obtained from purified human blood cell subpopulations. The plasminogen activators on microparticles were identified by flow cytometry and enzyme-linked immunosorbent assays; their capacity to generate plasmin was quantified with a chromogenic assay and their fibrinolytic activity was determined by zymography.

Results

Circulating microparticles isolated from patients generate a range of plasmin activity at their surface. This property was related to a variable content of urokinase-type plasminogen activator and/or tissue plasminogen activator. Using distinct microparticle subpopulations, we demonstrated that plasmin is generated on endothelial and leukocyte microparticles, but not on microparticles of platelet or erythrocyte origin. Leukocyte-derived microparticles bear urokinase-type plasminogen activator and its receptor whereas endothelial microparticles carry tissue plasminogen activator and tissue plasminogen activator/inhibitor complexes.

Conclusions

Endothelial and leukocyte microparticles, bearing respectively tissue plasminogen activator or urokinase-type plasminogen activator, support a part of the fibrinolytic activity in the circulation which is modulated in pathological settings. Awareness of this blood-borne fibrinolytic activity conveyed by microparticles provides a more comprehensive view of the role of microparticles in the hemostatic equilibrium.Key words: fibrinolytic microparticles, plasmin, plasminogen, uPA, tPA     

Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC

ATP-binding cassette transporter (and specially P-glycoprotein) activity is a well known prognostic factor in acute myeloid leukemia, but when compared to other molecular markers its prognostic value has not been well studied. Here we study relationships between this activity, fms-like tyro-sine kinase 3(FLT3/ITD), nucleophosmin(NPM1), CAAT-enhancer binding protein alpha(CEBPα), and brain and acute leukemia cytoplasmic protein (BAALC), in 111 patients with normal cytogenetics who underwent the same treatment, and evaluate its prognostic impact. Independent factors for survival were age (P=0.0126), ATP-binding cassette transporter activity (P=0.018) and duplications in the fms-like tyrosine kinase 3 (P=0.0273). In the 66 patients without fms-like tyrosine kinase 3 duplication and without nucleophosmin mutation, independent prognostic factors for complete remission achievement and survival were age and ATP-binding cassette transporter activity. In conclusion, ATP-binding cassette transporter activity remains an independent prognostic factor, and could assist treatment decisions in patients with no nucleophosmin mutation and no fms-like tyrosine kinase 3 duplication.     

Beer à no-go: learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition

Aims Previous research has shown that consistently not responding to alcohol‐related stimuli in a go/no‐go training procedure reduces drinking behaviour. This study aimed to examine further the mechanisms underlying this go/no‐go training effect. Design, setting and participants Fifty‐seven heavy drinkers were assigned randomly to two training conditions: in the beer/no‐go condition, alcohol‐related stimuli were always paired with a stopping response, while in the beer/go condition participants always responded to alcohol‐related stimuli. Participants were tested individually in a laboratory at Maastricht University. Measurements Weekly alcohol intake, implicit attitudes towards beer, approach–avoidance action tendencies towards beer and response inhibition were measured before and after the training. Findings Results showed a significant reduction in both implicit attitudes (P = 0.03) and alcohol intake (P = 0.02) in the beer/no‐go condition, but not in the beer/go condition. There were no significant training effects on action tendencies or response inhibition. Conclusions Repeatedly stopping pre‐potent responses towards alcohol‐related stimuli reduces excessive alcohol use via a devaluation of alcohol‐related stimuli rather than via increased inhibitory control over alcohol‐related responses.     

Different Effect of Rho Kinase Inhibition on Calcium Signaling in Rat Isolated Large and Small Arteries

In addition to its role in the regulation of artery contraction, Rho kinase (ROCK) was reported to be involved in the cytosolic calcium response to vasoconstrictor agonists in rat aorta and superior mesenteric artery (SMA). However, it remains to be determined whether ROCK also contributes to calcium signaling in resistance arteries, which play a major role in blood pressure regulation. The investigation of the effect of ROCK inhibition on the calcium and contractile responses of rat resistance mesenteric artery (RMA), in comparison with aorta and SMA, indicated that the calcium response to noradrenaline was inhibited by the ROCK inhibitor Y-27632 in aorta and SMA but not in RMA. The effect of Y-27632 on the calcium signal was unaffected by cytochalasin-D. ROCK activation in noradrenaline-stimulated arteries was confirmed by the inhibition of myosin light chain phosphorylation by Y-27632. Moreover, noradrenaline-induced calcium signaling was similarly inhibited by nimodipine in aorta, SMA and RMA, but nimodipine sensitivity of the contraction increased from the aorta to the RMA, suggesting that the contraction was controlled by different sources of calcium. In pressurized RMA, Y-27632 and H-1152 depressed pressure-induced calcium responses and abolished myogenic contraction. These results stress the important differences in calcium signaling between conductance and resistance arteries.     

GLP1 and cancer: friend or foe?

The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.     

Screening for determinants of self-care in patients with chronic heart failure

Heart failure self-care is vital to achieving clinical stability and improved health outcomes. Yet despite the attention it has been given, in both research and clinical practice, effective self-care remains elusive. It is recognised that there are many patient factors that impact on attaining effective self-care skills. Systematic research is warranted to resolve the knowledge gap of how patients process information and develop the necessary self-care skills. In addition, sound screening tools are needed to assess factors that hinder the development of effective heart failure self-care skills. In this manner, education and support strategies can be applied on an individualised needs basis to enhance health outcomes.