Acquired erythroderma in adults: a clinical and prognostic study

Background Erythroderma is a severe syndrome and prognostic studies are rare in the literature. Objectives Through a retrospective study of erythroderma in adults, we have analysed epidemiological and clinical data and precised the relevant aetiologies and survival in our patients. Methods This study was performed at the Department of Dermatology of Charles Nicolle Hospital of Tunis (1995–2007) including 82 cases of acquired erythroderma (>16 years). We have recorded epidemio‐clinical, biological and histological data, treatment and outcome. Clinical–histological correlation was analysed [kappa coefficient (κ)]. Follow‐up time and disease‐free survival time were calculated as were Kaplan–Meier estimates of overall survival and relapse‐free survival for some aetiologies. Results Erythroderma represented 0.44‰ of all dermatoses with an age of 55.13 ± 18.16 and no sex predilection. Psoriasis was the predominant aetiology (32.9%) with a median duration of 6.75 years and previous one or more episodes of erythroderma. Psoriasis was significantly associated with pruritus (P = 0.0001), pachyonychia (P = 0.00001), palmoplantar keratoderma (P = 0.0001) and hypereosinophilia (P = 0.008). The latter is then not specific for drug induced erythroderma (P = 0.004). Carbamazepine (27.8%) and penicillin (22.2%) were the most implicated drugs. Positive Clinical–histological correlation was found in 77% of cases (κ = 0.753). Relapse was seen in all aetiologies, but drug reactions and had occurred in the first 3 years in 90% of them. Mortality rate was 11.3 per 1000 patients‐years. Conclusions Our study illustrates the severity of erythroderma. It alters heavily the quality of life of patients which is initially altered by the pre‐existent dermatosis. It may be life threatening as mortality rate is high.     

Icosapent Ethyl for Primary Versus Secondary Prevention of Major Adverse Cardiovascular Events in Hypertriglyceridemia: Value for Money Analysis

BackgroundIcosapent ethyl (IPE) is approved for the prevention of major adverse cardiovascular events (MACE) in patients with hypertriglyceridemia. However, due to budget constraints, access to IPE will inevitably be limited to a fraction of eligible patients. To help maximize value for money spent, we estimated the number of preventable MACE when providing IPE for primary versus secondary prevention.MethodsThe number of preventable MACE was estimated by dividing the available budget by the cost needed to treat (CNT) to prevent one MACE. CNT was calculated as the product of the number needed to treat (NNT) to prevent 1 MACE by therapy cost. NNT values were determined according to the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) results. The budget limit was set as the United States’ threshold suggested by the Institute for Clinical and Economic Review. Sensitivity analysis was performed regarding the cost of IPE in the United States.ResultsThe NNT to prevent 1 MACE over 4.9 years in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial primary prevention cohort was 59 (95% confidence interval [CI]: 24-∞) versus 14 (11-21) for secondary prevention. At an annual IPE cost of $2915, the CNT to prevent 1 MACE was $842,726 (95% CI: $342,804-∞) and $199,969 ($157,118-$299,953) accordingly. A total of $819 million worth of IPE can avoid 4762 MACE (95% CI: 0-11,707) versus 20,069 (13,379-25,541), when provided as primary versus secondary prevention therapy; P < .001. The number of avoided MACE is sensitive to IPE price.ConclusionsPrioritizing IPE therapy for patients with an established cardiovascular disease may provide significantly more value for money than primary prevention.     

Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival

We investigated the mechanism by which B lymphocyte stimulator (BLyS)/BAFF, a tumor necrosis factor superfamily ligand, promotes B-cell survival and resistance to atrophy. BLyS stimulation activates 2 independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2-deficient B cells are readily protected from death by BLyS stimulation, but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim-deficient but not healthy hosts. BLyS-dependent survival requires the antiapoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal, respectively, and conditional deletion of the Mcl-1 gene renders B cells refractory to BLyS-mediated protection. Because BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could target pathogenic B cells.     

Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.     

Red cell membrane stiffness in iron deficiency

The purpose of this study was to characterize red blood cell (RBC) deformability by iron deficiency. We measured RBC deformability to ektacytometry, a laser diffraction method for determining the elongation of suspended red cells subjected to shear stress. Isotonic deformability of RBC from iron-deficient human subjects was consistently and significantly lower than that of normal controls. In groups of rats with severe and moderate dietary iron deficiency, RBC deformability was also reduced in proportion to the severity of iron deficiency. At any given shear stress value, deformability of resealed RBC ghosts from both iron-deficient humans and rats was lower than that of control ghosts. However, increase of applied shear stress resulted in progressive increase in ghost deformation, indicating that ghost deformability was primarily limited by membrane stiffness rather than by reduced surface area-to-volume ratio. This was consistent with the finding that iron-deficient cells had a normal membrane surface area. In addition, the reduced mean corpuscular hemoglobin concentration (MCHC) and buoyant density of the iron-deficient rat cells indicated that a high hemoglobin concentration was not responsible for impaired whole cell deformability. Biochemical studies of rat RBC showed increased membrane lipid and protein crosslinking and reduced intracellular cation content, findings that are consistent with in vivo peroxidative damage. RBC from iron-deficient rats incubated in vitro with hydrogen peroxide showed increased generation of malonyldialdehyde, an end-product of lipid peroxidation, compared to control RBC. Taken together, these findings suggest that peroxidation could contribute in part to increased membrane stiffness in iron- deficient RBC. This reduced membrane deformability may in turn contribute to impaired red cell survival in iron deficiency.     

Effects of transient increased afterload during experimentally induced acute myocardial infarction in dogs

Alterations in afterload may occur during acute myocardial infarction (AMI), but it is unknown whether such alterations cause long-term changes in the left ventricular topography or alter healing of the AMI. AMI was produced by ligation of the left anterior descending coronary artery in open-chest dogs. Eight dogs were randomized to a methoxamine group with an infusion dose of 30 micrograms/kg/min starting 1 hour after ligation for 4 hours to increase systemic systolic pressure by 40 to 50 mm Hg, and 8 were randomized to a saline control group (n = 8). Seven days later the dogs were killed and the hearts examined. The ratio of infarct wall thickness to noninfarct wall thickness was 1.13 +/- 0.03 (mean +/- standard error of the mean) in control dogs and was 0.98 +/- 0.03 in the dogs treated with methoxamine (p less than 0.005). An expansion index was determined as previously reported and expansion was considered to have occurred if this index exceeded 1.09. The expansion index was 0.98 +/- 0.06 in the control group and 1.18 +/- 0.07 in the methoxamine group (p less than 0.05). Histologic analysis suggested a lag in the healing rate in the methoxamine-treated dogs. Thus, early, brief increases in afterload cause infarct expansion and thinning and appears to slow the early healing phase of AMI in dogs.     

Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat.

The effects of administering insulin-like growth factor I (IGF-I) were examined in a model of ischemic acute tubular necrosis in rats. Injury was induced by 75 min of bilateral renal artery occlusion. Compared to rats administered vehicle, rats administered IGF-I (100 micrograms/day via continuous subcutaneous infusion) had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion. Glomerular filtration rate as determined by inulin clearance was examined on day 2 postocclusion and was significantly increased in IGF-I-treated animals (0.16 +/- 0.02 ml per min per 100 g of body weight) compared to vehicle-treated controls (0.08 +/- 0.02 ml per min per 100 g of body weight). The weight loss that occurred during the course of acute tubular necrosis was ameliorated by IGF-I. Mortality was reduced from 36.7% in vehicle-treated rats to 7.1% in rats administered IGF-I. Histologically, there was much less renal injury evident at day 7 postocclusion in the IGF-I-treated rats compared to vehicle-treated controls. In contrast, growth hormone (200 micrograms administered subcutaneously for 4 days) did not affect recovery of renal function or reduce mortality postreperfusion. This report demonstrates a beneficial effect of IGF-I administration in the setting of acute tubular necrosis. Several properties of IGF-I render it a pharmacological agent with excellent potential for treatment of this condition in humans.     

The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin

The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.