A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference

BackgroundPreclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells.MethodsSingle-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean ± SD age, 26.3 ± 7.7 years) homozygous for the F508del mutation received oral miglustat 200 mg t.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference.ResultsNo statistically significant changes in TCS, sweat chloride values or FEV₁ were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat.ConclusionsThere was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference.     

Low-molecular-weight heparin vs. unfractionated heparin in percutaneous coronary intervention: a combined analysis.

This meta-analysis assessed the rates of the efficacy and safety endpoints with intravenous low-molecular-weight heparin (LMWH) compared with unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI). Subcutaneous LMWH has compared favorably with UFH, but limited experience exists with intravenous LMWH for immediate anticoagulation in PCI. The meta-analysis included data from eight randomized trials in which patients received LMWH (n = 1,037) or UFH (n = 978) during PCI. Seven additional nonrandomized studies/registries were analyzed to assess the efficacy and safety of LMWH during PCI. Efficacy endpoints were ischemic events (usually a composite of death, myocardial infarction, and urgent revascularization) and the safety endpoint was bleeding (major, minor, or all bleeding). In the randomized studies, LMWH was comparable with UFH in terms of efficacy (6.2% vs. 7.5%) and major bleeding (0.9% vs. 1.8%). The analysis of pooled data, randomized or not, suggests potential improved efficacy (5.8% vs. 7.6%) and reduced major bleeding (0.6% vs. 1.8%) with LMWH (n = 3,787) compared with UFH (n = 978). During PCI, intravenous LMWH without coagulation monitoring has the potential to be at least as safe and efficacious as intravenous UFH. Further studies of LMWHs in PCI are therefore required.     

CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin

Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX₃CL1 (fractalkine) and its unique receptor, CX₃CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX₃CR1-deficient mice and upon blocking CX₃CL1–CX₃CR1 interactions in wild-type mice. CX₃CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX₃CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX₃CL1 and CX₃CR1 regulate the pathology by controlling effector CD4⁺ T cell survival within inflamed tissues, adoptive transfer experiments established CX₃CR1 as a key regulator of CD4⁺ T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX₃CR1 and CX₃CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.Atopic dermatitis (AD) is a common, chronic inflammatory dermatosis that frequently occurs in individuals with a personal or family history of atopic diseases. AD pathophysiology is complex and results from skin barrier dysfunction and a dysregulated immune response, influenced by genetic and environmental factors (Guttman-Yassky et al., 2011a,b). Indeed, most patients with AD have increased serum IgE levels, with specific IgE directed against allergens or microbial proteins such as Staphylococcus aureus (Leung et al., 2004). Lesions in AD are characterized by increased epidermal thickness and a dermal inflammatory cell infiltrate, consisting of mast cells, eosinophils, and T lymphocytes. In acute AD lesions a preferential recruitment of Th2 cells occurs, whereas in the chronic lesions a Th1 profile is predominant (Grewe et al., 1998); allergic asthma or allergic rhinitis are more exclusively Th2-dominated diseases.Chemokines and their receptors play a key role in leukocyte recruitment to inflamed skin (Schall and Proudfoot, 2011). Eotaxins 1, 2, and 3 (CCL11, -24, and -26) bind to CCR3 and attract eosinophils, and CCL26 appears to be particularly involved in AD (Kagami et al., 2003; Owczarek et al., 2010). CCL27 together with CCR10 and CCR4 expression ensures T cell skin domiciliation (Reiss et al., 2001; Homey et al., 2002). More recently, CCR8 and CCL8 have been elegantly demonstrated to direct Th2 cell recruitment into allergen-inflamed skin and draining LNs in a murine model of AD (Islam et al., 2011).Besides chemoattraction, chemokine–chemokine receptor interactions also regulate other functions. Indeed, we have recently demonstrated that CX₃CR1, the receptor for CX₃CL1 (fractalkine [CX₃]), identified also as a receptor for CCL26 (Nakayama et al., 2010) in humans, controls the development of allergic asthma by providing a survival signal to the CD4⁺ effector T lymphocytes in the inflammatory airways (Mionnet et al., 2010; Julia, 2012). In AD patients, CX₃CL1 is up-regulated in both endothelial cells and skin lesions, and serum CX₃CL1 levels are positively associated with disease severity (Echigo et al., 2004). Another study reported that, although CX₃CR1 mRNA expression is consistently up-regulated in AD skin, CX₃CL1 mRNA levels are only increased in some patients with a significant correlation to the disease severity (Nakayama et al., 2010), a result likely to explain the earlier failure to detect CX₃CL1 in skin lesions (Fraticelli et al., 2001). Furthermore, two CX₃CR1 single nucleotide polymorphisms have been associated with asthma and atopy in French-Canadian populations (Tremblay et al., 2006) and German children (Depner et al., 2007).Thus, to functionally delineate the role of CX₃CL1–CX₃CR1 in AD, we used a mouse model of epicutaneous sensitization, by a protein antigen in the absence of adjuvant, faithfully mimicking features of human AD. Unexpectedly, we found that CX₃CL1–CX₃CR1 controlled AD to an even greater extent than allergic asthma through a new and distinct mechanism.     

Clinical insights into a tertiary care center cohort of patients with bicuspid aortic valve

The International Journal of Cardiovascular Imaging - Although bicuspid aortic valve (BAV) is one of the most common congenital heart diseases, clinical data associated with valve dysfunction are...