Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema

Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.

Monocyte differentiation toward regulatory dendritic cells is not affected by respiratory syncytial virus-induced inflammatory mediators

Airway epithelial cells were shown to drive the differentiation of monocytes into dendritic cells (DCs) with a suppressive phenotype. In this study, we investigated the impact of virus-induced inflammatory mediator production on the development of DCs. Monocyte differentiation into functional DCs, as reflected by the expression of CD11c, CD123, BDCA-4, and DC-SIGN and the capacity to activate T cells, was similar for respiratory syncytial virus (RSV)-infected and mock-infected BEAS-2B and A549 cells. RSV-conditioned culture media resulted in a partially mature DC phenotype, but failed to up-regulate CD80, CD83, CD86, and CCR7, and failed to release proinflammatory mediators upon Toll-like receptor (TLR) triggering. Nevertheless, these DCs were able to maintain an antiviral response by the release of Type I IFN. Collectively, these data indicate that the airway epithelium maintains an important suppressive DC phenotype under the inflammatory conditions induced by infection with RSV.

A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome

Although the term 'reflex sympathetic dystrophy' has been replaced by 'complex regional pain syndrome' (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain ["sympathetically maintained pain" (SMP)], even in the absence of detectable neuropathophysiology.

Targeted cell replacement with bone marrow cells for airway epithelial regeneration

It has been suggested that some adult bone marrow cells (BMC) can localize to the lung and develop tissue-specific characteristics including those of pulmonary epithelial cells. Here, we show that the combination of mild airway injury (naphthalene-induced) as a conditioning regimen to direct the site of BMC localization and transtracheal delivery of short-term cultured BMC enhances airway localization and adoption of an epithelial-like phenotype. Confocal analysis of airway and alveolar-localized BMC (fluorescently labeled) with epithelial markers shows expression of the pulmonary epithelial proteins, Clara cell secretory protein, and surfactant protein C. To confirm epithelial gene expression by BMC, we generated transgenic mice expressing green fluorescent protein (GFP) driven by the epithelial-specific cytokeratin-18 promoter and injected BMC from these mice transtracheally into wild-type recipients after naphthalene-induced airway injury. BMC retention in the lung was observed for at least 120 days following cell delivery with increasing GFP transgene expression over time. Some BMC cultured in vitro over time also expressed GFP transgene, suggesting epithelial transdifferentiation of the BMC. The results indicate that targeted delivery of BMC can promote airway regeneration.

Simulation in training: one-year experience using an efficiency index to assess interventional radiology fellow training status

PURPOSE: To compare objective fellow and expert efficiency indices for an interventional radiology renal artery stenosis skill set with the use of a high-fidelity simulator. MATERIALS AND METHODS: The Mentice VIST simulator was used for three different renal artery stenosis simulations of varying difficulty, which were used to grade performance. Fellows' indices at three intervals throughout 1 year were compared to expert baseline performance. Seventy-four simulated procedures were performed, 63 of which were captured as audiovisual recordings. Three levels of fellow experience were analyzed: 1, 6, and 12 months of dedicated interventional radiology fellowship. The recordings were compiled on a computer workstation and analyzed. Distinct measurable events in the procedures were identified with task analysis, and data regarding efficiency were extracted. Total scores were calculated as the product of procedure time, fluoroscopy time, tools, and contrast agent volume. The lowest scores, which reflected efficient use of tools, radiation, and time, were considered to indicate proficiency. Subjective analysis of participants' procedural errors was not included in this analysis. RESULTS: Fellows' mean scores diminished from 1 month to 12 months (42,960 at 1 month, 18,726 at 6 months, and 9,636 at 12 months). The experts' mean score was 4,660. In addition, the range of variance in score diminished with increasing experience (from a range of 5,940-120,156 at 1 month to 2,436-85,272 at 6 months and 2,160-32,400 at 12 months). Expert scores ranged from 1,450 to 10,800. CONCLUSIONS: Objective efficiency indices for simulated procedures can demonstrate scores directly comparable to the level of clinical experience.

Isotopic constraints on marine and terrestrial N2O emissions during the last deglaciation

Nitrous oxide (N2O) is an important greenhouse gas and ozone-depleting substance that has anthropogenic as well as natural marine and terrestrial sources. The tropospheric N2O concentrations have varied substantially in the past in concert with changing climate on glacial–interglacial and millennial timescales. It is not well understood, however, how N2O emissions from marine and terrestrial sources change in response to varying environmental conditions. The distinct isotopic compositions of marine and terrestrial N2O sources can help disentangle the relative changes in marine and terrestrial N2O emissions during past climate variations. Here we present N2O concentration and isotopic data for the last deglaciation, from 16,000 to 10,000 years before present, retrieved from air bubbles trapped in polar ice at Taylor Glacier, Antarctica. With the help of our data and a box model of the N2O cycle, we find a 30 per cent increase in total N2O emissions from the late glacial to the interglacial, with terrestrial and marine emissions contributing equally to the overall increase and generally evolving in parallel over the last deglaciation, even though there is no a priori connection between the drivers of the two sources. However, we find that terrestrial emissions dominated on centennial timescales, consistent with a state-of-the-art dynamic global vegetation and land surface process model that suggests that during the last deglaciation emission changes were strongly influenced by temperature and precipitation patterns over land surfaces. The results improve our understanding of the drivers of natural N2O emissions and are consistent with the idea that natural N2O emissions will probably increase in response to anthropogenic warming.

Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.

BACKGROUND Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain. METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding. RESULTS A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).

Links between atmospheric carbon dioxide, the land carbon reservoir and climate over the past millennium

The stability of terrestrial carbon reservoirs is thought to be closely linked to variations in climate 1, but the magnitude of carbon–climate feedbacks has proved dificult to constrain for both modern 2–4 and millennial 5–13 timescales. Reconstructions of atmospheric CO2 concentrations for the past thousand years have shown fluctuations on multidecadal to centennial timescales 5–7, but the causes of these fluctuations are unclear. Here we report high-resolution carbon isotope measurements of CO2 trapped within the ice of the West Antarctic Ice Sheet Divide ice core for the past 1,000 years. We use a deconvolution approach 14 to show that changes in terrestrial organic carbon stores best explain the observed multidecadal variations in the 13 C of CO2 and in CO2 concentrations from 755 to 1850 CE. If significant long-term carbon emissions came from pre-industrial anthropogenic land-use changes over this interval, the emissions must have been offset by a natural terrestrial sink for 13 C-depleted carbon, such as peatlands. We find that on multidecadal timescales, carbon cycle changes seem to vary with reconstructed regional climate changes. We conclude that climate variability could be an important control of fluctuations in land carbon storage on these timescales.

New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.