Debates in allergy medicine: Specific immunotherapy in children with atopic dermatitis, the "con" view.

Atopic dermatitis (AD) is a common chronic skin condition in children that has a proven association with other atopic conditions and allergies. These associations, like the general pathophysiology of AD, are complex and not fully understood. While there is evidence for the efficacy of specific immunotherapy (SIT) in pediatric asthma and allergic rhinitis (AR), there is a lack of strong data to support its use in AD. IgE has been shown to be elevated in many patients with AD, but it is an unreliable biomarker due to variability and great fluctuation over time, poor positive predictive value for clinically relevant allergy, and poor correlation with disease state. In spite of this, almost all studies of SIT use either positive skin prick testing (SPT) or serum specific IgE levels to guide therapy. Allergen avoidance, with some exceptions, is generally not effective at controlling AD in children. The few studies that have investigated the efficacy of SIT in children with AD have produced conflicting results, and a lack of reproducibility with a standard treatment protocol. Limited studies have shown clinical improvement in mild to moderate AD cases, but no effect on more severe patients. Uncontrolled studies are difficult to interpret, due to the natural history of remission or "outgrowing" of AD over time in many patients without specific interventions. Drawbacks to SIT include the length of treatment, poor compliance, cost, and potential side effect profile. The potential for misdirection of time and energy away from skin directed therapy could negatively impact on AD outcomes

Is the slippery slope from steatosis to steatohepatitis paved with triglyceride or cholesterol?

Accumulation of hepatic lipids has been thought to trigger the inflammation, apoptosis, and fibrosis that characterize progression of hepatic steatosis to steatohepatitis and cirrhosis. In this issue of Cell Metabolism, Marí et al. (2006) provide evidence for excessive mitochondrial free cholesterol as a cause of the progession of steatosis to more severe liver disease

The metabolism of lipoprotein (a): an ever-evolving story.

Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) (LPA) was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism

Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials.

AimsThis analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials.Materials and methodsData from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C.ResultsLDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups.ConclusionsAcross study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status

A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration.

The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions

Statins in cardiometabolic disease: what makes pitavastatin different?

The term cardiometabolic disease encompasses a range of lifestyle-related conditions, including Metabolic syndrome (MetS) and type 2 diabetes (T2D), that are characterized by different combinations of cardiovascular (CV) risk factors, including dyslipidemia, abdominal obesity, hypertension, hyperglycemia/insulin resistance, and vascular inflammation. These risk factors individually and interdependently increase the risk of CV and cerebrovascular events, and represent one of the biggest health challenges worldwide today. CV diseases account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Furthermore, the risk of CV death is increased twofold to fourfold in people with T2D. Whilst the clinical management of CV disease has improved in Western Europe, the pandemic of obesity and T2D reduces the impact of these gains. This, together with the growing, aging population, means the number of CV deaths is predicted to increase from 17.1 million worldwide in 2004 to 23.6 million in 2030. The recommended treatment for MetS is lifestyle change followed by treatment for the individual risk factors. Numerous studies have shown that lowering low-density lipoprotein-cholesterol (LDL-C) levels using statins can significantly reduce CV risk in people with and without T2D or MetS. However, the risk of major vascular events in those attaining the maximum levels of LDL-C-reduction is only reduced by around one-third, which leaves substantial residual risk. Recent studies suggest that low high-density lipoprotein-cholesterol (HDL-C) (<1 .0 mmol/l; 40 mg/dl) and high triglyceride levels (≥1.7 mmol/l; 150 mg/dl) are independent risk factors for CV disease and that the relationship between HDL-C and CV risk persists even when on-treatment LDL-C levels are low (<1.7 mmol/l; 70 mg/dl). European guidelines highlight the importance of reducing residual risk by targeting these risk factors in addition to LDL-C. This is particularly important in patients with T2D and MetS because obesity and high levels of glycated hemoglobin are directly related to low levels of HDL-C and high triglyceride. Although most statins have a similar low-density lipoprotein-lowering efficacy, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects (for example, high-density lipoprotein-elevating efficacy), adverse event profiles, and drug-drug interactions. The choice of statin should therefore depend on the needs of the individual patient. The following reviews will discuss the potential benefits of pitavastatin versus other statins in the treatment of patients with dyslipidemia and MetS or T2D, focusing on its effects on HDL-C quantity and quality, its potential impact on atherosclerosis and CV risk, and its metabolic characteristics that reduce the risk of drug interactions. Recent controversies surrounding the potentially diabetogenic effects of statins will also be discussed

Correlating Pedestrian Flows and Search Engine Queries

An important challenge for ubiquitous computing is the development of techniques that can characterize a location vis-a-vis the richness and diversity of urban settings. In this paper we report our work on correlating urban pedestrian flows with Google search queries. Using longitudinal data we show pedestrian flows at particular locations can be correlated with the frequency of Google search terms that are semantically relevant to those locations. Our approach can identify relevant content, media, and advertisements for particular locations.Comment: 4 pages, 1 figure, 1 tabl

Relative Humidity and Activity Patterns of \u3cem\u3eIxodes scapularis\u3c/em\u3e (Acari: Ixodidae)

Laboratory studies have shown clear relationships between relative humidity (RH) and the activity and survival of Ixodes scapularis Say (blacklegged tick). However, field studies have produced conflicting results. We examined this relationship using weekly tick count totals and hourly RH observations at three field sites, stratified by latitude, within the state of Rhode Island. Records of nymphal tick abundance were compared with several RH-related variables (e.g., RH at time of sampling and mean weekly daytime RH). In total, 825 nymphs were sampled in 2009, a year of greater precipitation, with a weighted average leaf litter RH recorded at time of sampling of 85.22%. Alternatively, 649 nymphs were collected in 2010, a year of relatively low precipitation, and a weighted average RH recorded at time of sampling was 75.51%. Negative binomial regression analysis of tick count totals identified cumulative hours P = 0.0037; 2010: P \u3c 0.0001). Mean weekly daytime RH did not significantly predict tick activity in either year. However, mean weekly daytime RH recorded with 1-wk lag before sample date was a significant variable (P = 0.0016) in 2010. These results suggest a lag effect between moisture availability and patterns of tick activity and abundance. Differences in the relative importance of each RH variable between years may have been due to abnormally wet summer conditions in 2009

Metallic Xenon, Molecular Condensates, and Superconductivity

A possibility of explaining the light absorption observed to occur under pressure-induced xenon metallization as due to the transition to the superconducting state is analyzed. The mechanism of the van der Waals bonding is discussed.Comment: LaTeX 2.09 (RevTeX), 4 pages, 4 PostScript figures included in tex