The effect of a high cholesterol and saturated fat diet on serum high-density lipoprotein-cholesterol, apoprotein A-I, and apoprotein E levels in normolipidemic humans

The effects of a high cholesterol, high saturated fat diet on serum high density lipoprotein cholesterol, apo A-I, and apo E levels were studied in six normolipidemic subjects. The study was done on an outpatient basis and mixed natural foods normally consumed by humans were used. When compared with a low cholesterol (98 mg/day) high polyunsaturated fat (P/S ratio 1.6) diet, the high cholesterol (1021 mg/day), high saturated fat (P/S ratio 0.4) diet increased serum cholesterol (23%) by raising the cholesterol concentration in very low-density lipoproteins (59%), low-density lipoproteins (15%), and high-density lipoproteins (30%). The low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol ratio fell significantly from 1.78 to 1.58. The increased high-density lipoprotein-cholesterol was associated with an elevation of serum apo A-I but not apo E. Serum triglycerides did not change significantly.     

A cellular assay for measuring the modulation of glucose production in H4IIE cells

Type II diabetes and its associated complications are a major health concern of the developed world. One of the hallmarks of diabetes is insulin resistance, where secreted insulin no longer has any effect on its target tissues, namely, liver, muscle, and fat. An important therapeutic strategy is to modulate blood glucose levels using pharmacological agents. Glycogen synthase kinase-3 (GSK3) is a serine-threonine protein kinase that plays important roles in regulating glucose metabolism. It is a key negative regulator of insulin action and is an important contributing factor to insulin resistance in liver, muscle, and adipose tissue. We describe the development of a cell-based assay designed to measure glucose production in rat hepatoma cell line H4IIE liver cells in response to treatment with small molecule inhibitors, including GSK3 inhibitors. The assay is set up in a 96-well format, and glucose production is assessed using a convenient fluorescence-based readout. This disease-relevant cellular assay is a valuable tool for the progression of small molecules that modulate glucose production.     

Physiologic effects of noninvasive ventilation during acute lung injury

A prospective, crossover, physiologic study was performed in 10 patients with acute lung injury to assess the respective short-term effects of noninvasive pressure-support ventilation and continuous positive airway pressure. We measured breathing pattern, neuromuscular drive, inspiratory muscle effort, arterial blood gases, and dyspnea while breathing with minimal support and the equipment for measurements, with two combinations of pressure-support ventilation above positive end-expiratory pressure (10-10 and 15-5 cm H2O), and with continuous positive airway pressure (10 cm H2O). Tidal volume was increased with pressure support, and not with continuous positive airway pressure. Neuromuscular drive and inspiratory muscle effort were lower with the two pressure-support ventilation levels than with other situations (p < 0.05). Dyspnea relief was significantly better with high-level pressure-support ventilation (15-5 cm H2O; p < 0.001). Oxygenation improved when 10 cm H2O positive end-expiratory pressure was applied, alone or in combination. We conclude that, in patients with acute lung injury (1) noninvasive pressure-support ventilation combined with positive end-expiratory pressure is needed to reduce inspiratory muscle effort; (2) continuous positive airway pressure, in this setting, improves oxygenation but fails to unload the respiratory muscles; and (3) pressure-support levels of 10 and 15 cm H2O provide similar unloading but differ in their effects on dyspnea.     

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers

Purpose

Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of ^99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and ¹²³I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement.

Methods

We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4 h after injection (defined by HM4?≥?1.85) or abnormal HM4?<?1.85, and positive DPD uptake (grade?≥?1 of Perugini classification) or negative DPD uptake.

Results

Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e’ ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n?=?31), MIBG was abnormal in 48% (n?=?15) among whom 50% had a normal DPD; all those with a normal MIBG (n?=?16) had a normal DPD.

Conclusions

In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value.

     

Age- and dose-dependent effects of an eicosapentaenoic acid-rich oil on cardiovascular risk factors in healthy male subjects

Supplementation with fish oils, rich in n-3 polyunsaturated fatty acids, modifies cardiovascular risk factors. However, dose-response relationships are poorly defined and whether similar effects are seen in young and older subjects is not known. This study determined the effect of supplementing the diet of young and older male subjects with different amounts of an eicosapentaenoic acid (EPA)-rich oil. Healthy young (18-42 years) and older (53-70 years) males were randomized to placebo or 1.35, 2.7 or 4.05 g EPA/day for 12 weeks. There was no effect of EPA on blood pressure or on plasma total, LDL or HDL cholesterol. EPA lowered plasma triacylglycerols, with the maximal effect at the lowest dose. Plasma lipoperoxides decreased in all groups. EPA decreased the lag time of copper-induced lipoprotein peroxidation and the ratio of reduced to total glutathione in the older subjects. The highest dose of EPA increased soluble E-selectin in young subjects, while increasing EPA tended to decrease soluble intercellular adhesion molecule 1 in young and older subjects. Young and older males will gain cardiovascular benefit from increased intake of EPA. Young males are unlikely to suffer adverse consequences from high EPA intake, whereas older males may have an increased risk of lipoprotein peroxidation.     

Distinct expression of interleukin (IL)‐36α, β and γ, their antagonist IL‐36Ra and IL‐38 in psoriasis,rheumatoid arthritis and Crohn's disease

Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.     

IL‐1R1–MyD88 axis elicits papain‐induced lung inflammation

Allergic asthma is characterized by a strong Th2 response with inflammatory cell recruitment and structural changes in the lung. Papain is a protease allergen disrupting the airway epithelium triggering a rapid inflammation with eosinophilia mediated by innate lymphoid cell activation (ILC2) and leading to a Th2 immune response. In this study, we focused on inflammatory responses to a single exposure to papain and showed that intranasal administration of papain results in the recruitment of inflammatory cells, including neutrophils and eosinophils with a rapid production of IL‐1α, IL‐1β, and IL‐33. The inflammatory response is abrogated in the absence of IL‐1R1 and MyD88. To decipher the cell type(s) involved in MyD88‐dependent IL‐1R1/MyD88 signaling, we used new cell‐specific MyD88‐deficient mice and found that the deletion of MyD88 signaling in single cell types such as T cells, epithelial cells, CD11c‐positive or myeloid cells leads to only a partial inhibition compared to complete absence of MyD88, suggesting that several cell types contribute to the response. Importantly, the inflammatory response is largely ST2 and IL‐36R independent. In conclusion, IL‐1R1 signaling via MyD88 is critical for the first step of inflammatory response to papain.     

Large-scale study of phosphoproteins involved in long-term potentiation in the rat dentate gyrus in vivo

The mechanisms underlying the induction of synaptic plasticity and the formation of long-term memory involve activation of cell-signalling cascades and protein modifications such as phosphorylation and dephosphorylation. Based on a protein candidate strategy, studies have identified several protein kinases and their substrates, which show an altered phosphorylation state during the early phases of long-term potentiation (LTP), yet only a limited number of synaptic phosphoproteins are known to be implicated in LTP. To identify new phosphoproteins associated with LTP, we have undertaken a proteomic study of phosphoproteins at different time points following the induction of LTP in the dentate gyrus in vivo (0, 15 and 90 min). For each time point, proteins from the dentate gyrus were separated by two-dimensional gel electrophoresis and stained with Pro−Q^® Diamond, a fluorescent stain specific for phosphoproteins. Fourteen proteins whose phosphorylation state varied significantly following LTP were identified using matrix-assisted laser desorption ionization/time of flight mass spectrometry and electrospray ionization-Orbitrap tandem mass spectrometry (MS/MS). They are involved in various cellular functions implicated in synaptic plasticity, such as intracellular signalling, axonal growth, exocytosis, protein synthesis and metabolism. Our results highlight new proteins whose phosphorylation or dephosphorylation is associated with LTP induction or maintenance. Further studies focusing on the regulation of specific phosphorylation sites will lead to greater understanding of the individual implications of these proteins in LTP as well as of their molecular interactions.     

Indoor Air Quality and Sources in Schools and Related Health Effects

Good indoor air quality in schools is important to provide a safe, healthy, productive, and comfortable environment for students, teachers, and other school staff. However, existing studies demonstrated that various air pollutants are found in classrooms, sometimes at elevated concentrations. Data also indicated that poor air quality may impact children's health, in particular respiratory health, attendance, and academic performance. Nevertheless, it should be noted that there are other adverse health effects that are less documented. Few data exist for teachers and other adults that work in schools. Allergic individuals seem to be at a higher risk for adverse respiratory health consequences. Air quality improvement represents an important measure for prevention of adverse health consequences in children and adults in schools.