Postprandial Effect of a High-Fat Meal on Endotoxemia in Arab Women with and without Insulin-Resistance-Related Diseases

This study determined the effects of a high-fat meal on circulating endotoxin and cardiometabolic indices in adult Arab women. The cohort consisted of 92 consenting Saudi women (18 non-diabetic (ND)) control subjects; Age 24.4 ± 7.9 year; body mass index (BMI) 22.2 ± 2.2 Kg/m²), 24 overweight/obese (referred to as overweight-plus (overweight⁺)) subjects (Age 32.0 ± 7.8 year; BMI 28.5 ± 1.5 Kg/m²) and 50 type 2 diabetes mellitus (T2DM) patients (Age 41.5 ± 6.2 year; BMI 35.2 ± 7.7 Kg/m²). All were given a high-fat meal (standardized meal: 75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast of 12–14 h. Anthropometrics were obtained and fasting blood glucose, lipids, and endotoxin were serially measured for four consecutive postprandial hours. Endotoxin levels were significantly elevated prior to a high-fat meal in the overweight⁺ and T2DM than the controls (p < 0.05). Furthermore, the postprandial cardiometabolic changes led to a more detrimental risk profile in T2DM subjects than other groups, with serial changes most notable in glucose, triglycerides, high density lipoprotein-cholesterol (HDL-cholesterol), and insulin levels (p-values < 0.05). The same single meal given to subjects with different metabolic states had varying impacts on cardiometabolic health. Endotoxemia is exacerbated by a high-fat meal in Arab subjects with T2DM, accompanied by a parallel increase in cardiometabolic risk profile, suggesting disparity in disease pathogenesis of those with or without T2DM through the altered cardiometabolic risk profile rather than variance in metabolic endotoxinaemia with a high-fat meal.     

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics

Purpose

Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.

Methods

Seventy ST cases on clopidogrel identified from the PLATO trial (n =?58) and Mayo Clinic biorepository (n =?12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.

Results

Poor metabolizers (n =?4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n =?29) than controls (n =?18). Functional studies of CYP2C19 exonic variants (n =?11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n =?169) compared with controls (n =?84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.

Conclusion

NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

     

Massive pulmonary embolism in a patient with nephrotic syndrome and single lung

Journal of Thrombosis and Thrombolysis - We present a novel case of a patient with nephrotic syndrome and previous left pneumonectomy who had a massive pulmonary embolism of his remnant right...     

Comment on pregnancy and aortic root growth in the Marfan syndrome.

Meijboom and coworkers¹ reported on the aortic root growth rateof women with Marfan syndrome during pregnancy. They could notfind a significant increase in the aortic root diameter in 31pregnancies     

Budesonide once versus twice-daily administration: meta-analysis

OBJECTIVES: The aim of this study was to examine the efficacy of budesonide administered once daily compared to twice daily in asthma. METHODOLOGY: Meta-analysis of randomised controlled trials comparing budesonide administered once versus twice a day that presented data on at least one clinical outcome measure was conducted. RESULTS: A total of 10 studies, with 1922 children and adults with asthma, met the inclusion criteria. These studies were performed predominantly with mild to moderate asthmatic patients, using doses of budesonide ranging from 200 to 800 microg per day. There was no significant difference between daily dosing once or twice for all the clinical outcome variables, including withdrawals due to asthma, for which the odds ratio was 1.0 (95% confidence interval, 0.65-1.52). CONCLUSIONS: In mild to moderate asthma a once-daily budesonide regimen has a similar efficacy to a twice-daily regimen in doses up to 800 microg per day. A once-daily regimen has potential advantages in terms of patient compliance and satisfaction, when used in clinical practice.     

Treatment of the experimental chronic digitalisintoxication by hemoperfusion (author's transl)

In 5 adult dogs experimental chronic digitalis intoxication was produced by oral administration of different digitalis-types (digoxin, beta-methyl-, beta-acetyl-digoxin, digitoxin). 18 to 24 hours after the last application of digitalis, charcoal hemoperfusion was performed in Dipidolor-N2O-anesthesia and serum digitalis-concentrations in the arterial and venous lines of the hemoperfusion system were determined by RIA J125. The Ecg was registered continuously as a simple clinical parameter of cardiac digitalis intoxication. Initial multiple cardiac arrhythmias (AVII degree, SAII degree, tachycardia of the atrium) subsided in the dogs with digoxin, beta-methyl- and beta-acetyl-digoxin during hemocolperfusion within 130 to 160 min. The disturbances of rhythm persisted up to 200 min after onset of hemoperfusion in the dog intoxicated by digitoxin. The clearances of digoxin and derivatives (35.8--43.1 ml/min) are higher than the digitoxin clearance (17--23.2 ml/min) which is supposed to be the reason for cardiac detoxication in the digoxin-intoxicated dogs. Hemoperfusion using polymer coated charcoal appears to be effective for the elimination of digoxin leading to a marked improvement of cardiac arrhythmias. By contrast digitoxin induced cardiac arrhythmias are not influenced during hemoperfusion.     

Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis

OBJECTIVE: To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals. METHODS: MSU crystal-induced neutrophil migration was studied in the murine air-pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme-linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright-Giemsa staining of cytospins. RESULTS: MSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti-S100A8 and anti-S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout. CONCLUSION: S100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.     

Low-molecular-weight heparins in ischemic heart disease

PURPOSE OF REVIEW: The objective of this review was to summarize the recent developments regarding the use of low-molecular-weight heparins in the management of acute coronary syndromes. RECENT FINDINGS: In the setting of unstable angina and non-ST-elevation myocardial infarction, enoxaparin is superior to unfractionated heparin in reducing death, myocardial infarction, and recurrent ischemia both in the short-term and to 1 year. However, this does not necessarily imply a class effect of low-molecular-weight heparins in general. When combined with glycoprotein IIb/IIIa inhibitors, enoxaparin appears to be effective and safe even for patients treated according to an early invasive strategy. In patients receiving fibrinolytics for ST-elevation myocardial infarction, low-molecular-weight heparins are as effective as unfractionated heparin in maintaining patency of the infarct-related artery and in reducing the composite endpoint of death and reinfarction. However, serious bleeding is more common, especially among the elderly, and the optimal dosing regimen in ST-elevation myocardial infarction remains to be defined. SUMMARY: Low-molecular-weight heparins are safe and effective in the management of unstable angina and non-ST-elevation myocardial infarction, with or without concurrent administration of glycoprotein IIb/IIIa inhibitors. Ongoing studies will clarify the role of low-molecular-weight heparins as adjunctive therapy for fibrinolysis.