Antiplatelet effect of clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions – Limited inhibition of the P2Y12 receptor

IntroductionLarge individual variability in clopidogrel responses has been reported. However, mechanisms of the non-responsiveness are unclear. Our aim was to study the extent of platelet inhibition at the receptor level by in vitro receptor antagonists of P2Y₁₂ (AR-C69931MX, cangrelor) and P2Y₁ (adenosine 3’,5’diphosphate) in aspirin treated patients with coronary artery disease (CAD) prior to and after in vivo clopidogrel.Materials and Methods51 aspirin-treated (100 mg/day) patients participated. Blood was collected before and after administration of clopidogrel at 300 mg loading dose on day one, followed by 75 mg/d for four days. Aggregation in platelet-rich plasma was assessed.ResultsIn 20% of patients clopidogrel failed to inhibit platelet responses to ADP. These non-responders had also decreased sensitivity to an in vitro P2Y₁₂-receptor antagonist compared with the responders (mean inhibition of aggregation 25 vs. 32%, difference of means 7% (95% CI 2-12%), P < 0.02). Moreover, the P2Y₁₂-receptor inhibition by in vivo clopidogrel correlated with the inhibition by in vitro ARMX measured prior to administration of clopidogrel. Neither P2Y₁-receptor activity, thrombin generation while on aspirin nor basal platelet activity associated with clopidogrel responses.ConclusionsConcomitant aspirin and clopidogrel treatment failed to suppress platelet activity in 20% of patients. Non-responders to clopidogrel had decreased responses also to another ADP receptor antagonist, which suggests that the impaired response occurs at the level of P2Y₁₂-receptor.     

Disappearance of epiglottitis during large-scale vaccination with haemophilus influenzae type b conjugate vaccine among children in finland

Surveillance of blood-culture-proven epiglottitis was conducted in Finland from 1985 through 1992. Among children (<16 years), all bacteria causing epiglottitis, and among adults, Haemophilus influenzae were included. H influenzae type b (Hib) caused 226 (97%) of cases among children. Among adults with H influenzae epiglottitis (total of 20), 19 were caused by Hib In 1986, vaccine trials with Hib-conjugate vaccines started in Finland, with vaccination coverage of 94% to 98% of infants. Vaccinations did not yet have an effect on the occurrence of epiglottitis in 1985 or 1986 when the annual incidence among children was 5.3/100, 000, among those less than 5 years of age was 13.2/100, 000, and among adults was 0.08/100, 000. In 1987 through 1992 the proportion of vaccinated children increased steadily while the incidence of Hib epiglottitis decreased from 50 to 60 cases seen annually in 1985 and 1986 to 2 cases in 1992. There was no increase in the occurrence of epiglottitis caused by other pathogens In conclusion, there is now a safe and efficient way to prevent the majority of epiglottitis cases among children with the new Hib-conjugate vaccines.     

Personal and microenvironmental concentrations of particles and microbial aerosol in relation to health symptoms among teachers

A total of 81 randomly selected elementary school teachers participated in two sampling campaigns conducted 2 weeks apart during the winter. A 24-h sample collection was performed using personal and microenvironmental sampling from homes, and an 8-h sample collection was performed from workplaces of the studied subjects. Filters were analyzed for particle mass, absorption coefficient of the filter, and for both total and viable microorganisms. Comprehensive questionnaire responses were collected from the teachers concerning weekly occurred symptoms during the previous 12-month period, and they filled in symptom diaries immediately after each sampling campaign concerning symptoms during the previous 24-h and 7-day periods. The effect of different recall periods on agreement between questionnaire responses was assessed. Factor analysis was used in order to identify factors explaining the pattern of correlations within the personal, home, and work measurements. Moreover, associations between personal, home, and work measurements of pollutants and symptoms were analyzed using general estimation equations. The recall period of 7 days seemed to provide the most reliable data for the health effect assessment. Information from the factor analysis may allow reduction of variables related to the exposure assessment, and better interpretation of results. Both personal exposure and concentrations of pollutants at home were more frequently associated with health symptoms than concentrations at work. In multipollutant analyses, absorbance coefficient was positively associated with eye symptoms, and total bacteria with both cough and blocked nose.     

Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions

Aim Our aim was to evaluate the early efficacy and variabilityof the platelet inhibition exerted by 300 mg clopidogrel forthe purpose of acute percutaneous coronary interventions usingplatelet function tests. Methods and results Elective percutaneous coronary interventionwas used as a timely model in which clopidogrel was added toongoing acetylsalicylic acid (aspirin) (100 mg/day) at 2.5 hprior to procedure. Blood samples were collected before administrationof clopidogrel and immediately before the intervention from50 patients. Platelet functions were assessed with traditionalaggregation and PFA-100^®. At baseline, 14 (28%) patients were poor responders to aspirinaccording to PFA and 9 (18%) continued to show arachidonic acid-inducedaggregation. After clopidogrel ADP-triggered aggregation wasonly modestly inhibited in 40% of the patients. Eight percentof the study population was left without any measurable antiplateleteffect. The patients with modest response to clopidogrel hadhigher levels of c-peptide (1.5 nmol/L) than the ones respondingwell (0.9 nmol/L, ). Conclusion Neither ongoing aspirin treatment nor added clopidogreldid reach an expected extent of platelet inhibition. This studyshows that aspirin-treated patients undergoing PCI gain highlyvariable levels of platelet inhibition with short-term clopidogrel300 mg. At 2 h after adding clopidogrel it failed to enhance platelet inhibition in 40% of the patients.In future, targeted platelet function tests may be helpful toindividually select an effective antiplatelet medication forthese patients. This study suggests that for acute PTCA clopidogreldoes not reach the optimal antithrombotic efficacy in all patients.     

Safety and immunogenicity of an MF59(®)-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly

Background

The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59^®-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine.

Methods

Healthy adult (18–60 years, n = 3372) and elderly (≥61 years, n = 275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal^®) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study.

Results

Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5 μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15 μg antigen for each component strain.

Conclusions

Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.     

Impaired insulin-stimulated expression of the glycogen synthase gene in skeletal muscle of type 2 diabetic patients is acquired rather than inherited

To examine whether defective muscle glycogen synthase (GYS1) expression is associated with impaired glycogen synthesis in type 2 diabetes and whether the defect is inherited or acquired, we measured GYS1 gene expression and enzyme activity in muscle biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control subjects. The effect of insulin on GYS1 fractional activity, when expressed as the increment over the basal values, was significantly impaired in diabetic (15.7 +/- 3.3%; P < 0.01), but not in nondiabetic (23.7 +/- 1.8%; P = NS) twins compared with that in control subjects (28.1 +/- 2.3%). Insulin increased GYS1 messenger ribonucleic acid (mRNA) expression in control subjects (from 0.14 +/- 0.02 to 1.74 +/- 0.10 relative units; P < 0.01) and in nondiabetic (from 0.24 +/- 0.05 to 1.81 +/- 0.16 relative units; P < 0.01) and diabetic (from 0.20 +/- 0.07 to 1.08 + 0.14 relative units; P < 0.01) twins. The effect of insulin on GYS1 expression was, however, significantly reduced in the diabetic (P < 0.003), but not in the nondiabetic, twins compared with that in control subjects. The postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r = -0.61; P < 0.001). Despite the decrease in postclamp GYS1 mRNA levels, the GYS1 protein levels were not decreased in the diabetic twins compared with those in the control subjects (2.10 +/- 0.46 vs. 2.10 +/- 0.34 relative units; P = NS). We conclude that 1) insulin stimulates GYS1 mRNA expression; and 2) impaired stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes is acquired and most likely is secondary to chronic hyperglycemia.     

Osteoprotegerin Is an Independent Predictor of Vascular Events in Finnish Adults With Type 1 Diabetes

OBJECTIVEOsteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).RESULTSOnly patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01–1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13–1.88]; P = 0.004) during follow-up.CONCLUSIONSWe showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.Arterial calcification is strongly associated with the development and progression of vascular stiffening and arteriosclerosis leading to cardiovascular disease (CVD). This process is accelerated in patients with diabetes or chronic kidney disease (CKD) and especially in those with both (1). Many of the key regulators of bone mineralization also appear to be key mediators of osteogenic transformation of vascular smooth muscle cells and arterial calcification in diabetes (2,3). One of the most well known is osteoprotegerin (OPG) (4,5). OPG concentrations are positively correlated with coronary calcification (6), vascular stiffness (7), and the presence of unstable plaque (8) in nondiabetic individuals and an increased risk of cardiovascular (CV) mortality in patients with diabetes (9,10). In this study, we further explore the association between circulating concentrations of OPG and CV outcomes in a large well-characterized cohort of patients with type 1 diabetes (T1D) exploring mortality, coronary, stroke, and amputation events.