Biological mechanisms of microvessel formation in advanced atherosclerosis: The big Five

Advanced atherosclerotic lesions prone to rupture are characterized by a distinct histomorphology and pathobiology that became in recent years, increasingly related to the process of intraplaque neovascularization. Molecular mechanisms that regulate angiogenesis and that are active in the plaque region may destabilize advanced lesions by promoting microvessel growth and thus providing an entry route for inflammatory cells secondary to the luminal endothelium. In addition, angiogenic factors can also define intraplaque microvessel integrity and endothelial barrier function, determining the prevalence of intraplaque hemorrhaging. Here, we aim to compose a hypothetical model for angiogenic regulation of vulnerable plaque development, based on the evidence of clinical correlation and experimental functional studies that are provided for five of the most well-described angiogenic pathways in the current literature.     

Three monthly doses of palivizumab are not adequate for 5-month protection: A population pharmacokinetic analysis

Recent guidelines in British Columbia, Canada have suggested that the use of a maximum of 3 monthly doses of palivizumab 15 mg/kg intramuscularly for RSV immunoprophylaxis of high risk infants born prior to the RSV season is adequate to provide protection against severe RSV disease for a 5-month RSV season. Efficacy was established, however, with 2 large, randomized controlled clinical studies using 5 monthly doses of immunoprophylaxis. To evaluate the differences in expected palivizumab exposures between the 2 dosing regimens (3 vs 5 monthly doses across a 5-month period), we used a population pharmacokinetic (PK) model that was developed using palivizumab PK data collected from 22 clinical studies with a total of 1800 subjects. This model adequately described observed palivizumab concentrations from the different pediatric studies and was subsequently used to simulate expected palivizumab serum concentrations for 3 monthly doses compared with 5 monthly doses in children younger than 24 months with chronic lung disease of prematurity and infants younger than 6 months postnatal age who were born at ≤35 weeks gestational age. Results from the population PK model indicated lower serum concentrations of palivizumab during the fourth and fifth months, after an abbreviated 3-monthly–dose regimen when compared with the mean trough concentrations seen with the 5-monthly–dose regimen studied in the pivotal clinical trials in premature infants. Specifically, during the fourth and fifth months, 52% and 85%, respectively, would have levels below the lowest concentration (fifth percentile) in those receiving the 5-monthly-dose regimen. Simulations using this model did not support a 3-monthly–dose regimen to protect against severe RSV disease during the typical 5-month season.     

Blood groups,hemoglobin phenotypes and clinical disorders of consanguineous Yansi population

AIM: To study frequency of blood groups, prevalence of sickle-cell anemia trait and glucose-6-phosphate dehydrogenase deficiency (G6PD), among consanguineous Yansi tribe. METHODS: A total of 525 blood samples were collected, of which 256 among the Yansi population, and 269 for the unrelated control group in the Bandundu province of Democratic Republic of Congo. Blood group antigens were determined in the following systems: ABO, Rh, Kell, Duffy, Kidd and MNS. Blood grouping and extended phenotype tests were performed according to standard immunohematological procedures. Spot tests and tandem mass spectrometry were used respectively for the assessment of G6PD and sickle-cell anemia trait. RESULTS: The frequency of ABO phenotypes conformed to the following order O>A>B>AB with notably 62.5%, 23.8%, 12.1% and 1.6% for the Yansi, and 54.6%, 27.5%, 14.1% and 3.7% for the unrelated control group, respectively (P = 0.19). As for the Rh phenotypes, the most frequent were ccD.ee, ccD.Ee, CcD.ee, corresponding to 71.5%, 12.1% and 12.1% for the Yansi, and 70.6%, 15.6% and 8.2%, for the unrelated control group (P = 0.27). The frequency of MN and Ss phenotypes were statistically different between groups (P = 0.0021 and P = 0.0006). G6PD was observed in 11.3% of subjects in the Yansi group, and in 12.4% of controls (P = 0.74). The sickle-cell anemia trait was present in 22.4% of Yansi subjects and 17.8% in the control group (P = 0.24). Miscarriages and deaths in young age were more common among Yansi people. CONCLUSION: This study shows a significant difference in MNS blood group distribution between the Yansi tribe and a control population. The distribution of other blood groups and the prevalence of hemoglobinopathies did not differ in the Yansi tribe.     

Prone position as prevention of lung injury in comatose patients: a prospective,randomized, controlled study

OBJECTIVE: Comatose patients frequently exhibit pulmonary function worsening, especially in cases of pulmonary infection. It appears to have a deleterious effect on neurologic outcome. We therefore conducted a randomized trial to determine whether daily prone positioning would prevent lung worsening in these patients. DESIGN: Prospective, randomized, controlled study. SETTING: Sixteen-bed intensive care unit. PATIENTS: Fifty-one patients who required invasive mechanical ventilation because of coma with Glascow coma scores of 9 or less. INTERVENTIONS: In the prone position (PP) group: prone positioning for 4 h once daily until the patients could get up to sit in an armchair; in the supine position (SP) group: supine positioning. MEASUREMENTS AND RESULTS: The primary end point was the incidence of lung worsening defined by an increase in the Lung Injury Score of at least 1 point since the time of randomization. The secondary end point was the incidence of ventilator-associated pneumonia (VAP). A total of 25 patients were randomly assigned to the PP group and 26 patients to the SP group. The characteristics of the patients from the two groups were similar at randomization. The incidence of lung worsening was lower in the PP group (12%) than in the SP group (50%) ( p=0.003). The incidence of VAP was 20% in the PP group and 38.4% in the SP group ( p=0.14). There was no serious complication attributable to prone positioning, however, there was a significant increase of intracranial pressure in the PP. CONCLUSION: In a selected population of comatose ventilated patients, daily prone positioning reduced the incidence of lung worsening.     

Polyethylene glycol reduces early and long-term cold ischemia-reperfusion and renal medulla injury

Ischemia-reperfusion injury (IRI) after transplantation is a major cause of delayed graft function, which has a negative impact on early and late graft function and improve acute rejection. We have previously shown that polyethylene glycol (PEG) and particularly PEG 20M has a protective effect against cold ischemia and reperfusion injury in an isolated perfused pig and rat kidney model. We extended those observations to investigate the role of PEG using different doses (30g or 50g/l) added (ICPEG30 or ICPEG50) or not (IC) to a simplified preservation solution to reduce IRI after prolonged cold storage (48-h) of pig kidneys when compared with Euro-Collins and University of Wisconsin solutions. The study of renal function and medulla injury was performed with biochemical methods and proton NMR spectroscopy. Histological and inflammatory cell studies were performed after reperfusion (30-40 min) and on days 7 and 14 and weeks 4, 8, and 12. Peripheral-type benzodiazepine receptor (PBR), a mitochondrial protein involved in cholesterol homeostasis, was also studied. The results demonstrated that ICPEG30 improved renal function and reduced medulla injury. ICPEG30 also improved tubular function and strongly protect mitochondrial integrity. Post-IRI inflammation was strongly reduced in this group, particularly lymphocytes TCD4(+), PBR expression was influenced by IRI in the early period and during the development of chronic dysfunction. This study clearly shows that PEG has a beneficial effect in renal preservation and suggests a role of PBR as a marker IRI and repair processes.     

Age‐Varying Association Between Statin Use and Incident Alzheimer's Disease

OBJECTIVES: To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) ?4 allele. DESIGN: A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD. SETTING: Community based. PARTICIPANTS: Three thousand three hundred ninety‐two members of a health maintenance organization (HMO) aged 65 and older and without dementia. MEASUREMENTS: Statin use was identified from the HMO pharmacy database, and proportional hazards models were applied with statin use as a time‐dependent covariate to assess the association between statins and AD and the modifying effects of age and the APOE ?4 allele. RESULTS: Over an average of 6.1 years of follow‐up of 3,099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval (CI)=0.40–0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the association between statins and AD diminished with age (statin‐by–age at entry interaction P=.04); the aHR in those younger than 80 was 0.44 (95% CI=0.25–0.78), versus 1.22 (95% CI=0.61–2.42) for aged 80 and older. The interaction term for statin use–by–APOE ?4 was not significant (P=.65). CONCLUSION: This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with a lower risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.     

Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus.

Recent studies have demonstrated that reduced insulin-stimulated muscle glycogen synthesis is the major cause of insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM). This reduced rate has been assigned to a defect in either glucose transport or hexokinase activity. However it is unknown whether this is a primary or acquired defect in the pathogenesis of NIDDM. To examine this question, we measured the rate of muscle glycogen synthesis and the muscle glucose 6-phosphate (G6P) concentration using 13C and 31P NMR spectroscopy as well as oxidative and nonoxidative glucose metabolism in six lean, normoglycemic offspring of parents with NIDDM and seven age/weight-matched control subjects under hyperglycemic (approximately 11 mM)-hyperinsulinemic (approximately 480 pM) clamp conditions. The offspring of parents with NIDDM had a 50% reduction in total glucose metabolism, primarily due to a decrease in the nonoxidative component. The rate of muscle glycogen synthesis was reduced by 70% (P < 0.005) and muscle G6P concentration was reduced by 40% (P < 0.003), which suggests impaired muscle glucose transport/hexokinase activity. These changes were similar to those previously observed in subjects with fully developed NIDDM. When the control subjects were studied at similar insulin levels (approximately 440 pM) but euglycemic plasma glucose concentration (approximately 5 mM), both the rate of glycogen synthesis and the G6P concentration were reduced to values similar to the offspring of parents with NIDDM. We conclude that insulin-resistant offspring of parents with NIDDM have reduced nonoxidative glucose metabolism and muscle glycogen synthesis secondary to a defect in muscle glucose transport/hexokinase activity prior to the onset of overt hyperglycemia. The presence of this defect in these subjects suggests that it may be the primary factor in the pathogenesis of NIDDM.