Focus on anti-atherosclerotic therapy

Calcium antagonists (CA) exert an anti-atherosclerotic effect in cholesterol-fed rabbits through reduction of cholesterol accumulation in the arterial wall. Further studies in our Institute indicate that verapamil-like compounds and diltiazem stimulate receptor-mediated LDL uptake by human fibroblasts in culture, while nifedipine-like compounds and flunarizine are inactive. Verapamil and diltiazem stimulated LDL-receptor activity also in cells from a heterozygous FH patient, while they were inactive in a receptor defective homozygous FH patient. A basic group needs to be present on the CA molecule to modulate the LDL receptor expression. Preliminary data in our laboratory suggest that some CA can achieve concentrations in the aortic wall likely to exert effects on LDL receptors. This stimulatory activity may improve lipid metabolism in the arterial wall.Corresponding author     

An analysis of invasive airway management in a suburban emergency medical services system

INTRODUCTION: Airway management is the most critical and potentially life-saving intervention performed by emergency medical service (EMS) providers. Invasive airway management often is required in non-cardiac-arrest patients who are combative or otherwise uncooperative. The success of prehospital invasive airway management in this patient population was evaluated. METHODS: A retrospective review was undertaken of the records of all such patients requiring endotracheal intubation over a three-year period (1987-1989). The study population included 278 patients enrolled by five advanced life support (ALS) units serving a suburban population of 425,000. Field trip sheets were reviewed for diagnosis, intubation method and success, number of intubation attempts, provider experience, reasons for unsuccessful intubations, and complications. RESULTS: A total of 394 invasive airway management attempts were performed on 278 patients. The overall successful intubation rate was 75% (41% orotracheal, 52% nasotracheal, 7% other or unknown). The most common diagnoses were COPD and pulmonary edema (30%) and trauma (24%). Experienced providers were successful on the first attempt in 57% of cases compared to 50% by inexperienced providers (p=.24). Multiple intubation attempts were required in 33% of the patients. There was no statistically significant difference in success rates between the orotracheal and nasotracheal methods (p=.51). The most common reason for unsuccessful intubation was altered level of consciousness. Complications occurred with 7% of successful attempts and in 18% of unsuccessful attempts (p less than .001). Forty-six percent of the patients who were not intubated successfully in the field and required intubation in the emergency department (ED) received a neuromuscular blocking agent prior to successful intubation. CONCLUSION: Prehospital providers can intubate a high but improvable proportion of non-cardiac-arrested patients by both the orotracheal and nasotracheal routes. The use of pharmacologic adjuncts to facilitate the prehospital intubation of selected, non-cardiac-arrested patients is a promising adjunct that needs further evaluation.     

Normal human IgG prevents endothelial cell activation induced by TNFalpha and oxidized low-density lipoprotein atherogenic stimuli

Normal human immunoglobulin G (IgG) has anti-inflammatory and immuno-regulatory properties, which are exploited in the therapy of selected diseases. A putative mechanisms of action is the direct regulation of endothelial cell function by natural antiendothelial cell antibodies. Endothelium activation is a critical event in atherosclerosis. We have verified the ability of normal human IgG to modulate endothelial responses to the atherogenic stimuli tumour necrosis factor-alpha (TNFalpha) and oxidized low-density lipoproteins (oxLDL) in vitro. Confocal microscopy was used to visualize vascular cell adhesion molecule-1 (CD106) expression on endothelial cells, cytoplasmic free calcium ([Ca++]i) modifications and fluorescein-coupled oxLDL internalization. Cytokine secretion was measured by ELISA on cell supernatants. IgG prevented TNFalpha induced CD106 membrane expression and an increase in [Ca++]i, and inhibited the secretion of interleukin-6 (IL-6) and macrophage-colony-stimulating factor (M-CSF). IgG also inhibited CD106 expression induced by oxLDL and one pathway of their internalization, but were ineffective on oxLDL induced [Ca++]i rise and apoptosis. F(ab)'2 fragments from IgG, but not monoclonal IgG, reproduce IgG effects. These findings point to a regulatory role for specific antibodies included in circulating normal IgG towards proinflammatory responses of endothelial cells in atherogenesis and suggest possible development of new therapeutic strategies.     

Dendritic cell number is related to IL-4 expression in the airways of atopic asthmatic subjects

BACKGROUND: Airway dendritic cells are essential for stimulating naive T cells in response to inhaled antigen and for the development of allergic sensitization. IL-4 in vitro can distinguish dendritic cell lines from peripheral blood mononuclear cells. Our study had the following aims: 1) to compare the distribution of CD1a+ dendritic cells and IL-4+ cells, in the bronchial mucosa of asthmatics and controls 2) to determine the relationship between the numbers of CD1a+ dendritic cells and IL-4+ cells in the bronchial mucosa of asthmatics 3) to determine whether CD1a+ cells express the IL-4 receptor. METHODS: Twenty atopic asthmatic and eight normal subjects were studied. In each subject, bronchoscopy with bronchial biopsies was performed. CD1a, IL-4, and IL-4 receptor expressions were evaluated by immunohistochemistry. RESULTS: The number of CD1a+ and IL-4+ cells was significantly higher in asthmatics than controls. The number of CD1a+ cells was positively correlated to the number of IL-4 + cells. Bronchial biopsy serial section studies showed that CD1a+ cells express the receptor for IL-4. CONCLUSIONS: These results suggest that an increased amount of IL-4 may play a physiopathologic role in maintaining the dendritic cell pool in vivo. Therefore, because of possible IL-4 activity on antigen-presenting cells in T-cell immune responses to allergens, an important new role of IL-4 in asthma inflammation can be envisaged.     

A complex haemoglobinopathy diagnosis in a family with both beta zero- and alpha (zero/+)-thalassaemia homozygosity

The occurrence of point mutation alpha-thalassaemia and of complex combinations of haemoglobin defects is underestimated. Haemoglobinopathies, the most frequent monogenic recessive autosomal disorder in man, occur predominantly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now confronted with a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near future because of the endogamous growth of the ethnical minorities and the lack of prevention. We describe an Afghan family in which both partners of a consanguineous relationship are carriers of a beta- as well as an alpha-thalassaemia determinant. The combination of defects was revealed by the in vitro measurement of the beta/alpha biosynthetic ratio and was characterised at the DNA level. The molecular defects involved are the Cd5(-CT), a Mediterranean beta zero-thalassaemia mutation, and the alpha 2(zero/+)-thalassaemia AATA(-AA) polyadenylation defect. The alpha-thalassemia defect is a rare RNA-processing mutant described only twice before in heterozygous form in Asian-Indian patients. The mutation suppresses the expression of a alpha 2 gene and reduces the expression of the less efficient, 3' located alpha 1 gene as well, inducing a near alpha zero-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the children who, in addition to being homozygous for the alpha-thalassaemia point mutation, is also a carrier of the beta zero-thalassaemia defect. A previously described homozygous case of the alpha (zero/+)-thalassaemia condition, caused by a similar polyadenylation defect, was characterised by a severe HbH disease. However, the patient described here present at 7 years of age with severe caries, like his beta-thalassaemia homozygous brother but without hepatosplenomegaly, haemolysis or severe anaemia. The haematological analysis revealed 9.5 g/dl Hb; 5.4 x 10(12)/I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 pg MCH and 6.2% of HbA2. The biosynthetic ratio beta:alpha was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodies. The parents reported no complications during pregnancy, at birth, or in the neonatal period in rural Afghanistan. We presume therefore that the counterbalancing effect induced by the co-existing beta-thalassaemia defect could have modified a potentially severe perinatal HbH disease into a strongly hypochromic but well compensated 'alpha zero-like heterozygous' thalassaemia phenotype. The risk of a severe HbH disease, could have been easily missed in this family which was referred because of a child affected with beta-thalassaemia major.     

NMR studies of the inclusion complex between β-cyclodextrin and paroxetine

A ¹H and ¹³C NMR study on the inclusion complex of paroxetine with β-cyclodextrin was carried out in order to define the stoichiometry of the association and its strength. Proton and carbon chemical shift measurements of paroxetine and β-cyclodextrin were performed at several molar ratios and temperatures, allowing the determination of a 1:1 stoichiometry and an association constant value of the order of 2 × 10³ for the paroxetine–β-cyclodextrin complex. Overhauser effects in the rotating frame were also measured, and the experimental interproton distance constraints have been used for molecular model building of the complex. The obtained model indicates that the benzodioxolyl moiety of paroxetine is deeply inserted in the cavity of the cylindrical structure of β-cyclodextrin, while the fluoro-phenyl ring lays above the wider rim.