Effect of atorvastatin on adhesive phenotype of human endothelial cells activated by tumor necrosis factor alpha

We studied the effect of atorvastatin on the adhesive phenotype of human endothelial cells (HUVEC) stimulated by tumor necrosis factor (TNF)-alpha. Surface expression of adhesion molecules on HUVEC was examined by flow cytometry and confocal microscopy, and adhesion of monocytes (human THP-1 cell line) was measured in vitro under flow conditions. In TNF-alpha-activated HUVEC, atorvastatin significantly enhanced surface expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, E-selectin, and fractalkine, when compared with TNF-alpha stimulation alone. This enhancement was reversed by mevalonate or geranylgeranyl pyrophosphate (GGPP) and was mimicked by an inhibitor of geranylgeranylation. The enhancing effect of atorvastatin was restricted to TNF-alpha-inducible adhesion molecule and was the reflect of an increased protein synthesis (mRNA and protein) and not of a reduced shedding. Confocal microscopy examination showed that atorvastatin also altered the surface distribution of adhesion molecules. Adhesion of human THP-1 cells on TNF-alpha-activated HUVEC was significantly reduced by atorvastatin (-42% at 1 microM). Mevalonate or GGPP restored the TNF-alpha-induced adhesive potential. These results show that atorvastatin, by inhibiting prenylation of G proteins, enhances the TNF-alpha-induced expression of adhesion molecules at the endothelial cell surface and also alters their surface distribution which may account for the reduced binding of monocytes.     

Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine

Most antidepressants are metabolized by cytochrome P450 (CYP) 2D6, and it is well known that there may be significant interindividual variation in the capacity to metabolize xenobiotics. About 7 to 10% of whites are poor metabolisers (PM), and, on the contrary, about 5% are ultrarapid metabolizers (UM), inducing very different rates in the transformation of antidepressants extensively metabolized by CYP 2D6. CYP 2D6 polymorphism can be a potential risk factor for the development of side effects or a reason for the poor efficacy of the treatment. Various probe drugs may be used for phenotyping CYP 2D6, but genotyping is now available using leukocyte DNA and is independent of concomitant drug use. In this study, we used PCR-based methods for the identification of CYP 2D6 genotypes in 49 patients receiving standard doses of fluoxetine or paroxetine and found that plasma concentration of the antidepressant drugs was significantly correlated with genetic status. In one patient who displayed CYP 2D6 gene duplication (UM), paroxetine plasma concentration was extremely low. In PM fluoxetine-treated patients, drug plasma concentration was significantly higher than that seen in extensive metabolizers.     

Which medico-economic approaches must be taken to evaluate the impact of costly molecules in oncology? The model of Herceptin in the breast metastatic cancer

In an era where health care expenditure control is a necessity, weighing a new treatment's cost against its added benefits is of crucial importance. These medico-economic analyses may be planned for the evaluation of new molecules in their daily use. Different methods may be used. The medico-economic evaluation of a drug can be performed with the use of clinical studies or modelization techniques. "Clinical studies" include the following methods: randomized trials, so-called "experimental", non-randomized studies, and observational studies. This classification follows a downward evolution of both the investigator's intervention power and the level of proof. Finally, modelization is becoming a commonly used tool. Randomized trials are the "gold standard" but the other, more pragmatic study types, providing a lesser degree of proof can complete the evaluation of a new molecule. One must find the best compromise between the study's objectives and the study type.     

Evaluation of a dedicated dual phased-array surface coil using a black-blood FSE sequence for high resolution MRI of the carotid vessel wall

PURPOSE: To investigate the ability of magnetic resonance imaging (MRI) to visualize the carotid vessel wall using a phased-array coil and a black-blood (BB) fast spin-echo (FSE) sequence. MATERIALS AND METHODS: The phased-array coil was compared with a three-inch coil. Images from volunteers were evaluated for artifacts, wall layers, and wall signal intensity. Signal intensity and homogeneity of atherosclerosis were assessed. Lumen diameter and vessel area were measured. RESULTS: Comparison between the phased-array coil and the three-inch coil showed a 100% increase in signal-to-noise ratio. BB-FSE imaging resulted in good delineation between blood and vessel wall. Most volunteers had a two-layered vessel wall with a hyperintense inner layer. MRI showed both homogeneous hyperintense and heterogeneous plaques, which consisted of a main hyperintense part with hypointense spots and/or intermediate regions. MRI lumen and area measurements were performed easily. CONCLUSION: High resolution MRI of carotid atherosclerosis is feasible with a phased-array coil and a BB-FSE sequence.     

Perforations of cortical bone allografts improve their incorporation

The incorporation of perforated cortical bone allografts was compared with non-perforated allografts. A 5-cm circumferential defect in the middiaphysis at the tibia was created in adult sheep. A frozen tibial allograft was implanted and fixed with a locked nail for 6 months. There was no postoperative immobilization. Group I consisted of eight sheep with non-perforated allografts, whereas Group II was comprised of 10 sheep with perforated allografts. Union was evaluated radiographically, whereas the central part of the allograft had a densitometric evaluation. Creeping substitution was assessed on microradiographs from cross-sections of the central 3 cm of graft by measurement of porosity and percentage of new and old bone area within the confines of the graft. The width of periosteal and endosteal callus also was determined. There was no statistical difference between both groups for the union score and bone density. However, the cortical bone graft porosity and the amount of new bone within the cortical bone differed significantly between the perforated allografts and the non-perforated ones. Periosteal callus was similar in both groups, whereas endosteal callus was significantly more wide and extended in the perforated allografts. Perforation of a cortical bone substantially improved the amount of newly formed bone by the host when compared with a non-perforated bone. The creation of channels seemed to increase the interface between living soft tissues of the host and the allografted bone with a resulting enhanced incorporation.     

The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the progressive enlargement of cysts derived from tubules. Tubule cell proliferation and chloride-dependent fluid accumulation, mechanisms underlying cyst expansion, are accelerated by adenosine 3':5'-cyclic monophosphate (cAMP). This study examined the extent to which caffeine may stimulate the production of cAMP by cyst epithelial cells, thereby adversely increasing proliferation and fluid secretion. Mural epithelial cells from ADPKD cysts and normal human kidney cortex cells (HKC) were cultured, and cAMP levels were determined in response to caffeine and receptor-mediated agonists linked to adenylyl cyclase. Caffeine, a methylxanthine, slightly increased basal levels of cAMP, as did other nonselective phosphodiesterase (PDE) inhibitors, 1-methyl-3- isobutyl xanthine and theophylline and rolipram, a specific PDE IV inhibitor. More importantly, clinically relevant concentrations of caffeine (10 to 50 micro M) potentiated the effects of desmopressin (DDAVP), prostaglandin E(2) (PGE(2)), and isoproterenol to increase cAMP levels in both ADPKD and HKC cells. By contrast, at concentrations that augmented the DDAVP response, caffeine attenuated cAMP accumulation by adenosine, implicating an action apart from the inhibition of PDE. Caffeine enhanced the effect of DDAVP to stimulate transepithelial short-circuit current of polarized ADPKD monolayers, reflecting an increase in chloride secretion. Caffeine potentiated the effect of DDAVP and PGE(2) to increase the levels of phosphorylated extracellular signal-regulated kinase (P-ERK). By contrast, P-ERK levels in HKC cells were not raised by increased intracellular concentrations of cAMP. It is concluded that PDE inhibition by caffeine increases the accumulation of cAMP, and through this mechanism activates the ERK pathway to cellular proliferation and increases transepithelial fluid secretion in ADPKD cystic epithelium. Caffeine is, therefore, a risk factor for the promotion of cyst enlargement in patients with ADPKD.     

Interventional MR imaging at 1.5 T: quantification of sound exposure

Sound pressure levels (SPLs) during interventional magnetic resonance (MR) imaging may create an occupational hazard for the interventional radiologist (ie, the potential risk of hearing impairment). Therefore, A-weighted and linear continuous-equivalent SPLs were measured at the entrance of a 1.5-T MR imager during cardiovascular and real-time pulse sequences. The SPLs ranged from 81.5 to 99.3 dB (A-weighted scale), and frequencies were from 1 to 3 kHz. SPLs for the interventional radiologist exceeded a safe SPL of 80 dB (A-weighted scale) for all sequences; therefore, hearing protection is recommended.     

Experimental study of the sacroiliac joint micromotion in pelvic disruption

OBJECTIVE: To measure the sacroiliac (SI) joint micromotion when different ligamentous lesions are created to simulate various degrees of pelvic anteroposterior compression injury. DESIGN: Cadaveric study. MATERIALS AND METHOD: Six SI joints were studied using a special device that made it possible to vary up to 310 N the loads applied on the ischial tuberosity and to measure simultaneously the SI micromotion. RESULTS: SI micromotion increases when the sacrospinous and sacrotuberous ligaments, and even more when the interosseous ligaments, have been sectioned off. In these cases, the stability of the SI joint is not restored by an isolated pubic fixation. CONCLUSION: This microinstability of the SI joint could contribute to the pain and arthritic changes sometimes observed in patients after anteroposterior compression injury. These experimental results could justify a larger spectrum of indications of SI joint fixation, but this should be confirmed by clinical study.     

Tragic case of a dog bite in a young child: the dog stands trial

The authors present the tragic case of an 18-month-old child who was bitten by a dog, causing amputation of the forearm and substantial damage to the cutaneous muscle on his back, shoulder, thorax, and neck. A free latissimus dorsi flap was performed to preserve the humerus from which the periosteum had been torn away. A series of cutaneous expansions were then undertaken to graft skin back onto the back, the armpit, and the shoulder stump, to allow for a mechanical prosthesis. A study of the literature on this subject proves that dog bites are more frequent and serious (sometimes even fatal) in young children than in adults. In view of the current legislation, it would seem that the public health authorities are doing little to resolve this distressing problem.