The effects of paclitaxel on the three phases of restenosis: smooth muscle cell proliferation, migration, and matrix formation: an in vitro study

PURPOSE: We sought to evaluate the growth-modulating potential of paclitaxel on cultured human arterial smooth muscle cells depending on the administered dose. MATERIAL AND METHODS: For all experiments human arterial smooth muscle cells (SMCs) were used. SMCs were either cultured for 5 days or for 20 days with paclitaxel (doses: 10(-7) M, 10(-8) M, 10(-9) M). For a total period of 20 days, proliferation kinetics of the SMC were analyzed. To assess the clonogenic activity of the SMC colony-forming assays were performed. Drug- and dose-dependent cell cycle changes were analyzed by flow cytometry. The effect on cell migration was examined in a 2-chamber migration system. The effects of paclitaxel on the synthesis of tenascin were examined via immunofluorescence. RESULTS: Depending on the dose administered, paclitaxel proved to inhibit SMC proliferation effectively when administered during the total period of 20 days. When incubated for 5 days with doses of paclitaxel ranging between 10(-8) M and 10(-9) M, SMCs showed clear signs of regeneration. When being incubated with 10(-7) M of paclitaxel, however, SMCs reacted with a reduction in cell proliferation, a reduced clonogenic activity, and a drug-induced G2/M phase block. SMC migration was inhibited effectively as well as extracellular matrix formation. CONCLUSION: Paclitaxel is a potent inhibitor of SMC proliferation, SMC migration, and extracellular matrix formation in vitro, with all three phases of the restenosis process inhibited effectively.     

Quantification of aortic valve calcification with electron beam tomography: a histomorphometric validation study

RATIONALE AND OBJECTIVES: The exact quantification of the amount of calcification in aortic valves may be useful for the identification of risk factors for the progression of aortic valve calcification and to evaluate new therapeutic approaches for aortic valve disease. Electron beam tomography (EBT) allows the in vivo detection of calcifications in coronary vessels and in the aortic valve. The aim of this study was to validate the quantification of aortic valve calcification by EBT with in vivo and in vitro investigations. METHODS: In 15 patients (aortic stenosis in 13, aortic regurgitation in 2 cases), EBT was performed before aortic valve replacement (40 cross sections, 3-mm slice thickness, matrix 512 x 512, field of view 28 cm, ECG trigger at 40% of the cardiac cycle). EBT was repeated on the explanted aortic valve using the same protocol. In both data sets, the amount of aortic valve calcification was determined using a volumetric score. In serial cuts of the explanted valve (distance 1 mm), the calcified volume was determined by an independent investigator using histomorphometric analysis. RESULTS: The mean calcified volume of the aortic valves as quantified by EBT was 1650.0 +/- 1401.0 mm? in vivo (EBT1) and 1544.4 +/- 1266.5 mm? in vitro (EBT2). Histomorphometric analysis showed a mean calcified volume of 1555.7 +/- 1272.5 mm?. The mean difference between EBT1 and EBT2 was 4.2 +/- 14.7%, between EBT1 and histomorphometry 3.6 +/- 12.1%, and between EBT2 and histomorphometry -0.5 +/- 5.9%. CONCLUSION: EBT allows accurate in vivo quantification of aortic valve calcifications.     

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism

OBJECTIVE: The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. METHOD: The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. RESULTS: Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. CONCLUSIONS: These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.     

Molecular evidence for mitochondrial dysfunction in bipolar disorder

BACKGROUND: The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder. OBJECTIVE: To determine the expression of 12558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia. DESIGN: We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay. SUBJECTS: We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia. RESULTS: The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteasome degradation. CONCLUSIONS: These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate-dependent processes in bipolar disorder.     

A volumetric study of parietal lobe subregions in Turner syndrome

Turner syndrome, a genetic disorder that results from the complete or partial absence of an X chromosome in females, has been associated with specific impairment in visuospatial cognition. Previous studies have demonstrated a relationship between parietal lobe abnormalities and visuospatial deficits in Turner syndrome. We used high-resolution magnetic resonance imaging to measure parietal lobe subdivisions in 14 participants with Turner syndrome (mean age 13 years 5 months, SD 5 years) and 14 age-matched controls (mean age 13 years 5 months, SD 4 years 7 months) to localize neuroanatomical variations more closely. Scans were acquired and analyzed for 14 females with Turner syndrome. Analyses of variance were used to investigate differences in regional parietal lobes. Females with Turner syndrome showed a bilateral parietal lobe reduction, specifically in the superior parietal and postcentral gyri. Full-scale IQ scores were significantly positively correlated with postcentral tissue volume in the Turner syndrome group. Structural differences in the parietal lobe are localized specifically to the anterior and superior parietal lobe and might be related to the visuospatial and visuomotor deficits associated with Turner syndrome.     

Rituximab stabilizes multifocal motor neuropathy increasingly less responsive to IVIg

The authors report a patient with anti-GM(1) antibody-negative multifocal motor neuropathy (MMN) who was increasingly less responsive to IV immunoglobulins (IVIgs). Five yearly courses of the monoclonal anti-CD20 antibody rituximab were well tolerated and extended the interval of IVIg administration from 7 to 12 days (corresponding to 42% reduction of IVIg) during this period. Rituximab may be a benefit for patients with MMN.     

How does the blood leave the brain? A systematic ultrasound analysis of cerebral venous drainage patterns

The internal jugular veins are considered to be the main pathways of cerebral blood drainage. However, angiographic and anatomical studies show a wide anatomical variability and varying degrees of jugular and non-jugular venous drainage. The study systematically analyses the types and prevalence of human cerebral venous outflow patterns by ultrasound and MRI. Fifty healthy volunteers (21 females; 29 males; mean age 27±7 years) were studied by color-coded duplex sonography. Venous blood volume flow was measured in both internal jugular and vertebral veins in the supine position. Furthermore, the global arterial cerebral blood volume flow was calculated as the sum of volume flows in both internal carotid and vertebral arteries. Three types of venous drainage patterns were defined: a total jugular volume flow of more than 2/3 (type 1), between 1/3 and 2/3 (type 2) and less than 1/3 (type 3) of the global arterial blood flow. 2D TOF MR-venography was performed exemplarily in one subject with type-1 and in two subjects with type-3 drainage. Type-1 drainage was present in 36 subjects (72%), type 2 in 11 subjects (22%) and type 3 in 3 subjects (6%). In the majority of subjects in our study population, the internal jugular veins were indeed the main drainage vessels in the supine body position. However, a predominantly non-jugular drainage pattern was found in approximately 6% of subjects.This study was presented in part as an oral presentation at the 8th Meeting of Neurosonology and Hemodynamics, Alicante, Spain, 18–21 May 2003.     

Promotion of oxidative stress in the aquatic macrophyte Ceratophyllum demersum during biotransformation of the cyanobacterial toxin microcystin-LR

Cyanobacterial toxins have been shown to have adverse effects on mammals, birds and fish and are therefore being increasingly recognised as a potent stress and health hazard factor in aquatic ecosystems. Microcystins, which are cyclic heptapeptides and a main group of the cyanotoxins, are mainly retained within the producer-cells during cyanobacterial bloom development. However, these toxins are released into the surrounding medium by senescence and lysis of the blooms. The released toxins could then come into contact with a wide range of aquatic organisms including invertebrates, fish and aquatic plants. In many organisms, biotransformation of the toxins will take place via several glutathione-related conjugate. During the biotransformation process in which the toxin and the toxin conjugate are broken down, the formation of reactive oxygen species might occur. These reactive oxygen species activate several antioxidant enzymes such as superoxide dismutase, catalase, ascorbate peroxidase and also influence the glutathione-ascorbate cycle. Aim of this study was to investigate formation of the glutathione-conjugate, activation of glutathione S-transferases and the elevation of several antioxidant enzymes giving evidence for the promotion of oxidative stress by microcystins. During exposure of Ceratophyllum demersum to the cyanobacterial toxin microcystin-LR in an concentration of 5.0 microg/L, an elevation of microsomal and cytosolic glutathione S-transferase was measured, showing the beginning formation of the glutathione-toxin conjugate. The superoxide dismutase as well as in parallel the hydrogen peroxide level increased giving evidence for oxidative stress in the aquatic plant. Other reactive oxygen detoxifiying enzymes were also elevated and the glutathione pool, expressed in reduced glutathione and glutathione disulfide concentration was changed accordingly.