Pharmacokinetic and bioequivalence study of two gemfibrozil preparations

A comparative pharmacokinetic study has been performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over design with two preparations of gemfibrozil (CAS 25812-30-0) capsules each of them containing 300 mg active ingredient. The test preparation was Innogem 300 mg capsule. The plasma concentration of gemfibrozil was determined by a validated HPLC-UV analytical method. The statistical comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-oc Cmax, tmax) of the two capsule preparations was performed by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hanck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference. The relative bioavailability of the test preparation with respect to the reference preparation in terms of the AUC0-oc was 104.06 +/- 21.61%. No statistically significant difference was found between the pharmacokinetic parameters, calculated from plasma concentration-time curves, indicating that the two preparations were bioequivalent.     

Subcutaneous soft tissue tumours at the site of implanted microchips in mice

An experiment using 4279 CBA/J mice of two generations was carried out to investigate the influence of parental preconceptual exposure to X-ray radiation or to chemical carcinogens. Microchips were implanted subcutaneously in the dorsolateral back for unique identification of each animal. The animals were kept for lifespan under standard laboratory conditions. In 36 mice a circumscribed neoplasm occurred in the area of the implanted microchip. Females were significantly more frequently affected than male mice. An influence of age or different treatment on the s.c. tumour incidence in two mice generations could not be observed. Macroscopically, firm, pale white nodules up to 25 mm in diameter with the microchip in its center were found. Microscopically, soft tissue tumours such as fibrosarcoma and malignant fibrous histiocytoma were detected.     

Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis

OBJECTIVE: The structure of the collagen scar during healing of a myocardial infarction is a determinant of the function of the remodeled tissue. We hypothesize that the passive deformations of both scar and normal tissue are related to the underlying collagen uncoiling as the tissue stretches, and that the unloaded tortuosity of the collagen may be a determinant of tissue stiffness at low ventricular pressure. Hence collagen uncoiling and tissue strain were measured during passive loading in normal tissue, and in healing infarct tissue. METHODS: Left ventricles of rats were infarcted by ligation of the left anterior descending artery for 2 weeks. Surface strains were measured during passive inflation in the scar region in one set of excised hearts, and other arrested hearts were fixed at different ventricular pressures, after which collagen tortuosity was measured in the infarcted and normal tissue. RESULTS: Passive loading strains were smaller in the scar in both the fiber and cross-fiber directions. Tortuosity decreased with load in normal and infarcted tissue, with fibrils tending to straighten more in the scar tissue at higher pressures (1.056 +/- 0.009 vs. 1.024 +/- 0.009 at P = 20 mmHg) with similar tortuosities at zero pressure (1.110 +/- 0.012 vs. 1.098 +/- 0.019). The decrease in tortuosity with strain was greater for the infarcted tissue. CONCLUSIONS: The greater stiffness of infarcted tissue at low pressure is not due to 'straightened' collagen fibers, and there may be a different three-dimensional structure of infarct vs. normal coiled collagen fibers which can affect the material properties of these tissues.     

B7 blockade prevents activation-induced cell death of thymocytes

Although both B7 and its counter-receptor CD28 are expressed in the thymus, the role of B7 in thymic selection is not clear. We investigated the role of B7 in intrathymic deletion of antigen-specific T cells using a TCR transgenic model specific for antigen ovalbumin (OVA) and H-2Ad. Intraperitoneal injection of OVA induced apoptosis of thymocytes and drastic reduction of thymocyte numbers. This was significantly inhibited by co-injection of CTLA-4-Ig which blocks B7 co-stimulation. Deletion of T cells in the thymus following i.p. injection of OVA was associated with T cell pre-activation as demonstrated by T cell proliferation and cytokine production. Injection of CTLA-4-Ig blocked all these activation events and rescued thymocytes from activation-induced cell death. These results demonstrate that B7 is required for the activation-induced cell death of MHC class II-restricted thymocytes in vivo.     

Auswirkungen von Blitzschlägen auf 20-kV-Energiekabel

Recently appeared defects on high voltage cables have required an urgent evaluation of the impact of lightning strikes necessary. In some cases overvoltages between the copper wire screen of the cable and earth may appear which cause damages of the cablesheath. Field measurements with a classification of the voltage impulses at the copper wire screen have been made to evaluate the number of events. Additionally a numerical model was developed to study the effects of atmospheric discharges on underground cables with emphasis to the influence on the cablesheath. This numeric method was also applied to estimate the effectiveness of different protection arrangements. This contribution presents evaluation methods for overvoltages of cables and a model used firstly for calculating the stress caused by differential voltages and secondly to determinate the influence of protection measures.     

Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines

Certain bacterial immunostimulatory (i.s.) DNA sequences containing unmethylated CpG motifs stimulate antigen-presenting cells (APC) to express a full complement of costimulatory molecules and to produce cytokines including interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. While IL-12 is key to their T helper cell (Th)1-promoting adjuvant activity, secretion of toxic levels of TNF-alpha is harmful in that it promotes toxic shock. Given the beneficial as well as harmful consequences of i.s. DNA, we investigated the possibility of identifying DNA sequences, i.e. CpG oligodeoxynucleotides (ODN) which differentially activate IL-12 versus TNF-alpha cytokine production in APC. Here, we describe an i.s. DNA sequence with these characteristics. While its potential to induce IL-12 is preserved, its ability to trigger TNF-alpha release is strongly curtailed both in vitro and in vivo. I.s. DNA could be segregated into lethal and non-lethal in a mouse toxic shock model. The non-toxic i.s. DNA was useful as an adjuvant, thus allowing cytotoxic T cell responses to the soluble protein ovalbumin and conferring a resistant Th 1 phenotype to BALB/c mice lethally infected with Leishmania major. This i.s. CpG motif may thus be prototypic for a useful immunostimulating DNA sequence that lacks harmful side effects.     

Electrophysiological and Fos immunohistochemical evidence for the excitatory nature of the parafascicular projection to the globus pallidus

Extracellular recordings and immunohistological detection of c-Fos-like immunoreactive proteins were used to determine the synaptic effect of the parafascicular projection to the globus pallidus. Electrical stimulation of the parafascicular neurons induced a single-spike excitatory response with a stable latency of 2.3 ms, suggesting a monosynaptically driven effect. Pharmacological stimulation of the parafascicular nucleus with carbachol increased tonically the pallidal discharge rate by 142%. The discharge rate of the pallidal neurons was described by 37% in parafascicular-lesioned rats. These results demonstrate the excitatory nature and the tonic action of the parafasciculopallidal projection. Carbachol activation of parafascicular neurons also induced the synthesis of c-Fos-like immunoreactive proteins in the pallidal neurons. Control experiments in subthalamic-lesioned rats showed that the parafascicular excitation of the pallidal neurons remained, but both electrophysiological and expression of c-Fos-like immunoreactive proteins were attenuated. This suggests that the direct parafascicular excitation of the pallidal neurons is indirectly reinforced by the previously described parafascicular excitatory input to the subthalamic nucleus. Conversely, the effect of this last input to the subthalamic nucleus is dramatically enhanced in rats with pallidal lesion. Our results demonstrate the complex role of the parafascicular nucleus in activating both the globus pallidus and the subthalamic nucleus, two closely related structures. These results illustrate the integrative capacities of the globus pallidus, whose activity is modulated by multiple afferents.     

The in vivo metabolic pattern of low-grade brain gliomas: a positron emission tomographic study using 18F-fluorodeoxyglucose and 11C-L-methylmethionine

OBJECTIVE: The object of the present study was to identify metabolic differences between low-grade astrocytomas and oligodendrogliomas and to improve their diagnosis and noninvasive assessment, because both types of tumors look very similar from the point of view of clinical and radiological data (as assessed by computed tomography and magnetic resonance imaging). METHODS: Before any aggressive treatment, 22 patients with primary low-grade gliomas (astrocytomas in 12 patients and oligodendrogliomas in 10) were investigated with positron emission tomography for both glucose metabolism (18F-fluorodeoxyglucose) and amino acid uptake (11C-L-methylmethionine). An original software that allows a full metabolic analysis of the tumor region of interest (defined from the T1-weighted magnetic resonance image) and compares tumor tissue uptake tracer concentrations with average healthy tissue values has been implemented for data processing. Heterogeneity of each individual tumor has been taken into account and was expressed in histograms, which provided data about the mean and also extreme and intermediate values of tracer concentrations and the way these values are distributed among the full tumor mass. RESULTS: It has been shown that both tumor types exhibit a glucose hypometabolism (slightly more pronounced with astrocytomas), whereas they strongly differ in methionine uptake, which is high in all oligodendrogliomas and either decreased, normal, or moderately increased in astrocytomas. This latter metabolic difference between both tumor populations may be partially explained by their different cell densities. CONCLUSION: This study suggests that despite similar radiological and clinical presentations, these two kinds of low-grade gliomas are metabolically different and could therefore have specific responses to different therapies. Moreover, their in vivo metabolic follow-up with positron emission tomography should rely on different parameters, depending on their histological type; methionine uptake may be more relevant than glucose metabolism in the follow-up of oligodendrogliomas.     

Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.     

Compositional constraints in the extremely GC-poor genome of Plasmodium falciparum

We have analyzed the compositional properties of coding (protein encoding) and non-coding sequences of Plasmodium falciparum, a unicellular parasite characterized by an extremely AT-rich genome. GC% levels, base and dinucleotide frequencies were studied. We found that among the various factors that contribute to the properties of the sequences analyzed, the most relevant are the compositional constraints which operate on the whole genome.