Echigo-1: a panencephalopathic strain of Creutzfeldt-Jakob disease: ultrastructural studies of the optic nerve

The Echigo-1 strain of CJD was isolated by Mori and colleagues (1989) from a case of 33-year-old female with a panencephalopathic type of CJD. An incubation period following intracerebral inoculation of hamsters with 10% cleared suspension of the Echigo-1-affected brain was approximately six months. We report here ultrastructural changes which are comparable with those in the white matter of another panencephalopathic type of CJD, the Fujisaki strain of CJD (GSS) passaged in mice. Vacuoles developed within myelinated axons: within axoplasm or within the myelin sheath and these were accompanied by exuberant reaction of macrophages and hypertrophic astrocytes. Axons underwent Wallerian degeneration and dystrophic neurites were also seen. Most important, we observed proliferation of inner mesaxons. Cross-sectional profiles of innumerable myelinated fibers contained membranous organelles which were continuous with the inner lamellae of the oligodendroglial cells. These unusual proliferations of inner mesaxon formed whorls and elaborated loops. In some axons, proliferation was so severe that loops of mesaxon filled the whole cross-section of the axon. Occasionally, we observed intrusion of the membranous tongue of the inner mesaxon into axoplasm. This study presents a second panencephalopathic model of CJD available in small laboratory rodents. It is important because this is the only such model in hamsters and it may be used for comparative studies of different strains of agent in the same host; thus far only mouse and hamster model have been available for comparative studies.     

TNF-alpha binding ability as a sign of peripheral blood neutrophils preactivation in the course of multiple sclerosis

Usually neglected is the role of neutrophils in causing of immunological disturbances in patients with multiple sclerosis (MS). Nevertheless, it has been indicated over the recent years that these cells possess a sufficient potential to affect both immune response and inflammation. This potential may result in MS through the process of priming of these cells by proinflammatory cytokines like TNF. We studied TNF and its soluble receptors sp55 and sp75 serum levels and binding of fluorescein isothiocyanate (FITC)-stained TNF by neutrophils. We studied three different groups of MS patients: 10 patients in relapse of the disease, 13 in its remission, and 11 in its chronic progressive form (CP-MS). The control was provided by 14 neurological patients (OND) with non-inflammatory diseases. The performed studies showed higher TNF sp55 and sp75 soluble TNF receptors serum levels in the patients with relapse, comparing with other MS patients and OND. TNF binding by neutrophils of MS patients during relapse was also higher, than other MS patients and OND. These result suggest the preactivation of neutrophils in the relapse of MS.     

Deep sclerectomy ab externo with implant: description of surgery technique

The authors present the modified associated technique of deep sclerectomy ab externo with implant. The indications, advantages and disadvantages are presented.     

Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.     

Natural killer sensitivity of tumor cells isolated from primary and metastatic lesions of four Bomirski melanoma variants

Natural killer (NK) sensitivity of melanoma cells isolated from primary and metastatic lesions of four Bomirski melanoma variants was compared. The hamster melanomas differed in their growth rate and metastatic pattern. We found that during tumor growth of all the variants tested, NK sensitivity of melanoma cells at the metastasis formation stage was significantly lower in both primary and metastatic tumors than in cells isolated from primary tumors at transplantation. In the case of Ma, Ab and Ab-455, NK sensitivity of primary tumor cells was higher than that of the cells isolated from metastatic deposits. These data obtained from a spontaneous metastasis tumor model argue for the role of NK cells in preventing metastatic spread of Bormirski melanomas studied.     

Attempts at measuring low radioactivity using a Tristan-1024 spectrometer]

A method for measurement of cesium and potassium-40 in environmental samples with the use of a gamma Tristan-1024 spectrometer was presented. The method involves taking into account the influence of the Compton effect on the shape of the observed spectrum, and then counting of the impulses in appropriate energetic intervals. The results showed that it is possible to rapidly measure K-40 activities exceeding 30 Bq/kg as well as the activities of Cs-137 and Cs-134 isotopes of an order of several Bq/kg in so-called "fresh" sample, with no need for applying expensive preparative treatment. The low cost of measurements, as compared with radiochemical methods, is an advantage of the presented method.     

Adrenergic stimulation of isolated rat gastric mucosal cells

Summary Adrenergic stimulation of the adenylate cyclase (AC)-cAMP-system and ¹⁴C-aminopyrine accumulation, an indirect measure of parietal cell H⁺-production, was studied in different preparations of gastric mucosal cells.The ₂-adrenoceptor agonist hexoprenaline activated AC of crude homogenates from the gastric corpus of mouse, rat, guinea-pig, hog, dog and man. In isolated rat gastric cells (20% parietal cells), treated by low power sonication, 10^–8 to 10^–3 mol/l adrenaline and hexoprenaline activated AC equally potently and efficaciously by maximally 170%. Isoprenaline proved to be less effective activating up to 80%. 5·10^–5 mol/l GMP-PNP augmented basal activity 8.5 times and reduced the maximal efficacy. Adrenaline and hexoprenaline activated AC by maximally 120%, isoprenaline by 40%. The potency of adrenaline was 4 times lower, that of hexoprenaline 2 and that of isoprenaline 4 times higher in the presence of GMP-PNP. Adrenergic stimulation was inhibited by the -adrenoceptor antagonist propranolol, the effect of -adrenoceptor-blockade by phenoxybenzamine was less pronounced. In fractions with 7–80% of parietal cells, prepared by isopycnic centrifugation with Percoll, adrenaline and hexoprenaline activated AC or hexoprenaline enhanced the cellular level of cAMP in parietal cell poor and rich fractions. The degree of activation in response to histamine correlated with the number of parietal cells. ¹⁴C-Aminopyrine uptake was increasingly stimulated through 10^–8 to 10^–5 mol/l hexoprenaline, maximally by doubling the basal accumulation. 10^–4 mol/l histamine was 8 times more effective. 3·10^–7 mol/l propranolol inhibited the effect of 10^–5 mol/l hexoprenaline by 80%.The data suggest the localization of -adrenoceptors (likely -adrenoceptor) on parietal and other nonidentified gastric cells. At the parietal cell, adrenaline and hexoprenaline initiate activation of AC and hexoprenaline leads to H⁺-production. The responses are small compared to the effect of histamine. Thus, -adrenoceptor agonists exert intrinsic activity in relation to H⁺-production. Their influence on stimulated secretion of isolated cells remains to be elucidated.     

Effect of therapeutic drug monitoring of amitriptyline and genotyping on efficacy and safety of depression therapy

Modern pharmacotherapy is based on precise adjustment of a dosage schedule to individual requirements of patient. Therapeutic drug monitoring is a method that allows for a more effective treatment approach, especially in the case of a narrow therapeutic index of a drug. Tricyclic antidepressant drugs are characterised by narrow therapeutic index as well as relationship between serum drug concentration and side effects. It was demonstrated that interindividual variability of blood concentrations of tricyclic antidepressant drugs is related to genetic polymorphism of oxidating enzymes participating in metabolism of these drugs. The aim of the study was to estimate the impact of therapeutic drug monitoring of tricyclic antidepressant drugs as well as genotyping on efficacy and safety of endogenous depression therapy. The study included 9 patients with established diagnosis of endogenous depression. Blood serum concentrations of amitryptyline was measured by fluorescence polarisation immune assay (FPIA, Abbott system). Genotype of cytochrome P450 isoenzyme CYP2D6 was determined using PCR-RFLP method. It was demonstrated that monitoring therapy of tricyclic antidepressant drugs in combination with determination of the genotype seems to be more safe and effective. Monitoring therapy and genotyping may be less expensive than the costs of prolonged hospitalisation and risk of side effects.