In vivo mapping of temporospatial changes in manganese enhancement in rat brain during epileptogenesis

Mesial temporal lobe epilepsy is associated with structural and functional abnormalities, such as hippocampal sclerosis and axonal reorganization. The temporal evolution of these changes remains to be determined, and there is a need for in vivo imaging techniques that can uncover the epileptogenic processes at an early stage. Manganese-enhanced magnetic resonance imaging may be useful in this regard. The aim of this study was to analyze the temporospatial changes in manganese enhancement in rat brain during the development of epilepsy subsequent to systemic kainate application (10 mg/kg i.p.). MnCl(2) was given systemically on day 2 (early), day 15 (latent), and 11 weeks (chronic phase) after the initial status epilepticus. Twenty-four hours after MnCl(2) injection T1-weighted 3D MRI was performed followed by analysis of manganese enhancement. In the medial temporal lobes, there was a pronounced decrease in manganese enhancement in CA1, CA3, dentate gyrus, entorhinal cortex and lateral amygdala in the early phase. In the latent and chronic phases, recovery of the manganese enhancement was observed in all these structures except CA1. A significant increase in manganese enhancement was detected in the entorhinal cortex and the amygdala in the chronic phase. In the latter phase, the structurally intact cerebellum showed significantly decreased manganese enhancement. The highly differentiated changes in manganese enhancement are likely to represent the net outcome of a number of pathological and pathophysiological events, including cell loss and changes in neuronal activity. Our findings are not consistent with the idea that manganese enhancement primarily reflects changes in glial cells.     

Studies on the nature of the cell surface antigen reacting with cytolytic T lymphocytes in murine oncornavirus-induced tumors.

The nature of the target antigen, expressed on murine sarcoma virus (MSV) and related murine tumors which reacts with T killer lymphocytes, remains ill-defined. The experiments reported here show that: (a) the previously described H-2 restriction phenomenon is found under all experimental conditions including 3–4 and 16–20-h chromium release tests. With 16–20 h tests and highly efficient T lymphocytes however, quantitative methods are necessary to demonstrate the H-2 restriction. These results support the hypothesis that H-2 molecules may be determinant in the structure and/or in the function of the cytolytic T lymphocyte (CTL) reactive antigen. (b) Under syngeneic conditions (i.e. using H-2-identical immune lymphocytes, stimulators and target cells), the pattern of specificities recognized by anti-MSV or anti-Friend T killer cells on 20 different lymphomas suggests that the main reactive antigen is an “FMR-like” substance. Identical conclusions were drawn from competition experiments. (c) Blockings were obtained by pre-incubation of the target cells with a goat anti-gp70, suggesting a possible role of the viral gp70 in the antigen recognized. However, this could be due to nonspecific reactions as two other anti-gp70 sera as well as with antisera directed against the viral components gp45, pr60, p30, p15, p12 and p10 did not block. The CTL/tumor cell interaction was not inhibited by virion-associated antigens added to the medium. Lysostrip and co-capping experiments have failed to reveal an association between H-2 and gp70. The nature of the viral protein bearing the “FMR-like” substance therefore remains to be established.     

Effects of disopyramide on repolarisation and intraventricular conduction in man

Summary Right ventricular repolarisation and refractoriness after therapeutic doses of disopyramide have been studied in 10 patients with coronary artery disease by recording monophasic action potentials (MAP) during programmed stimulation. Using 2 catheters, with the tip of one in the apex and the other in the outflow tract of right ventricle, conduction intervals for propagation of stimuli in the ventricle were also measured. Disopyramide increased the duration of MAP signals at 90% repolarisation (MAP₉₀), the QT-interval and the right ventricular effective refractory period (V-ERP). The ratio refractoriness/action potential duration was slightly increased. Early premature action potentials were more markedly prolonged in relation to steady-state action potentials. The differences between the shortest and longest premature action potentials, however, were not changed significantly. The conduction intervals of the normal and premature paced beats were significantly prolonged.The observed effects of disopyramide on conduction and action potential duration may be of major importance for its effect on termination and slowing ventricular tachycardias. Its influence on the duration of premature action potentials in man is consistent with the results of in vitro studies.     

Drug metabolism and clearance system in tumor cells of patients with multiple myeloma

Resistance to chemotherapy is a major limitation of cancer treatments with several molecular mechanisms involved, in particular altered local drug metabolism and detoxification process. The role of drug metabolism and clearance system has not been satisfactorily investigated in Multiple Myeloma (MM), a malignant plasma cell cancer for which a majority of patients escapes treatment. The expression of 350 genes encoding for uptake carriers, xenobiotic receptors, phase I and II Drug Metabolizing Enzymes (DMEs) and efflux transporters was interrogated in MM cells (MMCs) of newly-diagnosed patients in relation to their event free survival. MMCs of patients with a favourable outcome have an increased expression of genes coding for xenobiotic receptors (RXRα, LXR, CAR and FXR) and accordingly of their gene targets, influx transporters and phase I/II DMEs. On the contrary, MMCs of patients with unfavourable outcome displayed a global down regulation of genes coding for xenobiotic receptors and the downstream detoxification genes but had a high expression of genes coding for ARNT and Nrf2 pathways and ABC transporters. Altogether, these data suggests ARNT and Nrf2 pathways could be involved in MM primary resistance and that targeting RXRα, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance.     

Lack of effect of the calcium antagonist isradipine on cyclosporine pharmacokinetics in renal transplant patients.

Hypertension has emerged as a frequent side effect in transplant recipients on effective doses of cyclosporine (CsA). To control hypertension in renal transplant patients, calcium channel blockers have been used; some of these, however, have been shown to cause significant increases in CsA levels. These findings point out that possible interactions of each calcium antagonist with CsA deserve investigation. We performed an open, placebo-controlled study in 12 stable renal transplant recipients to determine whether short-term isradipine influences CsA pharmacokinetics. All patients had mild to moderate hypertension and received triple immunosuppressive therapy with CsA, azathioprine, and prednisolone. Throughout a 4-week period of isradipine treatment, blood CsA levels (specific and nonspecific monoclonal antibodies) remained stable. The mean trough specific level was 121 +/- 14 micrograms/L following placebo, compared to 120 +/- 14 micrograms/L during isradipine. Corresponding non-specific values were 465 +/- 68 and 474 +/- 63 micrograms/L. Also, values for Cmax, AUC, and t1/2 were not significantly changed following 4 weeks of isradipine. Mean arterial pressure was significantly reduced at the end of the study. This study implies that isradipine does not influence CsA metabolism. Further studies should be carried out to determine its long-term effects on CsA pharmacokinetics and renal function in transplanted patients.     

Effects of propranolol on ventricular repolarization in man

Summary The acute effects on monophasic action potentials (MAP), QT interval, and right ventricle effective refractory period (V-ERP) of propranolol 0.2 mg · kg^–1 body weight have been studied in 10 patients with coronary artery disease.The median duration of MAP at 90% repolarization (MAP₉₀) was shortened from 238 to 228 ms at a constant paced heart rate of 100 beats · min^–1, while V-ERP remained unchanged.The median ratio V-ERP/MAP₉₀ increased from 1.00 to 1.03.The electrical restitution curves of the duration of premature action potentials, normalized to those paced at constant heart rate, were more horizontal after propranolol.Isometric handgrip shortened MAP₉₀ from 217 to 211 ms and after propranolol similar shortening was found (215 to 209 ms), although both values were slightly lower than before beta-blockade.     

Subjective health complaints in individuals with Ehlers-Danlos syndrome: a questionnaire study

Background

Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder where symptoms such as hyper mobile joints, fragile tissues, a bleeding tendency and chronic pain are frequent. Consequently, functional disability is common.

Objective

In the present study we investigated the prevalence of subjective health complaints in a Swedish EDS group.

Design, participants and method

Members of the Swedish EDS Association were invited to respond to the questionnaire Subjective Health Complaints Inventory (SHCI). Of the 365 individuals receiving questionnaires, 250 diagnosed individuals >18 years (mean age 46.15; SD 12) responded. The overall response rate was 68% (females 89.2%; n = 223).

Results

The total number of persons reporting any health complaint was 247 (99%). The mean number of complaints was 16.1 (SD 5.7) in the whole group. The complaints reported were musculoskeletal by 246 (98%), pseudoneurological by 241 (96%), gastrointestinal by 236 (94%), allergic by 182 (73%) and influenza-like by 144 (58%) persons. Substantial complaints were reported by 240 (96%) persons. Women reported a significantly higher number of complaints, mean total SHC, and severity per complaint compared to men and the reference group; the Norwegian general population.

Conclusion

Swedish females with EDS have higher number of and more substantial health complaints like tiredness and different localisations of pain than the compared Norwegian general population. Musculoskeletal, pseudoneurological and gastrointestinal complaints are most frequent in individuals with the hyper mobile EDS type.