Receptor fingerprinting the circling ci2 rat mutant: insights into brain asymmetry and motor control

Circling behaviour of the ci2 rat mutant, a model for hyperkinetic movement disorders, is associated with an abnormal asymmetry in striatal dopaminergic activity. Since it is more likely that imbalances in several neurotransmitter systems result in the cascade of neurochemical disturbances underlying disorders involving motor dysfunctions, we measured the densities of 12 neurotransmitter receptors in the basal ganglia and vestibular nuclei of adult circling mutants (ci2/ci2), non-circling littermates (ci2/+) and controls from the background strain (LEW/Ztm). In controls, the left caudate putamen (CPu) contains lower kainate and the left globus pallidus higher AMPA densities than their right counterparts. The medial vestibular nucleus of mutants ipsilateral to the preferred direction of rotation contained higher M₂ densities than the contralateral one. ci2/+ animals presented no interhemispheric differences, did not differ behaviourally from controls, but contained lower GABA_A densities in the CPu, nucleus accumbens (Acb) and reticular (Rt), ventromedial (VM) and ventral posterolateral (VPL) thalamic nuclei. Mutants contained lower GABA_A (CPu, Acb, Rt, VPL) but higher nicotinic (Rt, VM) densities than controls and higher GABA_A (CPu, VM) densities than ci2/+ rats. Hyperactivity level of mutants was positively correlated with the adenosine A_2A receptor densities in the ipsilateral Acb, but negatively correlated with those of the ipsilateral thalamus. Concluding, ci2/ci2 mutants show alterations in GABA_A, cholinergic and A_2A receptor densities. Our data add to the hypothesis that motor disorders such as hyperkinesias cannot be explained solely by absolute functional increases or decreases in the dopaminergic system, but are due to imbalances in several neurotransmitter systems.     

Septic arthritis due to Bacteroides fragilis in a patient with non-Hodgkin lymphoma and mixed connective tissue disease

We present a 53 year old woman with pre-existing mixed collagen tissue disease who developped highly-malignant non-Hodgkin lymphoma and 2 years later had left groin abscess, then septic tenosynovitis of the left ankle, septic artrhritis of the right shoulder and purulent tenosynovitis of the right hand. Bacteroides fragilis was identified in synovial fluid drawn from the right shoulder, in blood cultures and in culture of a central venous catheter tip. The primary infection site is presumed to have been the abdominal cavity, and the presence of an indwelling central venous catheter the reason for recurrence of infection. We treated her empyrically with intravenous ampicillin/sulbactam and clindamycine then oral metronidazol until definite resolution of the infection. Septic artrhritis due to Bacteroides fragilis is a rare entity mainly occurring in immunocompromised patients, as shown in this case.     

Marked differences in response to dopamine receptor antagonism in two rat mutants, ci2 and ci3, with lateralized rotational behavior

We have recently described two rat mutants, ci2 and ci3, in which abnormal lateralized rotational behavior and locomotor hyperactivity occur either spontaneously or in response to external stimuli, such as new environment. While cochlear and vestibular defects are found in ci2 rats, ci3 rats do not exhibit any inner ear abnormalities. Both mutants show abnormal lateralities in striatal dopamine and in the density of dopaminergic neurons in substantia nigra or ventral tegmental area, which may be involved in the behavioral phenotype of these rats. In line with this hypothesis, the circling behavior of the ci2 and ci3 mutants is intensified by amphetamine. In the present study, we evaluated the effects of dopamine receptor blockade on the abnormal behaviors of ci2 and ci3 rats. Haloperidol blocked the hyperactivity in both mutants, but this was most likely due to the known inhibitory effect on locomotion by this drug. When animals were observed during the light phase, the abnormal rotational behavior of the mutants was not significantly affected by haloperidol, whereas the dopamine D2 receptor-preferring antagonist raclopride significantly reduced rotations in ci2 rats. When the behavior of the ci3 rats was video-monitored during the dark phase, circling was significantly inhibited by haloperidol. The most striking difference between the two mutants was that ci2 rats were less susceptible than the unaffected littermates to the cataleptogenic effects of haloperidol and raclopride, whereas no such difference was observed in ci3 rats. These data demonstrate that, although there are several similarities between the ci2 and ci3 rat mutants, their cataleptogenic response to dopamine receptor blockade strikingly differs. The comparative evaluation of these two rat mutants may help to increase our understanding of the relationship between developmental anomalies of cerebral asymmetry and brain disorders.     

CNS-irrelevant T-cells enter the brain, cause blood-brain barrier disruption but no glial pathology

Invasion of autoreactive T-cells and alterations of the blood-brain barrier (BBB) represent early pathological manifestations of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Non-CNS-specific T-cells are also capable of entering the CNS. However, studies investigating the spatial pattern of BBB alterations as well as the exact localization and neuropathological consequences of transferred non-CNS-specific cells have been thus far lacking. Here, we used magnetic resonance imaging and multiphoton microscopy, as well as histochemical and high-precision unbiased stereological analyses to compare T-cell transmigration, localization, persistence, relation to BBB disruption and subsequent effects on CNS tissue in a model of T-cell transfer of ovalbumin (OVA)- and proteolipid protein (PLP)-specific T-cells. BBB alterations were present in both EAE-mice and mice transferred with OVA-specific T-cells. In the latter case, BBB alterations were less pronounced, but the pattern of initial cell migration into the CNS was similar for both PLP- and OVA-specific cells [mean (SEM), 95 x 10(3) (7.6 x 10(3)) and 88 x 10(3) (18 x 10(3)), respectively]. Increased microglial cell density, astrogliosis and demyelination were, however, observed exclusively in the brain of EAE-mice. While mice transferred with non-neural-specific cells showed similar levels of rhodamine-dextran extravasation in susceptible brain regions, EAE-mice presented huge BBB disruption in brainstem and moderate leakage in cerebellum. This suggests that antigen specificity and not the absolute number of infiltrating cells determine the magnitude of BBB disruption and glial pathology.     

Expression of cyclin A in human leukemia cell line HL-60 following treatment with doxorubicin and etoposide: the potential involvement of cyclin A in apoptosis

We investigated expression of cyclin A in HL-60 cells after induction of apoptosis with doxorubicin and etoposide. Following apoptotic trigger, both cells arrested in G2/M phase of the cell cycle and changes in morphology were noticed. Moreover, compared to control, the number of cells with cyclin A expression was changed and translocation of this protein from the nucleus to the cytoplasm was observed. The decrease in the number of cells with cyclin A expression, followed by the increase, and cyclin A distribution throughout the cell, appeared to be dose-dependent. Cells treated with lower doses of doxorubicin and etoposide as well as the untreated cells were found to have cyclin A scattered mainly throughout the nucleus. However, immunogold labeling of cyclin A in both cell lines treated with 5- and 10-microM doses of doxorubicin, and 20 and 200 microM of etoposide was observed more often in the cytoplasm than in the nucleus. Cells with features of apoptosis with bodies resembling micro-nuclei labeled with gold particles for cyclin A were recognized. However, the small amount of giant cells was also seen. These results suggest that cyclin A expression is linked to cell death pathways.     

Cooperative cytotoxicity of methyl jasmonate with anti-cancer drugs and 2-deoxy-D-glucose

The anti-cancer agent methyl jasmonate (MJ) acts in vitro and in vivo against various cancer cell lines, as well as leukemic cells from chronic lymphocytic leukemia (CLL) patients. Given the importance of multi-agent combinations in cancer chemotherapy, the purpose of this study was to identify super-additive combinations of MJ and currently-available chemotherapeutic drugs. We identified such cooperative effects in six cell lines arising from different major types of malignancies, i.e., breast, lung, prostate and pancreas carcinomas as well as leukemia. The chemotherapeutic drugs tested were adriamycin, taxol, BCNU and cisplatin. For instance, MJ exhibited strong cooperative effects with BCNU in MIA PaCa-2 pancreatic carcinoma cells. Furthermore, MJ enhanced significantly (pV=0.028) the anti-leukemic effect of adriamycin in vivo, in a CLL mouse model. Finally, MJ cooperated with the glycolysis inhibitor 2-deoxy-D-glucose in inducing death of several types of carcinoma cells. We conclude that administration of MJ with common chemotherapeutic drugs and glycolysis inhibitors bears a promise for effective anti-cancer therapy.