Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque

Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.     

Placental Thrombosis and Fetal Loss After Passive Transfer of Mouse Lupus Monoclonal or Human Polyclonal Anti-Cardiolipin Antibodies in Pregnant Naive BALB/c Mice

In the present study we evaluated the effect of passive transfer of a mouse monoclonal (CAM) or a human polyclonal anti-cardiolipin IgG on pregnancy outcome in BALB/c mice. The mice were immunized through the tail vein immediately after mating with 10 μg of monoclonal or polyclonal anti-cardiolipin antibodies. Two other groups of mice were given a mouse irrelevant monoclonal antibody or normal human polyclonal IgG respectively, at the same dose. In mice immunized with monoclonal or polyclonal anti-cardiolipin antibody we observed a significant increase in the number of fetal resorptions and a significant reduction of the mean weights of the embryos and the placentas. In mice immunized with CAM we also found a significant decrease in the number of healthy pups, while mice infused with human aCL antibody expressed a significant reduction in the fecundity rate. The histological examination showed widespread thrombosis and necrosis in the placentas derived from the mice immunized with the anti-cardiolipin antibodies. The model supports a possible direct pathogenetic effect of anti-phospholipid antibodies in recurrent fetal loss and points out that thrombotic events at placental level can be instrumental in the pathogenesis of the obstetric complications.     

An outbreak of amebiasis spread by colonic irrigation at a chiropractic clinic

From June 1978 through December 1980, at least 36 cases of amebiasis occurred in persons who had had colonic-irrigation therapy at a chiropractic clinic in western Colorado. Of 10 persons who required colectomy, six did. Of 176 persons who had been to the clinic in the last four months of 1980, 80 had received other forms of treatment. Twenty-one per cent of the colonic-irrigation group had bloody diarrhea, as compared with 1 per cent of the non-irrigation group (P = 0.00013). Thirty-seven per cent of the colonic-irrigation group who submitted specimens had evidence of amebic infection on either stool examination or serum titer, as compared with 2.4 per cent in the non-irrigation group (P = 0.00012). Persons who were given colonic irrigation immediately after a person with bloody diarrhea received it were at the highest risk for the development of amebiasis. Tests of the colonic-irrigation machine after routine cleaning showed heavy contamination with fecal coliform bacteria. The severity of disease in this outbreak may have been related to the route of inoculation.     

Evidence for the phagocytic transport of intestinal particles in dogs and rats.

Fluorescent latex beads of two different colors were implanted into separate intestinal segments in individual dogs and rats. Mesenteric lymph node phagocytes subsequently contained multiple beads of one or the other color but rarely both colors, indicating that intestinal phagocytes transported the latex beads to the draining lymph node. Fluorescent labeled Escherichia coli was implanted into rat ligated intestinal segments, and rare mesenteric lymph node phagocytes subsequently contained fluorescent bacteria, suggesting that intestinal bacteria might be transported in the same manner as inert latex beads.     

Vacuolar lesion profile in sheep scrapie: factors influencing its variation and relationship to disease-specific PrP accumulation

Detailed neuropathological examination for vacuolar lesions was performed on the brains of 42 sheep with clinical signs compatible with scrapie. The sheep were grouped according to their breed (Poll-Dorset, Cheviot, Welsh Mountain, Shetland and Suffolk), their PrP genotype at codons 136, 154 and 171 (VRQ/VRQ, VRQ/ARQ, VRQ/ARR and ARQ/ARQ) and the type of infection (experimental infection with SSBP/1, or natural disease). Twenty-two neuroanatomical sites from seven brain regions were examined for vacuolation in the neuropil and five sites at the level of the obex were examined for intraneuronal vacuolation. In 36 sheep, immunohistochemical examination for disease-specific PrP (PrP(d)) accumulation had also been performed in the same brain regions in an earlier study. The magnitude of total neuropil vacuolation was highest in the naturally affected ARQ/ARQ Suffolk sheep and lowest in the experimentally infected VRQ/VRQ Cheviot sheep and VRQ/ARR Poll-Dorset sheep. The severity of neuropil vacuolation at nine of the 22 neuroanatomical sites examined was used to generate a vacuolar lesion profile, which showed variations between the different sheep groups. These variations could be attributed to both PrP genotype and sheep breed and also possibly to scrapie agent; there was, however, considerable individual variation in lesion profile within sheep groups. All groups showed a similar ratio of neuropil vacuolation to neuronal vacuolation at the level of the obex. Although a positive correlation between neuropil vacuolation and PrP(d) deposition was generally observed, it was low except for the astrocyte-associated pattern of PrP(d) accumulation. The study suggests that vacuolar lesion profiles in sheep are affected by several factors and, by comparison with lesion profiles in mice, are of no more than limited value for discriminating between scrapie strains.     

Imaging attentional and attributional bias: an fMRI approach to the paranoid delusion

BACKGROUND: The pathophysiology of auditory hallucinations and delusions of control has been elucidated using functional imaging. Despite their clinical importance, there have been few similar attempts to investigate paranoid delusions. We have examined two components of social cognition (attentional and attributional biases) that contribute to the formation and maintenance of paranoid delusions, using functional magnetic resonance imaging (fMRI). METHOD: Normal subjects performed tasks requiring attentional and attributional judgements. We investigated the neural response particularly associated with attention to threatening material relevant to self and with the 'self-serving' attributional bias. RESULTS: The determination of relevance to self of verbal statements of differing emotional valence involved left ventrolateral prefrontal cortex (left inferior frontal gyrus, BA 47), right caudate and right cingulate gyrus (BA 24). Attention to threatening material relevant to self differentially activated a more dorsal region of the left inferior frontal gyrus (BA 44). Internal attributions of events, where the self was viewed as an active intentional agent, involved left precentral gyrus (BA 6) and left middle temporal gyrus (BA 39). Attribution of events in a non 'self-serving' manner required activation of the left precentral gyrus (BA 6). CONCLUSIONS: Anomalous activity or connectivity within these defined regions may account for the attentional or attributional biases subserving paranoid delusion formation. This provides a simple model for paranoid delusion formation that can be tested in patients.     

Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.     

Dual role for macrophages in vivo in pathogenesis and control of murine Salmonella enterica var. Typhimurium infections

Salmonella spp. are regarded as facultative intracellular bacterial pathogens which are found inside macrophages (Mphi) after i. v. infection. It is generally assumed that Mphi restrict the replication of the bacteria during infection. In this study we examined the in vivo activities of Mphi during experimental S. typhimurium infections, using a selective liposome-based Mphi elimination technique. Unexpectedly, elimination of Mphi prior to infection with virulent S. typhimurium decreased morbidity and mortality, suggesting that Mphi mediate the pathology caused by S. typhimurium. Removal of Mphi) during vaccination with attenuated S. typhimurium did not affect protection against challenge with virulent S. typhimurium, suggesting that Mphi are not required for the induction of protective immunity and that other cells must function as antigen-presenting cell to elicit T cell-mediated protection. However, Mphi appeared to be important effectors of protection against challenge infection since elimination of Mphi from vaccinated mice prior to challenge infection with virulent S. typhimurium significantly decreased protection. These results enhance our understanding of the control of S. typhimurium growth in vivo, and moreover suggest that Mphi play a major role in the pathology of virulent S. typhimurium infections. As such, these cells may present a novel target for therapeutic intervention.