Contribution of neo-electroencephalography in adult functional and psychiatric disorders]

Two comparative studies of the basic activity at rest, with closed eyes taken in conventional EEG and analysed in Neo-EEG are carried out in adults showing functional or psychiatric disorders. The first open study involves 18 subjects suffering from a affection called "neurodystony" and 24 depressed subjects. The second study made in double-blind compares the results of the conventional EEG with the Neo-EEG in 19 depressed patients, 28 alcoholic patients and 26 psychotic patients. The Neo-EEG discloses abnormalities in about 60% of the cases when the conventional EEG is normal. The conventional EEG as well as the Neo-EEG diagnose a greater number of low voltage in alcoholic subjects and clear abnormalities in psychotic subjects. Low voltage is never detected in psychotic patients. In depressives, the Neo-EEG shows about 65% of abnormalities of which an asymmetry of the basic frequency in the center of the two hemispheres when they are analysed separately. That asymmetry develops in parallel with the clinical state. The asymmetry is also found in psychotic patients. In nervous or neurodystonic subjects, the Neo-EEG only discloses 25% of abnormalities. The Neo-EEG appears as an easy method, able to detect dysfunctions which cannot be disclosed with the conventional EEG and useful to follow their developments. Moreover, the result of this technique brings to the fore abnormalities not detected with the conventional EEG: this eventually leads to prescribe other therapies than those initially considered.     

Search for Optimal Frequencies and Amplitudes of Therapeutic Electrical Carotid Sinus Nerve Stimulation by Application of the Evolution Strategy

In humans, electrical, bipolar, bilateral carotid sinus nerve stimulation (CSNS; impulse duration 0.35 ms) was applied, using frequencies between 10 and 110 Hz and voltages between individual thresholds and maximal amplitudes of stimulation. Ten anginal patients and two hypertensive patients were studied at an interval of up to 12 years after implantation of electrodes and a radiofrequency receiver for chronic therapeutic CSNS. In search of combinations of frequency and voltage of CSNS, eliciting largest ("optimal") depressor responses of blood pressure and heart rate in the individual patient, Rechenberg's evolution strategy was applied. This strategy simulates mutation and selection of biological evolution. In each patient and on each test stimulation, a value of quality was computed from actual heart rate and blood pressure values as a selection criterion for the strategy. Either responses to uninterrupted CSNS were investigated, while stimulation parameters were adjusted every 3 min, according to the strategy, or responses to 3 min of CSNS after a change in stimulation parameters were compared to intercalated 3-min control periods. In each patient, one or more combined settings of frequency and voltage elicited "optimal" responses. In principle, "optimal" CSNS frequencies ranged between 35 and 105 Hz with large interindividual differences. Due to chronic implantation of electrodes and technical features of radiofrequency transmitted stimulation energy, interindividually different voltages led to an optimal response to CSNS. Also according to the present results, the frequency of CSNS has to be determined individually. It is concluded that the evolution strategy was applied successfully, because voltage and frequency settings leading to "optimal" responses were found within 90-180 min, whereas intraindividual systematic investigations would not be feasible due to their necessarily very long duration. So far, only short-term responses have been evaluated. A broader use of the strategy in other applications is encouraged, as for example in pacemaker optimization and especially in functional electrostimulation.     

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma

Summary The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice — 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) — gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.Abbreviations 5FU 5-fluorouracil - LV leucovorin (folinic acid, 5-formyl-tetrahydrofolate) - FdUMP 5-fluoro 2-deoxyuridine 5monophosphate - TS thymidylate synthase - CH2-THF 5-10 methylenetetrahydrofolate - UR uridine - GDF growth delay factor - TD tumor doubling time - MTD maximum tolerated dose - T/C mean tumor volume of treated mice divided by mean tumor volume of control mice     

Enhancement of immunogenicity of Jeg3 cells by ectopic expression of HLA-A*0201 and CD80

PROBLEM: The choriocarcinoma cell line Jeg3 suppresses immunity in vitro by secretion of soluble factors like leukemia inhibitory factor suppressing leukocyte activation. The cells lack expression of classical human leukocyte antigen (HLA)-A and -B alleles but express some HLA-C, and non-classical HLA-G and -E. Upon binding to killing inhibitory receptor on natural killer (NK) cells, HLA-G prevents activation of cytolytic activity. We investigated whether Jeg3 cells are capable of immune stimulation after complementation with classical HLA and T cell costimulatory signal CD80. METHOD OF STUDY: Jeg3 cells were transduced to express HLA-A*0201 and/or CD80. Parental Jeg3 or transfectants Jeg3-A2, Jeg3-CD80 or Jeg3-CD80-A2 were used to stimulate allogeneic resting and activated peripheral blood lymphocytes (PBL). The different cell lines were loaded with a HLA-A2-restricted Epstein-Barr virus (EBV) recall antigen peptide epitope and antigen presenting ability was examined. T cell lines specific for Jeg3 and transfectants were generated from HLA-A2 matched and nonmatched donors and compared for expansion, phenotypes and cytolytic activity. RESULTS: While all Jeg3 cell lines induced only marginal proliferation of resting T cells, phytohemagglutinin (PHA)-activated T cells were stimulated by CD80 or CD80-A2 expressing Jeg3. Only the transfectant Jeg3-CD80-A2 was capable of specific T cell stimulation by EBV recall antigen presentation. T cell lines of HLA-A2 non-matched donors stimulated with the Jeg3 transfectants showed significant expansion only when HLA-A2 and the costimulus CD80 were present. T cells from HLA-A2 positive donors did not expand significantly or differentially. No NK cells grew under any condition. In Jeg3-CD80-A2 stimulated T cells lines CD8+ cells expanded preferentially. These T cells exerted cytolytic activity toward all Jeg3 cell lines. CONCLUSION: Our data suggest that, in spite of immunosuppressive mechanisms, proliferative and cytolytic T cell responses are induced by Jeg3 cells when classical HLA- and/or costimulatory signals are present on the cells.     

Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumours, and liver metastases

AIMS: Tumour cell growth results from a disturbance in the balance between the rate of proliferation and cell death. In this study, proteins involved in the regulation of cell cycle arrest and apoptosis were studied as possible factors responsible for uncontrolled cell growth in colorectal cancer. METHODS: The expression of proteins involved in these processes was investigated in 48 metastases from patients with colorectal cancer and compared with eight normal colon mucosa samples and 14 primary tumours. Both primary tumours and metastases were obtained from eight patients. The expression of thymidylate synthase (TS), p53, retinoblastoma protein (Rb), Fas receptor, Fas ligand, bcl-2, mcl-1, bax, and bcl-x was measured using immunohistochemistry. Proliferation was determined by Ki67 staining, whereas apoptosis was assessed by M30 immunostaining, which recognises cleaved cytokeratin 18. RESULTS: In the limited number of cases in which paired comparisons were possible, the expression of TS and Ki67 was significantly higher in metastases than in the matched primary tumour samples (p = 0.014 and 0.016, respectively), whereas Rb expression was lower in metastases than in primary tumours (p = 0.024). Fas receptor expression was high in normal mucosa but absent in primary tumours and metastases, whereas the opposite was seen for p53. The expression of bax, mcl-1, and bcl-x in normal mucosa was more apical than that seen in malignant cells, where a more diffuse expression pattern was seen (p < 0.04). Apoptosis was more abundant in primary tumours than in metastases. CONCLUSIONS: These results demonstrate that proliferation and apoptosis are disturbed during colorectal cancer progression, and this is accompanied by loss of Rb and Fas expression, the accumulation of p53 and TS, and changes in the expression patterns of bax, mcl-1, and bcl-xl.     

Dual effects of spinally delivered 8-bromo-cyclic guanosine mono-phosphate (8-bromo-cGMP) in formalin-induced nociception in rats

Interactions are known to occur in the brain between serotonin (5-HT) and substance P (SP). To investigate whether SP can directly influence serotonergic neurons, double immunohistochemical labelings were performed on rat brain sections with NK1 or NK3 affinity-purified antibodies and a 5-HT monoclonal antibody. It was found that the vast majority of serotonergic cell bodies do not colocalize NK1 or NK3 labeling. Only in the central linear nucleus and ventral part of the dorsal raphe nucleus were a few serotonergic neurons double-labeled for NK1 receptors (15 and 0.8% of serotonergic neurons, respectively). It is suggested that serotonergic neurons are not major direct targets for SP in the rat brain.     

Spontaneous activity of dorsal raphe neurons during defensive and offensive encounters in the tree-shrew

The general characteristics of these telemetrically recorded neurons of dorsal raphe, such as firing rate under nembutal anesthesia, reaction to illumination changes or acoustic stimuli were comparable to those in the literature. The firing rate of the dorsal raphe neurons increased during defensive encounters (+51%±29% S.D.; p<0.005) and defensive fights (+113%±91% S.D.; p<0.02) as compared to the neuronal activity of the undisturbed resting animal. The fearful interaction of the animal with the experimenter led to the strongest increase in the firing rate (+187%±114% S.D.; p<0.002) in all animals tested. The offensive animal showed decreased neuronal activity during offensive encounters (?21%±13% S.D.; p<0.02) and offensive fights (?42%±17%S.D.; p<0.05) as compared with the neuronal activity of the undisturbed resting animal. These findings indicate the crucial importance of the animals appraisal of the situational contex for the activity of dorsal raphe neurons.     

Role of Escherichia coli K capsular antigens during complement activation, C3 fixation, and opsonization.

Escherichia coli strains with K capsular polysaccharides are relatively resistant to phagocytosis by polymorphonuclear leukocytes, in contrast to E. coli strains without K antigens. This inhibition of phagocytosis is related to an impaired recognition of the K+ strains by the phagocytes due to ineffective opsonization. All five strains without K antigens were readily phagocytized after opsonization in 5% normal serum, compared with no uptake of the K+ strains. Evidence is presented that the decreased opsonization of the K+ strains in normal serum is caused by a low rate of complement activation of the strains, with subsequent absence of C3b fixation or C3d fixation or both to the cell wall of the bacteria. After removal of the K+ antigens by heating of a K+ E. coli strain, the strain was able to activate complement, to bind C3b or C3d or both, and to become opsonized. Complement was then activated via the classical and alternative pathways, which was comparable to the complement consumption by K- E. coli.     

Inhibitability and enhanceability of basophil histamine release in asthmatic and normal subjects

Circulating human basophils contain histamine, a potent mediator of inflammation. Previous in vitro studies have shown that histamine 'releasability' in asthmatic subjects differs from normal subjects but have not evaluated possible differences in the immunopharmacological control of the release of this mediator which might account for these differences. The purpose of the present study was to examine the immunopharmacologic control of basophil histamine release in 14 asthmatics and 10 normal subjects who were characterized by pulmonary function tests, allergic status (skin tests and serum IgE levels) and nonspecific airways reactivity to methacholine and histamine. Basophils were stimulated with anti-IgE, and the inhibitory effects of the H2 agonist, dimaprit, and dibutyryl cyclic AMP (dbcAMP), as well as the enhancing properties of 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and indomethacin on the modulation of histamine release, were investigated. Although no statistically significant differences were seen in the percent histamine release triggered by anti-IgE in these two groups, enhancement of histamine release by 5-HPETE was more consistent in the asthmatic subjects (10 of 10) than in control subjects (6 of 8). The percent increase in histamine release produced by 5-HPETE in asthmatic subjects averaged 3.9 +/- 1.3% using 0.03 micrograms anti-IgE/ml and 4.8 +/- 3.2% using 0.1 microgram anti-IgE/ml (p less than 0.002, Wilcoxon's signed rank test), and averaged 3.0 +/- 4.3 and 3.1 +/- 5.3%, respectively, in control subjects (p greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)