Depressed primary in vitro antibody response in untreated systemic lupus erythematosus. T helper cell defect and lack of defective suppressor cell function.

The in vitro antibody response of peripheral blood lymphocytes (PBL) from 19 patients with untreated systemic lupus erythematosus (SLE) was compared with that of 20 control patients and 44 normal subjects. Trinitrophenyl polyacrylamide beads (TNP-PAA) were used to induce IgM anti-TNP plaque-forming cells. SLE patients displayed a markedly depressed, and in most instances virtually absent, response. This was not due to an unusual kinetics of the response; nor could it be induced by preincubation of SLE patients' PBL. In co-cultures of SLE patients and normal PBL, the former, with few exceptions, did not exert a suppressive effect. In four patients the anti-TNP response of either unfractionated or T-depleted SLE PBL could be restored by T cells from a normal individual. Conversely in three of these patients, SLE T cells could not support the response of normal B cells, suggesting a T helper cell defect in SLE PBL. Concanavalin A (Con A)-induced suppressor cells of the antibody response could be assayed by two approaches: (a) in responder SLE patients, by the direct addition of Con A to TNP-PAA-stimulated cultures; (b) in seven patients by transfer of Con A-activated cells to the responding culture of a normal allogeneic donor. In both cases SLE PBL were able to exert a suppressive effect to the same extent as normal PBL.

Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes.

To document the in vivo interactions occurring between the immune system and HIV replicating cells, we analyzed using in situ hybridization the production of IL-1 beta, IL-6, IL-2, and INF-gamma in eight hyperplastic lymph nodes from HIV-1 infected patients. Numerous IL-1 beta- and IL-6-producing cells associated in clusters were detected in sinuses. Few individual IL-1 beta- and IL-6-producing cells were present in interfollicular and follicular areas. IL-2- and INF-gamma-producing cells were observed in all lymph node compartments, with a selective enrichment in germinal centers. The amount and distribution of IL-1 beta, IL-6-, and IL-2-producing cells in HIV lymph nodes were not different from those found in six HIV unrelated hyperplastic lymph nodes. In contrast, a higher level of INF-gamma production was observed in HIV-1 lymph nodes. The CD8+ cells that accumulate in germinal centers of HIV lymph nodes (and not in non-HIV germinal centers) were actively involved in this INF-gamma production. INF-gamma synthesizing cells were in direct contact with cells containing HIV core antigens and HIV RNA. Thus a high INF-gamma production may characterize anti-HIV T cell immune response, potentially contributing to control of viral spreading as well as to the development of follicle lysis.

Future treatment strategies in HIV infection.

UNLABELLED: EFFECTIVENESS OF EARLY TREATMENT WITH ZIDOVUDINE: In terms of progression to AIDS-related complex, AIDS or death, clinical trials have not yet shown any long-term benefit for early compared with deferred treatment with zidovudine. The Concorde trial showed a short-term benefit, as did two of the AIDS Clinical Trials Group studies, but the number of deaths in these short-term trials was too small to draw definitive conclusions. USE OF CD4 CELL COUNTS AS A MARKER OF AIDS: Most trials of zidovudine treatment have shown a slower decline in CD4 cell counts. However, it is still not clear whether these markers can predict long-term survival although they appear to have some value in predicting short-term benefits. SECOND-LINE THERAPY: In patients who are intolerant of or have failed to respond adequately to zidovudine, treatment with didanosine or zalcitabine has shown some short-term benefit, mainly in asymptomatic patients or those with AIDs-related complex. No substantial long-term benefit was observed. Zalcitabine appeared to show a slight increase in survival compared with didanosine. FUTURE PROSPECTS: Treatment strategies still being developed include multidrug combinations, the combination of a nucleoside with a non-nucleoside reverse transcriptase inhibitor, or the use of a combination of drugs that affect different stages of the HIV life cycle, such as proteinase inhibitors. More sensitive assays, such as RNA polymerase chain reaction, may allow treatment to be tailored more closely to the needs of the individual patient.

Inhibition of in vitro immunosuppressive effects of glucocorticosteroids by a competitive antagonist RU-486.

The 19-nor-steroid RU-486 is an antagonist of glucocorticosteroids acting competitively at the receptor level. Pharmacological and endocrinological studies have already shown that RU-486 is able to reverse glucocorticosteroid effects. The present study shows that RU-486 can counteract the inhibitory effect of glucocorticosteroids in two highly corticoid-sensitive in vitro immune responses: murine in vitro antibody response and human autologous mixed lymphocyte reaction.

Primary in vitro antibody response in human cord blood lymphocytes.

Human cord blood lymphocytes were stimulated with trinitrophenyl--polyacrylamide beads (TNP--PAA) in order to induce a primary IgM anti-TNP response. With few exceptions, no anti-TPN response was obtained, whereas peripheral blood lymphomonocytic cells (PBL) from 18-mth-old children were able to respond to TNP-PAA. The addition of lipopolysaccharide (LPS) or of mitomycin-treated adult PBL to cultures of cord blood lymphocytes significantly enhanced their anti-TNP response, thus showing that functional anti-TNP B cell precursors are present in the human neonate.

Hyperchloremic acidosis during grand mal seizure lactic acidosis.

OBJECTIVE: To evaluate the prevalence and the mechanism of hyperchloremic acidosis component (HClA) during lactic acidosis secondary to grand mal seizures. DESIGN: Retrospective study. SETTING: Medical intensive care unit in a university hospital. PATIENTS: 35 patients admitted for grand mal seizures with lactic acidosis (pH < 7.35, TCO2 < 20 mmol/l and PaCO2 < 8 kPa). MEASUREMENTS: HClA was defined by the ratio: excess anion gap/HCO3 deficit (delta AG/delta TCO2) < 0.8. A difference in the distribution space of protons and their accompanying anion, i.e., a displacement of chloride from cells by the entering lactate, was evaluated by the ratio natremia/chloremia (Na+/Cl-). RESULTS: Immediately after seizures, a profound lactic acidosis was observed (pH = 7.22 +/- 0.17 (mean +/- SD), AG: 23.8 +/- 7.1 mmol/l, TCO2 = 14.5 +/- 5.3 mmol/l, lactate: 14.6 +/- 6.9 mmol/. HClA was present on admission in 11 patients (31.5%). Its prevalence increased to 73% after recovery. delta AG/delta TCO2 ratios were unrelated to creatinine, level and PaCO2, but dependent on the ratio Na+/Cl- (r = 0.803; p < 0.001, delta AG/delta TCO2 = 6.4 x (Na+/Cl-)-7.9). These data demonstrate that HClA is not a respiratory or renal phenomenon and suggest differences in the distribution spaces of hydrogen ions and their accompanying anions. CONCLUSION: HClA component may be associated with lactic acidosis in grand mal seizures and appears to be secondary to a lactate antiport. This phenomenon could be an immediate physiological response to a sudden metabolic acidosis.

Participation of the red nucleus in motor initiation: unit recording and cooling in cats.

Cats were trained to release (Go) or not to release (No-go) a lever after a brief auditory signal, depending on the presence of an additional tone (No-go cue). Unit recording and cooling were made in the red nucleus (RN) contralateral to the performing limb. Three major results were found: (1) in the Go condition, we observed phasic increases of rubral firing, with a constant latency after the auditory signal and with an amplitude correlated to the latency of motor triggering (i.e. reaction time, RT); the tonic activity preceding the auditory signal could also be correlated to the RTs for some units; (2) in the No-go condition, there was no phasic increase of rubral firing after the auditory signal; the tonic activity during the presentation of the No-go cue was markedly decreased compared to the Go trials; (3) cooling of the RN increased the RTs and could also block the motor triggering. These results suggest that the RN is involved in setting and triggering a conditioned motor response according to sensory cues.

Changes in motor performance and rubral single unit activity in cats after microinjections of serotonin into the red nucleus area.

The serotonergic control exerted on the red nucleus (RN) was studied in unrestrained cats during the performance of a simple reaction time task which consisted of releasing a lever in response to an auditory go-signal. The effects of microinjections of serotonin-oxalate salt into the rubral area on the motor activity and on the firing of neurons recorded concomitantly in the red nucleus were investigated. Injections of serotonin (5-HT) (200-400 ng) into the red nucleus or its dorsal border induced subtle alterations in the conditioned motor performances but had no major effects on the spontaneous motor behavior. The changes in the conditioned motor output (an increase in the static force exerted on the lever and a speeding up of the lever release) are reminiscent of the facilitatory influence of serotonin on various motor reflexes previously reported. Changes in the neuronal activity were observed concomitantly with the effects on the motor output: 5-HT either enhanced or reduced the firing rate of the rubral neurons. These effects were apparently dependent on the discharge pattern of the neurons during the static motor activity. The results suggest that the serotonergic input to the red nucleus may participate in motor control by exerting a dual modulatory action on the activity of rubral neurons.

ANTI-IL-2 Receptor Antibody Treatment for Lymphoproliferative Disease: Transient Response in A Case of Ki-1+ Anaplastic Large Cell Lymphoma.

Most cases of Ki-1 + anaplastic large cell lymphomas (ALCL) express the CD25 antigen, and we have recently shown that IL-2 producing cells can also be detected in these lymphomas. The latter cells may thus constitute targets for anti-CD25 Mab treatment. In one patient with a chemoresistant disseminated Ki-1 + ALCL such a therapeutic approach was undertaken. We report the dramatic antitumoral effect of anti-CD25 Mab obtained in this patient. This confirms the observation, previously reported in adult T cell leukemia, showing that this therapeutic regimen is also efficient in CD25 + solid tumors.

Activity of caudate nucleus neurons in cat performing a reaction time task.

During a reaction time task, single units were recorded in the caudate nucleus of freely moving cats. Neuronal changes of activity were related to CS, to initiation of movement or to reinforcement. It is suggested that these changes of activity are involved in a process in which informations on the CS and on the on-going movement are associated with information on the occurrence of reinforcement.

[Glomerular nephropathies and B virus: apropos of 4 cases in adults, with an immunofluorescence study and review of the literature]. / Néphropathies glomérulaires et virus B: à propos de 4 observations chez l'adulte, avec étude en immunofluorescence, et revue de la littérature.

The association of glomerulonephritis and persistent HBs antigenemia is reported in 4 adults with nephrotic syndrome: 2 cases of membranous glomerulonephritis associated with chronic persistent hepatitis and 2 cases of membrano-proliferative glomerulonephritis associated with active cirrhosis. In 3 patients, all positive for HBsAg, anti-HBc and HBeAg by radioimmunoassay, indirect immunofluorescent study was performed on kidney and liver biopsies. Glomerular deposit of HBcAg was detected in two cases. HBsAg and HBcAg were not found in the liver. The pathogenesis of such glomerulonephritis remains uncertain and the role of HBs antigen-antibody circulating immune complexes is not clearly proved. Two patients were treated with vidarabine intravenously. Vidarabine produced a transitory decrease of HBsAg concentration in 2 cases and a transitory loss of DNA-polymerase activity associated with a decrease of HBeAg concentration in one case. Neither seroconversion nor improvement of the glomerular disease were ascertained.

[Recommendations for the study of drug combination therapy for the treatment of AIDS and cancer. Round Table No 7 at Giens XIII]. / Recommandations pour l'étude des associations de plusieurs médicaments dans les cas du traitement du SIDA et des cancers. Table Ronde No 7 de Giens XIII.

Medicine combinations for AIDS and cancer treatment are becoming common practice in most clinical stages. These combinations are based on clinical developments which do not follow established guidelines such as those for fixed combinations. There are no current recommendations which can guide these developments and we have tried to identify the critical steps. The main difficulty is to balance the fast development required by the poor prognosis of these diseases and the protection of patients who can only be subjected to combinations for which reasonable expectation of a favourable therapeutic index is foreseen. For each pathology, the pre-clinical evidence-needed before pilot clinical studies and the surrogate clinical end-points are considered (viral load for AIDS and response rate for cancer). These are prerequisities for randomized clinical trials, which are the only means of definitive assessment of new combinations versus existing therapies.

[Pleuropulmonary manifestations of systemic lupus erythematosus]. / Les manifestations pleuropulmonaries du lupus érythémateux systémique.

Pleuro-pulmonary manifestations are frequent in systemic lupus erythematosus (SLE), being found in 40 to 70% of patients with this disease. However, these manifestations can be attributed to SLE only when other pathologies, and notably infections, have been excluded. The truly SLE-related pleuro-pulmonary manifestations can be divided into five types: pleurisy, interstitial pneumonia, lupus pneumonia and two new entities: diffuse pulmonary haemorrhage and pulmonary arterial hypertension. The most frequent manifestation, pleurisy, only requires symptomatic treatment combined with non-steroidal anti-inflammatory agents. Corticosteroids are seldom necessary, but they must be used in lupus pneumonia or in diffuse interstitial pneumonia, owing to the severity and potentially poor prognosis of these two manifestations. Pulmonary haemorrhage is a serious and probably underestimated manifestation; it is diagnosed by bronchoalveolar lavage which also enables other causes, in particular infections, to be excluded. As soon as the aetiological diagnosis is made, high-dose corticosteroid therapy, usually combined with immunosuppressants, is mandatory. Pulmonary arterial hypertension is a classical, but hitherto unrecognized manifestation of SLE which benefits from new exploratory techniques, such as doppler-ultrasonography. At present, its diagnosis rests on data supplied by cardiac catheterization which is generally performed too late, making it irreversible and resistant to all treatments. Some of these pleuro-pulmonary manifestations are probably underestimated and they require new methods of investigation, such as bronchoalveolar lavage or doppler-ultrasonography, resulting in earlier diagnosis and treatment at an accessible stage.

[Hyperchloremic acidosis in metabolic acidosis with anion gap excess. Comparison with diabetic ketoacidosis]. / Acidose hypercholorémique au cours des acidoses métaboliques à trou anionique augmenté. Comparaison avec les acidocétoses diabétiques.

The occurrence of hyperchloremia during diabetic ketoacidosis (DKA) recovery and the lack of correlation between anion gap excess (delta AG) and bicarbonate deficit (delta TCO2) on admission suggest an hyperchloremic acidosis (HCLA) component. The hypothesis that this phenomenon is not specific of DKA and can occur in other metabolic acidoses with increased anion gap was tested. HCLA component, defined by the ratio delta AG/delta TCO2 less than or equal to 0.80, was evaluated on admission and during therapy in 31 patients with DKA and 53 patients with non diabetic metabolic acidosis (ND-MA). HCLA component prevalence was similar on admission (32 p. 100 for DKA versus 41 p. 100 for ND-MA), but it increased during therapy only in DKA patients (86 p. 100 at 9 h - P less than 0.001). In view of the significant correlation (r = 0.636; P less than 0.001) observed between delta AG/delta TCO2 and creatinine, kidney acid base defense appears clearly in DKA patients: the more severe the volume depletion, the greater the ketone retention and the less prominent the HCLA. This phenomenon seems to be secondary to a large tubular excretion of ketones. In the 53 ND-MA patients no correlation between delta AG/delta TCO2 and creatinine could be found. A transfer of chloride from cells to the extracellular space secondary to intracellular diffusion of lactate ions could explain the HCLA component.

[Recurrent thrombocytopenic thrombotic purpura associated to prostatic cancer. A case]. / Purpura thrombocytopénique thrombotique récidivant associé à un cancer prostatique. Une observation.

The association between thrombocytopenic thrombotic purpura (TTP) and infectious or multisystem disease, pregnancy, transplantation, drugs and toxins is well known. The onset of TTP in the course of neoplasm is rarely described. The authors report one case of TTP associated with prostatic tumor. TTP preceded the discovery of neoplasm by 12 months. Moreover, TTP showed an original course with four recurrences despite antiplatelet and hormonal therapies; the successive regressions were obtained with less and less effort, as TTP was discovered at an early stage.

[Good clinical practice:impediment of source of progress?]. / Bonnes pratiques cliniques: frein ou source de progrès?

On the bases of the Declaration of Helsinki (1964), the law called Huriet-Sérusclat (1988) and several subsequent decrees have clearly defined the appropriate organization and management of clinical trials in France. The law on the Commission de l'informatique et des libertés (1978) and several European regulations have also to be taken into account. This extensive legal and regulatory system has been the source of a major improvement in the scientific quality of clinical trials and in the security of participating persons. Indirectly, it has also improved daily clinical care, as physicians have learned how to inform their patients and have been trained to use protocols and standard operative procedures. However, the legal and regulatory pressure has increased the cost and complexity of trials to such an extent that no clinician with his own resources is now able to be the sponsor of a trial involving more than a few patients. In addition to trials organized by pharmaceutical companies for drug development, health authorities in France and Europe should consider to support major clinical trials on therapeutic strategies with public health implications. A few examples can be acknowledged thus far, but a real policy remains to be defined.

[Antiretroviral treatments in human immunodeficiency virus infection]. / Les traitements antirétroviraux dans l'infection par le virus de l'immunodéficience humaine (VIH).

Antiretroviral drugs already registered or currently in clinical trials are shortly described, including dideoxynucleosides, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, tat inhibitors and antisens molecules. In a second part, the treatment of patients with the nucleosides already on the market or in a pre-registration phase is reviewed, on the basis of an analysis of available phase III clinical trials. The third part describes the strategy of clinical trials and explains why "surrogate markers" including markers of viral replication cannot yet be the main criteria to evaluate the efficacy of a new drug in a phase III trial.