Clinical relevance of circulating immune complexes in human leukemia. Association in acute leukemia of the presence of immune complexes with unfavorable prognosis.

The occurrence of circulating immune complexes was investigated in 467 serum samples from 230 leukemia patients using the [(125)I]Clq-binding test. There was an increased serum [(125)I]Clq-binding activity in 40% of patients with acute myeloid leukemia, 23% with acute lymphatic leukemia, 46% in blastic crisis of chronic myeloid leukemia, 12% with chronic lymphatic leukemia, and 13% with chronic myeloid leukemia. In 48 patients, serum was also tested for soluble immune complexes by the Raji cell radioassay; the correlation between results of the two tests was significant. The Clq-binding material had properties identical with those of immune complexes. It sedimented as 14-28s material on sucrose density gradient. It contained IgG which could be dissociated at acid pH. Its Clq-binding properties could be removed after passage through anti-IgG immuno-absorbant or after a mild reduction-alkylation treatment, but were not sensitive to deoxyribonuclease treatment. Circulating immune complexes were found most commonly during the blastic stage of leukemia.Remission took place in 75.4% of patients with no detectable circulating immune complexes at the onset of acute leukemia, but in only 32.7% of those with detected complexes during this period. Median survival times of the former group of patients were more than 18 mo in acute myeloid leukemia and acute lymphatic leukemia and more than 8(1/2) mo in blastic crisis of chronic myeloid leukemia. The corresponding median survival times in the latter patient group were 64, 135, and 90 days. These findings were unrelated to prognostic features already known.

HLA antigens are risk factors for development of AIDS.

HLA-A, -B, -C, -DR, and -DQ antigens were determined by serology and in cases of severe lymphopenia by RFLP-DNA typing in 51 Caucasians with a diagnosis of AIDS (32 with opportunistic infections and 19 with secondary cancers). In addition, 86 HIV-1 seropositive and 39 HIV-1 seronegative drug abusers and 148 healthy controls were also studied. No significant differences in HLA antigen frequencies were found in comparison of HIV-1 seropositive and HIV-1 seronegative drug abusers with controls, suggesting that HLA polymorphism does not represent a genetic risk for infection with HIV-1. In contrast, a significant increased frequency of B35 (p less than 0.01) and CW4 (p less than 0.01) was observed in both groups of AIDS patients as compared to controls. Moreover, DR2 was increased in frequency in patients with opportunistic infections (p less than 0.01) and DR3 was completely absent in patients with secondary cancers (p less than 0.05). In the latter group, the DR5 frequency was increased, although nonsignificantly. These findings provide strong evidence for the existence of HLA-linked factors of susceptibility and host resistance to AIDS.

Characteristics and clinical relevance of autolymphocytotoxins in patients with aplastic anemia.

Serum of 68 patients with aplastic anemia was tested for the presence of autolymphocytotoxins (auto-LTs). Prior to specific disease treatment, 16 patients (24%) displayed antibodies cytotoxic to their own lymphocytes. These antibodies had the characteristics of cold-reactive lymphocytotoxins. Their detection in patients' sera was found unrelated to a viral or toxic cause of the disease or the patients' HLA genotype. Broadly reactive anti-HLA antibodies were less frequent in pretreatment sera containing auto-LTs, suggesting that these autoantibodies could modulate alloantibody production. However, after specific disease treatment, the alloantibody frequency was comparable in patients with or without auto-LTs. We found no significant difference in response to antilymphocyte serum or bone marrow graft outcome in the patients in relation to the presence or absence of pretreatment auto-LTs. This observation suggests that the detection of these autoantibodies in aplastic anemia has no clinical relevance.

Association of a better kidney graft survival with the presence of circulating immune complexes before transplantation.

The presence of circulating immune complexes was investigated using the C1q-binding assay before and after kidney transplantation in 48 patients with renal failure. Circulating immune complexes were found in 54% of the patients. The presence of circulating immune complexes prior to grafting was associated with a better renal graft survival. Median survival time of grafts in patients with circulating immune complexes was more than 18 months as compared with 21/2 months in patients without such complexes. The incidence of circulating immune complexes in patients before transplant could not be related to the renal disease, viral infections, blood transfusions, or serum levels of lymphocytotoxic antibodies, IgG, or IgM.

Effect of factors inhibiting HLA-DR antibodies before transplantation on kidney graft survival.

Blood transfusions administered before renal allografts are known to enhance graft survival. Among alternative hypotheses proposed to explain this effect, one of the most attractive is the possible induction of antiidiotypic antibodies directed against the specific antigen-binding site of donor-specific antibodies. In order to determine if such blocking antibodies are generated after blood transfusions, serial serum samples obtained before transplantation from 44 kidney recipients were analyzed for the development of HLA-DR alloantisera inhibitory activity by a microcytotoxicity inhibition assay. A significant correlation was found between the presence of inhibitory factors before transplantation and prolonged graft survival. However a clear relation between the development of inhibitory factors and the administration of transfusions could not be established. In addition the sera of 36 patients were studied for the presence of circulating immune complexes (CIC) before grafting. The presence of CIC was clearly associated with that of inhibitory factors, and with a prolonged graft survival. Thus these studies provide support for the development of blocking (possibly antiidiotypic) antibodies to anti-MHC in human renal graft recipients.

Characterization of human presenilin 1 transgenic rats: increased sensitivity to apoptosis in primary neuronal cultures.

Mutations in the gene for presenilin 1 are causative for the majority of cases of early onset familial Alzheimer's disease. Yet, the physiological function of presenilin 1 and the pathological mechanisms of the mutations leading to Alzheimer's disease are still unknown. To analyse potential pathological effects of presenilin 1 over-expression, we have generated transgenic rats which express high levels of human presenilin 1 protein in the brain. The over-expression of presenilin 1 leads to saturation of its normal processing and to the appearance of full-length protein in the transgenic rat brain. The transgenic protein is expressed throughout the brain and is predominantly found in neuronal cells. Cultured primary cortical neurons derived from these transgenic rats are significantly more sensitive than non-transgenic controls to apoptosis induced by standard culture conditions and to apoptosis induced by trophic factor withdrawal. Furthermore, the observed apoptosis is directly correlated with the expression of the transgenic protein. The results further emphasize the role of presenilin 1 in apoptotic cell death in native neuronal cultures.

Influence of biological variables upon pharmacokinetic parameters of intramuscular methotrexate in rheumatoid arthritis.

The pharmacokinetics of methotrexate were studied in 22 patients receiving 5-15 mg per week in a single i.m. administration for rheumatoid arthritis. The data consisted of 3 plasma levels per patient, taken at 2, 6, and 12 hours after the administration. The concentration of methotrexate was determined by fluorescence polarization immunoassay. The pharmacokinetic parameters of a 2-compartment model were determined by Bayesian estimation using the population values of Bressolle et al. [1996]. The fitted parameters were: total plasma clearance of methotrexate (CL), first-order absorption constant (ka), volume of central compartment (V1), and transfer constants between the 2 compartments (k12 and k21). Additional parameters were derived from the fitted ones: maximal concentration (Cmax), time to maximum (tmax), volume of distribution at steady-state (Vss), and terminal half-life (t1/2). Twenty-one biological covariates were considered to explain the interpatient variability. The relationships between these covariates and the pharmacokinetic parameters were investigated by principal component analysis and multiple regression analysis. About 90% of the variability of CL were explained by 4 variables (sex, age, height and serum creatinine). About 50%-70% of the variability of the other pharmacokinetic parameters were explained by a set of covariates including age, height, creatinine, creatinine clearance, and dose. The effect of dose was noticed mainly on k12, Vss, and t1/2, thus suggesting that the transfer of the drug from plasma to tissues may be nonlinear. The possibility of predicting CL with a good precision would facilitate the computation of dosage regimens in these patients.

Macro-creatine kinase type 1. Immunological studies in 14 patients with comments on clinical significance.

Circulating autoantibodies directed at creatine kinase (CK) BB isozyme are detected in plasma in the form of an immune complex (immunoglobulin CK BB) termed macro-CK type 1. Fourteen patients presented a falsely elevated CK MB isozyme fraction as measured by the immunoinhibition method; they were found to have IgG-CK BB complexes, which was considered to be indirect evidence of circulating anti-CK BB autoantibodies. No evident clinical association between the detection of this autoantibody in complexed form and autoimmune disease could be established, there was no significantly increased incidence of other autoantibodies, and there was no specific alteration in immunoglobulin and complement levels; however, the HLA haplotype A1,B8,DR3, which is known to be associated with autoimmunity, was present in five patients.

[Methotrexate and non-steroidal anti-inflammatory agent combination in rheumatoid arthritis]. / Association méthotrexate et anti-inflammatoire non stéroïdien au cours de la polyarthrite rhumatoïde.

It is well known that methotrexate (MTX), used at high dosage in cancer patients, must not be combined with a non-steroidal anti-inflammatory drug (NSAID) because of high risk of side effects; prescribed at low dosage (< or = 15 mg per week) in rheumatoid arthritis patients, MTX is often combined with an NSAID. Some cases reported in the literature underline the potential toxicity of the association of low dose MTX with an NSAID, but most of the pharmacological studies do not confirm this hypothesis. Except for salicylates, NSAIDs do not affect the absorption, distribution, protein binding, area under the curve, half-life, or the elimination of MTX. Therefore, if necessary, MTX (< or = 15 mg per week) can be combined with an NSAID during the treatment of rheumatoid arthritis.

The feasibility of home polysomnographic recordings prescribed for sleep-related neurological disorders: a prospective observational study.

OBJECTIVE: Home polysomnography is being increasingly developed for sleep studies, with various grades of quality. This study aimed to determine the feasibility of affordable, high quality home polysomnographic recordings prescribed for suspected sleep-related neurological disorders. PATIENTS AND METHODS: We prospectively screened all patients referred to the specialist sleep disorders clinic in Nancy University Hospital between May 2011 and August 2011. Patients were eligible for inclusion if they required polysomnography for the diagnosis of a sleep-related neurological disorder. One-night, polysomnography was performed in each patient's home by a trained sleep technician. Financial cost was determined prior to inclusion. A recording was considered as satisfactory if all the following criteria were present: at least, one EEG channel with continuous signal allowing determination of sleep stages and wake during more than 66% of sleep time; at least, one usable respiratory channel (airflow or either band) during more than 66% of sleep time; and usable oximetry during more than 66% of sleep time. RESULTS: Forty-eight of the 139 screened patients were included. Among the 48 home polysomnography recordings, 35 (72.9%) were satisfactory. Thirteen (27.1%) tracings displayed an unsatisfactory loss of EEG data, including seven (14.6%) tracings with an unsatisfactory loss of respiratory data. CONCLUSION: Home polysomnography prescribed for suspected sleep-related neurological disorders is feasible, with affordable costs, whilst maintaining high quality recording. Further studies are needed to measure the real medico-economic impact of promoting outpatient domiciliary explorations for sleep-related neurological disorders.

[HLA markers in leukemia patients]. / Marqueurs HLA chez les malades leucémiques.

The relationship of genes of the HLA system with leukemogenesis has been controversial for many years. However HLA antigens such as A2, B12 and DR7, have been found associated with prolonged survival in patients with acute leukemia. Recent studies have also shown an excess of shared HLA antigens (especially DR) among the parents of patients with acute leukemia. This phenomenon may possibly reflect the expression in patients of recessive immune response genes linked to the HLA complex; the role of such immune response genes in susceptibility or resistance to virus-induced leukemia has clearly been established in mice.

Shoplifting and mental illness.

A survey of 1,649 shoplifting convictions at a Montreal area municipal court found that a relatively low percentage (3.2%) of the cases involved mentally ill patients and that there is a comparatively closer link between shoplifting and affective disorders, alcoholism and drug addiction. The survey also showed that shoplifting is related more to mental illness than to the use of psychotropic drugs. The authors therefore reject the hypothesis of pharmacogenic shoplifting which has been reported in some studies on small numbers of shoplifters.

Serial measurement of circulating immune complexes in the sera of patients with leukaemia.

The occurrence of circulating immune complexes was studied in 220 sera of 86 patients with leukaemia. Three tests were used in parallel: the 125I-C1q-binding assay, the complement consumption test and C1q solubility test. Positive results in at least two assays were found in 64% of the patients and in 88% of the 32 serially investigated patients. An association was found between the elevated immune complex level and the blastic phase of the disease. A fluctuation of the immune complex level-independent of the clinical course of leukaemia-could also be demonstrated. The peaks of these types of fluctuations obtained by the different tests did not coincide on several occasions. These findings suggest that the composition of immune complexes changes in the course of the disease.

Burden of care of families not living with young schizophrenic relatives.

A program that provides comprehensive support services to young schizophrenic adults and their families in Montreal was evaluated after one year to assess the needs of families, especially single-parent families, after the young adult patient left home. Results of the evaluation, which employed a case-control design, showed that compared with families receiving the usual services, families in the program reported feeling less burdened by the patients' personal problems. They also received more services and had more contact with professionals. Patients living away from home spent more than 18 hours a week in face-to-face contact with their families. Single parents of mentally ill young adults spent much less time with their offspring and expressed more need for services and a greater burden of care than married parents.

[Immunologic study of pleural neoplastic effusions: Detection of immune complexes and complement activation]. / Etude immunologique des épanchements pleuraux néoplasiques: détection de complexes immuns et activation du complément.

Occurrence of immune complexes in malignant pleural effusions has been investigated by the 125I-c1q binding test. 55% of the pleural effusions had C1q binding activity levels higher than those found in transudates used as controls. The levels of C1q binding activity in effusions were significantly higher than those found in the serum of the same cancer patients. High levels of C1q binding activity were found in malignant effusion independently of type or differentiation of the tumors involved. The C1q binding material had properties of immune complexes. The levels of CH50 and C3d, i.e. the degradation product of C3, in malignant effusion were similar to those of transudates. These observations show a high incidence of immune complexes in malignant effusions and a slight activation of complement inadequate for its local consumption. The persistence in major quantity of immune complexes in malignant effusion suggests local formation or decreased clearance.

[Incidence and specificity of circulating immune complexes in infectious mononucleosis (proceedings)]. / Incidence et spécificité des complexes immuns circulants dans la mononucléose infectieuse.

Occurrence of immune complexes in infectious mononucleosis has been investigated by the 125I Clq binding assay. Increased serum Clq-binding activity was found in 87% of the 23 patients studied during the acute stage of the disease. The serum Clq-binding material detected has properties identical to those of immune complexes. IgG antibodies dissociated from the complexes at acid pH and F (ab)'2 fragments obtained after treatment by pepsin appeared to be directed against the viral capsid antigen of Epstein-Barr virus.