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.

Long-term cyclosporin continuation rates in rheumatoid arthritis patients.

OBJECTIVE: To evaluate the continuation rate of cyclosporin therapy in rheumatoid arthritis patients followed for at least three years. METHODS: Retrospective medical chart review of rheumatoid arthritis patients on cyclosporin. Treatment efficacy was assessed based on a visual analog scale pain score, Ritchie's articular index, and Lee's functional index. Nonparametric Kaplan-Meier survival curves were used to evaluate continuation rates. RESULTS: 24 cyclosporin-treated patients with a mean age of 58 years and a mean disease duration of ten years were included in the study; 87% had received three second-line drugs prior to cyclosporin. Mean cyclosporin treatment duration was 28 months (range, 1-103 months). Overall cyclosporin continuation rates were 75% after four months and 50% after 36 months. Toxicity and inefficacy caused 33% and 13% of cyclosporin discontinuations, respectively. CONCLUSION: The continuation rate of cyclosporin was satisfactory and similar to that reported for other second-line drugs.

Mapping the APP/presenilin (PS) binding domains: the hydrophilic N-terminus of PS2 is sufficient for interaction with APP and can displace APP/PS1 interaction.

Mutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we confirmed this interaction and have mapped the interaction domains on both PS2 and APP. Using several carboxy-terminal truncated forms of PS2, we demonstrated that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) was sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpart was shown to interact with APP. For APP, we could demonstrate interaction of PS2 with the last 100 but not the last 45 amino acids of APP, including therefore the A beta region. Accordingly, SecPS2NT is capable of binding to A beta-immunoreactive species in conditioned medium. In addition, a second region in the extracellular domain of APP also interacted with PS2. Comparable results with PS1 indicate that the two presenilins share similar determinants of binding to APP. Confirming these results, SecPS2NT is able to inhibit PS1/APP interaction. Such a competition makes it unlikely that the PS/APP interaction results from nonspecific aggregation of PS in transfected cells. The physical interaction of presenilins with a region encompassing the A beta sequence of APP could be causally related to the misprocessing of APP and the production of A beta1-42.

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.

Is there an optimal time to administer methotrexate in the treatment of rheumatoid arthritis?

OBJECTIVE: To determine the optimal time to administer methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: In a crossover study 23 patients were administered MTX intramuscularly at either 10 AM or 6 PM. A 2 week interval separated the 2 injections. MTX concentrations were measured using a fluorescence polarization immunoassay. Pharmacokinetic variables were estimated using a Bayesian approach. The morning and evening schedules were compared using analysis of variance to determine the optimal time of injection. RESULTS: No statistical difference was found in the pharmacokinetics of MTX according to hour of injection. A difference in the creatinine clearance, however, was observed in the samples obtained at noon and 8 PM, but clearance of MTX was unchanged. CONCLUSION: Pharmacokinetic variables suggest that MTX can be administered either in the morning (10 AM) or evening (6 PM) in the treatment of RA.

Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients.

OBJECTIVE: To develop a population pharmacokinetics of vinorelbine in a population of non-small-cell lung cancer (NSCLC) patients using a Bayesian estimation in order to calculate for any further patient, individual pharmacokinetic parameters from few blood samples. METHODS: Vinorelbine was given by a 15-min infusion (30 mg x m(-2)) to eight patients with NSCLC. Its serum concentration was determined by HPLC and its pharmacokinetics was described by a three-compartment open model with elimination from the central compartment. Volume of the central compartment (V1) and rate constants (k10, k12, k21, k13, k31) were selected as population pharmacokinetic parameters and computed by non-linear regression (two-step approach) from 14 to 18 concentration measurements per course. Subsequently, these parameters were used by the Bayesian estimator to calculate individual pharmacokinetics from only 2 or 3 measured concentrations. RESULTS: The population mean values (CV%) of V1, k10, k12, k21, k13, k31, CL, t1/2gamma were respectively 21 l (55%), 3.2 h(-1) (29%), 7.7 h(-1) (74%), 1.3 h(-1) (67%), 4.7 h(-1) (53%), 0.04 h(-1) (20%), 57 l x h(-1) (31%) and 43 h (36%). The comparison of results obtained from the Bayesian estimator and from the three-compartment model showed that CL and t1/2gamma were well predicted (relative deviation: +/- 12 to 22%) by the Bayesian method using only two blood samples. CONCLUSION: We demonstrated that Bayesian estimation allows, at minimal cost and minimal disturbance for the patient, the determination of several vinorelbine pharmacokinetic parameters and therefore dose adaptation from as few as two drug concentrations, measured at 6 h and 24 h after infusion.

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.

[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.

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.

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.

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.

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.

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.

[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.

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.

[Incidence, characteristics and clinical importance of autolymphocytotoxins in aplastic anemias]. / Incidence, caractéristiques et importance clinique des autolymphocytotoxines dans les anémies aplastiques.

Sixteen (24%) of 68 patients with aplastic anemia had antibodies cytotoxic to their own lymphocytes before specific disease treatment. These antibodies displayed the characteristics of cold reactive lymphocytotoxins (LTs). No correlation existed between the detection of auto-LTs and a viral or toxic cause of the disease or the patients' HLA genotype. A lower frequency of anti-HLA antibodies was recorded in the pretreatment sera of patients with auto-LTs. However, the response rate to antilymphocyte serum treatment and the outcome of the bone marrow grafts were comparable among the patient's groups with or without pretreatment auto-LTs.

Identification of components of IC purified from human sera. I. Immune complexes purified from sera of patients with SLE.

Immune complexes (IC) were purified by affinity chromatography on conglutinin columns from human sera (five SLE, one AML and one leishmaniasis) and compared with IC formed in vitro in the presence of normal serum (NHS). First, analysis by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated a common qualitative pattern, but with marked quantitative differences, in IC obtained from five patients' sera (four SLE, one leishmaniasis) and for in vitro formed IC. In two other patients (one SLE, one AML), the pattern of IC components was very different, with a major band in the 26 kD region. Secondly, after electrophoretic transfer of the SDS-PAGE bands to nitrocellulose membranes, the nature of IC components was studied by defining the reactivity of the bands with antisera against human serum antigens. Several serum proteins were identified in the purified IC:IgG, IgA, IgM, C1q, C1r, C1s, C3bi and Bb. A few bands did not correspond with any normal serum protein. One of them, at 26 kD was shown to react with anti-C reactive protein (CRP) antiserum. From all the constituents observed in the SDS-PAGE analysis of purified IC, only two bands in one SLE patient might be corresponding to unidentified antigens.

Circulating immune complexes and the prognosis of acute myeloid leukemia.

We studied the relation between the clinical course and the presence of circulating immune complexes at diagnosis and/or during complete remission in 186 patients with acute myeloid leukemia. Patients with immune complexes at diagnosis had significantly fewer complete remissions (32 vs. 94 per cent), remissions of shorter duration (median, 4.3 vs. 15.0 months), and shorter survival times (median, 1.8 vs. 22.3 months) than patients without such complexes (all comparisons, P less than 0.01). All patients with immune complexes during the first two months of remission remained in remission for less than six months, whereas only 11 per cent of patients without complexes within this period had such early relapse. Of 23 patients who relapsed after long remissions, 18 (78 per cent) had immune complexes that preceded hematologic evidence of relapse by three weeks to six months (median, 3.7 months). These findings suggest that circulating immune complexes may reflect an important aspect of the pathophysiology of acute myeloid leukemia, and that measurement of these complexes can provide useful prognostic information at diagnosis and during remission.