[Predictive factors of seclusion duration in patients hospitalized in psychiatry settings. A prospective multisite study in the DTRF Paris-Sud]. / Facteurs prédictifs de la durée d'isolement chez les patients hospitalisés en psychiatrie. Une étude prospective multicentrique au sein du DTRF Paris-Sud.

INTRODUCTION: In psychiatric inpatient settings seclusion is a last resort to ensure the safety of the patient, other patients, and staff from disturbed behaviors. Despite its major interest for patients, seclusion could negatively impact treatment adherence and patient/staff relationships. Indeed, some secluded patients report a feeling of guilt during the measure and do not consider seclusion to be a healthcare intervention. To be more beneficial and to reduce the feeling by patients of being forced, seclusions should be as short and rare as possible. In other words, measures to reduce seclusion are available and have been clearly identified. Such measures could be applied, in the first instance, in patients with longer duration. In this way, the aim of this study was to investigate predictive factors of a seclusion of long duration. METHODS: Our study was based on the dataset of the EPIC study, an observational prospective French multicenter study of seclusion and restraint. The EPIC study occurred in seven French psychiatric hospitals in the southern region of Paris. Inclusions were realized for 73days and allowed a data collection of 302 seclusion measures. Of these measures 236 were effectively a seclusion in a standardized room. Because the median duration was 7days, we defined two groups of patients: duration<7days and duration ≥ 7 days. Our variable to be explicated was duration ≥ 7 days. Explicative variables available in EPIC study were age, sex, forced hospitalization, autoagressivity, heteroagressivity, use of sedative treatment (oral or intramuscular), history of seclusion and patient diagnoses. We used bivariate and multivariate analyses to explore the association between a seclusion duration ≥ 7 days and explicative variables. Diagnoses were classified as psychotic disorders, mood disorders and others diagnoses. To be included in multivariate logistic regressions, diagnoses were treated as dummy variables (mood disorder vs psychotic disorders; psychotic disorders vs others; mood disorders vs others). Statistical analyses were performed using SPSS software 20.0 and R 3.4.0. RESULTS: Of the 236 measures of seclusion the mean age was 38.2 (±12.8), 196 (83%) patients were forcibly hospitalized prior to their seclusion, 147 (62%) had a diagnosis of psychotic disorder, 43 (18%) a diagnosis of mood disorder and 33 (14%) an "other diagnosis". Mean duration was 10.2 (1.5) days and median was 7.1 days. One hundred and thirty-five (47%) patients were in the group of duration ≥ 7 days. In bivariate analyses, variables associated with a duration ≥ 7 days were: being in forced hospitalization prior to the seclusion (P=0.04), administration of a sedative treatment (P=0.01) and against the group of others diagnoses the diagnosis of mood disorders (P<0.0005) and psychotic disorders (P=0.001). Multivariate analyses showed that, against the group of other diagnoses, the group of psychotic disorders [OR=3.3, CI 95% (1.3-8.4), P=0.01], the group of mood disorder [OR=2.7, CI 95% (1.4-4.9), P=0.002] and administration of sedative treatment [OR=8.1, CI 95% (2.0-32.5), P=0.003] were significantly associated with a duration ≥ 7 days. These results were independent from other confusion variables. Considering the hospitalization status, psychotic disorders was the only diagnosis which showed an association between duration ≥ 7 days and forced hospitalization [OR=2.9 CI 95% (1.1-7.8), P=0.03]. CONCLUSION: Our study highlighted two profiles of higher risk to remain ≥ 7days in seclusion. The first one is patients with a diagnosis of mood disorder who needed sedative treatment. The second one is patients with a diagnosis of psychotic disorder who needed sedative treatment and forced hospitalized before seclusion. Thus, these two profiles could be a good target to practice, in the first instance, measures to reduce seclusion duration in psychiatry settings.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

Skin conductance while facing emotional pictures at day 7 helps predicting antidepressant response at three months in patients with a major depressive episode.

There are currently no reliable biological markers to identify antidepressant responders in patients suffering from major depressive disorder. In this longitudinal pilot study, we measured skin conductance response (SCR) to assess patients' emotional reactivity after antidepressant treatment initiation. Fifty-four adult patients with a major depressive episode were recruited and followed up for 3 months. After one day of antidepressant treatment (D1) and then at day 7 (D7), emotional stimuli were presented on a computer screen while SCR and subjective emotional response were recorded. Three months later, we used Montgomery and Åsberg Depression Rating Scale (MADRS) to screen patients for treatment response, and distinguished responders (N = 28) from non-responders (N = 15). While SCR at D1 did not differ between responders and non-responders, SCR at D7 was higher in responders for both positive, negative and neutral stimuli. Skin conductance rates at D7 had a relatively poor negative predictive value (38%) but a strong positive predictive value (95%). Further studies are needed to replicate in a larger sample, and validate, these preliminary results which suggest that electrodermal activity after treatment initiation could help predict antidepressant efficacy.

The human immune response to the OKT3 monoclonal antibody is oligoclonal.

The availability of highly specific and homogeneous antibodies to human T cells by the hybridoma technique has elicited new interest in the clinical use of antibodies to lymphocytes as immunosuppressive agents. OKT3 is the murine monoclonal antibody that has been the most widely used in clinical transplantation to induce immunosuppression. This antibody recognizes a membrane molecular complex, exclusively present on mature human T lymphocytes, which is tightly linked to the T-cell antigen receptor. The long-term therapeutic use of murine monoclonal antibodies in vivo is hampered by the intense antibody response that occurs in most human patients. Thus, when administered alone, OKT3 manifests its immunosuppressive activity only during the 10 to 15 days that precede the onset of sensitization. The results presented here show, by use of isoelectrofocusing, that the antibody response to OKT3, already reported to be restricted in its specificity (only anti-isotypic and anti-idiotypic antibodies are produced), is in addition oligoclonal. This restriction of the anti-monoclonal response may suggest that an efficient way to circumvent the sensitization problem would be to administer consecutively different monoclonal antibodies presenting the same specificity but distinct idiotypes.

Aberrant T cell-mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production.

The authors examined the immune status at the cellular and humoral levels of 16 untreated schizophrenic patients. No abnormality in the distribution of T cell subsets (CD4+, CD8+) was detected. The proliferative response to the T cell mitogen phytohemagglutinin was normal. No increase in the number of T cells showing activation markers, such as human leukocyte antigens and interleukin-2 receptors, was noted. Conversely, function studies revealed a clear deficiency in interleukin-2 production by purified T cells. This lower production was probably intrinsic to the patients' T cells, since interleukin-2 production showed normal sensitivity to prostaglandin E2-mediated down-regulation by autologous monocytes.

Anti-histone antibodies in schizophrenia and affective disorders.

Sera from 81 psychiatric patients (51 with schizophrenia and 30 with affective disorders) were analyzed using several assays in parallel for the presence of non-organ-specific autoantibodies, namely anti-nuclear antibodies, anti-deoxyribonucleic acid antibodies (native and denatured DNA), anti-histone antibodies, anti-centromere antibodies, and anti-nuclear antigen antibodies. Nine out of the 81 sera studied were positive for the presence of anti-nuclear antibodies. Moreover, in 15 patients, significant titers of anti-histone antibodies were detected. No correlation can be drawn concerning the presence of anti-histone antibodies and the clinical situation. Although no clear association was noted with a specific class of drugs, it cannot be excluded at present that the therapeutic regimen received by the patients may explain the results observed.

Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: the infinity study.

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.

[Exercise-induced renal ischemia after kidney transplantation: report of two cases]. / Ischémie rénale d'effort sur rein transplanté : à propos de deux cas.

INTRODUCTION: Renal transplant patients are high cardiovascular risk patients. Regular ultrasound surveillance of the renal transplant artery and the iliac artery upstream from the anastomosis is required to detect potential arterial stenosis. The purpose of this article was to illustrate the hemodynamic impact of exercise in such patients and the screening efficiency of Doppler ultrasound stress testing. METHODS: Two renal transplant patients were hospitalized in our center for impaired renal function, worsening hypertension, and intermittent claudication. This association of peripheral vascular disease and renal dysfunction led us to perform a Doppler ultrasound stress test to search for vascular stenosis upstream from the graft. Hemodynamic fluctuations in the ipsilateral leg were recorded during flexion-extension exercises. RESULTS: Iliac artery lesions were found in both patients: the Doppler examination showed decreased systolic velocity in the graft artery during exercise, compatible with iliac steal syndrome. Surgical treatment was performed in both patients. After surgery, the control Doppler ultrasound stress test showed that systolic flow did not decline in the graft vessels during exercise. Renal function stabilized in one patient and improved in the other; claudication disappeared after surgery. CONCLUSION: Doppler ultrasound stress testing can be a valuable tool for detecting exercise-induced renal graft ischemia in transplant patients. Its screening performance should be determined in a larger population before routine use.

[Transplantation without corticosteroids]. / Transplantation sans corticostéroïdes.

Used in kidney transplantation to prevent and treat rejection, corticosteroids induce a number of adverse side effects over the long term. With the arrival of new immunosuppressive drugs, trials on rapid corticosteroid interruption, a few days or weeks after transplantation, and transplantation without corticosteroids other than the intraoperative bolus, have been conducted in patients at low immunological risk and on particular patient profiles such as children and Afro-Americans. These studies show that early cessation of corticosteroids, whether in these two categories of patients or in patients at low immunological risk, make it possible to reduce the adverse side effects with no harmful influence on patient or graft survival or renal function. The increase in the rejection rate observed with this procedure has no consequences over the medium term after treatment. However, for full success, this strategy must absolutely be carried out under the cover of an induction and an immunosuppressive bitherapy. In these conditions, early interruption of corticosteroids also has beneficial effects over the longer term: it encourages the reduction in the frequency and/or severity of diabetes, weight gain, hypertension, or dyslipidemia and seems to better preserve patients'bone status.

Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids.

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 +/- 27 vs. 57 +/- 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 +/- 19 vs. 60 +/- 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

Characterization of histamine H1 binding sites on human T lymphocytes by means of 125I-iodobolpyramine. Preferential expression of H1 receptors on CD8 T lymphocytes.

The presence of histamine H1 receptors on lymphocytes has been indirectly suggested by the various effects of agonists or antagonists on the functionally distinct T lymphocyte subsets. Recently, a new H1 antagonist, 125I-iodobolpyramine, whose structure is similar to mepyramine, has become available for the detection of H1 receptors in guinea pig brain. When using 125I-iodobolpyramine on human T lymphocytes, the presence of a single highly specific H1 binding site was evidenced. The binding of 125I-iodobolpyramine to human T cells was reversible when using 1000-fold excess of the cold H1 antagonist, d-chlorpheniramine. Binding saturation was achieved at 0.60-0.65 nM of 125I-iodobolpyramine, the binding equilibrium was reached in 20-30 min at 27 degrees C. The dissociation constant was KD = 0.41 +/- 0.07 (mean +/- SE) and the number of receptors per T cell was 3407 +/- 592 (mean +/- SE) as deduced from saturation and kinetic curves. In competition experiments using a panel of H1 ligands, the T cell binding sites detected by 125I-iodobolpyramine showed a pharmacological behavior characteristic of histamine H1 receptors. It was of particular interest that 125I-iodobolpyramine binding displayed clearcut stereoselectivity as assessed by the higher affinity of the d-configuration of chlorpheniramine than the l form. Study of purified CD4 and CD8 T cells showed that twice as much H1 histamine receptors were expressed by CD8 T lymphocytes (6615 +/- 1125) as compared to CD4 T cells (3545 +/- 459). These results underline the need for studying the functional properties of such pharmacologically defined T lymphocyte H1 binding sites.

Fine specificity of antibodies produced in rhesus monkeys following in vivo treatment with anti-T cell murine monoclonal antibodies.

The immune response of 23 rhesus monkeys against different murine monoclonal antibodies (mAb) administered in vivo as immunosuppressive agents has been analyzed. Seven mAb specific for either helper-inducer (CD4 molecules) or cytotoxic/suppressor (CD8 molecules) T cells, that cross-react with monkey lymphocytes, were administered i.v. for 10 consecutive days in rhesus monkeys. Nineteen of the animals were recipients of a skin or renal allotransplant. Nineteen out of the 23 monkeys developed a significant immune response against the injected monoclonal. This response was restricted in its specificity since unrelated murine monoclonals were not recognized by the monkeys' anti-monoclonal immunoglobulins. Fine analysis of the monkeys' sera revealed that the antibodies produced against the xenogeneic proteins selectively exhibited two major specificities i.e., anti-isotypic and anti-idiotypic. On a practical basis, these results suggest that an animal already immunized against a given mAb should still be sensitive to the therapeutic effect of another monoclonal sharing the same specificity but different idiotype.

[Abdominal complications in peritoneal dialysis]. / Les complications abdominales en dialyse péritonéale.

We conducted a 4-year retrospective study (1996-1999) in order to assess the abdominal events in patients on peritoneal dialysis (PD), as well as the technique failure and the death incidence. We enrolled 127 patients in two french dialysis centers, who presented 9 enteric bacterial peritonitis (13.2% of the total peritonitis episodes), occurring 7.6 +/- 7.9 months after PD treatment. Surgery (8 patients) and definitive technique failure (7 patients) were necessary. Hernias were the most frequent with 32.6% of the total abdominal complications. They were either umbilical (7 patients), or inguinal (5 patients) or hiatal (3 patients). Six patients continued on PD without disruption whereas 6 patients had a transient stop and thereafter returned to PD. The other abdominal complications such as gastric and duodenal ulcus (5 patients), oesophagogastric reflux (5 patients), liver diseases (9 patients) occurred during PD treatment without any relationship with the treatment modality. In the diabetic population, abdominal complications were not more frequent but they took place more quickly than in the non diabetic population (5.5 +/- 3.8 months versus 12.9 +/- 16.3 months with p < 0.01). A rapid diagnosis, especially in case of enteric peritonitis, is mandatory to avoid "abdominal catastrophes" mainly due to visceral injury. The incidence of hernia could be decreased if a good clinical approach is effective before PD treatment.

Polyclonal and monoclonal antibodies directed against SK & F 94461, a specific H1 histamine receptor ligand.

SK & F 94461, an aminopentyl analogue of mepyramine, is a recently described H1 receptor antagonist. At variance with the other available H1 receptor ligands, SK & F 94461 offers the possibility of coupling to a protein carrier to render the molecule immunogenic. SK & F 94461 coupled to succinylated bovine serum albumin was used as an immunogen to raise polyclonal antibodies in rabbits and BALB/c mice. In parallel, spleen cells from immunized mice were used to produce hybridomas by somatic cell fusion. Thus, six different murine monoclonal antibodies sharing anti-SK & F 94461 specificity were selected for further detailed characterization of their binding properties. Pharmacologic studies of competitive inhibition using a set of 11 histaminergic agents allowed analysis of the fine specificity of anti-SK & F 94461 antibodies. Both polyclonal and monoclonal anti-SK & F 94461 antibodies showed very high affinity for the immunizing molecule (i.e., Ka values for monoclonal antibodies 8 and 12 were, respectively, 3 X 10(10) and 1.4 X 10(10) M-1). Both types of antibodies bound with high affinity (IC50 ranging from 10(-10) to 10(-12) M) to mepyramine, which has a chemical structure closely resembling that of SK & F 94461. Moreover, these antibodies displayed clear-cut stereoselectivity inasmuch as they bound the d-configuration of chlorpheniramine with significantly higher affinity than the l-form. Thus, all six monoclonal antibodies showed IC50 values 1 to 6 log units lower for d- than for l-chlorpheniramine. For some monoclonal antibodies, spectroscopic and fluorescence spectra studies showed that their different binding capacities correlated with their optical properties. Similarly, polyclonal anti-SK & F 94461 antibodies showed a 500-fold lower affinity for l- than for d-chlorpheniramine. All these results indicate that the polyclonal and the majority of monoclonal anti-SK & F 94461 antibodies recognized with high affinity structural configurations known to be important for the pharmacologic activity of H1 ligands, namely the presence of the dimethylaminoethyl side chain and, with stereochemical selectivity, the d-configuration of chlorpheniramine. These data extend for the first time to an H1 histamine receptor ligand results reported in other hormone systems.