[Comparison of medical and economic benefits of antipsychotics in the treatment of schizophrenia in France]. / Comparaison des bénéfices médico-économiques des antipsychotiques dans la prise en charge de la schizophrénie en France.

INTRODUCTION: The course of schizophrenia can vary widely, and patients experience remission phases alternating with relapse episodes, which generally lead to hospitalisation and have a significant impact on the burden of disease. The prevalence of schizophrenia in France is estimated to be approximately 600,000 people, with an incidence of 10,000 new patients per year. Patients with schizophrenia represent the largest group of hospitalised patients in French public institutions and specialised centres, and the French authorities recognise that the management of schizophrenia is a major public health concern. The Haute Autorité de Santé (HAS) and most of the evidence-based guidelines for the maintenance treatment of schizophrenia recommend long-acting injectable (LAI) antipsychotics to be used predominantly in the prevention of relapse for non-compliant patients; however, in clinical practice, the use of LAIs remains low. OBJECTIVE: This analysis aimed to estimate and to compare the cost-effectiveness of the most common antipsychotic strategies in France in the management of schizophrenia. METHODS: A Markov model was developed to simulate the progression of a cohort of patients with schizophrenia through four health states (stable treated, stable non-treated, relapse and death) and considered up to three lines of treatment to account for changes in treatment management. Antipsychotics including aripiprazole LAI (ALAI), olanzapine LAI (OLAI), paliperidone LAI (PLAI), risperidone LAI (RLAI), haloperidol decanoate (HD) and oral olanzapine (OO) were compared in terms of costs and clinical outcomes. Thus, costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over five years based on three-month cycles from a French health insurance perspective with a discount rate of 4 %. Patients were considered to be stabilised after clinical decompensation and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on French real-life data in order to capture adherence effects. Safety and utility data were derived from international publications. Additionally costs were retrieved from French health insurance databases and publications. Robustness of results was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: First and second generations of LAIs were found to have similar costs over five years; i.e. approximately € 55,000, except for PLAI which was associated with a discounted cost of € 50,880. Oral antipsychotics were found to be less costly (i.e. OO cost € 50,379 after five years) but associated with a lower number of QALYs gained and relapse avoided. PLAI and RLAI were associated with the greatest number of QALYs gained; i.e. PLAI dominated ALAI, OLAI and HD and was associated with an incremental costs-effectiveness ratio (ICER) of € 2411 per QALY gained versus OO. Finally, PLAI and OLAI were associated with the lowest number of relapses; i.e. PLAI dominated RLAI, ALAI and HLAI and was associated with an ICER of € 1782 per avoided relapse compared to OO. OO and HD were found to have led to the highest number of relapses. CONCLUSION: This analysis, to the best of our knowledge, is the first of its kind to assess the cost-effectiveness of antipsychotics based on French observational data. PLAI was associated with the highest probability of being the optimal treatment from the French health insurance perspective.

Presence of HHV-6 genome in spermatozoa in a context of couples with low fertility: what type of infection?

Human herpesvirus-6 (HHV-6) is a betaherpesvirus whose genome may integrate into human chromosomes. Chromosomally integrated HHV-6 (ciHHV-6) may be transmitted vertically from parents to children. HHV-6 DNA has been detected in semen, but its integrated or extrachromosomal status has not yet been characterised. The aim of this study was to determine the prevalence of HHV-6 DNA and to search for ciHHV-6 forms in spermatozoa purified from semen obtained from subjects explored for low fertility. A total of 184 sperm samples were purified using PureSperm(®) . HHV-6 viral load and species identification were performed by real-time polymerase chain reaction. Of 179 sperm specimens analysed, three were positive for HHV-6 (1.7%). Two samples (1.1%) had viral loads of 680 232 and 2 834 075 copies per million spermatozoa, compatible with loads expected for a ciHHV-6 form. The viral load of the third positive sample (73 684 copies per million spermatozoa) was lower than would be expected for ciHHV-6 infection, implying that the HHV-6 DNA detected in spermatozoa corresponds mainly to ciHHV-6. However, viral DNA may also be detected at a low level that is not in favour of the presence of ciHHV-6. Further studies are necessary to determine the origin of detected viral genomes.

Transducing properties of a pre-structured α-helical DPT-peptide containing a short canine adenovirus type 2 E4orf4 PP2A1-binding sequence.

BACKGROUND: Induction of the death pathway resulting from the specific interaction of the PP2A1 phosphatase with adenoviral E4orf4 protein is a promising approach for cancer therapy. With the aim of deregulating tumor pathways, and mimicking E4orf4 anti-cancer signal, we have previously proposed the DPT technology concept, based on design of specific PP1/PP2A interacting penetrating peptides. METHODS: Using biochemical, structural and cell survival experiments, we have characterized new DPT-peptides containing short PP2A binding sequences. RESULTS: We identified overlapping sequences, located within the N-terminal domain E4orf423-46 of canine adenoviral E4orf4 protein, that interact with the PP2A-Bα subunit of PP2A1 holoenzyme. We characterized DPT-E4orf44 and TAT-E4orf44, two bi-partite cell penetrating peptides containing the 12 PP2A1 binding residues of the canine type 2 E4orf427-38 sequence, respectively fused to the DPT-sh1 and TAT shuttle sequences. Surprisingly DPT-E4orf44, in contrast to inactive TAT-E4orf44, adopted a well defined α-helical structure and co-precipitated PP2A1 from HeLa cell extracts. DPT-E4orf44 also internalized streptavidin-HRP and inhibited survival of HeLa cells more efficiently than TAT, TAT-E4orf44 or the previously published anti-tumor TAT-derived peptide shepherdin. DPT-E4orf44 also efficiently inhibited the survival of human adherent transformed cells, including wild type and p53 mutated colonic HCT116 cells, without affecting survival of human non-transformed fibroblasts. CONCLUSIONS: We characterized the transducing properties of a new α-helical DPT-E4orf44 peptide containing a short PP2A-interacting sequence from canine Adenoviral E4orf4 protein. GENERAL SIGNIFICANCE: Our results suggest that α-helical structured DPT peptides specifically interacting with PP2A could be a valuable anti-cancer drug design scaffold.

Functional near-infrared spectroscopy-based neurofeedback training targeting the dorsolateral prefrontal cortex induces changes in cortico-striatal functional connectivity.

Due to its central role in cognitive control, the dorso-lateral prefrontal cortex (dlPFC) has been the target of multiple brain modulation studies. In the context of the present pilot study, the dlPFC was the target of eight repeated neurofeedback (NF) sessions with functional near infrared spectroscopy (fNIRS) to assess the brain responses during NF and with functional and resting state magnetic resonance imaging (task-based fMRI and rsMRI) scanning. Fifteen healthy participants were recruited. Cognitive task fMRI and rsMRI were performed during the 1st and the 8th NF sessions. During NF, our data revealed an increased activity in the dlPFC as well as in brain regions involved in cognitive control and self-regulation learning (pFWE < 0.05). Changes in functional connectivity between the 1st and the 8th session revealed increased connectivity between the posterior cingulate cortex and the dlPFC, and between the posterior cingulate cortex and the dorsal striatum (pFWE < 0.05). Decreased left dlPFC-left insula connectivity was also observed. Behavioural results revealed a significant effect of hunger and motivation on the participant control feeling and a lower control feeling when participants did not identify an effective mental strategy, providing new insights on the effects of behavioural factors that may affect the NF learning.

Peptidergic nerves in the ureter.

Vasoactive intestinal peptide (VIP) and substance P were demonstrated in the pig ureter by immunohistochemical techniques. Nerves containing these materials were related mainly to the smooth muscle layer in the normal and obstructed ureter. In isolated ureteral segments, VIP caused relaxation at doses exceeding 0.18 micrograms/ml, with no significant difference seen in the effect on normal and obstructed ureter. Vasoactive intestinal polypeptide may play a role in the regulation of ureteral smooth muscle tone.

Laparoscopic partial nephrectomy: initial case report for benign disease.

On February 12, 1992, a laparoscopic partial nephrectomy was performed on a woman with a lower-pole caliceal diverticulum containing a stone. By incorporating the laparoscopic argon beam coagulator and a tourniquet device, the procedure was completed in 6 hours and 10 minutes. The postoperative course and period of convalescence was markedly improved over that expected from open surgery. This laparoscopic intervention demonstrates the expanding horizons of minimally invasive surgery and the remarkable development of new laparoscopic devices.

Postoperative clostridium difficile gastroenteritis.

Clostridium difficile gastroenteritis can be the cause of an enigmatic postoperative syndrome of high temperature and marked leukocytosis, out of proportion to the initially mild constitutional symptoms. Patients may suffer delayed onset of diarrhea, which will test positive for the C. difficile enterotoxin by latex agglutination. We report 5 cases of C. difficile gastroenteritis that occurred within a 2-year period. We believe that the combination of preoperative bowel preparation, and intraoperative and postoperative systemic antibiotics is the primary operant factor. All patients responded rapidly when oral antibiotics specific for C. difficile were instituted. The sequelae of C. difficile colitis can include toxic megacolon with perforation and peritonitis, increasing the importance of early recognition and appropriate treatment.