NUTRISEP: Assessment of the nutritional status of patients with multiple sclerosis and link to fatigue.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (PwMS) and reduces quality of life. Several hypotheses for the pathogenesis of fatigue in MS are proposed ranging from neurological lesions to malnutrition, but none has been conclusively validated through clinical research. OBJECTIVES: The goal of this study was to examine the correlation between fatigue and nutritional status and dietary habits in PwMS. METHODS: This was a cross-sectional, multicenter study conducted at 10 French MS centers and enrolling PwMS with an Expanded Disability Status Scale (EDSS) score between 0 and 7. Plasma level of albumin, magnesium, calcium, iron, vitamin D and B12 evaluated nutritional status. A semi-structured eating behavior questionnaire has been developed to evaluate dietary habits. Evaluation of fatigue used specific questionnaire (EMIF-SEP). Quality of sleep was evaluated by visual analogue scale (VAS), depression with Beck Depression Inventory (BDI-II); dysphagia by DYsphagia in MUltiple Sclerosis questionnaire (DYMUS) and taste disorders by gustometry. Association between nutritional deficiencies and different data such as socio-demographic data, disease characteristics, swallowing and taste disorders, food intake, depression and sleep quality was investigated. RESULTS: A total of 352 patients mean age: 48.1±10.1 years, mean duration of MS: 15.3±9.1 years and median EDSS: 4 were analyzed. Bivariate and multivariate analyses showed a statistically significant correlation between fatigue and depression and use of sleeping pills, while none of the variables related to dietary habits or nutritional status correlated significantly with fatigue. CONCLUSIONS: Dietary habits and nutritional status have little impact on fatigue and general population nutrition recommendations remain the rule for PwMS. In cases of fatigue, specific attention should be paid to depression and use of sleeping pills.

Low back pain in patients with multiple sclerosis: A systematic review and the prevalence in a French multiple sclerosis population.

PURPOSE: The prevalence and management of back pain in MS patients was assessed by a systematic review, and the results of a survey on the characteristics of low back pain in a sample of French MS patients are reported. METHODS: A systematic search was conducted according to the PRISMA guidelines. The outcomes of interest included the prevalence of back pain, severity of pain and impact on daily activities. Moreover, the prevalence of low back pain and its consequences on daily living in a large French MS population were assessed. RESULTS: Fourteen studies were included in the systematic review. The prevalence of back pain in MS patients ranged from 8.6 to 50%, but that of low back pain in particular ranged from 41.6 to 52.4%. Concerning the survey, 237 patients participated in the online questionnaire. The prevalence of low back pain in the French MS patients was 76.4%. The patients with chronic low back pain had more limitations in their daily life activities than those without chronic low back pain. CONCLUSION: Patients with MS commonly suffer from low back pain, but it is still an underdiagnosed cause of pain that reduces one's ability to perform activities in daily life.

Monitoring Salmonella, Campylobacter, Escherichia coli and Staphylococcus aureus in traditional free-range 'Label Rouge' broiler production: a 23-year survey programme.

AIM: 'Label Rouge' broiler free-range carcasses have been monitored since 1991, and broiler flocks since 2010, for contamination by the main foodborne zoonotic bacteria. METHODS AND RESULTS: Initially, the monitoring plan mainly focused on the surveillance of Salmonella, and on indicators of the overall microbiological quality of free-range broiler carcasses such as Staphylococcus aureus and coliforms, but was extended in 2007 to include Campylobacter enumeration on carcasses and in 2010, to Salmonella in the environment of live birds. Salmonella contamination of free-range broiler carcasses rose to a peak of 16% in 1994 but less than 1% of carcasses are now regularly found to be positive. Indicators of the overall microbiological quality of carcasses are also improving. These results correlate with the low prevalence of Salmonella in free-range broiler breeding and production flocks, and with the continuous improvement of hazard analysis and critical control points in slaughterhouses, the implementation of a good manufacturing practice guide since 1997 and the application of EU regulations on Salmonella since 1998 in France. Regarding Campylobacter counts on carcasses, the situation has been improving continuously over the last few years, even if 2·5% of the carcasses are still contaminated by more than 1000 Campylobacter per g of skin. CONCLUSIONS: Although the current control system focusing on Salmonella is based on firm epidemiologic data and offers effective means of control (e.g. slaughtering of positive breeder flocks), existing information on Campylobacter makes it more difficult to formulate an effective control plan for free-range broilers, due to their particular exposure to environmental contamination. SIGNIFICANCE AND IMPACT OF THE STUDY: This long-term surveillance programme provided an extended view of the evolution of the contamination of free-range broilers and a direct measurement of the impact of mandatory and profession-driven interventions on the microbiological quality of carcasses.

Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach. MATERIALS AND METHODS: We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records. RESULTS: Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment). CONCLUSIONS: Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.

Effectiveness of home-based rehabilitation using active video games on quality of life, cognitive and motor functions in people with Parkinson's disease: a systematic review.

PURPOSE: We summarized the effectiveness of home-based active video game interventions on physical and cognitive functions, as well as quality of life in adults with Parkinson's disease. We also assessed the feasibility, safety, adherence, and retention of benefits of these interventions. METHOD: We searched studies in eight databases from 1st March to 30th November 2020. Two authors independently performed the selection, data extraction and risk of bias evaluation (PROSPERO ID: CRD42020178138). RESULTS: Nine studies were included in this systematic review (412 participants). All in all, home-based active video games were found effective in improving gait and balance functions in people with Parkinson's disease, equivalent to usual care and conventional therapy. No conclusion can be drawn on cognition and quality of life. Home-based active video games seemed feasible, safe, and were enjoyed by people with Parkinson's disease. The optimal dose, the need for supervision and the retention of benefits of these interventions are still to be determined. These results should be interpreted carefully, considering the limited number of included studies and their small sample sizes, the widespread heterogeneity of included studies and their medium average methodological quality. CONCLUSION: Future research should focus on the effects of home-based active video games on impairments specific to Parkinson's disease, such as falls, freezing of gait and attention, as well as the dose, need for supervision and retention of the benefits of these interventions.IMPLICATIONS FOR REHABILITATIONHome-based active video games are effective in improving motor functions in people with PD.No conclusion can be drawn regarding cognition in people with PD.No conclusion can be drawn regarding quality of life in people with PD.Home-based active video games seem feasible and safe, and are enjoyed by people with PD.The dose, need for control and retention of the benefits still need to be determined.

Predictive value of motor evoked potentials in clinically isolated syndrome.

OBJECTIVES: To assess the predictive role of several measures obtained by transcranial magnetic stimulation (TMS) in patients with clinically isolated syndrome (CIS) for the risk of conversion to multiple sclerosis (MS) during the first 2 years. MATERIALS AND METHODS: We investigated 34 patients with CIS. After 2 years of follow-up and classification into two groups according to MS diagnosis, initial TMS measures were compared to determine their predictive values for conversion to MS. RESULTS: Sixteen patients developed MS. We observed a significant difference between the two groups for contralateral silent period and no significant difference for the central motor conduction time, amplitude ratio, motor threshold, ipsilateral silent period, and the transcallosal conduction time. CONCLUSIONS: Contralateral silent period (SP) seems to be a valuable parameter to early distinguish patients who will develop MS or not. This result about SP during CIS has never been described until now. An increased contralateral silent period would predict a conversion to MS with a positive predictive value of 75%, but this result needs to be confirmed in larger groups.

Biopsychosocial determinants of visuospatial memory performance according to different spaces.

Visuospatial memory (VSM) performance depends on intrinsic (biopsychosocial parameters) and extrinsic (space) factors. We aimed at characterizing the determinants of VSM performance according to space. Young healthy adults, 20 males and 41 females (23 ±â€¯3 years old), were assessed for VSM performance through a pathway learning task, in reaching (eCorsi Block Tapping task) and walking space (Virtual Walking Corsi Task). We evaluated psychosocial factors through seven questionnaires - Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Fatigue Severity Scale, Profile of the Mood States, 2nd edition, short version, Coping Inventory for Stressful Situations, Measurement of Ambiguity Tolerance, Motives for Physical Activities Measure-Revised, mental rotation capabilities and locomotor characteristics (physical activity level through embedded trackers and the International Physical Activity Questionnaire, and gait parameters). The most explanatory biopsychosocial determinants of VSM performance were i) mental rotation capabilities and fatigue indicator in reaching space, and ii) mental rotation capabilities and physical activity level (tracked active energy expenditure only) in walking space. These results suggest that specific parameters should be preferred for the evaluation and strengthening of VSM capabilities in both reaching or walking spaces.

Effects of exergames and cognitive-motor dual-task training on cognitive, physical and dual-task functions in cognitively healthy older adults: An overview.

This overview aims to summarize the effectiveness of cognitive-motor dual-task and exergame interventions on cognitive, physical and dual-task functions in healthy older adults, as well as the feasibility, safety, adherence, transfer and retention of benefits of these interventions. We searched for systematic reviews or meta-analyses assessing the effects of cognitive-motor dual-task and exergame interventions on cognitive, physical and dual-task functions in cognitively healthy older adults through eight databases (CDSR (Cochrane), MEDLINE (PubMed), Scopus, EMBASE, CINAHL, PsycINFO, ProQuest and SportDiscus). Two reviewers performed the selection, data extraction and risk of bias evaluation independently (PROSPERO ID: CRD42019143185). Eighteen reviews were included in this overview. Overall, positive effects of cognitive-motor dual-task interventions on cognitive, physical and dual-task functions, as well as exergames on cognitive functions only, were observed in cognitively healthy older adults. In contrast, the effects of exergames on physical functions are more controversial, and their effects on dual-task functions have not been studied. The feasibility, safety, adherence, transfer and retention of benefits for both intervention types are still unclear. Future studies should follow more rigorous methodological standards in order to improve the quality of evidence and provide guidelines for the use of cognitive-motor dual-task and exergame interventions in older adults.

Functional specialization of stable and dynamic microtubules in protein traffic in WIF-B cells.

We found that the magnesium salt of ilimaquinone, named 201-F, specifically disassembled dynamically unstable microtubules in fibroblasts and various epithelial cell lines. Unlike classical tubulin- interacting drugs such as nocodazole or colchicine which affect all classes of microtubules, 201-F did not depolymerize stable microtubules. In WIF-B-polarized hepatic cells, 201-F disrupted the Golgi complex and inhibited albumin and alpha1-antitrypsin secretion to the same extent as nocodazole. By contrast, 201-F did not impair the transport of membrane proteins to the basolateral surface, which was only affected by the total disassembly of cellular microtubules. Transcytosis of two apical membrane proteins-the alkaline phosphodiesterase B10 and dipeptidyl peptidase IV-was affected to the same extent by 201-F and nocodazole. Taken together, these results indicate that only dynamically unstable microtubules are involved in the transport of secretory proteins to the plasma membrane, and in the transcytosis of membrane proteins to the apical surface. By contrast, stable microtubules, which are not functionally affected by 201-F treatment, are involved in the transport of membrane proteins to the basolateral surface. By specifically disassembling highly dynamic microtubules, 201-F is an invaluable tool with which to study the functional specialization of stable and dynamic microtubules in living cells.

99mTc-HMPAO labelled white blood cell scintigraphy in patients with osteoarticular infection: the value of late images for diagnostic accuracy and interobserver reproducibility.

The objectives of this study were to evaluate the diagnostic value of 99mTc-HMPAO labelled white blood cell scintigraphy (WBCS) in patients with suspected osteomyelitis using late images and to study interobserver reproducibility. This study prospectively included 120 patients, and after a follow-up of one year, only 70 patients (n = 49 with implants, n = 21 without implants) were selected. The final diagnosis of infection was based either on microbiological data (n = 54) or follow-up (n = 16). We performed WBCS with 4 h and 24 h scans. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 77%, 72%, 83%, 64%, and 75% at 4 h, and 74%, 87%, 91%, 59%, and 79% at 24 h, respectively. The interobserver reproducibility shows a 63% prevalence of agreement between results (kappa = 0.5) at 4 h and 80% (kappa = 0.74) at 24 h, respectively. WBCS with 24-h images improves specificity and interobserver reproducibility in patients with suspected osteoarticular sepsis.

[Quality of life after cystectomy: French national survey conducted by the French Association of Urology (AFU), the French Federation of Stoma Patients (FSF) and the French Association of Enterostomy Patients (AFET) in patients with ileal conduit urinary diversion or orthotopic neobladder]. / Qualité de vie après cystectomie: enquête nationale de l'Association française d'urologie (AFU), la Fédération des stomisés de France (FSF) et de l'Association française des entérostomathérapeutes (AFET) chez des patients ayant eu une dérivation urinaire cutanée non continente ou un remplacement vésical orthotopique.

OBJECTIVE: National multicentre study based on specific self-administered quality of life questionnaires in patients with Bricker ileal conduit urinary diversion or orthotopic neobladder. MATERIAL AND METHOD: Questionnaires were distributed by three associations (FSF, AFU, AFET) and comprised general questions and questions specific to the type of diversion. A disability score was also included. RESULTS: Between September 2003 and March 2004, out of a total of 5739 questionnaires, 909 were returned and 877 were analysed: 738 patients with Bricker ileal conduit and 139 with orthotopic neobladder. The two populations differed at the time of the study (Bricker: 69% of men with a mean age of 70 years, orthotopic neobladder: 95.7% of men with a mean age of 64 years). The mean interval since the operation was seven years. Ninety-four percent of patients with Bricker ileal conduit and 93% of patients with orthotopic neobladder were satisfied or very satisfied with the diversion, despite mean disability scores of 5.2+/-3.7 and 3.1+/-3.6, respectively. A correlation between this score and patient satisfaction (Wilcoxon: p<0.0001) was only observed for patients with a Bricker ileal conduit. This score was significantly related to the presence of urinary incontinence with the two types of diversion. Incontinence was frequent (16.1% with Bricker ileal conduit) and 78% of patients feared episodes of incontinence, mainly due to the appliance. Daytime incontinence was frequent for 18.1% of patients with orthotopic neobladder and 40% of patients used at least one protection per day. Out of the patients with neobladder, 82.6% experienced nocturnal incontinence, interfering with sleep in 31.9% of cases. Sexual disorders and altered bowel habit (40%) were very frequent. Stoma-therapy management was insufficient for Bricker ileal conduit and exceptional after bladder replacement. CONCLUSION: Cystectomy with either ileal conduit urinary diversion or orthotopic neobladder alters many aspects of the patient's life, but patients finally accept and adapt to their new way of life.

Prediction of biological activity profiles of cyanobacterial secondary metabolites.

Over the past decade cyanobacteria have become an interesting source of new classes of pharmacologically active natural products. Some cyanobacterial secondary metabolites (CSMs) are also well known for their toxic effects on living species. The PASS (Prediction of Activity Spectra for Substances) computer program, which is able to simultaneously predict more than one thousand biological and toxicological activities from only the structural formulas of the chemicals, was used to predict the biological activity profile of 681 CSMs. Multivariate methods were employed to structure and analyse this wealth of biological and chemical information. PASS predictions were successfully compared to the available information on the pharmacological and toxicological activity of these compounds.

Practice of pathological examinations in stillbirths: A 10-year retrospective study.

OBJECTIVES: To describe the practice of fetal and placental pathological examinations in a large series of spontaneous stillbirths over 10 years. MATERIALS AND METHODS: Inclusion of cases recorded by the Lower Normandy Regional Fetal-Infant Mortality Observatory (observatoire régional de mortalité fœto-infantile) from January 1, 2005 to December 31, 2014. The possible cause of death was coded in accordance with the ReCoDe classification system. RESULTS: Seven hundred and forty-four cases were recorded. The placental examinations were conducted in 93.7% of cases (CI95%[91.7-95.3]), increasing over the study period, and an autopsy was proposed in 87.2% of cases (CI95%[84.8-89.6]). Autopsy was conducted less frequently during the most recent period, with parental refusal increasing over time. In multivariate analysis, no factor was associated with a higher frequency of placental examinations, while autopsy was proposed more often under certain circumstances: less than 4 pregnancies (P<10-2), birth weight from 1000 to 1500 grams (P=0.05), singleton (P<10-2), clinical context not suggesting a cause (P<10-3), type 1 or 2 maternity ward (P<10-2), antepartum death (P<10-3). CONCLUSION: Placental analysis was almost systematically realized, as suggested by international guidelines. Fetal autopsy was often performed, however only in some specific circumstances. New practice guidance to realize customized fetal autopsies appear to be necessary.

GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α.

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.

Regional cerebral blood flow measurements with Xenon-CT in the prediction of delayed encephalopathy after carbon monoxide intoxication.

Reported evaluations of CBF with Xe/CT were performed in 11 patients during the lucid interval following CO intoxication. Results were compared with clinical and SPECT data. Two patients developed neuropsychiatric behavior (delayed encephalopathy) one month following the initial recovery. The symptoms persisted in one of them 15 months later. Their CBF values as well as those in most of the other patients, monitored at the basal ganglia and white matter areas, were in relation with the clinical outcome, However, further studies with a larger number of patients, are needed to confirm the predictive significance of Xe/CT measurements for the long term sequelae of CO poisoning.

In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide.

Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine-10,11-epoxide to healthy volunteers was decreased 26% by progabide. Therapeutic concentrations of progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 mumol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 mumol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of progabide, although inhibitory concentrations are higher than concentrations observed after progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro.

Stiripentol kinetics in epilepsy: nonlinearity and interactions.

Stiripentol kinetics during oral therapy were assessed in six patients with epilepsy who were receiving other antiepileptic drugs. Steady-state levels at 600, 1200, and 2400 mg/day increased in a nonlinear fashion, indicating Michaelis-Menten kinetics. Oral clearance of stiripentol at 600 mg/day was 41.5 +/- 23.4 l/day/kg (mean +/- SD), greater than that at 1200 mg/day (20.3 +/- 8.8 l/day/kg; P less than 0.05) or 2400 mg/day (8.5 +/- 3.8 l/day/kg; P less than 0.01). The apparent in vivo Michaelis-Menten parameters were determined from three mean steady-state concentrations. The average velocity of conversion of stiripentol to its metabolites (Vm), Michaelis constant (Km), and the ratio Vm/Km were 49.3 +/- 13.1 mg/day/kg, 1.35 +/- 1.08 mg/l, and 50.2 +/- 27.5 l/day/kg. Stiripentol reduced the elimination clearances of concomitant antiepileptic drugs. Phenytoin clearance was reduced in all five subjects who received this drug, from a mean control of 29.5 +/- 13.4 l/day to 18.5 +/- 4.6 l/day at a stiripentol dose of 1200 mg/day (P = 0.05) and to 6.48 +/- 2.59 l/day at 2400 mg/day (P less than 0.01). Stiripentol reduced the clearance of carbamazepine in one subject from a control value of 209 l/day to 128 l/day (1200 mg/day) and 61 l/day (2400 mg/day). Stiripentol reduced phenobarbital clearance in two subjects from 3.8 and 5.1 l/day to 2.3 and 3.4 l/day (2400 mg/day). The Michaelis-Menten kinetics of stiripentol, as well as its interactions with other antiepileptic drugs, have important implications in the designing of controlled clinical trials.

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation.

On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (less than 1 mmol/L) and valpromide (less than 10 mumol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (KI = 5 mumol/L) was 100 times more potent than valproic acid (KI = 550 mumol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration approximately 113 mumol/L) and 67% by valpromide (blood concentration less than 10 mumol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.

Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid.

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4-ene-VPA was increased twofold in the valproic acid-carbamazepine and valproic acid-phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4-ene-VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.