Circadian rhythm in toxic effects of cystemustine in mice: Relevance for chronomodulated delivery

Cystemustine is a new nitrosourea with high anti-tumor activity and a short plasma half-life in mice. The influence of circadian dosing time upon its toxicities was first investigated in a total of 368 synchronized male B6D2F1 mice. Late survival rate varied from 4% in mice receiving a single dose of cystemustine (conventional lethal dose 50%) at 7 hours after 1ight onset (HALO) up to 88% in mice treated at 15 or at 19 HALO. Target organ toxicities (bone marrow, circulating blood cells, spleen, colon and duodenum) were studied following a single slightly lower dose of cystemustine. Leukopenia was the major hematologic effect encountered. Leukocyte count nadir occurred 7 days after injection and was lowest following cystemustine at 7 HALO as compared to 13 or 19 HALO. Recovery was faster after cystemustine at 19 HALO as compared to other dosing times. Bone-marrow necrotic lesions were more pronounced I day after cystemustine at 7 HALO than after cystemustine at 19 HALO. Thus, a large-amplitude circadian rhythm characterized the toxicity of this nitrosourea in mice. The lowest cystemustine toxicity was found near the middle of the active span of the rest-activity circadian cycle of mice. © 1996 Wiley-Liss, Inc.     

Prescription,Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists’ and patients’ perspectives. Cardiologists provided the patients’ clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.     

Transient cortico-cortical disconnection during psychogenic nonepileptic seizures (PNES)

Psychogenic nonepileptic seizures (PNES) are paroxysmal clinical events that are often misdiagnosed as epileptic seizures, but which are not associated with electrographic discharge. Brain connectivity changes occurring during PNES are not known. We studied functional connectivity (Fc) in two patients with drug-resistant epilepsy, explored by stereotactic electroencephalography (EEG), in whom we recorded both epileptic seizures (ES) and PNES. Functional connectivity using pair-wise nonlinear correlation was computed between signals from seven brain areas: amygdala, hippocampus, lateral temporal cortex, anterior insula, orbitofrontal cortex, prefrontal cortex, and lateral parietal cortex. We assessed changes in global Fc during PNES in comparison with a background period. During PNES, a global decrease of Fc occurred between the different brain regions studied, compared with the interictal period. In both patients, decreased Fc was prominent in connections involving the anterior insula and parietal cortex. In conclusion, some PNES are associated with ictal functional disconnection between brain areas, particularly involving the parietal cortices and the anterior insula.     

Leptospirosis in Reunion Island (Indian Ocean): analysis of factors associated with severity in 147 confirmed cases

Objective Analysis of risk factors associated with severity in patients with confirmed leptospirosis. Design and setting Retrospective study in 147 leptospirosis-confirmed patients at two tertiary nonteaching hospital in Reunion Island. Patients 138 men and 9 women, aged 36 ± 14 years, 80 in the ICU and 67 in medical wards. Measurements and results We collected demographic, clinical, biological, and radiographic data and performed univariate and multivariate analysis to examine risk factors associated with admission in ICU and mortality. Pulmonary forms were more frequent (85%) than in previous reports, with 85 cases (65.3%) on abnormal chest radiography. Among the 38 patients who underwent bronchoalveolar lavage at admission 31 (81.5%) had alveolar hemorrhage. Independent factors related to ICU admission were: age over 46 years (OR 3.02), creatinine higher than 200 μmol/l (6.69), shock (13.87), and acute respiratory failure (20.69). Mortality was 12.9%. The only factor independently related to mortality was need for mechanical ventilation (OR 20.94). Icterohemorrhagiae serogroup was found in 62 cases (42.8%) but was not related to death. Conclusions Pulmonary involvement is a major feature in leptospirosis disease but is not associated with poor outcome. Identification of clinical and laboratory findings on admission may help to better characterize severe cases. Mailing address: Arnaud Bourdin is currently at the Service de Pneumologie, CHU Montpellier, France.     

Endoscopic ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts

BACKGROUND: Surgery is the traditional treatment for symptomatic pancreatic pseudocysts, but the morbidity is still too high. Minimally invasive endoscopic approaches have been encouraged. AIMS: To evaluate the efficacy of endoscopic ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts. METHODS: From January, 2003 to August, 2006, 31 consecutive symptomatic patients submitted to 37 procedures at the same endoscopic unit were retrospectively analysed. Chronic and acute pancreatitis were found in, respectively, 17 (54.8%) and 10 (32.3%) cases. Bulging was present in 14 (37.8%) cases. Cystogastrostomy or cystoduodenostomy were created with an interventional linear echoendoscope under endosonographic and fluoroscopic control. By protocol, only a single plastic stent, without nasocystic drain, was used. Straight or double pigtail stents were used in, respectively, 22 (59.5%) and 15 (40.5%) procedures. RESULTS: Endoscopic ultrasound-guided transmural drainage was successful in 29 (93.5%) patients. Two cases needed surgery, both due to procedure-related complications. There was no mortality related to the procedure. Twenty-four patients were followed-up longer than 4 weeks. During a mean follow-up of 12.6 months, there were six (25%) symptomatic recurrences due to stent clogging or migration, with two secondary infections. Median time for developing complications and recurrence of the collections was 3 weeks. These cases were successfully managed with new stents. Complications were more frequent in patients treated with straight stents and in those with a recent episode of acute pancreatitis. CONCLUSIONS: Endoscopic transmural drainage provides an effective approach to the management of pancreatic pseudocysts.     

Human adipocyte fatty acid-binding protein (aP2) gene promoter-driven reporter assay discriminates nonlipogenic peroxisome proliferator-activated receptor gamma ligands

Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and carbohydrates. PPARgamma activity increases insulin sensitivity and adipocyte differentiation at the expense of adipogenesis and weight gain. The goal of this study was to 1) clone the promoter of the human adipocyte fatty acid binding protein (aP2) gene, namely fatty acid-binding protein-4, 2) characterize its pharmacological regulation, and 3) determine its putative predictability for adipogenesis. Among the selected PPAR agonists, rosiglitazone and pioglitazone displayed the highest maximal efficacy (E(max)) on reporter-gene assays in COS-7 cells cotransfected by either a galactosidase 4-response element-based or a human aP2 promoter-based Luc reporter vector, along with either chimeric or full-length human PPAR expression plasmids. The non-subtype-selective 2-(4-[2-(3-[2,4-difluorophenyl]-1-heptylureido)ethyl]phenoxy)-2-methyl-butyric acid (GW-2331) and the compounds [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxyl]phenoxy]-acetic acid (L-165041), (4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)-benzoic acid (GW-0072), and indomethacin behaved as partial agonists relative to pioglitazone in full-length human aP2-PPARgamma2. Beyond their partial PPARgamma agonist properties, these compounds elicited a lower maximal up-regulation of mouse aP2 mRNA in 3T3-L1 adipocytes as compared with pioglitazone; these properties paralleled a time-dependent increase in neutral lipids. By contrast, the selective PPARalpha agonist 2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid (BM-17.0744) neither stimulated the human aP2-PPARalpha promoter reporter-gene assay, thus demonstrating a specific interaction between PPARgamma and the aP2 promoter, nor affected lipogenesis in 3T3-L1 cells. Altogether, these data characterized a functional promoter of the human aP2 gene; its in vitro pharmacological regulation in PPARgamma-mediated reporter-gene assay may represent an interesting complement or an alternative to time-consuming procedures aiming at discriminating PPAR ligands with low lipogenic properties.     

Cardiac rehabilitation in chronic heart failure: effect of an 8-week, high-intensity interval training versus continuous training

Freyssin C, Verkindt C, Prieur F, Benaich P, Maunier S, Blanc P. Cardiac rehabilitation in chronic heart failure: effect of an 8-week, high-intensity interval training versus continuous training.ObjectiveTo compare the effects of an 8-week, high-intensity interval training protocol versus continuous training.DesignRandomized controlled trial.SettingCardiac rehabilitation center.ParticipantsPatients (N=26; mean age ± SD, 54±12y) with chronic heart failure were enrolled in a cardiac rehabilitation program for 8 weeks.InterventionsPatients were randomly assigned into 2 groups that performed either interval training (IT) or continuous training (CT). IT consisted of 3 sessions of 12 repetitions of 30 seconds of exercise at very high intensity, followed by 60 seconds of complete rest. The CT group performed CT exercises, which consisted of 45 minutes of aerobic exercise.Main Outcome MeasuresParameters of gas exchanges: peak oxygen consumption (Vo₂peak), first ventilator threshold (VT1), distance at six-minute walk test (6MWT), and level of anxiety and depression were measured.ResultsThe IT group increased significantly their Vo₂peak, the duration of the exercise test, the oxygen pulse, oxygen consumption at the VT1, and the distance walked during the 6MWT. The CT group only increased the time at the VT1 and the distance performed at the 6MWT. The improvement in the time at the VT1 was significantly higher for the IT group than for the CT group.ConclusionsThis study shows that IT at very high intensity for patients with heart failure appears to be more effective than CT in improving indices of submaximal exercise capacity.     

BCL2 mutations do not confer adverse prognosis in follicular lymphoma patients treated with rituximab

BCL2 mutations have been suggested to confer an adverse prognosis to follicular lymphoma (FL) patients, but their prognostic value has not been assessed in patients treated with a rituximab‐containing regimen. Here we evaluated the prognostic value of BCL2 mutations in a large prospective cohort of 252 patients with FL treated with immunochemotherapy in the PRIMA randomized trial. Using a DNA‐targeted sequencing approach, we detected amino acid altering mutations in 135 patients (54%) and showed that these mutations were probably mediated by the over‐activation of AICDA (activation‐induced cytidine deaminase) in the context of the t(14;18) translocation. The BCL2 variants identified in PRIMA patients affected the BH1, BH2, and BH3 functional motifs at a lower frequency than the N‐terminus and flexible loop domain, with mostly conservative aminoacid changes. With a median follow‐up of 6.7 years, we did not observe any impact of BCL2 mutations either on overall survival or progression‐free survival.