Modeling longitudinal daily seizure frequency data from pregabalin add-on treatment

The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in a stepwise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (relative standard error [RSE] 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Interindividual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year?1 (RSE 26.8%). A mixture model was applied to classify responders/nonresponders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg?1 (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation-based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/nonresponders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.     

Performance in population models for count data,part I: maximum likelihood approximations

There has been little evaluation of maximum likelihood approximation methods for non-linear mixed effects modelling of count data. The aim of this study was to explore the estimation accuracy of population parameters from six count models, using two different methods and programs. Simulations of 100 data sets were performed in NONMEM for each probability distribution with parameter values derived from a real case study on 551 epileptic patients. Models investigated were: Poisson (PS), Poisson with Markov elements (PMAK), Poisson with a mixture distribution for individual observations (PMIX), Zero Inflated Poisson (ZIP), Generalized Poisson (GP) and Negative Binomial (NB). Estimations of simulated datasets were completed with Laplacian approximation (LAPLACE) in NONMEM and LAPLACE/Gaussian Quadrature (GQ) in SAS. With LAPLACE, the average absolute value of the bias (AVB) in all models was 1.02% for fixed effects, and ranged 0.32–8.24% for the estimation of the random effect of the mean count (λ). The random effect of the overdispersion parameter present in ZIP, GP and NB was underestimated (−25.87, −15.73 and −21.93% of relative bias, respectively). Analysis with GQ 9 points resulted in an improvement in these parameters (3.80% average AVB). Methods implemented in SAS had a lower fraction of successful minimizations, and GQ 9 points was considerably slower than 1 point. Simulations showed that parameter estimates, even when biased, resulted in data that were only marginally different from data simulated from the true model. Thus all methods investigated appear to provide useful results for the investigated count data models.     

Revelation of an acute lymphoblastic leukemia in the delivery room]

Acute leukemia is uncommon in neonates and has a much poorer prognosis than in older children. We report on a case of acute lymphoblastic leukemia observed in a neonate who had bleeding and hepatosplenomegaly at birth, which justified intensive care during the first postnatal week. Despite early appropriate treatment, the patient died at 7 months of age. We present here physical and laboratory findings, which indicate a grim prognosis. These criteria should be considered carefully in order to ensure a realistic information for the parents and appropriate decisions.     

Phage DNA transport across membranes

Phage nucleic acid transport is atypical in bacterial membrane transport: it is unidirectional and concerns a unique molecule the size of which may represent 50 times that of the bacterium. The rate of DNA transport, although it varies from one phage to another, can reach values as high as 3000 bp s(-1). This raises the following questions which will be discussed in this review. Is there a single mechanism of transport for all types of phages? Does the phage genome cross the outer and inner membranes by a unique mechanism? Is it transported as a free molecule or in association with proteins? How does it avoid periplasmic nucleases? Is such transport dependent on phage and/or host cell components? What is the driving force for transport? Recent cryoelectron microscopy experiments will be presented which show that it is possible to encapsulate a phage genome (121000 bp) into unilamellar liposomes. The interest of such a model system in gene delivery and in the study of the mechanisms of DNA compaction will be discussed.     

Hypoxia-induced cytoskeleton disruption in alveolar epithelial cells

Alveolar hypoxia, a common feature of many respiratory disorders, has been previously reported to induce functional changes, particularly a decrease of transepithelial Na and fluid transport. In polarized epithelia, cytoskeleton plays a regulatory role in transcellular and paracellular transport of ions and fluid. We hypothesized that exposure to hypoxia could damage cytoskeleton organization, which in turn, may adversely affect ion and fluid transport. Primary rat alveolar epithelial cells (AEC) were exposed to either mild (3% O(2)) or severe (0.5% O(2)) hypoxia for 18 h or to normoxia (21% O(2)). First, mild and severe hypoxia induced a disorganization of actin, a major protein of the cytoskeleton, reflected by disruption of F-actin filaments. Second, alpha-spectrin, an apical cytoskeleton protein, which binds to actin cytoskeleton and Na transport proteins, was cleaved by hypoxia. Pretreatment of AEC by a caspase inhibitor (z-VAD-fmk; 90 microM) blunted hypoxia-induced spectrin cleavage as well as hypoxia-induced decrease in surface membrane alpha-ENaC and concomitantly induced a partial recovery of hypoxia-induced decrease of amiloride-sensitive Na transport at 3% O(2). Finally, tight junctions (TJs) proteins, which are linked to actin and are a determinant of paracellular permeability, were altered by mild and severe hypoxia: hypoxia induced a mislocalization of occludin from the TJ to cytoplasm and a decrease in zonula occludens-1 protein level. These modifications were associated with modest changes in paracellular permeability at 0.5% O(2,) as assessed by small 4-kD dextran flux and transepithelial resistance measurements. Together, these findings indicate that hypoxia disrupted cytoskeleton and TJ organization in AEC and may participate, at least in part, to hypoxia-induced decrease in Na transport.