CMTX1 patients' cells present genomic instability corrected by CamKII inhibitors.

BACKGROUND: We previously described that fibroblasts from animal models of CMTX1 present genomic instability and poor connexon activity. In vivo, these transgenic mice present motor deficits. This phenotype could be significantly reverted by treatment with (CamKII) inhibitors. The objective of this study is to translate our findings to patients. METHODS: We cultured fibroblasts from skin biopsies of CMTX1 patients and analyzed cells for genomic instabilty, connexon activity, and potential correction by CamKII inhibitors. RESULTS: The phenotypic analysis of these cells confirmed strong similarities between the GJB1 transgenic mouse cell lines and CMTX1 patient fibroblast cell lines. Both present mitotic anomalies, centrosome overduplication, and connexon activity deficit. This phenotype is corrected by CamKII inhibitors. CONCLUSIONS: Our data demonstrate that fibroblasts from CMTX1 patients present a phenotype similar to transgenic lines that can be corrected by CamKII inhibitors. This presents a track to develop therapeutic strategies for CMTX1 treatment.

Investigating the effects of the fixed and varying dispersion parameters of Poisson-gamma models on empirical Bayes estimates.

Traditionally, transportation safety analysts have used the empirical Bayes (EB) method to improve the estimate of the long-term mean of individual sites; to correct for the regression-to-the-mean (RTM) bias in before-after studies; and to identify hotspots or high risk locations. The EB method combines two different sources of information: (1) the expected number of crashes estimated via crash prediction models, and (2) the observed number of crashes at individual sites. Crash prediction models have traditionally been estimated using a negative binomial (NB) (or Poisson-gamma) modeling framework due to the over-dispersion commonly found in crash data. A weight factor is used to assign the relative influence of each source of information on the EB estimate. This factor is estimated using the mean and variance functions of the NB model. With recent trends that illustrated the dispersion parameter to be dependent upon the covariates of NB models, especially for traffic flow-only models, as well as varying as a function of different time-periods, there is a need to determine how these models may affect EB estimates. The objectives of this study are to examine how commonly used functional forms as well as fixed and time-varying dispersion parameters affect the EB estimates. To accomplish the study objectives, several traffic flow-only crash prediction models were estimated using a sample of rural three-legged intersections located in California. Two types of aggregated and time-specific models were produced: (1) the traditional NB model with a fixed dispersion parameter and (2) the generalized NB model (GNB) with a time-varying dispersion parameter, which is also dependent upon the covariates of the model. Several statistical methods were used to compare the fitting performance of the various functional forms. The results of the study show that the selection of the functional form of NB models has an important effect on EB estimates both in terms of estimated values, weight factors, and dispersion parameters. Time-specific models with a varying dispersion parameter provide better statistical performance in terms of goodness-of-fit (GOF) than aggregated multi-year models. Furthermore, the identification of hazardous sites, using the EB method, can be significantly affected when a GNB model with a time-varying dispersion parameter is used. Thus, erroneously selecting a functional form may lead to select the wrong sites for treatment. The study concludes that transportation safety analysts should not automatically use an existing functional form for modeling motor vehicle crashes without conducting rigorous analyses to estimate the most appropriate functional form linking crashes with traffic flow.

Estimating countermeasure effects for reducing collisions at highway-railway grade crossings.

Frequently transportation engineers are required to make difficult safety investment decisions in the face of uncertainty concerning the cost-effectiveness of different countermeasures. For certain types of highway-railway grade crossings, this problem is further aggravated due to the lack of observed before and after collision data that reflects the impact of specific countermeasures. This study proposes a Bayesian data fusion method as an attempt to overcome these challenges. In this framework, we make use of previous research findings on the effectiveness of a given countermeasure, which could vary by jurisdictions and operating conditions to obtain a priori inference on its expected effects. We then use locally calibrated models, which are valid for a specific jurisdiction, to develop the current best estimates regarding the countermeasure effects. By using a Bayesian framework, these two sources are integrated to obtain the posterior distribution of the countermeasure effectiveness. As a result, the outputs provide information not only of the expected collision response to a specific countermeasure but also its variance and corresponding probability distribution for a range of likely values. Examples from Canadian highway-railway grade crossing data are used to illustrate the proposed methodology and the specific effects of prior knowledge and data likelihood on the combined estimates of countermeasure effects.

Comparative urodynamic patterns of bladder pressure, contractility and urine flow in man and rat during micturition.

A urodynamic characterization of the distinctive patterns of normal micturition in man and rat was undertaken. Data were obtained from experimental studies where bladder pressure was measured suprapubically obviating urethral instrumentation. Ambulatory urodynamic studies were conducted with 17 asymptomatic male volunteers. Bladder pressure was monitored via a supra-pubic catheter and abdominal pressure via a rectal balloon using a UPS2020 ambulatory system. Average duration of each monitoring period was 20.5 hours. Detrusor pressure and flow rate records from each subject were identified and consecutive filling and voiding phases were averaged over the entire monitoring period using the onset of micturition as a time marker. The averaged pattern of pressure, flowrate, cumulative volume, and contractility curves for each subject as well each for group was computed and graphically presented. For comparison, the micturition phase of 18 anesthetized rats were used. A continuous CMG was performed and bladder pressure was recorded suprapubically. For each group the averaged parameters of urethral opening pressure, Max Detrusor pressure, Detrusor pressure at Max flowrate, bladder capacity, and WF were extracted and compared statistically. Numerical values are M +/- SE. The urodynamic temporal patterns observed during the micturition phase of the CMG in terms of detrusor pressure and associated flow, in both man and rat posses striking qualitative similarities. These are particularly striking during the onset of micturition in the great majority of animals. Furthermore the pressures generated by the bladder before and during micturition are quantitatively similar. However there were also distinct differences particularly in the pattern observed during voiding when bladder pressure was oscillatory. The temporal sequence of detrusor pressure and flow in man and rat contains many qualitative and quantitative similarities rendering the rat's potential as a particularly useful model in the study of the onset of micturition.