Congenital factor XIII deficiency caused by two mutations in eight Tunisian families: molecular confirmation of a founder effect

Inherited factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by an umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding spontaneous intracranial hemorrhage, and soft tissue hemorrhages. Congenital FXIII deficiency is an autosomal recessive disorder, usually attributed to a defect in the FXIIIA and B subunits coding, respectively, by F13A and F13B genes. The aim of this study was to determine the molecular defects responsible for congenital factor XIII deficiency in eight Tunisian families. Molecular analysis was performed by direct DNA sequencing of polymerase chain reaction amplified fragments spanning the coding regions and splice junctions of the FXIIIA subunit gene (F13A) in probands and in families' members and compared with the reported sequence of this gene. In all patients, FXIIIA activity was undetectable and the FXIIIB was within the normal range. Direct sequencing of the F13A gene in all probands showed two mutations: the c.869insC mutation found in eight patients and the c.1226G?>?A transition found in only one. We also confirmed the presence of a founder effect for the first frequent mutation by using two microsatellite markers, HUMF13A01 and a generated ployAC marker (HUMF13A02). We describe here molecular abnormalities found in nine Tunisian probands diagnosed with FXIIIA deficiency. The identification of the founder mutation and polymorphisms allowed a genetic counseling in relatives of these families, and the antenatal diagnosis is now available.     

New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of -dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.     

Magnetic resonance imaging spatial and time study of lung water content in newborn lamb: methods and preliminary results

To study the lung liquid clearance in vivo at the time of birth, magnetic resonance experiments were conducted on newborn lambs immediately after uterine incision deliverance. Images obtained with a fast spin echo magnetic resonance imaging sequence enable to quantify lung liquid each 5 minutes for 30 minutes, then each 10 minutes for 1.5 hours. After manually determining lung contours, pulmonary volume, pulmonary water, and spatial gradient of pulmonary water were studied. At 2 hours of life, the total pulmonary water content was still high and the liquid clearance was slower in the lower part of the lung. Air inflation increased the size of the distal airways and shifted liquid from the lung lumen towards the pulmonary interstitial tissue. The lung liquid washout was belated, and the passage to the aerial life was performed by progressive liberation of the superior pulmonary spaces, water flowing out by gravity toward the lower spaces.     

Optimal trajectory generation and robust flatness–based tracking control of quadrotors

This work proposes an optimal trajectory generation and a robust flatness–based tracking controller design to create a new performance guidance module for the quadrotor in dense indoor environments. The properties of the differential flatness, the B‐spline, and the direct collocation method are exploited to convert the constrained optimization problem into a nonlinear programming one, which can be easily resolved by a classic solver. After that, the obtained optimal reference trajectory is applied to the dynamic quadrotor model and two different flatness‐based controllers, namely, one based on feedback linearization and one based on feedforward linearization, are developed and compared to ensure the trajectory tracking despite the existence of disturbances and parametric uncertainties. Numerical simulation is executed to evaluate the proposed optimal trajectory generation approach and the robust tracking strategies. It turns out that the controller based on feedforward linearization outperforms the feedback linearization one in robustness and permits obtaining a performance guidance law for an uncertain quadrotor system.     

Attention impairment in temporal lobe epilepsy: A neurophysiological approach via analysis of the P300 wave

Purpose: Attention is often impaired in temporal lobe epilepsy (TLE). The P300 wave (an endogenous, event‐related potential) is a correlate of attention which is usually recorded during an “oddball paradigm,” where the subject is instructed to detect an infrequent target stimulus presented amongst frequent, standard stimuli. Modifications of the P300 wave's latency and amplitude in TLE have been suggested, but it is still not known whether the source regions also differ. Our hypothesis was that temporal lobe dysfunction would modify the P3 source regions in TLE patients. Methods: A comparative, high density, 128‐channel electroencephalographic analysis of the characteristics of P300 (P3b latency and amplitude) was performed in 10 TLE patients and 10 healthy controls during auditory and visual oddball paradigms. The P3b sources were localized on individual 3D MR images using the LORETA method and intergroup statistical comparisons were performed using SPM2® software. Results: Our main results (in both individual analyses and intergroup comparisons) revealed a reduction in temporal (and more particularly mesiotemporal) sources and, to a lesser extent, frontal sources in TLE patients, compared with controls. Discussion: This reduction may reflect direct, local cortical dysfunction caused by the epileptic focus or more complex interference between epileptic networks and normal attentional pathways. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Quantitative approach to early neonatal EEG visual analysis in hypoxic-ischemic encephalopathy severity: Bridging the gap between eyes and machine

ObjectivesTo identify relevant quantitative parameters for early classification of neonatal hypoxic-ischemic encephalopathy (HIE) severity from conventional EEGs.MethodsNinety EEGs, recorded in full-term infants within 6 h of life after perinatal hypoxia, were visually classified according to the French EEG classification into three groups of increasing HIE severity.Physiologically significant EEG features (signal amplitude, continuity and frequency content) were automatically quantified using different parameters. The EEG parameters selection was based on their ability to reproduce the visual EEG classification. Post hoc analysis based on clinical outcome was performed.ResultsSix EEG parameters were selected, with overall EEG classification performances between 61% and 70%. All parameters differed significantly between group 3 (severe) and groups 1 (normal-mildly abnormal) and 2 (moderate) EEGs (p < 0.001). Amplitude and discontinuity parameters were different between the 3 groups (p < 0.01) and were also the best predictors of clinical outcome. Conversely, pH and lactate did not differ between groups.DiscussionThis study provides quantitative EEG parameters that are complementary to visual analysis as early markers of neonatal HIE severity. These parameters could be combined in a multiparametric algorithm to improve their classification performance. The absence of relationship between pH lactate and HIE severity reinforces the central role of early neonatal EEG.     

A dose verification tool for high-dose-rate interstitial brachytherapy treatment planning in accelerated partial breast irradiation

PurposeTo develop a dose verification tool for high-dose-rate interstitial brachytherapy treatment planning in accelerated partial breast irradiation.Methods and MaterialsWe have developed a software tool for interstitial brachytherapy treatment planning assessment. The software contains a database of seven ¹⁹²Ir source models and is able to estimate the dose distribution using the Task Group 43 and the Sievert integral algorithms. Dose–volume histogram analysis and dose quality assurance (QA) criteria including conformity (COnformal INdex [COIN] and conformation number [CN]), homogeneity (homogeneity index [HI]) parameters were implemented in the software to evaluate and to compare between the doses estimated by the two algorithms and a dose extracted from an external treatment planning system (TPS).ResultsThe tool was evaluated and validated on four clinical cases treated by high-dose-rate interstitial brachytherapy. The doses provided by the Task Group 43 and the Sievert integral algorithms were evaluated by establishing the dose–volume histogram analysis and then by calculating the QA criteria. The algorithms were validated by comparing the dose at different anatomic points with their corresponding dose points provided from TPS. The differences were considered in good agreement (within 5%).ConclusionsPretreatment dose verification is an important step in the QA of brachytherapy accelerated partial breast irradiation. A simple, fast, and accurate method of dose verification is therefore needed. The software proposed in this study could fulfill these requirements. In addition, it is freely available for using by anyone wishing to do a QA on any TPS.     

Assessment of an uncalibrated pressure waveform device's ability to track cardiac output changes due to norepinephrine dose adjustments in patients with septic shock: A comparison with Doppler echocardiography

Objectives

The FloTrac^® Vigileo^® (FTV) estimates cardiac output (CO) on the basis of an uncalibrated arterial pressure waveform. To assess the ability of the third-generation of FTV (v.3.02) to track changes in CO following norepinephrine dose adjustment in patients with septic shock, we performed a comparative study using Doppler echocardiography (DE).

Study design

Prospective observational study.

Patients

We prospectively included 20 mechanically ventilated patients receiving norepinephrine and monitored with the FTV. Five minutes after each change in norepinephrine dose (decided by the attending physician), CO was measured simultaneously with the FTV (CO_FTV) and DE (CO_DE). The changes in CO were compared. ROC curves were built to assess the ability of FTV to detect significant changes in CO_DE of at least 15%.

Results

Ninety pairs of CO variations measurements were made. The intertechnique correlation coefficient for changes in CO of at least 15% was r = 0.59; P = 0.0009. The AUC of a ROC curve built to test the FTV's ability to detect a CO_DE increase of 15% or more was 0.783 (± 0.083) (P = 0.005). A CO_FTV threshold value of 15% had a sensitivity of 54% (25–81) and a specificity of 87% (77–94). For a CO_DE decrease of 15% or more, the ROC curve had an AUC of 0.616 (± 0.075) (P = 0.12) and a CO_FTV threshold value of 13% yielded a sensitivity of 53% (27–79) and a specificity of 72% (60–82).

Conclusions

The FTV was unable to accurately track changes in CO following norepinephrine dose adjustments in critically ill patients with septic shock.