Recurrent benign paroxysmal positional vertigo in two DFNB16 siblings: A CARE case report.

INTRODUCTION: Deletions or variants of the STRC gene coding for stereocilin cause congenital bilateral mild-to-moderate sensorineural hearing loss without vestibular disorder: DFNB16. Stereocilin is a protein present in vestibular kinocilia embedded in the otoconial membrane of the utricular macula. Benign paroxysmal positional vertigo (BPPV) is a rare form of vertigo in children. The present study reports recurrent positional vertigo in two DFNB16 siblings. OBSERVATION: Two patients, 10 and 15 years old, presented with recurrent disabling positional vertigo episodes, triggered by turning over in bed, with a falling sensation. The diagnosis of right posterior canal BPPV was confirmed on Dix-Hallpike maneuvers in one of the patients. Variations in the response of ocular vestibular-evoked myogenic potentials were observed. Probable BPPV was diagnosed in the second patient. Their other two siblings did not have hearing loss or vertigo. CONCLUSION: The absence of stereocilin due to homozygous deletions of the STRC gene in DFNB16 patients can cause vestibular dysfunction, including BPPV.

Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability.

Language processing is a highly integrative function, intertwining linguistic operations (processing the language code intentionally used for communication) and extra-linguistic processes (e.g., attention monitoring, predictive inference, long-term memory). This synergetic cognitive architecture requires a distributed and specialized neural substrate. Brain systems have mainly been examined at rest. However, task-related functional connectivity provides additional and valuable information about how information is processed when various cognitive states are involved. We gathered thirteen language fMRI tasks in a unique database of one hundred and fifty neurotypical adults (InLang [Interactive networks of Language] database), providing the opportunity to assess language features across a wide range of linguistic processes. Using this database, we applied network theory as a computational tool to model the task-related functional connectome of language (LANG atlas). The organization of this data-driven neurocognitive atlas of language was examined at multiple levels, uncovering its major components (or crucial subnetworks), and its anatomical and functional correlates. In addition, we estimated its reconfiguration as a function of linguistic demand (flexibility) or several factors such as age or gender (variability). We observed that several discrete networks could be specifically shaped to promote key functional features of language: coding-decoding (Net1), control-executive (Net2), abstract-knowledge (Net3), and sensorimotor (Net4) functions. The architecture of these systems and the functional connectivity of the pivotal brain regions varied according to the nature of the linguistic process, gender, or age. By accounting for the multifaceted nature of language and modulating factors, this study can contribute to enriching and refining existing neurocognitive models of language. The LANG atlas can also be considered a reference for comparative or clinical studies involving various patients and conditions.

Myringoplasty without tympanomeatal flap elevation in children: A systematic review.

OBJECTIVES: Systematic review of the literature on myringoplasty techniques without tympanomeatal flap elevation in children. MATERIAL AND METHODS: A systematic review following PRISMA guidelines reported papers on patients under 18years of age undergoing myringoplasty for chronic tympanic perforation on a transcanal approach without tympanomeatal flap elevation. Tympanic closure rates and audiometric results were analyzed. RESULTS: Twenty studies were included. Nine reported the butterfly technique, using a microscope or endoscope, with closure rate of 82.3% (246/299), for perforations of various sizes. Ten reported the fat-plug technique, with closure rate of 86.8% (869/1001), mostly for perforations of less than one-third of the tympanum. Both techniques improved audiometric results. Morbidity was very low. The absence of chronic otitis or co-morbidities (contralateral otitis media with effusion, craniofacial malformations, Down's syndrome) implies that patient selection technique may be necessary to obtain the best results. CONCLUSION: Fat-plug myringoplasty, for small perforations, and butterfly cartilage myringoplasty seem to be reliable procedures in selected patients, with low morbidity in children.

Brain networks of rats under anesthesia using resting-state fMRI: comparison with dead rats, random noise and generative models of networks.

OBJECTIVE: Connectivity networks are crucial to understand the brain resting-state activity using functional magnetic resonance imaging (rs-fMRI). Alterations of these brain networks may highlight important findings concerning the resilience of the brain to different disorders. The focus of this paper is to evaluate the robustness of brain network estimations, discriminate them under anesthesia and compare them to generative models. APPROACH: The extraction of brain functional connectivity (FC) networks is difficult and biased due to the properties of the data: low signal to noise ratio, high dimension low sample size. We propose to use wavelet correlations to assess FC between brain areas under anesthesia using four anesthetics (isoflurane, etomidate, medetomidine, urethane). The networks are then deduced from the functional connectivity matrices by applying statistical thresholds computed using the number of samples at a given scale of wavelet decomposition. Graph measures are extracted and extensive comparisons with generative models of structured networks are conducted. MAIN RESULTS: The sample size and filtering are critical to obtain significant correlations values and thereby detect connections between regions. This is necessary to construct networks different from random ones as shown using rs-fMRI brain networks of dead rats. Brain networks under anesthesia on rats have topological features that are mixing small-world, scale-free and random networks. Betweenness centrality indicates that hubs are present in brain networks obtained from anesthetized rats but locations of these hubs are altered by anesthesia. SIGNIFICANCE: Understanding the effects of anesthesia on brain areas is of particular importance in the context of animal research since animal models are commonly used to explore functions, evaluate lesions or illnesses, and test new drugs. More generally, results indicate that the use of correlations in the context of fMRI signals is robust but must be treated with caution. Solutions are proposed in order to control spurious correlations by setting them to zero.

Hearing impairment and osteogenesis imperfecta: Literature review.

The goal is to clarify the epidemiology of hearing loss in patients with osteogenesis imperfecta (OI), so as to improve management. A literature review analyzed data from 15 patient series. Hearing loss prevalence in OI varied widely, from 2% to 94.1%. Typically, hearing loss was conductive in young patients and sensorineural in older patients. Prevalence increased with age, but after 50 years the increase was slight, and seldom became total. Hearing loss was usually bilateral, but not necessarily symmetrical. There were no correlations between type of mutation (COL1A1 or COL1A2), prevalence, type or severity of hearing loss, or age of symptom onset; there was intra-familial variability. There was also no correlation between mutated gene, type of mutation and auditory phenotype. Frequency, type and severity of hearing loss were unrelated to other clinical parameters. Hearing loss prevalence depended on type of OI: higher in type I and lower in type IV. Incidence of otitis media was higher in children with OI, related to the associated craniofacial dysmorphia. Hearing screening before 5 years of age with long-term follow-up are recommended.

Reliability of graph analysis of resting state fMRI using test-retest dataset from the Human Connectome Project.

The exploration of brain networks with resting-state fMRI (rs-fMRI) combined with graph theoretical approaches has become popular, with the perspective of finding network graph metrics as biomarkers in the context of clinical studies. A preliminary requirement for such findings is to assess the reliability of the graph based connectivity metrics. In previous test-retest (TRT) studies, this reliability has been explored using intraclass correlation coefficient (ICC) with heterogeneous results. But the issue of sample size has not been addressed. Using the large TRT rs-fMRI dataset from the Human Connectome Project (HCP), we computed ICCs and their corresponding p-values (applying permutation and bootstrap techniques) and varied the number of subjects (from 20 to 100), the scan duration (from 400 to 1200 time points), the cost and the graph metrics, using the Anatomic-Automatic Labelling (AAL) parcellation scheme. We quantified the reliability of the graph metrics computed both at global and regional level depending, at optimal cost, on two key parameters, the sample size and the number of time points or scan duration. In the cost range between 20% to 35%, most of the global graph metrics are reliable with 40 subjects or more with long scan duration (14min 24s). In large samples (for instance, 100 subjects), most global and regional graph metrics are reliable for a minimum scan duration of 7min 14s. Finally, for 40 subjects and long scan duration (14min 24s), the reliable regions are located in the main areas of the default mode network (DMN), the motor and the visual networks.

Directed differential connectivity graph of interictal epileptiform discharges.

In this paper, we study temporal couplings between interictal events of spatially remote regions in order to localize the leading epileptic regions from intracerebral EEG (iEEG). We aim to assess whether quantitative epileptic graph analysis during interictal period may be helpful to predict the seizure onset zone of ictal iEEG. Using wavelet transform, cross-correlation coefficient, and multiple hypothesis test, we propose a differential connectivity graph (DCG) to represent the connections that change significantly between epileptic and nonepileptic states as defined by the interictal events. Postprocessings based on mutual information and multiobjective optimization are proposed to localize the leading epileptic regions through DCG. The suggested approach is applied on iEEG recordings of five patients suffering from focal epilepsy. Quantitative comparisons of the proposed epileptic regions within ictal onset zones detected by visual inspection and using electrically stimulated seizures, reveal good performance of the present method.

Global Functional Disconnections in Post-anoxic Coma Patient.

Disorders of consciousness have been related to different disconnection patterns as assessed by neuroimaging tools such as PET or fMRI. In this report, we use resting-state functional MRI acquisition and a functional connectivity analysis by graph of brain networks, to investigate the global residual connection pattern in a patient with consciousness disorders following post-anoxic injury. We then compare this pattern with those of a group of twenty controls. We observed that the patient's graph presents multiple disconnections in primary areas and in high-order associative areas. This pattern is consistent with a vegetative state, as reported by other groups. Further, the informations conveyed by this approach are consistent with those provided by PET, fMRI and EP. This new approach presents a very strong potential for diagnosis for consciousness disorder patients since it is applicable very early after the insult.

Comparison of five directed graph measures for identification of leading interictal epileptic regions.

Directed graphs (digraphs) derived from interictal periods of intracerebral EEG (iEEG) recordings can be used to estimate the leading interictal epileptic regions for presurgery evaluations. For this purpose, quantification of the emittance contribution of each node to the rest of digraph is important. However, the usual digraph measures are not very well suited for this quantification. Here, we compare the efficiency of recently introduced local information (LI) measure and a new measure called total global efficiency with classical measures like global efficiency, local efficiency and node degree. For evaluation, the estimated leading interictal epileptic regions based on five measures are compared with seizure onset zones obtained by visual inspection of epileptologists for five patients. The comparison revealed the superior performance of the LI measure. We showed efficiency of different digraph measures for the purpose of source and sink node identification.

The amyloid peptide induces early genotoxic damage in human preneuron NT2.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the extracellular deposition of amyloid beta-peptide (Abeta) in the brain. Abeta is involved in the pathogenesis of AD but the molecular mechanisms of its neurotoxicity are unknown. Here, we report that Abeta exposure on human preneuronal NT2 cells provoked a strong and early up-regulation of growth arrest and DNA damage inducible gene (Gadd45 mRNA), an indicator of DNA damage and DNA excision-repair processes, strongly suggesting that Abeta causes an early DNA strand breakage leading to a cellular DNA repair response. Comet assay clearly demonstrated that both full-length Abeta (1-42), and its minimal cytotoxic fragment Abeta (25-35), caused DNA breakage as early as 3h after the start of Abeta exposure. This extensive DNA damage provoked by Abeta constitutes an early event in the pathogenic cascade leading to neuronal death which could contribute to the neuropathogenesis of AD.

Assessment of quality of life during intensive chemotherapy or bone marrow transplantation.

Quality of life (QOL) of 179 patients with hematological malignancies, hospitalized for induction chemotherapy, allogeneic or autologous bone marrow transplantation (BMT), was analyzed on three time points at 10 days interval after completion of the cytotoxic treatment. The instruments used were the EORTC questionnaire--with modifications of the physical and social functioning subscales, in order to adapt to the prolonged stay in the hospital--, the Hospital Anxiety and Depression Scale, and a specifically designed leukemia/BMT module. The psychometric properties of the scales were confirmed, except for the physical functioning and social subscales, for which further methodological studies are warranted. A relatively high frequency of somatic symptoms, fatigue, anxiety and depression was observed, with a trend to improvement at the end of hospitalization. The overall self-assessed QOL correlated mainly with fatigue and emotional disorders but not with the somatic symptoms. Randomized disclosure of the collected information to the staff allowed them to better identify patients who needed a psychotherapeutic intervention, but did not influence the psychological and QOL outcomes.

Induction of apoptosis in rat hepatocarcinoma cells by expression of IGF-I antisense c-DNA.

BACKGROUND/AIMS: We have developed a gene therapy strategy based on the observation that insulin-like growth factor I (IGF-I) is necessary for the acquisition and maintenance of the transformed phenotype in hepatocarcinoma. This strategy consists in transfecting the rat hepatoma cell line with an episomal vector expressing the antisense IGF-I c-DNA under the control of the metallothionein I promoter inducible by zinc, decreasing therefore the level of IGF-I in these cells. The transfected clones lost their tumorigenic properties, and were able to induce, in vivo, the regression of an established tumor in syngeneic rats. To understand the loss of tumorigenic properties of these transfected clones, we have quantified, by different approaches, the number of apoptotic cells according to the level of IGF-I expression. METHODS: IGF-I antisense synthesis in transfected cells was stimulated using zinc. We then characterized and quantified apoptosis, in these transfected clones, by morphological and DNA fragmentation analyses, flow cytometry and comet assay. RESULTS: We have demonstrated that IGF-I inhibits the development of apoptosis in parental cells, that the transfected clones are able to restore the spontaneous apoptotic programme, and that apoptosis increases massively when overexpression of IGF-I antisense is caused by zinc stimulation of the metallothionein I promoter. CONCLUSION: The present results allow us to conclude that the level of apoptotic pathway in liver cell lines is directly related to the amount of IGF-I deficiency.

FK506 (Tacrolimus) decreases the cytotoxicity of cyclosporin A in rat hepatocytes in primary culture: implication of CYP3A induction.

Tacrolimus (FK506) and cyclosporin A (CsA) are two potent immunosuppressants mainly metabolized by hepatic cytochrome P-450 3A (CYP3A) monooxygenase. The aim of this study was to compare the toxic effects of the two drugs on hepatocytes in primary culture as a function of their metabolism and to explore the variations of cytotoxicity when both drugs are associated. The cytotoxicity of FK506 and CsA, as expressed by their IC50 values, was of the same order but with a switch according to whether hepatocytes were induced or uninduced by dexamethasone, CsA being more toxic in its native form and FK506 through its metabolism. Similar results were obtained with the intracellular calcium content. When both drugs were associated at their IC50 values, the expected additive cytotoxic effect was not observed. Moreover, when small quantities of FK506 were added to CsA at its IC50, cell viability improved in the induced cultures. It is hypothesized that the interaction between the two drugs relies on a mechanism involving both competition of FK506 and CsA for CYP3A and of their immunophilin complexes for a common site on the calcineurin-calmodulin complex.

Study of the stability of a paramagnetic label linked to mesoporous silica surface in contact with rat mesothelial cells in culture.

Stable radicals detectable by electron paramagnetic resonance (EPR) may be use in the investigation of early events in cell-particle toxicity. Piperidine-N-oxyl derivatives (nitroxides), covalently linked to the surface of a high surface area silica (used as model solid for the technique), served as probes in the investigation of the effects of incubation of silica particles with mesothelial cells. A mesoporous silica (MCM-41), prepared by precipitation from a micellar solution, was the most appropriate silica-based particle for this purpose, as its channels allow direct contact with small molecules but not with macromolecules. The cytotoxicity of this amorphous silica is very low, allowing relatively high particle loading in the cell cultures. Both the high surface area of the sample and the large amount of inorganic material extracted from the cell culture provide enough material to run reasonably intense EPR spectra. Computer-aided analysis of the EPR spectra of silica-bound nitroxides provided information on the sensitivity of the labeled silica monitoring different environments, e.g., to follow the path of particles in a mammalian cell culture. Upon contact of the particles with mesothelial cells, the mean distance among the labels at the silica surface decreased as a consequence of the release of oxidizing and/or radical moieties from the cells.

Implication of CYP 3A in the toxicity of cyclosporin G (CsG), cyclosporin A (CsA) and FK506 on rat hepatocytes in primary culture.

FK506, cyclosporin A (CsA), and its structural analog cyclosporin G (CsG) are immunosuppressant drugs mainly metabolized by hepatic cytochrome P-450 3A (CYP 3A) oxygenase. FK506 metabolites exhibit greater toxicity than the parent drug, while CsA metabolites are far less toxic than CsA itself. The aim of our study was to compare the toxicity of CsG with CsA and FK506 as a function of CYP 3A induction. Hepatocytes from Wistar rats with or without dexamethasone (DEX) induction (200 mg/kg per day, p.o for 4 days) were used in primary culture. The DEX-inductive effect on CYP 3A was assessed by SDS-PAGE. After 6 h incubation with CsG, CsA or FK506 (5 to 200 microM), cell viability (expressed as IC50), intracellular calcium content and apoptosis were evaluated. Concerning cytotoxicity, IC50 values for CsG, CsA and FK506 were 75, 50 and 180 microM respectively in non-induced cultures, and 150, 120 and 25 microM in induced cultures. For intracellular calcium content, a dose-dependent increase was observed in all cultures. However this increase is more important for CsG and CsA in non-induced cultures (150%) compared to induced cultures (110%) at 150 microM. Conversely for FK506, this increase is greater in induced cultures (150%) than in non-induced cultures (127%). Estimation of the percentage of apoptotic cells shows similar variations. Our results show that the toxicity of the three drugs in rat hepatocytes is dependent on CYP 3A induction: increased for FK506, decreased for CsA and CsG. Moreover, with regard to the three tests used, the toxic effects of CsG are close to those of CsA, indicating that CsG metabolites are also less toxic than the parent drug.

Modulation of energy status and cytotoxicity induced by FK506 and cyclosporin A in a renal epithelial cell line.

FK506 and cyclosporin A (CsA) are two potent immunosupressants with similar toxicity profile. Nephrotoxicity is the main adverse effect of both compounds. The aim of this study is to compare the in vitro nephrotoxic effects on renal epithelial cell line LLC-PK1 by measuring cell viability and energy status as evaluated by concentrations of ATP and ATP metabolites. Cell viability (expressed as IC50 was assessed via thiazolyl blue (MTT) assay after incubation for 4-24 h with FK506 or CsA. ATP and its metabolites were determined by HPLC after 4 and 6 h incubation with FK506 or CsA alone at the respective IC50. Both FK506 and CsA decreased cell viability to similar extents, in a dose- and time-dependent manner. After 4 h incubation, both drugs decreased ATP levels (-25%) and increased uric acid levels. However, the latter percentage increase was twofold higher with CsA (18%) than with FK506 (9%). The energy charge, calculated according to levels of adenine nucleotides, was decreased by 10% in FK506-treated cells and by 27% in CsA-treated cells. At the end of 6-h incubation, FK506-treated cells maintained ATP levels coupled with energy charge at near control levels whereas the levels were 32% lower in CsA treated cells. Compared to the 4 h-incubation, the increase in uric acid was similar for FK506 but was doubled with CsA. The decrease in cell integrity and ATP depletion induced by CsA in LLC-PK1 cells was only transiently observed with FK506. By preserving energy status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor potential nephrotoxicity.

Protective effect of nifedipine against cytotoxicity and intracellular calcium alterations induced by acetaminophen in rat hepatocyte cultures.

Alteration of calcium homeostasis has been proposed to play a major role in cell necrosis induced by a variety of chemical agents such as acetaminophen (APAP). In this study, a potential protective effect of the dihydropyridine calcium channel blocking agent, nifedipine, was investigated in vitro on acetaminophen-induced hepatocyte damage. Rat hepatocytes were exposed during 20 hours to various concentrations of APAP (0.50 to 4.00 mM). The following metabolic and functional parameters were investigated: -lactate dehydrogenase (LDH) release as an indicator of plasma membrane integrity, -cell viability evaluated by the colorimetric MTT assay, and intracellular calcium concentration as evaluated by two fluorimetric methods: a scanning laser cytometer using indo-1-AM as fluorescent probe and a fluorescence plate reader using fluo-3-AM as calcium indicator. Incubation of hepatocytes with APAP alone in the range 0.50 to 4.00mM resulted in a dose-response relationship with regard to LDH release (243% to 750% of control) and to the loss of cell viability (0 to 67% of control). Moreover these results were correlated with a significant increase in cytosolic calcium content (189 to 406 nM). Nifedipine treatment prior to APAP exposure, partially prevented LDH release, the plasma membrane blebbing, and thereby the loss of viability. In addition, intracellular calcium level progressively returned within the limits of the control values with increasing concentrations of nifedipine. It can be concluded that, in vitro conditions, nifedipine pretreatment exhibits a preventive effect against acetaminophen hepatocyte injury.