Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A.
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Abnormalities, Multiple↗
Biomedical subjects
P Cau
Publications and source records attributed to P Cau.
[Are we sectioning the cochlear efferent system during vestibular neurotomy?].
INTRODUCTION: In addition to sensory neurons which transmit information from the inner ear to the brain, there is a system of efferent feedback fibers, called the olivocochlear system, carrying signals from the brain to the ear. Over the past half-century, the efferent system has been extensively studied in animals and results provided theories as to the functional significance of these efferents: to improve signal-to-noise ratio in the auditory periphery, to mediate selective attention, and to protect the inner ear from acoustic overexposure. The results of several studies conducted in man rely on the study of patients who have undergone a vestibular neurectomy. Indeed, anatomical data show that olivocochlear efferents could travel along or inside the vestibular part of the auditory nerve before reaching the organ of Corti. Therefore, these patients may be considered as an experimental model of unilaterally de-efferented subjects. However, to date, none has reported the existence of olivocohlear efferents in the vestibular section following neurectomy. MATERIALS AND RESULTS: In this study, we present the histological results from 18 vestibular sections and show the absence of olivocochlear efferents. CONCLUSION: These results provide a reason to reconsider the results of previous experiments conducted in similar patients and ask for further studies on the olivocochlear efferents pathways.
Cochlea↗
[Skin stem cells].
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Cytological Techniques↗
[An experimental study on the systemic distribution of calibrated talc after intra-pleural injection].
INTRODUCTION: Among the agents used to produce pleural symphysis talc is the most effective and least expensive. However, its use is controversial on account of the description of respiratory complications associated with subsequent systemic spread of the talc particles. This hypothesis rests on clinical and experimental observations of talc particles in the viscera. However, all talc preparations are not identical and this extra-pleural spread could be dependent on particle size. This experimental study was undertaken to determine whether there was systemic spread of a calibrated talc preparation used routinely in clinical practice following intra-pleural administration in rats. METHODS: 48 rats received 20 mg (11 rats) and 40 mg (33 rats) of calibrated talc suspended in 1 ml of physiological saline by intra-pleural injection. The animals were randomised for sacrifice at 24 hours (22 rats) and 72 hours (22 rats) after the injection. The lungs, parietal pleura, diaphragm, liver, spleen, pericardium, brain and blood were examined by light microscopy and polarised light to search for bi-refringent particles. RESULTS: No deaths occurred during the procedure. At the time of sacrifice no pleural symphysis was seen. In 5 animals some talc particles were seen in the extra-thoracic organs: in the liver in 3 in the spleen in 1 and one particle in the brain of one animal examined by electron microscopy. No talc particles were found in the blood. CONCLUSIONS: Intra-pleural injection of calibrated talc, (Steritalc-Novatech-Plan de Grasse-France) has a weak systemic spread in > small animals. These results may be related to the diameter of the talc particles used (mean 33.6 microns; median 31.3 microns). The hypothesis that systemic spread is influenced by the diameter of the talc particles needs to be supported by experimental studies using talc particles of smaller diameter in order to compare the systemic distribution of the different preparations.
Animals↗
IMHS clinical experience in the treatment of peritrochanteric fractures. The results of a multicentric Italian study of 981 cases.
This retrospective study evaluates the results obtained in five Italian departments of traumatology in the treatment of peritrochanteric (pertrochanteric and subtrochanteric) fractures by the intramedullary hip screw (IMHS; Smith & Nephew Richards, Memphis, TN, USA) nail. One thousand two hundred and seventy-three patients were treated with the IMHS nail between March 1992 and February 2000. The results of these operations were evaluated clinically and radiological in 981 patients. The 90.3% of patients could walk unaided or with simple support. Because of the low complication rate requiring re-operation (postoperative shaft fractures, screw penetrated the acetabulum, cut out and non-union) (1.7%), we think that this device is an advance in the treatment of peritrochanteric fractures.
Adult↗
The alpha(1A) subunits of rat brain calcium channels are developmentally regulated by alternative RNA splicing.
Calcium influx through voltage-gated calcium channels governs important aspects of CNS development. Multiple alternative splicings of the pore-forming alpha(1) subunits have been evidenced in adult brain but little information about their expression during ontogenesis is presently available. The aim of this study was to focus on the expression of three rat voltage-gated calcium channel alpha(1A) splice variants (alpha(1A-a), alpha(1A-b) and alpha(1A-EFe)) during brain ontogenesis in vivo. Using a reverse transcription-polymerase chain reaction strategy, we found that the three isoforms have different timings of development throughout the brain: alpha(1A-b) is expressed from embryonic to the adult stage, alpha(1A--EFe) is restricted to the embryonic period whereas alpha(1A-a) is expressed only postnatally. In situ hybridization indicated that alpha(1A-a) and alpha(1A-b) isoforms develop with different regional and cellular patterns. In hippocampus and cerebellum, alpha(1A-b) represented the predominant isoform at all developmental stages. Taken together, these data reveal that alternative RNA splicing may modulate the alpha(1A) calcium channel properties during development.
Alternative Splicing↗
PMP22 overexpression causes dysmyelination in mice.
Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by fibroblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease.
Animals↗
Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.
Animals↗
Absence of hepatitis C genome in semen of infected men by polymerase chain reaction, branched DNA and in situ hybridization.
BACKGROUND/AIMS: The presence or absence of hepatitis C virus (HCV) RNA in the semen of infected man remains controversial, mainly due to technical difficulties associated with nucleic acid detection. The aims of this study were to assess the presence of HCV RNA in spermatozoa and in seminal fluid using different polymerase chain reaction (PCR)- and non-PCR-dependent methods and, in the case of HCV presence, to correlate this detection with the viraemia. METHODS: Serum and semen from 25 chronically infected hepatitis C patients were studied. The semen was separated into spermatozoa and seminal fluid and HCV RNA was analysed in the two fractions using RT-PCR and branched DNA. The presence of HCV RNA in pelleted cells was also assessed using in situ hybridization. RESULTS: All three approaches failed to demonstrate HCV RNA in semen. The presence of an inhibitor of the PCR was demonstrated in seminal fluid but not in spermatoza. CONCLUSION: Our results confirmed the lack of detection of HCV RNA in semen by PCR- and non-PCR-dependent techniques and support the view that viral contamination in semen remains, if present, at a very low level. Nevertheless, epidemiological studies are required to definitively assess the absence of sexual transmission of HCV
Adolescent↗
ARP3beta, the gene encoding a new human actin-related protein, is alternatively spliced and predominantly expressed in brain neuronal cells.
A cDNA encoding a new human actin-related protein (ARP) was cloned. The corresponding protein is highly conserved with the previously described ARP3 protein, suggesting that it represents a second isoform of the human ARP3 subfamily. This new actin-related protein was subsequently named ARP3beta and represents the second example of multiple isoforms of an actin-related protein in a single organism. The ARP3beta gene was mapped to chromosome band 7q34, centromeric to Sonic Hedgehog. Gene structure analysis revealed that at least part of the observed ARP3beta mRNA heterogeneity is caused by alternative splicing resulting in exon skipping. Transcripts produced after exon 2 skipping are predicted to encode truncated products, whose functionality is still unclear. An ARP3beta pseudogene was detected on chromosome 2p11 by database searching. Several ARP3beta mRNA species were detected by Northern blotting and their abundance varied importantly among tissues: the highest expression levels were detected in fetal and adult brain, whereas lower levels were observed in liver, muscle and pancreas. In contrast, ARP3 mRNAs were detected in all tissues tested. Using in situ hybridization, the expression of ARP3beta in brain was shown to be restricted to neurons and epithelial cells from choroid plexus. This suggests a specific function for ARP3beta in the physiology of the development and/or maintenance of distinct subsets of nerve cells.
Actin-Related Protein 3↗
Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Functional and bronchoalveolar lavage cell findings.
As defined by the International Society for Heart and Lung Transplantation, the diagnosis of posttransplant obliterative bronchiolitis (OB) is based on histopathologic features and/or spirometric staging criteria, using FEV(1) to determine the extent of disease. However, this last parameter reflects an advanced bronchiolar process. The present study investigated whether physiologic parameters reflecting smaller airways dysfunction on one hand, and neutrophils in bronchoalveolar lavage fluid (BALF) on the other hand, could be useful for the earlier detection of bronchiolitis obliterans syndrome (BOS). We analyzed data obtained both from 765 pulmonary function test results and from 467 BALF specimens from 45 patients who survived at least 1 yr after surgery (n = 47, including two retransplantations). Of the transplant procedures, 22 were associated with BOS and 25 were not. The mean delay from transplantation to the diagnosis of BOS was 578 d (range: 122 to 2,619 d). The threshold values of the following parameters were studied: decline in the forced expiratory flow rate at 25% to 75% of FVC (FEF(25-75)) to </= 70% of the predicted value and of baseline values, increase in the slope of the nitrogen washout curve (DeltaN(2)) > 3%, and alveolar neutrophilia >/= 20% of the total BALF cell count. Agreement on the diagnosis of BOS (using the decline in FEV(1)) was equally good for each of the four markers (kappa coefficient > 0.65, p < 10(-)(5)). In the OB group, mean delays after the threshold was reached for each of these parameters were 110 d (p = 0.09), 173 d (p = 0.03), 150 d (p = 0.003), and 131 d (p = 0.1), respectively, before the FEV(1) criteria were fulfilled. At the chosen threshold values, the decline in FEF(25-75), increase in DeltaN(2), and development of a substantial alveolar neutrophilia all occurred significantly before a decline in FEV(1) in posttransplant OB.
Adult↗
Two Nkx-3-related genes are expressed in the adult and regenerating central nervous system of the urodele Pleurodeles waltl.
We report the isolation and characterization of two NK-3-related genes (PwNkx-3.2 and PwNkx-3.3) and their expression patterns during embryonic development, in the adult CNS, and during tail regeneration in the urodele Pleurodeles waltl. PwNkx-3.2 is the ortholog of the mouse and Xenopus genes, Bapx 1 and Xbap, but PwNkx-3.3 has no known homologue in any other vertebrate. We demonstrate that PwNkx-3.2 and PwNkx-3.3 exhibit graded axial expression patterns in adult spinal cord. During tail regeneration, the two genes are expressed in the wound epidermis, the regenerating muscle masses, the regenerating neural tube, the spinal ganglia, and the cartilage rod. The spatial distribution of transcripts in the CNS suggests that these genes could participate in maintaining the position information along the anteroposterior axis and may explain the ability of the adult CNS to regenerate. During tail regeneration, both genes could be implicated in the reformation of the axial skeleton.
Amino Acid Sequence↗
Regulation of calcium channel alpha(1A) subunit splice variant mRNAs in kainate-induced temporal lobe epilepsy.
P/Q-type voltage-gated Ca(2+) channels (VGCC) regulate neurotransmitter release in the hippocampus and molecular alterations of their alpha(1A) pore-forming subunits are involved in various animal and human CNS diseases. We evaluated, using RT-PCR and in situ hybridization, the spatio-temporal activation of two alpha(1A) subunits splice variants (alpha(1A-a) and alpha(1A-b)) in control and kainic acid (KA)-treated rats. Six hours after KA treatment, alpha(1A-a) and alpha(1A-b) mRNAs increased, decreased or remained unchanged with area specific patterns. These changes were evidenced in the hippocampus and the dentatus gyrus and absent in the cerebellum. The alpha(1A) mRNA upregulation lasted for at least 7 days after KA treatment. Altogether, these results indicate that alpha(1A-a) and alpha(1A-b) mRNAs following seizure onset exhibit a complex and specific spatio-temporal pattern. The long-lasting changes in alpha(1A) subunit mRNA contents suggests that VGCC may be involved in the mechanisms generating chronic focal hyperexcitability and/or cellular damage in temporal lobe epilepsy.
Alternative Splicing↗
mRNA coding for voltage-gated sodium channel beta2 subunit in rat central nervous system: cellular distribution and changes following kainate-induced seizures.
The cellular distribution of sodium channel beta2 subunit mRNA was examined in the central nervous system from adult Wistar rats using a non-radioactive in situ hybridization method with digoxigenin-labeled cRNA probes. The expression of the subunit was strong in cerebral and cerebellar cortex, in medulla oblongata and in the spinal cord whereas heterogeneous in hippocampus. The distribution was evaluated in hippocampus and cerebral cortex from 1 to 72 h after kainate injection and compared to control rats using densitometric analysis. In these areas, a transient increase was seen 1 h after the drug administration, followed, in the hippocampus, by a significant decrease. These variations differ from those we previously reported for alpha subunits and might play a role in cellular excitability changes occurring in the course of seizures.
Animals↗
Effect of gamma knife radiosurgery on rat brain sodium channel subunit mRNA expression.
Several lines of evidence underscore a possible and delayed antiepileptic effect of Gamma Knife irradiation. This effect could be related to structural and molecular changes. Since voltage-gated Na+ channels (NaChs) play a crucial role in neuron excitability, we studied the effect of Gamma Knife (GK) irradiation on the distribution of Na+ channel (NaCh) subunit mRNAs in rat brains. A left side irradiation was performed in rats using a stereotactic device adapted for GK radiosurgery. A dose of 100 Gy was administered with the 4 mm collimator. The left dentate gyrus and thalamus coordinates were based on De Groot's rat stereotactic atlas. The isodose curve distribution was calculated with the dose planning software used in Gamma Knife and superimposed on the target. Na+ channels alpha unit and mRNAs (subtype II and subtype III) expression was studied 1 hour, 30 days and 60 days later. We used non-radioactive in situ hybridization with subtype-specific digoxigenin-labeled cRNA probes. Labeling intensity was evaluated with a densitometric analysis of digitized images from the control side (right) and lesioned side (left) in each rat. No morphological changes were observed one hour after GK irradiation. 30 days later, the upper thalamic nuclei exhibited a few necrotic regions associated with gliosis. In contrast, no lesions were observed in the hippocampus. 60 days later, the necrotic region involving thalamic nuclei was enlarged. NaCh II and III mRNAs expression did not appear to be modified after GK at the three times studied here. In particular, neurons surrounding the GK necrosis continued to express high levels of NaCh mRNAs. Thus, regulation of NaCh II and III subtypes do not appear to explain the functional antiepileptic effect of GK.
Animals↗
NHE-3 isoform of the Na+/H+ exchanger in human gallbladder. Localization of specific mRNA by in situ hybridization.
BACKGROUND/AIMS: Electroneutral absorption of NaCl by the gallbladder mucosa is likely to depend at least in part on a Na+/H+ exchanger. In intestine and colon, absorption due to Na+/H+ exchanger is explained by the presence of specific isoforms of the exchanger, the NHE-3 isoform and possibly the NHE-2 isoform. The aim of the present work was to determine whether the mRNAs coding for NHE-2 and NHE-3 are expressed in epithelial cells of human gallbladder. METHODS: Total RNAs from human gallbladder were subjected to reverse transcription-polymerase chain reaction using specific primers. No message was observed with NHE-2 specific primers, showing that NHE-2 isoform plays no role in gallbladder absorption. With NHE-3 specific primers, a 239 bp cDNA fragment was obtained and showed a high homology with the NHE-3 isoform, confirming the presence of NHE-3 in the gallbladder wall. This fragment was cloned in a pLitmus vector in order to produce cRNA probes by in vitro transcription. Cellular localization of the NHE-3 mRNA was studied on cryostat sections using the cRNA probes labeled with Digoxigenin-11-UTP, controls included assays with sense probe, antibodies without probe and RNaseA treated tissue. A specific staining of the NHE-3 mRNAs was found to be strictly localized to the gallbladder epithelial cells. RESULTS/CONCLUSIONS: Expression of NHE-3 in the gallbladder was found only in the absorptive epithelial cells. The NHE-3 isoform of the Na+/H+ exchanger is likely to be involved in water and electrolyte absorption from bile.
Base Sequence↗
Increase in mRNAs encoding neonatal II and III sodium channel alpha-isoforms during kainate-induced seizures in adult rat hippocampus.
Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.
Animals↗
Changes in the mRNAs encoding subtypes I, II and III sodium channel alpha subunits following kainate-induced seizures in rat brain.
Several lines of evidence underscore a possible role of voltage-gated Na+ channels (NaCH) in epilepsy. We compared the regional distribution of mRNAs coding for Na+ channel alpha subunit I, II and III in brains from control and kainate-treated rats using non-radioactive in situ hybridization with subtype-specific digoxigenin-labelled cRNA probes. Labelling intensity was evaluated by a densitometric analysis of digitized images. Heterogeneous distribution of the three Na+ channel mRNAs was demonstrated in brain from adult control rats, which confirmed previous studies. Subtype II mRNAs were shown to be abundant in cerebellum and hippocampus. Subtype I mRNAs were also detected in these areas. Subtype III mRNAs were absent in cerebellar cortex, but significantly expressed in neurons of the medulla oblongata and hippocampus. The three subtypes were differentially distributed in neocortical layers. Subtype II mRNAs were present in all of the layers, but mRNAs for subtypes I and III were concentrated in pyramidal cells of neocortex layers IV-V. During kainate-induced seizures, we observed an increase in Na+ channel II and III mRNA levels in hippocampus. In dentate gyrus, subtype III mRNAs increased 3 h after KA administration to a maximum at 6 h. At this latter time, a lower increase in NaCh III mRNAs was also recorded in areas CA1 and CA3. NaCh III overexpression in dentate gyrus persisted for at least 24 h. In the same area, NaCh II mRNAs were also increased with a peak 3 h after KA injection and a return to control levels by 24 h. No changes in NaCh I mRNAs were seen. The KA-induced up-regulation in NaCh mRNAs probably resulted in an increase in hippocampal neuronal excitability.
Animals↗