[Infants poisoned with cannabis]. / L'intoxication au cannabis chez le nourrisson.

We reported three cases of infants poisoned with cannabis. These patients presented with acute neurological disorders such as drowsiness accompanied by hypotonia, mydriasis and seizure. Cannabis was found in all children either in the urine or in the blood. These cases illustrated that young age should not exclude toxicologic analysis in acute neurological disorders. Cannabis poisoning in infants is a rare reason for consultation. Clinical signs and symptoms are unspecific and severe manifesta- tions in pediatric age are not well known by emergency physicians and paediatricians.

Nous rapportons trois cas de nourrissons intoxiqués au cannabis. Ces patients s'étaient présentés avec des troubles aigus du comportement de type somnolence accompagnés d'hypotonie, de mydriase et de convulsions pour l'un d'eux. Du cannabis était présent soit dans les urines soit dans le sang dans les trois cas. Ces cas illustrent que le jeune âge ne doit pas exclure la recherche de toxiques dans les mises au point de troubles neurologiques aigus. L'intoxication au cannabis du nourrisson est un motif rare de consultation. La clinique est aspécifique et les manifestations sévères plus fréquentes à l'âge pédiatrique sont peu connues.

Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Guidelines of the French Society of ENT (SFORL): Drug-induced sleep endoscopy in adult obstructive sleep apnea syndrome.

OBJECTIVES: To determine the indications, anesthesiological and surgical procedure and interest of drug-induced sleep endoscopy in the treatment of adult obstructive sleep apnea syndrome. DESIGN: A redactional committee of 17 experts was set up. Conflicts of interest were disclosed and followed up throughout the process of drawing up the guidelines. The work received no funding from any firm dealing in health products (drugs or devices). The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was applied to assess the quality of the data on which the guidelines were founded. It was stressed that strong recommendations should not be made on the basis of poor-quality or insufficient data. METHODS: The committee studied 29 questions on 5 topics: indications and contraindications, anesthetic technique, surgical technique, interpretation and reporting of results, and management guided by results. RESULTS: Expert review and application of the GRADE method led to 30 guidelines: 10 with high level of evidence (Grade 1+ or 1-), 19 with low level (GRADE 2+ or 2-) and 1 expert opinion. CONCLUSION: Experts fully agreed on the strong guidelines formalizing the indications and modalities of drug-induced sleep endoscopy for adult obstructive sleep apnea syndrome.

Stratification of the channel domain in neurotransmitter receptors.

Analyses of the ionic pore of ligand-gated ion channels at the amino acid level reveal a structural and functional stratification of the M2 channel domain. Mutations in the equatorial and outer regions affect channel gating, whereas mutations of other amino acid rings alter ionic permeability or selectivity.

Asynchronous assembly of the acetylcholine receptor and of the 43-kD nu1 protein in the postsynaptic membrane of developing Torpedo marmorata electrocyte.

The assembly of the nicotinic acetylcholine receptor (AchR) and the 43-kD protein (v1), the two major components of the post synaptic membrane of the electromotor synapse, was followed in Torpedo marmorata electrocyte during embryonic development by immunocytochemical methods. At the first developmental stage investigated (45-mm embryos), accumulation of AchR at the ventral pole of the newly formed electrocyte was observed within columns before innervation could be detected. No concomitant accumulation of 43-kD immunoreactivity in AchR-rich membrane domains was observed at this stage, but a transient asymmetric distribution of the extracellular protein, laminin, which paralleled that of the AchR, was noticed. At the subsequent stage studied (80-mm embryos), codistribution of the two proteins was noticed on the ventral face of the cell. Intracellular pools of AchR and 43-kD protein were followed at the EM level in 80-mm electrocytes. AchR immunoreactivity was detected within membrane compartments, which include the perinuclear cisternae of the endoplasmic reticulum and the plasma membrane. On the other hand, 43-kD immunoreactivity was not found associated with the AchR in the intracellular compartments of the cell, but codistributed with the AchR at the level of the plasma membrane. The data reported in this study suggest that AchR clustering in vivo is not initially determined by the association of the AchR with the 43-kD protein, but rather relies on AchR interaction with extracellular components, for instance from the basement membrane, laid down in the tissue before the entry of the electromotor nerve endings.

NH2-terminal amino acid sequences of precursor and mature forms of the ribulose-1,5-bisphosphate carboxylase small subunit from Chlamydomonas reinhardtii.

A precursor (pS) to the small subunit (S) of ribulose1-,5-bisphosphate carboxylase is the major product of cell-free protein synthesis directed by poly(A) containing RNA from Chlamydomonas reinhardtii. We present sequence data for in vitro-synthesized pS, for in vitro-synthesized S that in generated from pS by posttranslational incubation with a Chlamydomonas cell extract, and for in vitro-synthesized, mature S. We show that pS contains an NH2-terminal extension of 44 amino acid residues that is removed by cleavage at the correct site when pS is converted to S by an endoprotease present in the Chlamydomonas cell extract.

Acetylcholine receptor: an allosteric protein.

The nicotine receptor for the neurotransmitter acetylcholine is an allosteric protein composed of four different subunits assembled in a transmembrane pentamer alpha 2 beta gamma delta. The protein carries two acetylcholine sites at the level of the alpha subunits and contains the ion channel. The complete sequence of the four subunits is known. The membrane-bound protein undergoes conformational transitions that regulate the opening of the ion channel and are affected by various categories of pharmacologically active ligands.

[Cost of radiotherapy for bone metastases in France: A monocentric retrospective study]. / Coût de la radiothérapie des métastases osseuses en France : étude rétrospective monocentrique.

PURPOSE: The cost of radiotherapy is a concern for health systems. The conventional non fractionated or multifractionated schemes have shown the same efficacy in terms of pain relief but a non fractionated treatment seems less expensive. However, in general practice, multifractionated treatments are still the majority, which represents an additional cost for society. Moreover, the use of stereotactic body radiotherapy becomes more democratic and offers new curative perspectives, but at what price? MATERIAL AND METHODS: A monocentric retrospective study was conducted in a French radiotherapy department to evaluate and compare the cost of irradiation of uncomplicated bone metastases according to the selected radiotherapy regimen : 30Gy in 10 fractions, 20Gy in five fractions, 8Gy in one fraction or stereotactic body radiotherapy. RESULTS: Between January 2014 and December 2015, 91 patients receiving 116 treatments were included in the study, including 44 men (48%) and 47 women (52%) were 63 years old (25-88 years). Thirty-four treatments (29%) were performed by 30Gy in 10 fractions (30Gy group), 24 treatments (21%) by 20Gy in 5 fractions (20Gy group), 25 treatments (22%) by 8Gy in one fraction (8Gy group) and 33 treatments (28%) by stereotactic body radiotherapy (SBRT group). The cost of stereotactic body radiotherapy was significantly higher than that of three-dimensional treatments (P<0.001). If the cost of transport was added to this cost, stereotactic body radiotherapy remained the most expensive (P<0.001). The cost of the irradiation delivering 30Gy treatment was significantly higher than the cost of treatment with 20Gy (P=0.006) or 8Gy (P<0.001), even after adding the transport cost (P<0.001), with no significant difference between 20Gy and 8Gy (P=0.11). For the overall cost of treatment including the total cost of treatments, associated transport and reirradiation, stereotactic body radiotherapy was the most expensive treatment (P<0.001) and this cost was significantly higher in the 30Gy group than in the 20Gy group (P=0.012) or 8Gy group (P=0.001), with no significant difference between 20Gy and 8Gy (P=0.38). There was no significant difference in the cost of follow-up between 30Gy, 20Gy, 8Gy and stereotactic body radiotherapy at one month (P=0.09) but at three months (P=0.01) and six months (P=0.0001), this cost was significantly higher after a three-dimensional treatment. There was no significant difference in overall cost including initial radiotherapy, transport and overall follow-up over 6 months between groups (P=0.04). CONCLUSION: Stereotactic body radiotherapy is an efficient and curative irradiation technique but more expensive. It is preferred for some patients with a longer life expectancy in a non-palliative treatment setting. The treatment delivering 8Gy treatment appears to be the most cost-effective while leading to an equivalent efficiency to multifractionated treatments and preserving the quality of life of patients.

[Skull base meningioma: Clinical and radiological efficacy based on a quantitative volumetric analysis]. / Méningiomes de la base du crâne : efficacité clinique et radiologique basée sur une analyse volumétrique quantitative.

PURPOSE: To date, no correlation has been found between clinical and radiological efficacy after irradiation of skull base meningiomas. However, the evaluation of the radiological response was most often made by questionable methods that may have underestimated the radiological effectiveness of radiotherapy. The objective of this work is to verify this hypothesis by quantitative volumetric analysis. MATERIAL AND METHODS: Data from 35 patients treated with either helical tomotherapy (45.7%) or fractionated stereotactic radiotherapy (54.3%) were retrospectively analysed. These were mainly women (94%) aged 59 (43-81) with lesions mainly of the cavernous sinus (60%). There was a median of 2 (1-4) symptoms and the main symptoms were visual impairment (39%), cranial nerve deficits (23.4%) and headaches (17.2%). RESULTS: Median tumour volume decreased significantly (P<0.05) from 9.6mL (0.3-36.6) to 6.8mL (0.1-26.5) after median follow-up of 44 months (24-77). Sixty-three percent of patients had an improvement of at least one symptom. In univariate analysis, clinical efficacy (P<0.05), radiotherapy technique (P<0.05), tumor topography (P<0.05) and initial tumor volume (P<0.05) were predictive factors for radiological response. In multivariate analysis, only the inverse correlation between radiological response and initial tumor volume remained significant (ρ: -0.47 95% CI -3.2 to 5.7; P<0.05). CONCLUSION: The quantitative volumetric monitoring demonstrates a major radiological efficiency of radiotherapy. However, no clear correlation between clinical and radiological efficacy was found.

Regulation of muscle AChR alpha subunit gene expression by electrical activity: involvement of protein kinase C and Ca2+.

Using primary cultures of chicken myotubes, we investigated the involvement of protein kinase C and Ca2+ in the repression of nicotinic acetylcholine receptor (AChR) biosynthesis by electrical activity. Treatment with the Ca2+ channel blocker verapamil or the Na+ channel blocker tetrodotoxin increased alpha subunit mRNA levels 11.5- to 15-fold. The effect of tetrodotoxin was abolished in the presence of the Ca2+ ionophore A23187. Dantrolene, which blocks Ca2+ efflux from the sarcoplasmic reticulum, caused only a 1.7-fold increase in alpha subunit mRNA levels. Down regulation of protein kinase C by prolonged exposure to the phorbol ester TPA or inhibition of protein kinase C by staurosporine led to 8- to 10-fold increases in alpha subunit mRNA levels. Mature and precursor forms of AChR alpha subunit mRNA were found to vary in parallel throughout all of these treatments, suggesting that protein kinase C and Ca2+ ions may modulate AChR alpha subunit biosynthesis at the transcriptional level.

Identification of the amino acid subsets accounting for the ligand binding specificity of a glutamate receptor.

In a situation so far unique among neurotransmitter receptors, glutamate receptors share amino acid sequence similarities with the bacterial periplasmic binding proteins (PBPs). On the basis of the primary structure similarity of two bacterial periplasmic proteins (lysine/arginine/ornithine- and phosphate-binding proteins) with the chick cerebellar kainate-binding protein (KBP), a member of the ionotropic glutamate receptor family, we have generated a three-dimensional model structure of the KBP extracellular domain. By an interplay between homology modeling and site-directed mutagenesis, we have investigated the kainate binding properties of 55 different mutants (corresponding to 43 positions) and studied the interactions of some of these mutants with various glutamatergic ligands. As a result, we present here the subsets of amino acids accounting for the binding free energies and specificities of KBP for kainate, glutamate, and CNQX and propose a three-dimensional model, at the microarchitectural level, of the glutamatergic binding domain.

Differential expression of the neuronal acetylcholine receptor alpha 2 subunit gene during chick brain development.

In situ hybridization histochemistry reveals localized expression of the nicotinic acetylcholine receptor (nAChR) alpha 2 subunit mRNA restricted to the lateral spiriform nucleus (SpL) of the chick diencephalon. The alpha 2 nAChR transcripts are not detected in immature SpL neurons at 4.5-5 days of embryonic development. They begin to accumulate in the SpL at embryonic day 11 and increase until the newborn stage. Specific alpha 2 cDNA amplification by the polymerase chain reaction shows that during this period, the absolute content of alpha 2 mRNA increases about 20-fold. The expression of the alpha 2 nAChR gene is thus developmentally regulated and appears concomitant with the entry of cholinergic fibers into the SpL, as demonstrated by choline acetyltransferase immunohistochemistry.

Mutational analysis of the charge selectivity filter of the alpha7 nicotinic acetylcholine receptor.

In the alpha7 nicotinic acetylcholine receptors, we analyze the contribution of mutations E237A and V251T, together with the proline insertion P236', in the conversion of the charge selectivity from cationic to anionic. We show that the triple mutant exhibits spontaneous openings displaying anionic selectivity. Furthermore, at position 251, hydrophilic or even negatively charged residues are compatible with an anionic channel. In contrast, the additional proline yields an anionic channel only when inserted between positions 234 and 237; insertion before 234 yields a cationic channel and after 238 alters the receptor surface expression. The coiled 234-238 loop thus directly contributes to the charge selectivity filter of the alpha7 channel.

Evaluation of pollutant exposure by chemical and biological markers in a Mediterranean French urban stream: a step for in situ calibration of multixenobiotic resistance transporter expression as biomarker in Chironomidae larvae.

This study was aimed at semi-quantifying the membrane density of multixenobiotic resistance (MXR) transporters in Chironomidae Orthocladiinae larvae from an urban stream by ELISA assay. The relationships between the MXR transporter membrane density and limnological parameters and pollutant concentrations, 16 priority polycyclic aromatic hydrocarbons (PAHs), as per the US Environmental Protection Agency (EPA) and seven polychlorobiphenyl congeners (PCBs), were assessed. Midge larvae were collected, and limnological parameters and pollutant concentrations were measured in three sites of a French Mediterranean urban stream, two located after sewage treatment plants, and one closed to the river mouth, and in two additional sites, one on the stream tributary, and one in a non-urbanized stream located in the same region. Results show that the PAH and PCB contamination levels are different between sites and that some congener concentrations are above their threshold toxic effect level (TEL). The MXR transporter membrane density was significantly higher in larvae from the tributary, the most polluted site, as compared with larvae from the non-urbanized stream. The MXR transporter density was positively correlated with 10 of the 16 US-EPA PAH concentrations and the increase in the MXR transporter density seems to be due to the US-EPA PAH concentrations that were above their TEL. No relations with PCB concentrations or limnological parameters were found. The results suggest that the MXR transporter membrane density in Chironomidae larvae could be an interesting biological marker of PAH exposure in freshwater ecosystems.

ELISA detection of multixenobiotic resistance transporter induction in indigenous freshwater Chironomidae larvae (Diptera): A biomarker calibration step for in situ monitoring of xenobiotic exposure.

A new simple and sensitive method to distinguish chemically polluted from unpolluted situations in freshwater ecosystems is reported. For this purpose, Chironomus gr thumni larvae were collected from a polluted urban river downstream a sewage treatment plant. For the first time, ELISA assay was used to semi-quantify the multixenobiotic resistance transporters (MXR) in these small pertinent bioindicators. The use of samples immediately fixed in the field gives a delay to isolate larvae and allows multi-sampling along a longitudinal transect in a river at a given time. Results exhibit an induction of MXR proteins in larvae from the polluted river and a deinduction in larvae maintained 11days in unpolluted water. They show new evidences to use midge larvae in biomonitoring environmental programs. They answer to first biomarker calibration steps for the ongoing development of MXR transporters as a detection tool of xenobiotic impacts on bioindicator invertebrates in their freshwater habitats.

[Bone metastases radiotherapy: Multi-approaches literature review]. / Radiothérapie des métastases osseuses : revue multi-approches de la littérature.

External beam radiation therapy is an efficient treatment, which relieves pain associated with bone metastases, and is prescribed in worldwide. Although bone metastases palliative irradiation recommendations exist, international clinical practices remain variable. The purpose of this article is to show the clinical practices evolution though clinical trials, cost studies and techniques' progression.

[Radiotherapy of bone metastases in France: A descriptive monocentric retrospective study]. / Radiothérapie des métastases osseuses en France : étude descriptive rétrospective monocentrique.

PURPOSE: Bone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients. MATERIAL AND METHODS: A retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed. RESULTS: Ninety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25-88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re-irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001). CONCLUSION: This study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients.

How well can molecular modelling predict the crystal structure: the case of the ligand-binding domain of glutamate receptors.

The concept that the ligand-binding domain of vertebrate glutamate receptor channels and bacterial periplasmic substrate-binding proteins (PBPs) share similar three-dimensional (3D) structures has gained increasing support in recent years. On the basis of a dual approach that included computer-assisted molecular modelling and functional studies of site-specific mutants, theoretical 3D models of this domain have been proposed. This article reviews to what extent these models could predict the crystal structure of the ligand-binding domain of an ionotropic glutamate receptor subunit recently determined at high resolution by X-ray diffraction studies.

Chromosomal localization of the mouse genes coding for alpha 2, alpha 3, alpha 4 and beta 2 subunits of neuronal nicotinic acetylcholine receptor.

The chromosomal localization of four neuronal nicotinic acetylcholine receptor subunit genes was performed by following the mendelian segregation of their corresponding alleles in backcrosses involving the mouse species Mus spretus and the laboratory strains C57BL/6 or BALB/c. A similar analysis previously performed with muscle nicotinic acetylcholine receptor subunits revealed that the genes coding for the alpha and beta subunits are respectively located on chromosome 2 and 11, whereas the gamma and delta subunit coding genes are linked and located on mouse chromosome 1. In this study, we show that the genes coding for the neuronal nicotinic acetylcholine receptor alpha 2, alpha 3 and beta 2 subunits are dispersed on three different mouse chromosomes, viz. 14, 9 and 3 respectively. Moreover, the alpha 4 subunit gene is located on chromosome 2 but is not genetically linked to the alpha 1 subunit gene.