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Objectives The aim of the study was to describe the ultrasonographic characteristics of feline aortic thromboembolism (ATE) and determine potential associations between ultrasonographic findings and prognosis. Methods Data were retrospectively collected from the medical records (2013–2021) of cats that were diagnosed ultrasonographically with ATE based on the presence of a thromboembolus (TE) in the distal aorta beginning after the departure of the renal arteries. Results Twenty-nine cats were included in this study. The most frequent location for an ATE was at the aortic trifurcation. The median length of TEs was 9 mm (range 3.5–42.9). TEs appeared homogeneous and isoechoic to surrounding tissues in all cases. No correlation was found between the appearance of the TE and the duration of clinical signs. The obstruction of blood flow in the distal aorta at the aortic trifurcation was complete in 66% of cases and incomplete in 34% of cases. The survival rate was significantly lower when the obstruction was complete (11%, 95% confidence interval [CI] 2–34) compared with incomplete (70%, 95% CI 35–92). The arterial wall characteristics were as follows: smooth and thin (62%), and hyperechoic (38%). Conclusions and relevance Increased vascular obstruction of TEs was associated with a lower survival rate.

Computed tomography (CT)is increasingly available in veterinary referral practices; however, published studies describing CT lesions of the equine elbow are currently lacking. In this single-center, retrospective, observational study, horses undergoing elbow CT at Equitom between July 2015 and October 2018 were reviewed. Subchondral bone sclerosis; resorption of the radius, ulna, and humerus; osteophyte; and enthesophyte lesions were graded. One hundred thirty-nine elbows of 99 horses (16 with elbow pain and 123 control elbows) were included (median age, 9 years). Osseous cyst-like lesions (n = 13), only seen in the proximomedial radius and medial humerus, were the most common cause of lameness in horses with elbow pain (n = 16), with significantly higher grades of bone resorption (including osseous cyst-like lesions) in this group. One elbow had an avulsion fracture of the lateral epicondyle, two others showed signs of osteoarthritis. Significantly higher grades of sclerosis in the proximomedial radius were seen in horses with elbow pain; however, mild to moderate subchondral bone sclerosis was seen in all horses at the medial aspect of the joint. Osteochondral fragmentation lesions of the weight-bearing surface of the medial radius (2/16 vs 1/123; P = .0025) and intra-articular gas (4/16 vs 2/123; P .0001) were significantly more common in horses with elbow pain compared to control horses. Mild linear resorptive subchondral bone lesions were often not clinically relevant (32/123 vs 5/16 in medial humerus; 19/123 vs 2/16 in medial radius). In conclusion, elbow CT is a feasible method for detecting clinically relevant lesions in adult Warmblood horses with elbow pain.

International audience; Despite well-documented neurotoxic and ototoxic properties, styrene remains commonly used in industry. Its effects on the cochlea have been extensively studied in animals, and epidemiological and animal evidence indicates an impact on balance. However, its influence on the peripheral vestibular receptor has yet to be investigated. Here, we assessed the vestibulotoxicity of styrene using an in vitro model, consisting of three-dimensional cultured newborn rat utricles filled with a high‑potassium (K+) endolymph-like fluid, called “cysts”. K+ entry in the cyst (“influx”) and its exit (“efflux”) are controlled by secretory cells and hair cells, respectively. The vestibular epithelium's functionality is thus linked to K+ concentration, measured using a microelectrode.Known inhibitors of K+ efflux and influx validated the model. Cysts were subsequently exposed to styrene (0.25; 0.5; 0.75 and 1 mM) for 2 h or 72 h. The decrease in K+ concentration measured after both exposure durations was dose-dependent, and significant from 0.75 mM styrene. Vacuoles were visible in the cytoplasm of epithelial cells from 0.5 mM after 2 h and from 0.25 mM after 72 h.The results presented here are the first evidence that styrene may deregulate K+ homeostasis in the endolymphatic space, thereby altering the functionality of the vestibular receptor.; Le styrène est encore largement utilisé dans l’industrie malgré ses propriétés neurotoxiques et ototoxiques bien documentées. Bien que ses effets sur la cochlée aient été bien étudiés chez l’animal, aucune étude n’a montré l’impact de ce composé industriel sur le récepteur vestibulaire périphérique. Cependant, plusieurs études épidémiologiques et expérimentales, réalisées chez l’animal, ont montré des effets néfastes du styrène sur le système de l’équilibre. Le but de cette étude est d’évaluer la vestibulotoxicité du styrène en utilisant des « cystes », sphères gonflées remplies d’un liquide riche en potassium et de composition chimique proche de celle de l’endolymphe, obtenus à partir de rats nouveau-nés et cultivés dans un milieu tridimensionnel. Dans ce modèle in vitro, l’homéostasie du K+ est liée à la fonctionnalité des cellules sécrétrices et sensorielles, respectivement impliquées dans l’influx et dans l’efflux du K+. La concentration potassique, mesurée à l’aide d’une microélectrode sélective aux ions K+ peut donc être utilisée comme biomarqueur fonctionnel de l’épithélium vestibulaire. Dans un premier temps, la fonctionnalité du modèle a été validée avec un traitement à la gentamicine et au gadolinium connus tous les deux pour inhiber l’efflux du K+ en bloquant les canaux de mécano-transduction des cellules ciliées. Ces deux molécules ont entrainé une augmentation significative de la concentration en K+, tandis que des traitements avec l’ouabaïne et la bumétanide – inhibiteurs de la Na/K-ATPase et de NKCC1 – ont généré une diminution de la concentration potassique. Les cystes ont ensuite été exposés à différentes concentrations de styrène (0,25 ; 0,5 ; 0,75 ; 1 mM) durant 2h ou 72h. Une diminution de la concentration potassique, dépendante de la concentration de styrène utilisée, a été mesurée après 2h et 72h d’exposition. La baisse de la concentration de K+ devient significative à partir de 0,75 mM de styrène après 2h ou 72h de traitement. Des vacuoles ont pu être observées dans le cytoplasme des cellules épithéliales à partir de 0,5 mM après 2h d’exposition et à partir de 0,25 mM après 72h d’exposition. Les résultats de cette étude montrent, pour la première fois, que le styrène peut déréguler la concentration de K+ dans l’espace endolymphatique et ainsi altérer la fonctionnalité du récepteur vestibulaire.

Epidemiological and experimental studies indicate that a number of aromatic solvents widely used in the industry can affect hearing and balance following chronic exposure. Animal studies demonstrated that long-term exposure to aromatic solvents directly damages the auditory receptor within the inner ear: the cochlea. However, no information is available on their effect on the vestibular receptor, which shares many structural features with the cochlea and is also localized in inner ear. The aim of this study was to use an in vitro approach to assess and compare the vestibular toxicity of different aromatic solvents (toluene, ethylbenzene, styrene and ortho-, meta-, para-xylene), all of which have well known cochleotoxic properties. We used a three-dimensional culture model of rat utricles (“cysts”) with preserved functional sensory and secretory epithelia, and containing a potassium-rich (K+) endolymph-like fluid for this study. Variations in K+ concentrations in this model were considered as biomarkers of toxicity of the substances tested. After 72 h exposure, o-xylene, ethylbenzene and styrene decreased the K+ concentration by 78 %, 37 % and 28 %, respectively. O- xylene and styrene both caused histopathological alterations in secretory and sensory epithelial areas after 72 h exposure, whereas no anomalies were observed in ethylbenzene-exposed samples. These in vitro results suggest that some widely used aromatic solvents might have vestibulotoxic properties (o-xylene, styrene and ethylbenzene), whereas others may not (p-xylene, m-xylene, toluene). Our results also indicate that variations in endolymphatic K+ concentration may be a more sensitive marker of vestibular toxicity than histopathological events. Finally, this study suggests that cochleotoxic solvents might not be necessarily vestibulotoxic, and vice versa.

Background Carbon disulfide (CS2) exacerbates the effect of noise on hearing, and disrupts the vestibular system. The goal of this study was to determine whether these effects are also observed with intermittent CS2 exposure. Methods Rats were exposed for 4 weeks (5 days/week, 6 h/day) to a band noise at 106 dB SPL either alone or combined with continuous (63 ppm or 250 ppm) or intermittent (15 min/h or 2 × 15 min/h at 250 ppm) CS2. Hearing function was assessed by measuring distortion product otoacoustic emissions (DPOAEs); balance was monitored based on the vestibulo-ocular reflex (VOR). Functional measurements were performed before, at the end of exposure and 4 weeks later. Histological analyses of the inner ear were also performed following exposure and after the 4-week recovery period. Results The results obtained here confirmed that CS2 exposure exerts two differential temporary effects on hearing: (1) it attenuates the noise-induced DPOAE decrease below 6 kHz probably through action on the middle ear reflex when exposure lasts 15 min per hour, and (2) continuous exposure to 250 ppm for 6 h extends the frequency range affected by noise up to 9.6 kHz (instead of 6 kHz with noise alone). With regard to balance, the VOR was reversibly disrupted at the two highest doses of CS2 (2 × 15 min/h and continuous 250 ppm). No morphological alterations to the inner ear were observed. Conclusion These results reveal that short periods of CS2 exposure can alter the sensitivity of the cochlea to noise at a dose equivalent to only 10 times the short-term occupational limit value, and intermittent exposure to CS2 (2 × 15 min/h) can alter the function of the vestibular system.

Ce volume est la publication des actes d’un colloque international tenu a l’universite Ca’Foscari a Venise en mars 2015. Il marque l’aboutissement d’un programme de recherche, lance en 2010 par des chercheurs francais sur le theme : « La competition (400-1100) ». Le colloque de Ca’Foscari en 2015 est le dernier d’une serie de quatre rencontres internationales, organisees dans le cadre de ce programme de recherche, toutes publiees dans la meme collection haut Moyen Âge chez Brepols : Agon. La ...

Occupational noise can damage workers’ hearing, and the phenomenon is even more dangerous when noise is associated with an ototoxic solvent. Aromatic solvents are known to provoke chemical-induced hearing loss, but little is known about the effects on hearing of carbon disulfide (CS 2 ) when combined with noise. Co-exposure to CS 2 and noise may have a harmful effect on hearing, but the mechanisms involved are not well understood. For instance, CS 2 is not thought to have a cochleotoxic effect, but rather it is thought to cause retrocochlear hearing impairment. In other words, CS 2 could have a distal neuropathic effect on the auditory pathway. However, a possible pharmacological effect of CS 2 on the central nervous system (CNS) has never been mentioned in the literature. The aim of this study was to assess, in rats, the effects of a noise (continuous vs. impulse), associated with a low concentration of CS 2 [(short-term threshold limit value) x 10 as a safety factor] on the peripheral auditory receptor. The noise, whatever its nature, was an octave band noise centered at 8 kHz, and the 250-ppm CS 2 exposure lasted 15 min per hour, 6 h per day, for 5 consecutive days. The impact of the different experimental conditions on hearing loss was assessed using distortion product oto-acoustic emissions and histological analyses. Although the LEX,8 h (8-h time-weighted average exposure) for the impulse noise was lower (84 dB SPL) than that for the continuous noise (89 dB SPL), it appeared more damaging to the organ of Corti, in particular to the outer hair cells. CS 2 exposure alone did not have any effect on the organ of Corti, but co-exposure to continuous noise with CS 2 was less damaging than exposure to continuous noise alone. In contrast, the cochleo-traumatic effects of impulse noise were significantly enhanced by co-exposure to CS 2 . Therefore, CS 2 can clearly modulate the middle-ear reflex function. In fact, CS 2 may have two distinct effects: firstly, it has a pharmacological effect on the CNS, modifying the trigger of the acoustic reflex; and secondly, it can make the organ of Corti more susceptible to impulse noise. The pharmacological effects on the CNS and the effects of CS 2 on the organ of Corti are discussed to try to explain the overall effect of the solvent on hearing. Once again, the results reported in this article show that the temporal structure (continuous vs. impulse) of noise should be taken into consideration as a key parameter when establishing hearing conservation regulations.

Some volatile aromatic solvents have similar or opposite effects to anesthetics in the central nervous system. Like for anesthetics, the mechanisms of action involved are currently the subject of debate. This paper presents an in vivo study to determine whether direct binding or effects on membrane fluidity best explain how solvents counterbalance anesthesia's depression of the middle-ear reflex (MER). Rats were anesthetized with a mixture of ketamine and xylazine while also exposed to solvent vapors (toluene, ethylbenzene, or one of the three xylene isomers) and the amplitude of their MER was monitored. The depth of anesthesia was standardized based on the magnitude of the contraction of the muscles involved in the MER, determined by measuring cubic distortion product oto-acoustic emissions (DPOAEs) while triggering the bilateral reflex with contralateral acoustic stimulation. The effects of the aromatic solvents were quantified based on variations in the amplitude of the DPOAEs. The amplitude of the alteration to the MER measured in anesthetized rats did not correlate with solvent lipophilocity (as indicated by logKow values). Results obtained with the three xylene isomers indicated that the positions of two methyl groups around the benzene ring played a determinant role in solvent/neuronal cell interaction. Additionally, Solid-state Nuclear Magnetic Resonance (NMR) spectra for brain microsomes confirmed that brain lipid fluidity was unaffected by solvent exposure, even after three days (6h/day) at an extremely high concentration (3000ppm). Therefore, aromatic solvents appear to act directly on the neuroreceptors involved in the acoustic reflex circuit, rather than on membrane fluidity. The affinity of this interaction is determined by stereospecific parameters rather than lipophilocity.

Premature udder development constitutes an alarm signal in pregnant mares. The objective of this clinical case report is to highlight the importance of transabdominal ultrasound examination of the fetus in these cases and to report a unique case of prenatal diagnosis of obstructive uropathy based on the observation of severe fetal hydronephrosis and megacystitis in utero. A 4-year-old French chaser primiparous mare was referred for evaluation of premature udder development during the ninth month of pregnancy. The mare had clinical signs within normal limits, a developed and sensitive udder with secretions, and no vulvar discharge. Transrectal examination revealed the presence of an immobile fetus. Combined uteroplacental thickness was within normal limits. Transabdominal ultrasound revealed a single live fetus in posterior presentation with several abdominal abnormalities. Unilateral hydronephrosis and megacystitis lead to a hypothetical diagnosis of fetal multiple urinary tract malformation with outflow obstruction. Treatment was discontinued and the mare was monitored. Abortion occurred spontaneously a week later. Postmortem examination revealed a ruptured bladder of abnormally large dimensions and a severely distended left kidney without parenchyma (filled with free urine) and lack of permeability in the left ureter and urethra. Postmortem diagnosis was consistent with our prenatal ultrasonographic diagnosis. Even though described during human pregnancy with various etiologies and severity, prenatal diagnosis of fetal hydronephrosis and megacystitis has not been reported in equine veterinary medicine before. These malformations need to be characterized more precisely in the future. This case highlights the importance of transabdominal ultrasonography to detect equine fetal abnormalities.

Summary: Introduction: In the early phase of the coronavirus disease (COVID-19) epidemic in France, knowledge of SARS-COV-2 characteristics was limited, and personal protective equipment (PPE) was lacking. Thus, health care workers (HCWs) were exposed to nosocomial transmission. Methods: A multicenter regional descriptive study of fifty-two heath care facilities covering 30,533 HCWs in western Normandy, France, from March 3 to March 27, 2020, before the incidence threshold of 10/100,000 inhabitants was crossed in the study area. The incidence rate of COVID-19 in HCWs, the attack rates and the serial interval distribution of nosocomial transmission were computed. Demographic characteristics of HCWs, contacts with index cases, and the use of personal protective equipment were collected by a structured questionnaire. Results: The incidence rate of COVID-19 in HCWs was 2.7‰. Among 19 situations (13 clusters >2 cases), 10 were HCW-HCW and 9 patient-HCW transmission, the global attack rate was 13.7% (95% confidence interval, 10.6%–17.3%), and 68 HCWs were involved (10 index cases, with 58 secondary cases). Exposure of secondary cases was only in the presymptomatic phase of the index case in 29% of cases, 48% for HCW-HCW and 10% for patient-HCW transmission (P

The metacarpophalangeal joint is a common site of pain in horses. Little information is available about bone marrow lesions in the distal condyles of the third metacarpal bone in sports and pleasure horses. Aims of this prospective, retrospective, observational study were to evaluate the prevalence of bone marrow lesions in the distal condyles of the third metacarpal bone, to describe their anatomic distribution and to correlate lesions with the presence of lameness and the level and type of activity. All sports and pleasure horses undergoing standing low-field MRI of the front fetlock region between 2009 and 2016 were included and divided into three lameness groups according to the results of diagnostic analgesia. Bone marrow lesions were analyzed and graded by one reader. Grades were compared between anatomical locations and between lameness groups. A total of 166 horses were sampled. The prevalence of bone marrow lesions was 76.5% (127/166). The dorsal aspects of the medial condyle (31%, 39/127) and of the sagittal ridge (28%, 36/127) were the most commonly affected locations. There was no significant difference between both forelimbs (lame limb and non-lame limb) of the same horse. Lesion severity was neither significantly associated with the lameness group nor with the type or level of activity. The prevalence of bone marrow lesions in the distal condyles of the third metacarpal bone is high in this population and the clinical significance is not always clear. Further studies are required to elucidate the clinical significance of this finding in sports and pleasure horses.

Chronic occupational exposure to carbon disulfide (CS2) has debilitating motor and sensory effects in humans, which can increase the risk of falls. Although no mention of vestibulotoxic effects is contained in the literature, epidemiological and experimental data suggest that CS2 could cause low-frequency hearing loss when associated with noise exposure. Low-frequency noise might also perturb the peripheral balance receptor through an as-yet unclear mechanism. Here, we studied how exposure to a low-frequency noise combined with 250-ppm CS2 affected balance in rats. Vestibular function was tested based on post-rotary nystagmus recorded by a video-oculography system. These measurements were completed by behavioral tests and analysis of the cerebellum to measure expression levels for gene expression associated with neurotoxicity. Assays were performed prior to and following a 4-week exposure, and again after a 4-week recovery period. Functional measurements were completed by histological analyses of the peripheral organs.Nystagmus was unaltered by exposure to noise alone, while CS2 alone caused a moderate 19% decrease of the saccade number. In contrast, coexposure to 250-ppm CS2 and low-frequency noise decreased both saccade number and duration by 33% and 34%, respectively. After four weeks, recovery was only partial but measures were not significantly different from pre-exposure values. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis of cerebellar tissue revealed a slight but significant modification in expression levels for two genes linked to neurotoxicity in CS2-exposed animals. However, neither histopathological changes to the peripheral receptor nor behavioral differences were observed. Based on all these results, we propose that the effects of CS2 were due to reversible neurochemical disturbance of the efferent pathways managing post-rotatory nystagmus. Because the nervous structures involving the vestibular function appear particularly sensitive to CS2, post-rotary nystagmus could be used as an early, non-invasive measurement to diagnose CS2 intoxication as part of an occupational conservation program.

International audience; Methylethylketone (MEK) is widely used in industry, often in combination with other compounds. Although nontoxic, it can make other chemicals harmful. This study investigates the fate of MEK in rat blood, brain and urine as well as its hepatic metabolism following inhalation over 1 month (at 20, 200 or 1400 ppm). MEK did not significantly accumulate in the organism: blood concentrations were similar after six-hour or 1-month inhalation periods, and brain concentrations only increased slightly after 1 month’s exposure. Urinary excretion, based on the major metabolites, 2,3-butanediols (± and meso forms), accounted for less than 2.4% of the amount inhaled. 2-Butanol, 3-hydroxy-2-butanone and MEK itself were only detectable in urine in the highest concentration conditions investigated, when metabolic saturation occurred. Although MEK exposure did not alter the total cytochrome P450 concentration, it induced activation of both CYP1A2 and CYP2E1 enzymes. In addition, the liver glutathione concentration (reduced and oxidized forms) decreased, as did glutathione S-transferase (GST) activity (at exposure levels over 200 ppm). These metabolic data could be useful for pharmacokinetic model development and/or verification and suggest the ability of MEK to influence the metabolism (and potentiate the toxicity) of other substances.; La méthyléthylcétone (MEK) est largement utilisée dans l'industrie, souvent en combinaison avec d'autres composés. Bien que non toxique, elle peut rendre d'autres produits chimiques nocifs. Cette étude s'est intéressée au devenir de la MEK dans le sang, le cerveau et l'urine ainsi qu'à son métabolisme hépatique chez le rat exposé par inhalation pendant 1 mois à 20, 200 ou 1400 ppm. La MEK ne s'est pas accumulée de manière significative dans l'organisme: les concentrations sanguines mesurées après 6 heures ou 1 mois d'exposition par inhalation étaient similaires, tandis que les concentrations cérébrales n'ont que légèrement augmenté après 1 mois d'exposition. L'excrétion urinaire, par l'intermédiaire du 2,3-butanediol (métabolite principal présent sous les formes ± et méso), représentait moins de 1,3% de la quantité inhalée. Les autres métabolites, le 2-butanol, la 3-hydroxy-2-butanone ainsi que la MEK (sous sa forme inchangée) n'étaient détectable dans l'urine que pour des concentrations atmosphériques élevées au delà desquelles un phénomène de saturation métabolique se met en place. Bien que l'exposition à la MEK n'ait pas modifié la concentration totale en cytochromes P450, les activités enzymatiques des deux isoformes CYP1A2 et CYP2E1 ont été induites. En outre, la concentration en glutathion dans le foie (formes réduite et oxydée) a diminué, tout comme l'activité des glutathion-S-transférases (GST). Ces données métaboliques fournissent une preuve supplémentaire sur la capacité de la MEK à influencer le métabolisme (et potentialiser la toxicité) d'autres substances.

Objectives To determine whether call center dispatchers wearing headsets are subject to auditory fatigue at the end of a work shift. Material and methods Data was gathered at times when call centers were busiest. All call operators wore a headset for up to 12 h. Acoustic environment and noise exposure under the headset were continuously recorded during the entire work shift. Variations in auditory parameters were assessed using pure-tone air-conduction audiometry and an objective test based on distortion product otoacoustic emissions - contralateral suppression of distortion product otoacoustic emission (DPOAE) amplitudes (EchoScan test). Thirty-nine operators and 16 controls, all volunteers, were selected from 3 call centers (sales, assistance, and emergency) where all cognitive tasks were accomplished by phone and on computers. Results No acoustic shock was detected during the investigation. The highest normalized noise exposure (daily noise exposure level - LEX,8 h) measured was 75.5 dBA. No significant variation in auditory performances was detected with either pure-tone air-conduction audiometry or the EchoScan test. Nevertheless, dispatchers expressed a feeling of tiredness. Conclusions For an equivalent diffuse field noise exposure, the use of a headset does not seem to worsen auditory fatigue for call center operators. The dispatcher's fatigue was probably due to the duration of the work shift or to the tasks they performed rather than to the noise exposure under a headset. Int J Occup Med Environ Health 2018;31(2):217-226.

Carbon disulfide (CS2) is used in industry; it has been shown to have neurotoxic effects, causing central and distal axonopathies.However, it is not considered cochleotoxic as it does not affect hair cells in the organ of Corti, and the only auditory effects reported in the literature were confined to the low-frequency region. No reports on the effects of combined exposure to low-frequency noise and CS2 have been published to date. This article focuses on the effects on rat hearing of combined exposure to noise with increasing concentrations of CS2 (0, 63,250, and 500ppm, 6h per day, 5 days per week, for 4 weeks). The noise used was a low-frequency noise ranging from 0.5 to 2kHz at an intensity of 106dB SPL. Auditory function was tested using distortion product oto-acoustic emissions, which mainly reflects the cochlear performances. Exposure to noise alone caused an auditory deficit in a frequency area ranging from 3.6 to 6 kHz. The damaged area was approximately one octave (6kHz) above the highest frequency of the exposure noise (2.8kHz); it was a little wider than expected based on the noise spectrum.Consequently, since maximum hearing sensitivity is located around 8kHz in rats, low-frequency noise exposure can affect the cochlear regions detecting mid-range frequencies. Co-exposure to CS2 (250-ppm and over) and noise increased the extent of the damaged frequency window since a significant auditory deficit was measured at 9.6kHz in these conditions.Moreover, the significance at 9.6kHz increased with the solvent concentrations. Histological data showed that neither hair cells nor ganglion cells were damaged by CS2. This discrepancy between functional and histological data is discussed. Like most aromatic solvents, carbon disulfide should be considered as a key parameter in hearing conservation regulations.

1. Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK). 2. Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated. 3. Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations. 4. In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.

Occupational noise exposure can damage workers' hearing, particularly when combined with exposure to cochleotoxic chemicals such as styrene. Although styrene-induced cochlear impairments only become apparent after a long incubation period, the pharmacological impact of styrene on the central nervous system (CNS) can be rapidly measured by determining the threshold of the middle-ear acoustic reflex (MER) trigger. The aim of the study was to evaluate the effects of a noise (both continuous and impulse), and a low concentration of styrene [300ppm

Toluene (Tol) is an organic solvent widely used in the industry. It is also abused as an inhaled solvent, and can have deleterious effects on hearing. Recently, it was demonstrated that Tol has both anticholinergic and antiglutamatergic effects, and that it also inhibits voltage-dependent Ca(2+) channels. This paper describes a study of the effects of inhaled Tol on rats anesthetized with isoflurane, pentobarbital, or a mixture of ketamine/xylazine. Hearing was tested using distortion product oto-acoustic emissions (DPOAEs) associated with a contralateral noise to evaluate contraction of the middle-ear muscles. This allowed us to assess the interactions between the effects of Tol and anesthesia on the central nervous system (CNS). Although both anesthetics and Tol are known to inhibit the middle-ear acoustic reflex, our data indicated that inhaled Tol counterbalances the effects of anesthetic in a dose-dependent manner. In other terms, Tol can increase the amplitude of the middle-ear reflex in anesthetized rats, whatever the nature of the anesthetic used. This indicates that inhaling Tol (a Ca(2+)-channel-blocking drug) modifies the potency of anesthesia, and thereby the amplitude of the middle-ear reflex.

Presbycusis, or age-related hearing loss is a growing problem as the general population ages. In this longitudinal study, the influence of noise or styrene exposure on presbycusis was investigated in Brown Norway rats. Animals were exposed at 6 months of age, either to a band noise centered at 8 kHz at a Lex,8h = 85 dB (86.2 dB SPL for 6 h), or to 300 ppm of styrene for 6 h per day, five days per week, for four weeks. Cubic distortion product otoacoustic emissions (2f1-f2 DPOAEs) were used to test the capacity of the auditory receptor over the lifespan of the animals. 2f1-f2DPOAE measurements are easy to implement and efficiently track the age-related deterioration of mid- and high-frequencies. They are good indicators of temporary auditory threshold shift, especially with a level of primaries close to 60 dB SPL. Post-exposure hearing defects are best identified using moderate, rather than high, levels of primaries. Like many aging humans, aging rats lose sensitivity to high-frequencies faster than to medium-frequencies. Although the results obtained with the styrene exposure were not entirely conclusive, histopathological data showed the presbycusis process to be enhanced. Noise-exposed rats exhibit a loss of spiral ganglion cells from 12 months and a 7 dB drop in 2f1-f2DPOAEs at 24 months, indicating that even moderate-intensity noise can accelerate the presbycusis process. Even though the results obtained with the styrene exposure are less conclusive, the histopathological data show an enhancement of the presbycusis process.

Human and animal studies have shown that certain aromatic solvents such as toluene can cause hearing loss and can exacerbate the effects of noise. The latter effects might be due to a modification of responses of motoneurons controlling the middle-ear acoustic reflex. In the present investigation, the audition of Long-Evans rats was evaluated by measuring cubic (2f1 - f2) distortion otoacoustic emissions (f1 = 8000 Hz; f2 = 9600 Hz; f1/f2 = 1.2) prior to, during, and after activation of the middle-ear acoustic reflex. A noise suppressor was used to modify the amplitude of the 2f1 - f2 distortion otoacoustic emissions. It was delivered either contralaterally (band noise centered at 4 kHz), or ipsilaterally (3.5 kHz sine wave) to test the role played by the central auditory nuclei. This audiometric approach was used to study the physiological efficiency of the middle-ear acoustic reflex during an injection of a bolus of Intralipid (as a vehicle) containing 58.4, 87.4, or 116.2mM toluene via the carotid artery. The results showed that toluene could either increase or decrease middle-ear acoustic reflex efficiency, depending on the toluene concentration and the ear receiving noise suppressor. A new neuronal circuit of the middle-ear acoustic reflex has been proposed to explain findings obtained in this investigation. Finally, the depressing action of toluene on the central auditory nuclei driving the middle-ear acoustic reflex might explain the synergistic effects of a co-exposure to noise and aromatic solvents.

A specific liquid chromatography-mass spectrometric (LC-MS) method using an ion trap spectrometer was developed for the quantitation of articaine in human plasma. Articaine and the internal standard (trazodone) were extracted in a single step with diethyl-ether from 0.5 mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (40:60, v/v). It was delivered at a flow rate of 0.3 mL/min. The effluent was monitored by MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200 degrees C. Articaine was identified and quantified in SIM mode at m/z 185. Calibration curves were linear over the concentration range of 78.1-5000 ng/mL with determination coefficients>0.996. This method was fast (total run-time

Objectif : Decrire la distribution du meprobamate dans differents tissus et fluides biologiques collectes lors de l'autopsie concernant huit cas de deces pour lesquels le meprobamate a ete identifie dans le sang peripherique. Methodes : Les prelevements autopsiques disponibles etaient le plus souvent le sang peripherique, le sang cardiaque, l'humeur vitree, la bile, le foie, le rein, le poumon, le coeur et le cerveau. Les echantillons (fluides et homogenats tissulaires) etaient analyses par LC-MS n a trappe d'ions, apres extraction liquide-liquide en presence de carisoprodol (etalon interne). Resultats : Les concentrations de meprobamate dans le sang peripherique variaient de 9 a 160 mg/L. Les coefficients de distribution post-mortem du meprobamate, exprimes par le rapport [concentration dans le tissu (mg/kg) ou fluide d'interet (mg/L)]/[concentration dans le sang peripherique (mg/L)], etaient de 0,97 pour le sang cardiaque ( n=8 ), 0,83 pour l'humeur vitree ( n=6 ), 1,16 pour la bile ( n=8 ), 2,63 pour le foie ( n=6 ), 1,82 pour le rein ( n=8 ), 1,81 pour le coeur ( n=8 ), 1,83 pour le cerveau ( n=8 ) et 1,74 pour le poumon ( n=8 ). Les coefficients de variation associes a ces moyennes etaient tous inferieurs a 25 %, excepte pour le foie (31 %). Conclusion : Avec des coefficients de distribution moyens proches de 1, le meprobamate ne semble pas s'accumuler dans l'humeur vitree et la bile. Dans les autres tissus, ces coefficients varient de 1,7 a 2,6, objectivant ainsi une distribution tissulaire moderee, en accord avec le volume apparent de distribution peu eleve du meprobamate (0,7 L/kg). En depit du nombre limite de cas etudies, la variabilite inter-individuelle relativement peu importante de la distribution tissulaire de meprobamate pourrait theoriquement suggerer l'utilisation des concentrations tissulaires post-mortem en vue d'une estimation des concentrations dans le sang peripherique, lorsque cette matrice n'est pas disponible a l'autopsie. Pour etre confirmes, ces resultats necessitent d'etre completes dans une plus large etude.

International audience

Numerous studies using rats in stroke models have failed to translate into successful clinical trials in humans. The Stroke Therapy Academic Industry Roundtable (STAIR) has produced guidelines on the rodent stroke model for preclinical trials in order to promote the successful translation of animal to human studies. These guidelines also underline the importance of anaesthetic and monitoring techniques. The aim of this literature review is to document whether anaesthesia protocols (i.e., choice of agents, mode of ventilation, physiological support and monitoring) have been amended since the publication of the STAIR guidelines in 2009. A number of articles describing the use of a stroke model in adult rats from the years 2005 and 2015 were randomly selected from the PubMed database and analysed for the following parameters: country where the study was performed, strain of rats used, technique of stroke induction, anaesthetic agent for induction and maintenance, mode of intubation and ventilation, monitoring techniques, control of body temperature, vascular accesses, and administration of intravenous fluids and analgesics. For each parameter (stroke, induction, maintenance, monitoring), exact chi-square tests were used to determine whether or not proportions were significantly different across year and p values were corrected for multiple comparisons. An exact p-test was used for each parameter to compare the frequency distribution of each value followed by a Bonferroni test. The level of significant set at < 0.05. Results show that there were very few differences in the anaesthetic and monitoring techniques used between 2005 and 2015. In 2015, significantly more studies were performed in China and significantly fewer studies used isoflurane and nitrous oxide. The most striking finding is that the vast majority of all the studies from both 2005 and 2015 did not report the use of ventilation; measurement of blood gases, end-tidal carbon dioxide concentration, or blood pressure; or administration of intravenous fluids or analgesics. The review of articles published in 2015 showed that the STAIR guidelines appear to have had no effect on the anaesthetic and monitoring techniques in rats undergoing experimental stroke induction, despite the publication of said guidelines in 2009.

International audience; Noise is one of the most pervasive hazards in the workplace. Despite regulations and preventive measures, noise-induced hearing loss is common. The current reference test is pure-tone air-conduction audiometry (PTA), but this test cannot be used to detect early hearing loss. Objective: In this study, we assess one-day auditory fatigue using both PTA and efferent reflexes (ER) measured using DPOAEs associated with contralateral acoustic stimulation (CAS DPOAEs). Design: The noise exposure history, PTA, and ER detection were performed in seven different companies where the LEX,8h was 85 dB(A). Hearing was tested before and at the end of the working day. Study sample: Forty-six volunteers were selected to carry out this study. Results: After a single working day, a greater impact of noise was measured using ER thresholds than PTA or DPOAEs. ER measurements are objective, easy to perform, and do not require a sound-attenuated booth. Conclusion: Screening workers by periodically measuring ER thresholds using CAS DPOAEs helps detect early changes in hearing status, before the onset of noise-induced hearing loss. These tests can be readily applied as part of a hearing conservation program.

The neuropharmacological and cochleotoxic effects of styrene can exacerbate the impact of noise on the peripheral auditory receptor. The mechanisms through which co-exposure to noise and styrene impairs hearing are complex as the slowly developing cochleotoxic process can be masked in the short-term by the rapid pharmacological effect on the central nervous system. The current investigation was therefore designed to delineate the auditory frequency range sensitive to noise, to styrene, and to noise and styrene combined. In case of different frequency ranges targeted by noise and styrene, it would be possible to point out the main factor responsible for cases of deafness by looking at the location of the audiometric deficits. Male Brown-Norway rats were exposed to 600-ppm styrene, to an octave band noise centered at 8 kHz, or to both noise and styrene. The noise exposure was of two different types: impulse noise with a LEX,8h (equivalent continuous noise level averaged over 8 h) of 80 dB and continuous noise with a LEX,8 h of 85 dB SPL. Hearing was tested using a non-invasive technique based on distortion product otoacoustic emissions. Hearing data were completed with histological analysis of cochleae. The results showed that exposure to styrene alone caused outer hair cell losses in the apical cochlear region, which discriminates low frequencies. In contrast, noise-induced hearing loss was located at half an octave above the central frequency of the spectrum, around 10-12 kHz. Damage due to impulse noise was significantly exacerbated by styrene, and the noise spectrum defined the location of the cochlear trauma. Combined exposure caused greater cell losses than the sum of losses measured with the impulse noise and styrene alone. The fact that the tonotopicity of the styrene-induced damage depends on the associated noise spectrum complicates the diagnosis of styrene-related hearing loss with a tone-frequency audiometric approach. In conclusion, there is not really a frequency specificity of impairments due to styrene.

The BRCA1 and BRCA2 genes are involved in breast and ovarian cancer susceptibility. About 2 to 4% of breast cancer patients with positive family history, negative for point mutations, can be expected to carry large rearrangements in one of these two genes. We developed a novel diagnostic genetic test for the physical mapping of large rearrangements, based on molecular combing (MC), a FISH-based technique for direct visualization of single DNA molecules at high resolution. We designed specific Genomic Morse Codes (GMCs), covering the exons, the noncoding regions, and large genomic portions flanking both genes. We validated our approach by testing 10 index cases with positive family history of breast cancer and 50 negative controls. Large rearrangements, corresponding to deletions and duplications with sizes ranging from 3 to 40 kb, were detected and characterized on both genes, including four novel mutations. The nature of all the identified mutations was confirmed by high-resolution array comparative genomic hybridization (aCGH) and breakpoints characterized by sequencing. The developed GMCs allowed to localize several tandem repeat duplications on both genes. We propose the developed genetic test as a valuable tool to screen large rearrangements in BRCA1 and BRCA2 to be combined in clinical settings with an assay capable of detecting small mutations.

Animal studies have shown that toluene can cause hearing loss and can exacerbate the effects of noise by inhibiting the middle ear acoustic reflex. In this investigation, carried out in Long-Evans rats, the tensor tympani tendon was cutoff and the stapedius muscle was electrocoagulated in one or both middle ears. Rat hearing was evaluated by measuring cubic distortion otoacoustic emissions (2f1-f2; f1 5 8000 Hz; f2 5 9600 Hz; f1/f2 5 1.2) prior to, during, and after activation of the olivocochlear (OC) reflex. A band noise centered at 4 kHz was used as suppressor noise. It was delivered contralaterally to decrease 2f1-f2 amplitude. The strength of the inner ear acoustic reflex was tested by increasing contralateral noise intensity, and toluene injected into the carotid artery was used to study physiological efficacy. Results showed that the protective effect of the OC reflex is intensity dependent. In addition, the OC reflex was found to be less sensitive to toluene than the middle ear acoustic reflex. This may be because the efferent neurons involved in inner ear and middle ear reflexes are located differently. In conclusion, the synergistic effects on hearing of co-exposure to noise and aromatic solvents are because of solvents depressing the central nuclei, which mainly drive the middle ear acoustic reflex.

Background Avian coccidiosis is a major parasitic disease of poultry, causing severe economical loss to poultry production by affecting growth and feed efficiency of infected birds. Current control strategies using mainly drugs and more recently vaccination are showing drawbacks and alternative strategies are needed. Using genetic resistance that would limit the negative and very costly effects of the disease would be highly relevant. The purpose of this work was to detect for the first time QTL for disease resistance traits to Eimeria tenella in chicken by performing a genome scan in an F2 cross issued from a resistant Fayoumi line and a susceptible Leghorn line. Results The QTL analysis detected 21 chromosome-wide significant QTL for the different traits related to disease resistance (body weight growth, plasma coloration, hematocrit, rectal temperature and lesion) on 6 chromosomes. Out of these, a genome-wide very significant QTL for body weight growth was found on GGA1, five genome-wide significant QTL for body weight growth, plasma coloration and hematocrit and one for plasma coloration were found on GGA1 and GGA6, respectively. Two genome-wide suggestive QTL for plasma coloration and rectal temperature were found on GGA1 and GGA2, respectively. Other chromosme-wide significant QTL were identified on GGA2, GGA3, GGA6, GGA15 and GGA23. Parent-of-origin effects were found for QTL for body weight growth and plasma coloration on GGA1 and GGA3. Several QTL for different resistance phenotypes were identified as co-localized on the same location. Conclusion Using an F2 cross from resistant and susceptible chicken lines proved to be a successful strategy to identify QTL for different resistance traits to Eimeria tenella, opening the way for further gene identification and underlying mechanisms and hopefully possibilities for new breeding strategies for resistance to coccidiosis in the chicken. From the QTL regions identified, several candidate genes and relevant pathways linked to innate immune and inflammatory responses were suggested. These results will be combined with functional genomics approaches on the same lines to provide positional candidate genes for resistance loci for coccidiosis. Results suggested also for further analysis, models tackling the complexity of the genetic architecture of these correlated disease resistance traits including potential epistatic effects.