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To develop and assess the efficacy of an ultrasound (US)-guided pericapsular hip desensitization (PHD) technique in dogs.Prospective, randomized, anatomical study and a case series.A total of 30 healthy dogs, eight canine cadavers and seven dogs with hip osteoarthritis.After studying the US anatomy of the medial aspect of the coxofemoral joint and determining an acoustic window to perform an US-guided PHD in healthy dogs, the US-guided PHD was performed bilaterally in canine cadavers. A low [(LV) 0.1 mL kgThe US-guided PHD could be performed by inserting the needle between the iliopsoas muscle and the periosteum of the ilium. The articular branches of the femoral and obturator nerves were stained in all cadavers using both volumes. The main femoral nerve was never stained, but the main obturator nerve was stained in 37.5% and 100% of injections using LV and HV, respectively (p = 0.026). Treated animals showed decreased dynamic pain response after the injection. Compared with baseline, CBPI scores were reduced by ≥ 50% for ≥ 12 weeks in all but one dog.The US-guided PHD with both 0.1 and 0.2 mL kg

Objective To describe the sonoanatomy of the abdominal wall in live cats and to compare the distribution pattern of two versus three ultrasound-guided transversus abdominis plane (TAP) injections using clinically applicable volumes of lidocaine–dye solution in cat cadavers. Study design Prospective anatomical study. Animals A total of eight client-owned healthy cats and eight cat cadavers. Methods Ultrasound anatomy of the abdominal wall, landmarks and sites for needle access were determined in live cats. Ultrasound-guided TAP injections were performed in eight thawed cat cadavers. Volumes of 0.25 or 0.16 mL kg−1 per point of a lidocaine–dye solution were injected using either two [subcostal and preiliac (SP)] or three [subcostal, retrocostal and preiliac (SRP)] injection points, respectively. Each cadaver was then dissected to determine the injectate distribution and the number of thoracolumbar nerves stained with each approach. The target nerves were defined as the ventromedial branches of the thoracic nerves 10 (T10), T11, T12, T13 and lumbar nerves 1 (L1) and L2. Results Sonoanatomy was consistent with anatomy upon dissection and the TAP was identified in all cadavers. A total of 16 subcostal, 16 preiliac and nine retrocostal TAP injections were performed. The overall staining success rate of the target nerves was 66.7% and 92.6% for the SP and SPR approaches, respectively (p = 0.02). The ventromedial branches of T10, T11, T12, T13, L1 and L2 were stained in 57.1%, 100.0%, 85.7%, 28.6%, 42.9% and 85.7%, and in 66.7%, 100.0%, 100.0%, 100.0%, 88.9% and 100.0% of the cases with the SP and SRP approaches, respectively. Conclusions and clinical relevance The SRP approach allowed a broader distribution around the target nerves, whereas a staining gap was observed at T13 and L1 with the SP approach. Further studies are necessary to investigate the analgesic effect of these approaches in a clinical setting.

Objective To develop an ultrasound-guided approach to intercostal nerve injection and to compare the success rate of intercostal nerve injections using blind or ultrasound-guided technique in canine cadavers. Study design Prospective, randomized, descriptive, experimental anatomic study. Animals A total of 14 mid-sized adult canine cadavers. Methods Ultrasound landmarks were identified by dissection of four cadavers and used to develop an ultrasound-guided technique. The remaining 10 cadavers were randomly assigned to blind (five cadavers) or ultrasound-guided (five cadavers) injections of the third to the ninth intercostal nerves bilaterally with 0.03 mL kg–1 of colorant per injection. The target for intercostal injections was the caudal border of the respective rib, between the internal intercostal membrane and the parietal pleura. Additionally, displacement of the parietal pleura without visible intramuscular distribution was considered the end point for ultrasound-guided injections. For each cadaver, a practitioner in training performed the blocks on one hemithorax, while an experienced practitioner performed the blocks on the opposite hemithorax. Injections were considered successful if ≥1 cm of the target nerve was stained with colorant upon dissection. Success rates and length of nerve staining were analyzed with Fisher’s exact and t tests, respectively. Data were considered statistically different with p Results Success rates of blind and ultrasound-guided technique were 57.1% and 91.4%, respectively (p Conclusions and clinical relevance Ultrasound guidance improves the accuracy of intercostal nerve injections when compared with blind technique, independently of the level of expertise in regional anesthesia.

Aspergillus fumigatus is an opportunistic fungal pathogen responsible for a spectrum of clinical manifestations. Dendritic cells recognize pathogen-associated molecular patterns of Aspergillus via two main receptor families, Toll-like receptors (TLRs) and C-type lectin receptors (CLR). Here, the importance of TLR and CLR signaling in the regulation of T-helper cell type 2 (Th2) responses was analyzed using a mouse model based on the transfer of bone marrow-derived dendritic cells (BMDCs) pulsed with A. fumigatus conidia. BMDCs were generated from mice deficient in either MyD88 or MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1). Both the MyD88 and MALT1 signaling pathway in BMDCs contributed to the production of inflammatory cytokines induced by A. fumigatus conidia. Mice sensitized with MyD88-/- BMDCs pulsed in vitro with A. fumigatus conidia showed an exacerbated allergic inflammation, with stronger eosinophil recruitment in the BAL and higher Th2 cytokine production compared with mice sensitized with wild-type or MALT1-/- BMDCs. This exacerbation was not observed when MyD88-/- BMDCs were pulsed with Cladosporium sphaerospermum, a nonpathogenic mold. A lack of TLR2 signaling recapitulated the exacerbation of the A. fumigatus Th2 response observed in the absence of MyD88 signaling, whereas TLR2 agonist dampened the response induced with A. fumigatus and C. sphaerospermum conidia. IL-10 production by BMDCs in response to A. fumigatus was dependent on the expression of TLR2 and MyD88. IL-10-/- BMDCs exacerbated, whereas MyD88-/- BMDCs supplemented with exogenous IL-10 decreased the allergic pulmonary inflammation. These results indicate that TLR2/MyD88-specific recognition of PAMPs from A. fumigatus conidia can upregulate IL-10 production and downregulate lung eosinophilia and the development of a Th2 response.

Objective To compare the dye distribution following either two lateral abdominal or one lateral abdominal and one subcostal ultrasound-guided transversus abdominis plane (TAP) injections of a clinically relevant volume of dye solution in dogs. Study design Randomized cadaveric study. Animals A total of eight canine cadavers. Methods On one side of each cadaver, two TAP injections were performed on the lateral aspect of the abdomen (approach LL), caudal to the last rib and cranial to the iliac crest. On the contralateral hemiabdomen, one subcostal (caudal to the costal arch) and one lateral abdominal injection (between last rib and iliac crest), were performed (approach SL). Side allocation was randomly determined. A spinal needle was introduced in-plane to the transducer for each injection of methylene blue (0.25 mL kg−1). All cadavers were dissected to assess dye distribution and number of stained target nerves. Results All injections were performed in the TAP. The proportion of target nerve staining was 53.5% versus 80.4% with approaches LL and SL, respectively (p = 0.005). Approach LL stained the first lumbar (L1) spinal nerve in 100% of injections and ninth thoracic (T9), T10, T11, T12, T13 and L2 were stained in 0%, 0%, 37.5%, 62.5%, 87.5% and 87.5% of injections, respectively. Approach SL stained T11, L1 and L2 in 100% of injections and T9, T10, T12 and T13 were stained in 37.5%, 87.5%, 75% and 62.5% of injections, respectively. Approach SL resulted in greater staining of nerves cranial to T12 compared with approach LL. The two approaches were equivalent in staining nerves caudal to T12. Conclusions and clinical relevance Approach SL provided a broader distribution of the injected solution than approach LL, which may result in a larger blocked area in live animals undergoing celiotomy.

To investigate the injectate spread and nerve staining of ultrasound-guided erector spinae plane (ESP) injections at the thoracolumbar spine in canine cadavers.Prospective, randomized, descriptive, anatomic study.A total of 15 canine cadavers.The location of the medial and lateral branches of the dorsal branches of the spinal nerves (DBSN) from the tenth thoracic (T10) to the third lumbar vertebra (L3) were identified by dissection of three cadavers. ESP injections of dye (0.5 mL kgGross anatomic dissections showed that the medial and lateral branches of the DBSN change their path in relation to the epaxial muscles caudal to T11. Approaches ESPThese results suggest that the mammillary process should be used as anatomic landmark to perform ultrasound-guided ESP blocks in the thoracolumbar spine caudal to T11 when targeting the medial branches of the DBSN. Injections should be performed one spinal segment caudal to the level intended to desensitize.

The incorporation of nerve stimulation and ultrasound guidance to veterinary regional anesthesia allows accurate performance of techniques to block the thoracic limb and the thorax. When performed correctly, regional anesthesia can either constitute an alternative to the use of opioids and other systemic analgesics, or have a significant opioid-sparing effect. This article provides an overview of some techniques described using objective methods of nerve location, which can be used to provide perioperative locoregional anesthesia and analgesia to the thoracic limb and thorax. The approaches described may be used to decrease the perioperative use of opioids in small animals.

We compared the performance of SARS-CoV-2 neutralising antibody testing between 12 European laboratories involved in convalescent plasma trials. Raw titres differed almost 100-fold differences between laboratories when blind-testing 15 plasma samples. Calibration of titres in relation to the reference reagent and standard curve obtained by testing a dilution series reduced the inter-laboratory variability ca 10-fold. The harmonisation of neutralising antibody quantification is a vital step towards determining the protective and therapeutic levels of neutralising antibodies. ispartof: EUROSURVEILLANCE vol:26 issue:27 ispartof: location:Sweden status: published

Background The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. Methods DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. Discussion This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. Trial registration ClinicalTrials.gov NCT04429854 .Registered on 12 June 2020 - Retrospectively registered., info:eu-repo/semantics/published

Group B streptococcus (GBS) is a human-pathogenic bacterium inducing a strong inflammatory response that may be detrimental for host tissues if not finely regulated. The inflammatory response can be modulated by different molecular mechanisms, among which growing evidence points toward the crucial role of microRNAs (miRNAs). Regarding innate inflammatory response, studies have reported that miR-223 is essential for the control of granulocyte proliferation and activation. Moreover, a number of investigations on miRNA expression profiling performed in various inflammatory settings have revealed that miR-223 is among the top differentially expressed miRNAs. Yet the dynamic pattern of expression of miR-223 in vivo with respect to the evolution of the inflammatory process, especially in microbial infection, remains elusive. In this study, we analyzed the kinetic expression of miR-223 in an inflammatory model of GBS-induced murine pneumonia and looked for correlates with inflammatory markers, including innate cell infiltrates. We found that miR-223 expression is rapidly induced at very early time points (3 to 6 h postinfection [p.i.]) mainly by lung-infiltrating neutrophils. Interestingly, the level of miR-223 accumulating in the lungs remains higher at later stages of infection (24 h and 48 h p.i.), and this correlates with reduced expression of primary inflammatory cytokines and chemokines and with a shift in infiltrating monocyte and macrophage subtypes toward a regulatory phenotype. Transient inhibition of miR-223 by an antagomir resulted in significant increase of CXCL2 expression and partial enhancement of infiltrating neutrophils in GBS-infected lung tissues. This suggests the potential contribution of miR-223 to the resolution phase of GBS-induced acute inflammation., info:eu-repo/semantics/published

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., For this Viewpoint, Nature Reviews Immunology asked the presidents of 16 immunology societies from around the world to discuss how their society and its members responded to the COVID-19 pandemic. Their answers highlight the incredible contributions that immunologists around the globe have made following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background Most of the findings related to the noxious effect of mold sensitization on asthma come from investigations based on Alternaria alternata, Cladosporium herbarum, and Aspergillus fumigatus. However, species such as Penicillium spp, Cladosporium sphaerospermum, Cladosporium cladosporioides, or Aspergillus versicolor display a more pronounced indoor tropism, and their potential harmful respiratory effects cannot be neglected. Objective The goal of this work was to relate mold sensitizations with asthma severity and with the level of indoor mold contamination among mold-sensitized patients with asthma and nonsensitized patients with asthma. Methods A case-control study was conducted and several asthma severity markers were compared between patients with asthma with and without mold sensitization. Indoor contamination of patients’ dwellings was also investigated. Results Our findings confirmed the association between sensitization to A fumigatus and severity for patients with asthma in contrast with sensitization to other species. Indoor mold contamination was detected in approximately 90% of dwellings. Overall mold exposure was not associated with asthma severity. However, regardless of the sensitization, exposure to A fumigatus and Penicillium spp in dust was linked to an increased risk of severe asthma. Conclusion The harmful nature of mold sensitization and mold exposure for patients with asthma was not confirmed in this study. However, sensitization to A fumigatus was associated with an increased risk for severe asthma. A better investigation of the properties of Penicillium spp is recommended because its exposure was found to be associated with a more pronounced impairment of lung function.

Objective Anticholinesterase drugs may produce paradoxical neuromuscular block when administered at shallow levels of neuromuscular block. The objective of this study was to evaluate the effects of neostigmine and edrophonium when administered at near-complete reversal from nondepolarizing block in anesthetized dogs. Study design Incomplete crossover, randomized, blinded experimental study. Animals A total of 12 Beagle dogs. Methods Each dog was anesthetized twice with propofol and maintained with isoflurane and dexmedetomidine. Intravenous (IV) vecuronium (0.1 mg kg−1) was administered. When the mechanographic train-of-four (TOF) ratio had spontaneously recovered to ≥0.9, either neostigmine (0.04 mg kg−1) or edrophonium (0.5 mg kg−1) was administered IV, preceeded by atropine. Changes in twitch height or TOF ratio were measured for the next 10 minutes. Recurarization was considered to be present if values decreased by ≥10%. Results Data from four dogs in each treatment were excluded from analysis, resulting in data from five dogs administered both treatments, three dogs administered neostigmine and three dogs administered edrophonium. There was no difference between groups for age, weight, T1 and T4 twitch heights or TOF ratio values, before or after anticholinesterase administration. The TOF ratio decreased by 17% and 18% in two of the eight dogs administered neostigmine, resulting from a larger increase in T1 relative to T4. No reductions in individual twitch amplitudes were recorded in those dogs. When edrophonium was used, no cases of recurarization were observed. Conclusions and clinical relevance The results support use of edrophonium for reversal of shallow neuromuscular block. The decreases in TOF ratio recorded after neostigmine does not necessarily indicate muscular weakness. Although the clinical implications are uncertain, the results suggest that, at these doses, edrophonium may be preferable to neostigmine for reversal of shallow neuromuscular block in dogs.

Most studies on molds focus on Alternaria alternata and Aspergillus fumigatus. Here, we report on inflammatory and allergenic properties of more typical indoor species Aspergillus versicolor, P. chrysogenum, C. cladosporioïdes, and C. sphaerospermum that were compared to A. alternata and A. fumigatus. In a mouse model, after intranasal instillation, A. alternaria, A. versicolor, and C. sphaerospermum induced the early recruitment of neutrophils and the strong expression of inflammatory markers in the bronchoalveolar lavages fluids. A. fumigatus also induced the early accumulation of neutrophils but with lower levels of inflammatory markers. Chronic treatment induced variable response according to species: P. chrysogenum and A. fumigatus appeared strong pro-allergenic inducers compared to A. alternata and C. sphaerospermum while A. versicolor and C. cladosporioides induced a mixed pro-allergenic/pro-inflammatory response. In mold-sensitized asthmatics, mold-specific Immunoglobulin E (IgE) were detected with an in-house dot-blot assay. A. fumigatus and A. alternata were the most frequent sensitizers. Altogether, P. chrysogenum, P. brevicompactum, C. sphaerospermum, and C. cladosporïoides were the "major sensitizer" (defined as the strongest response against a single mold species) for almost 30% of the asthmatics. These results show that, not only A. alternata and A. fumigatus, but also indoor species have strong inflammatory and allergic properties and a harmful potency.

Three dogs were anaesthetised for various procedures. Endotracheal intubation was achieved with cuffed silicone tubes. No difficulty was reported during the intubation in two out of the three cases, whereas in one case the tube could only be advanced a few centimetres past the glottis. Before extubation, the cuff was deflated in all cases, but the tubes could not be withdrawn past the point where the cuff was positioned within the arytenoids. Endoscopy was performed in two of the three cases and revealed no visible causes of movement hindrance. Computed tomography (CT) previously performed in one of the cases revealed that the outer surface of the tube was in contact with the tracheal wall. In all cases, the tubes could eventually be removed with lubrication and movement. These cases suggest that large silicone endotracheal tubes relative to the airway diameter may result in difficult extubation, and care should be taken with tube size selection.

Epidural anesthesia, often used during cesarean surgery, can exacerbate hypotension from general anesthesia and delay discharge due to motor block. Decreasing the local anesthetic dose might reduce those complications. Cases of dogs undergoing cesarean section that were anesthetized without epidural (n = 29) (control) and dogs with low-dose epidural bupivacaine with fentanyl or buprenorphine (n = 37) were reviewed. The incidence of hypotension was equal between groups. Intraoperative opioids were administered more to control (93%) than to treated dogs (18%; P < 0.0001). Epidural bupivacaine 0.0625–0.125% combined with an opioid reduced the use of intraoperative opioids and did not exacerbate arterial hypotension during cesarean section in anesthetized dogs.

The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-α) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.

The synthesis of mycobacterial mycolic acid related wax esters and of their trehalose di- and mono-esters is described. The trehalose dimycolates (TDMs) synthesised activated bone marrow derived dendritic cells (BMDCs) in vitro more strongly than trehalose dibehenate or the trehalose monomycolates (TMMs). The inflammatory effects were similar to those of TDM from either a synthetic keto- or methoxy-mycolic acid, but somewhat stronger than those of a TDM from an α-mycolic acid. In vivo, the effects of one wax ester TDM were similar to those of the methoxy-MA and α-mycolic acid TDMs and trehalose dibehenate.

Objective To evaluate whether fentanyl administered at analgesic doses in pain-free anesthetized dogs increases the serum cortisol or blood glucose concentrations and is associated with postanesthetic dysphoria. Study design Experimental, blinded, randomized crossover. Animals A group of six adult research dogs. Methods Each dog was anesthetized twice and was administered fentanyl or saline with a 15-day wash-out period. Treatment allocation was randomly assigned via a closed envelope technique. Cortisol and glucose concentrations were measured on arrival in the research room (TPRE), induction of general anesthesia (TIND), extubation (TEXT) and 1 hour after extubation (TPOST). Dogs were premedicated with methadone (0.1 mg kg−1) and carprofen (4 mg kg−1) intravenously (IV), anesthesia induced with propofol (4–6 mg kg−1) IV and maintained with isoflurane in oxygen. Standard anesthesia monitoring was performed throughout the experiment. Fentanyl (5 μg kg−1 over 90 seconds followed by 7.5 μg kg−1 hour −1) or an equivalent amount in mL of saline solution were administered IV for 60 minutes. TPRE behavior scores and recovery scores were evaluated using descriptive 4-point scales. Data from serum cortisol and blood glucose concentrations were analyzed with a Split Plot on time test, whereas recovery scores were analyzed using a Wilcox match-pairs signed rank test. Statistical significance was set at p Results There were no significant increases in serum cortisol and blood glucose concentrations over time, and there were no differences between treatments. None of the dogs developed postanesthetic dysphoria with either treatment. Conclusions and clinical relevance Fentanyl, administered at analgesic doses to healthy, pain-free, anesthetized dogs, was not associated with significant changes in serum cortisol or glucose concentrations in the studied population.

Rabies virus is a neurovirulent RNA virus, which causes about 59,000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-kappa B signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in Malt1(-/-) compared to Malt1(-/-) mice, and this effect was associated with lower viral load, proinflammatory gene expression, and infiltration and activation of immune cells in the brain. Specific deletion of Malt1 in T cells also delayed disease development, while deletion in myeloid cells, neuronal cells, or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in the case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence and reveal the potential of MALT1 inhibition for therapeutic intervention. IMPORTANCE: Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11-infected mice, providing new insights in the biology of MALT1 and rabies virus infection.

BACKGROUND Myopathies are generally considered to increase the risk for succinylcholine-induced hyperkalaemia and may affect the duration of action of neuromuscular blockers. Centronuclear (myotubular) myopathy (CNM) is congenital and produces various degrees of muscular weakness and associated complications such as respiratory failure. The effects of succinylcholine and the potentially lethal consequences of hyperkalaemia on patients with CNM are unknown due to its rarity. One source of information is the dog, as CNM occurs naturally in dogs. Because of its remarkable similarity with the disease in man, canine CNM can serve as a model to further our knowledge of the effects of succinylcholine. OBJECTIVES We examined the kalaemic and neuromuscular effects of succinylcholine in dogs with and without autosomal-recessive CNM. DESIGN A prospective, experimental study. SETTING Anaesthesiology laboratory, College of Veterinary Medicine, Cornell University, New York, USA. PATIENTS Six dogs with autosomal-recessive CNM and six control dogs. INTERVENTIONS Dogs received succinylcholine 0.3 mg kg during isoflurane anaesthesia. MAIN OUTCOME MEASURES Whole blood potassium concentration was measured 5 min before and after succinylcholine administration. Neuromuscular function was measured with acceleromyography and single twitch stimulation. RESULTS All dogs recovered uneventfully from anaesthesia. The increase in potassium concentration [mean (SD)] following succinylcholine was similar between groups: CNM 0.5 (0.4) mmol l and control 0.7 (0.4) mmol l (P = 0.47). Recovery of the single twitch to 25, 75 and 90% was longer in the CNM group (all P

MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1 −/− mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1 −/− mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1 −/− mice at 10 dpi compared to MALT1 +/+ infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1 +/+ mice. Moreover, MALT1 −/− mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain. IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.