Ultrasound-guided fasciotomy in forearm chronic exertional compartment syndrome: Preliminary results in 12 cases.

INTRODUCTION: Forearm chronic exertional compartment syndrome is a rare condition in athletes and musicians who perform repeated prolonged forced gripping movements. It mainly affects young men, and presents with cramp-like pain, beginning on the anteromedial side of the forearm and progressively extending to the entire circumference, and may be associated with muscle weakness and neurologic symptoms. The objective of this study was to report preliminary results of ultrasound-guided fasciotomy in the treatment of forearm chronic exertional compartment syndrome. MATERIAL AND METHODS: A single-center retrospective observational study was conducted. Forearm chronic exertional compartment syndrome was diagnosed on clinical presentation and pathological intramuscular pressure measurement, defined as >30 mmHg at 1 min after effort. The series comprised 7 men, with bilateral involvement. Mean age was 30 years. All patients were motorcyclists. The mean preoperative intramuscular pressure at 1 min after effort was 60.75 mmHg (range: 30-81 mmHg). The main study endpoint was change in pain on visual analogic scale. Secondary endpoints comprised patient satisfaction, change in competitive sports level, and time to return to sport. Complications were noted. RESULTS: Six patients (12 forearms) were evaluated. Mean follow-up was 22.5 months (range: 3-48 months). Mean pain rating was 7.3/10 (range: 6-9) preoperatively, and 0/10 postoperatively. All patients were satisfied with the procedure. Mean time to return to sports was 25.5 days (range: 21-30 days). No patients decreased their competitive sports level after the procedure. One patient presented a postoperative hematoma, not requiring surgery. CONCLUSION: Ultrasound-guided fasciotomy in the treatment of Forearm chronic exertional compartment syndrome is an innovative technique with promising preliminary results. LEVEL OF EVIDENCE: IV; retrospective cohort.

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed considerable heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in nicotine consumption even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified ß4-containing nicotinic acetylcholine receptors of IPN neurons as molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate for individual variabilities and adaptations in nicotine consumption.

SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress.

Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

Chronic nicotine increases midbrain dopamine neuron activity and biases individual strategies towards reduced exploration in mice.

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated in mice the impact of chronic nicotine on midbrain dopamine neuron activity and its consequence on the trade-off between exploitation and exploration. Model-based and archetypal analysis revealed substantial inter-individual variability in decision-making strategies, with mice passively exposed to nicotine shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of dopamine neurons using optogenetics, and found that photo-stimulated mice adopted a behavioral phenotype similar to that of mice exposed to chronic nicotine. Our results reveal a key role of tonic midbrain dopamine in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects the exploration/exploitation balance and decision-making.

Validation of the French version of the Self-Administered International Hip Outcome Tool-12 Questionnaire and determination of the Minimal Clinically Important Difference (MCID) in the French speaking population.

BACKGROUND: Patient-Reported Outcomes tools are becoming the gold standard in the evaluation of results in orthopaedic surgery. In 2012, the International Hip Outcome Tool-12 (iHOT-12) was developed. This self-administered questionnaire was designed to address the day-to-day clinical setting with faster completion and easier patient flow. In 2021, a French translation of the iHOT-33 questionnaire, from which the iHOT-12 is derived, proved to be valid. Since there is not data in French regarding iHOT-12, we performed a prospective study aiming to answer: (1) is this French version of the iHOT-12 questionnaire as valid, (2) can the minimal clinically important difference (MCID) value for patients undergoing hip arthroscopy for femoro-acetabular impingement (FAI) be defined? HYPOTHESIS: It is hypothesized that the iHOT-12-Fr would be valid and responsive to change in a cohort treated for FAI. PATIENTS AND METHODS: Using the COSMIN recommendations, a multicentric prospective cohort study was conducted to evaluate the reliability, validity, responsiveness and MCID of the iHOT-12-Fr. RESULTS: In total, 101 patients were recruited for participation in the project. The reliability of the iHOT-12-Fr questionnaire was assessed with the intraclass correlation coefficient (ICC=0.84) and the internal consistency with a Cronbach's alpha (α=0.86). The standard error of measurement (SEM=6.7) and the smallest detectable change (SDC=1.8) were calculated. Construct validity was evaluated with Pearson's correlation coefficients (r) by comparing the iHOT-12-Fr with the iHOT-33-Fr (r=0.96), the Hip disability and Osteoarthritis Outcome Score-Fr (r=0.68) and Nonarthritic Hip Score-Fr (r=0.82). Responsiveness was shown with a standardized effect size of 1.18, standardized response mean of 0.73, responsiveness ratio of 1.4 and an MCID of 11 points. DISCUSSION: Metrological qualities of the iHOT-12-Fr are comparable to the original version and other versions translated into different languages. This study proves that the French translation of the iHOT-12 is valid, reliable and compares to the original iHOT-12. LEVEL OF EVIDENCE: IV prospective study.

Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety.

Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on ß2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.

Above-the-knee amputation versus knee arthrodesis for revision of infected total knee arthroplasty: Recurrent infection rates and functional outcomes of 43 patients at a mean follow-up of 6.7 years.

INTRODUCTION: In cases of repeated treatment failure of periprosthetic joint infections (PJI) of the knee, above-the-knee amputation (AKA) or knee arthrodesis can be proposed to reduce the risk of recurrent infection, especially in cases with major bone defects or irreparable damage to the extensor mechanism of the knee. Since AKA versus knee arthrodesis results have been rarely assessed for these indications, we conducted a retrospective case-control study to compare both the rates of recurrent infection and functional outcomes. Hypothesis Patients who underwent AKA had fewer recurrent infections than those who had arthrodesis. MATERIALS AND METHODS: Twenty patients who underwent AKA and 23 patients who had knee arthrodesis, between 2003 and 2019, were retrospectively included in this study. These two groups were comparable in age (73.8 versus 77.7 years (p=.31)) and sex (10 women and 10 men versus 16 women and seven men (p=.19)). Each group was analyzed individually and then compared in terms of survival (recurrent infection) and functional outcomes using clinical assessment scores (visual analog scale (VAS), French neuropathic pain questionnaire (DN4), Parker and Palmer mobility score and the 36-item short-form survey (SF-36)). RESULTS: The rate of recurrent infection was 10% (two out of 20 patients) for the AKA group and 21.75% (five out of 23 patients) for the arthrodesis group (p=.69). The mean follow-up for the AKA group was 4.18 years (1.2-11.8) and 9.7 years (1.1-14.33) for the arthrodesis group (p=.002). The number of previous revisions (three (1.5-4) for AKA and two (2-3) for arthrodesis) and the time between the primary arthroplasty and surgical procedure were significantly greater in the AKA group (48.0 (12.0-102.0) months) than the arthrodesis group (48.0 (24.0-87.0) months) (p<001). The AKA group had significantly better clinical results for VAS (2.7±2.2 vs. 3.1±3.3), DN4 (1.5±2.1 vs. 2.6±2.9), Parker and Palmer (5.2±1.7 vs. 4.6±1.4), and SF-36 (30.9±15.6 vs. 26.9±17.0) (p<001). CONCLUSION: Above-the-knee amputation and knee arthrodesis showed no differences in the rate of recurrent sepsis. However, the comparison of the two groups demonstrated that patients who underwent an AKA had less pain, were more autonomous and had a better quality of life. LEVEL OF EVIDENCE: III; retrospective case-control.

Knee arthrodesis using a custom modular intramedullary nail in failed, infected knee arthroplasties: A concise follow-up note of 31 cases at a median of 13 years post-arthrodesis.

INTRODUCTION: Knee arthrodesis utilizes an arthrodesis nail as a salvage technique for infected total knee arthroplasty (TKA), especially when the extensor mechanism is damaged, or the skin is compromised. This implant helps to minimize or prevent leg length discrepancy, while allowing immediate weight bearing without requiring bone fusion. However, there is a risk of infection. Surgical revisions were required in 19% of patients at 50 months' follow-up in our team's initial 31-patient case series. Since there is little long-term outcome data, we reviewed this same group of patients after a mean of 13 years to determine: (1) the implant's long-term survival, (2) the functional outcomes, (3) the microbiological changes in revision cases. HYPOTHESIS: The long-term survival of knee arthrodesis using an arthrodesis nail for failed infected TKA is acceptable. MATERIAL AND METHODS: Thirty-one patients operated on between January 2005 and December 2008 were retrospectively included in the initial study. The functional outcomes consisted of pain on a visual analog scale (VAS), neuropathic pain (DN4) and the Oxford Knee Score. All surgical revisions were documented with repeat microbiology samples. RESULTS: The median follow-up time was 13.1 years [11.5-13.5]. No mechanical failure (implant failure or aseptic loosening) was observed. Eight patients were re-operated on due to new infections. The nail had to be removed in five of these patients. None of the patients required an amputation. Among the eight patients who were re-operated on, only two (25%) had been re-operated on since the initial study and underwent a two-stage arthrodesis revision. At 10 years, the cumulative incidence of surgical revision at the knee was 26% [95% CI: 12%-43%] and 16% [95% CI: 5.7%-31%] for an implant change. Six (75%) of the re-operated patients had their revision within the first 72 months of the initial TKA, while 4 (50%) had it within the first 26 months. Among the 15 patients who were still alive, the median Oxford Knee Score was 17/48 [12-28]. At the final assessment, the median pain level was 0 [0-5], although 4 of the 10 analyzable patients (of the 15 living patients, 3 had a cognitive impairment and 2 refused to participate) had neuropathic pain and pain on VAS of 3/10. The microbiologic findings were the same during the surgical revision in five of the eight re-operated patients (62%); however, one patient who had a Staphylococcus aureus infection had acquired a resistance to methicillin. In one patient, only one of the two bacteria identified initially was still present (methicillin-susceptible Coagulase-negative staphylococci [CNS]) and while in two patients, the infectious agent changed completely (shift from Gram-negative bacilli to methicillin-susceptible CNS, and the opposite for the other patient). DISCUSSION: Knee arthrodesis with a custom modular intramedullary nail is a viable limb salvage option in failed infected TKA cases with long-term survival, and it is comparable to other arthrodesis techniques. In most cases, recurrence of the infection occurred in the short term (<72 months). Later recurrences of the infection (>72 months) were rarer and were found in only two of our patients (6%). There were no mechanical failures. LEVEL OF EVIDENCE: IV; Retrospective cohort study.

Validation of the French version of the self-administered international hip outcome tool-33 questionnaire.

INTRODUCTION: To evaluate the effectiveness of new treatments, whether conservative or surgical, a self-administered questionnaire for hip pain targeted at physically active patients 18 to 60 years of age, named the international Hip Outcome Tool-33 (iHOT-33), was developed and validated in 2012. Since there is no French version available and we are acutely aware of transcultural variations, we conducted a prospective study to: 1) translate, and then 2) validate this questionnaire into international French. HYPOTHESIS: The iHOT-33-Fr questionnaire is a valid and reliable tool for evaluating hip pain in a young, francophone population. MATERIALS AND METHODS: Translation of the questionnaire was done according to the standardized method described by Beaton and the final version of the iHOT-33-Fr was validated using the COSMIN methodology. The data were collected prospectively at multiple sites. The reliability of the iHOT-33-Fr questionnaire was evaluated using the intraclass correlation coefficient (ICC) and its internal consistency using Cronbach's alpha. The standard error of measurement and minimum detectable change were calculated. The construct validity was evaluated using Pearson's correlation coefficient by comparing the iHOT-33-Fr with the Hip disability and Osteoarthritis Outcome Score (HOOS-Fr) and Nonarthritic Hip Score (NAHS-Fr). RESULTS: In all, 101 patients filled out the questionnaires. The ICC was 0.87. The Cronbach alpha was 0.95. The standard error of measurement was 6.4 and the minimum detectable change was 1.8. The correlation between the iHOT-33-Fr and the HOOS-Fr was 0.86, while the correlation between the iHOT-33-Fr and the NAHS-Fr was 0.75. DISCUSSION: Our results show that the metrological qualities of the iHOT-33-Fr are comparable to those of the original version and the versions translated into other languages. This study demonstrates that the iHOT-33-Fr is valid, reproducible and comparable to the original iHOT-33. It can be used by francophone surgeons treating symptomatic hip disease in young, active patients. LEVEL OF EVIDENCE: IV.

Probing the ionotropic activity of glutamate GluD2 receptor in HEK cells with genetically-engineered photopharmacology.

Glutamate delta (GluD) receptors belong to the ionotropic glutamate receptor family, yet they don't bind glutamate and are considered orphan. Progress in defining the ion channel function of GluDs in neurons has been hindered by a lack of pharmacological tools. Here, we used a chemo-genetic approach to engineer specific and photo-reversible pharmacology in GluD2 receptor. We incorporated a cysteine mutation in the cavity located above the putative ion channel pore, for site-specific conjugation with a photoswitchable pore blocker. In the constitutively open GluD2 Lurcher mutant, current could be rapidly and reversibly decreased with light. We then transposed the cysteine mutation to the native receptor, to demonstrate with high pharmacological specificity that metabotropic glutamate receptor signaling triggers opening of GluD2. Our results assess the functional relevance of GluD2 ion channel and introduce an optogenetic tool that will provide a novel and powerful means for probing GluD2 ionotropic contribution to neuronal physiology.

Neurotransmitters are chemicals released by the body that trigger activity in neurons. Receptors on the surface of neurons detect these neurotransmitters, providing a link between the inside and the outside of the cell. Glutamate is one of the major neurotransmitters and is involved in virtually all brain functions. Glutamate binds to two different types of receptors in neurons. Ionotropic receptors have pores known as ion channels, which open when glutamate binds. This is a fast-acting response that allows sodium ions to flow into the neuron, triggering an electrical signal. Metabotropic receptors, on the other hand, trigger a series of events inside the cell that lead to a response. Metabotropic receptors take more time than ionotropic receptors to elicit a response in the cell, but their effects last much longer. One type of receptor, known as the GluD family, is very similar to ionotropic glutamate receptors but does not directly respond to glutamate. Instead, the ion channel of GluD receptors opens after being activated by glutamate metabotropic receptors. GluD receptors are produced throughout the brain and play roles in synapse formation and activity, but the way they work remains unclear. An obstacle to understanding how GluD receptors work is the lack of molecules that can specifically block these receptors' ion channel activity. Lemoine et al. have developed a tool that enables control of the ion channel in GluD receptors using light. Human cells grown in the lab were genetically modified to produce a version of GluD2 (a member of the GluD family) with a light-sensitive molecule attached. In darkness or under green light, the light-sensitive molecule blocks the channel and prevents ions from passing through. Under violet light, the molecule twists, and ions can flow through the channel. With this control over the GluD2 ion channel activity, Lemoine et al. were able to validate previous research showing that the activation of metabotropic glutamate receptors can trigger GluD2 to open. The next step will be to test this approach in neurons. This will help researchers to understand what role GluD ion channels play in neuron to neuron communication.

Morscher Osteotomy Through Surgical Dislocation Approach for True Femoral Neck Lengthening with Greater Trochanter Transposition.

BACKGROUND: Young adults presenting with hip pain can be affected by proximal femoral growth disturbances as seen in Legg-Calvé-Perthes disease (LCPD) or as a complication of surgical treatment of developmental dysplasia of the hip (DDH). In 1988, Morscher proposed a novel femoral neck lengthening osteotomy to address these issues. The purpose of this study was to evaluate the effectiveness and safety of the Morscher osteotomy as a procedure to complement the well-documented surgical hip dislocation, to increase femoral offset, to distalize the greater trochanter, and to increase the overall limb length. METHODS: This study was a retrospective case series from 3 hip-preservation-expert surgeons. Morscher osteotomies performed through a surgical dislocation approach by 3 surgeons between January 2008 and September 2019 were reviewed. Fifteen patients with a median age at surgery of 17 years (range, 13 to 28 years) and a minimum follow-up of 3 months (until union) were included. Surgical indications, clinical findings, comparative radiographic analyses including the change in horizontal femoral offset and the position of the greater trochanter, and complications were assessed. RESULTS: Surgical indications included DDH and LCPD. The horizontal femoral offset improved in all patients, to a median of 32.5 mm (range, 4 to 46.4 mm). The articular-trochanteric distance increased to >5 mm in all patients. Limb length improved by a median of 11.5 mm (range, 3 to 30 mm). Complementary periacetabular osteotomy was performed in 14 patients. The lateral center-edge angle and the acetabular index improved in patients with an associated periacetabular osteotomy, to a median of 28.2° (range, 9° to 37.7°) and 7.9° (range, 0° to 20°), respectively. Two patients demonstrated osteoarthritis progression from Tönnis stage 0 to stage 1, and 6 patients had a decrease of the joint space. Complications included 1 pulmonary embolism, 1 case of asymptomatic fibrous union of the greater trochanter, and 1 transient sciatic nerve palsy. CONCLUSIONS: The time-tested Morscher osteotomy indicated for complex proximal femoral reconstruction is effective in increasing horizontal femoral offset, distalization of the greater trochanter, and limb length. Combining the Morscher osteotomy with the versatility of surgical hip dislocation and the improved coverage capacity of periacetabular osteotomy proved complementary in the arsenal of hip preservation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine.

The addictive component of tobacco, nicotine, acts via nicotinic acetylcholine receptors (nAChRs). The ß2 subunit-containing nAChRs (ß2-nAChRs) play a crucial role in the rewarding properties of nicotine and are particularly densely expressed in the mesolimbic dopamine (DA) system. Specifically, nAChRs directly and indirectly affect DA neurons in the ventral tegmental area (VTA). The understanding of ACh and nicotinic regulation of DA neuron activity is incomplete. By computational modeling, we provide mechanisms for several apparently contradictory experimental results. First, systemic knockout of ß2-containing nAChRs drastically reduces DA neurons bursting, although the major glutamatergic (Glu) afferents that have been shown to evoke this bursting stay intact. Second, the most intuitive way to rescue this bursting-by re-expressing the nAChRs on VTA DA neurons-fails. Third, nAChR re-expression on VTA GABA neurons rescues bursting in DA neurons and increases their firing rate under the influence of ACh input, whereas nicotinic application results in the opposite changes in firing. Our model shows that, first, without ACh receptors, Glu excitation of VTA DA and GABA neurons remains balanced and GABA inhibition cancels the direct excitation. Second, re-expression of ACh receptors on DA neurons provides an input that impedes membrane repolarization and is ineffective in restoring firing of DA neurons. Third, the distinct responses to ACh and nicotine occur because of distinct temporal patterns of these inputs: pulsatile versus continuous. Altogether, this study highlights how ß2-nAChRs influence coactivation of the VTA DA and GABA neurons required for motivation and saliency signals carried by DA neuron activity.

A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats.

Tobacco addiction is a chronic and relapsing disorder with an important genetic component that represents a major public health issue. Meta-analysis of large-scale human genome-wide association studies (GWASs) identified a frequent non-synonymous SNP in the gene coding for the α5 subunit of nicotinic acetylcholine receptors (α5SNP), which significantly increases the risk for tobacco dependence and delays smoking cessation. To dissect the neuronal mechanisms underlying the vulnerability to nicotine addiction in carriers of the α5SNP, we created rats expressing this polymorphism using zinc finger nuclease technology and evaluated their behavior under the intravenous nicotine-self-administration paradigm. The electrophysiological responses of their neurons to nicotine were also evaluated. α5SNP rats self-administered more nicotine at high doses and exhibited higher nicotine-induced reinstatement of nicotine seeking than wild-type rats. Higher reinstatement was associated with altered neuronal activity in several discrete areas that are interconnected, including in the interpeduncular nucleus (IPN), a GABAergic structure that strongly expresses α5-containing nicotinic receptors. The altered reactivity of IPN neurons of α5SNP rats to nicotine was confirmed electrophysiologically. In conclusion, the α5SNP polymorphism is a major risk factor for nicotine intake at high doses and for relapse to nicotine seeking in rats, a dual effect that reflects the human condition. Our results also suggest an important role for the IPN in the higher relapse to nicotine seeking observed in α5SNP rats.

Manipulating midbrain dopamine neurons and reward-related behaviors with light-controllable nicotinic acetylcholine receptors.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through ß2-containing (ß2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine.

Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self-administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.

Nicotine enhances alcohol intake and dopaminergic responses through ß2* and ß4* nicotinic acetylcholine receptors.

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of ß4 * nAChRs, but not ß2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (ß2-/- and ß4-/- mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in ß2-/- and ß4-/- mice, suggesting that nicotine triggers ß2* and ß4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.

First Case of Actinomycetoma in France Due to a Novel Nocardia Species, Nocardia boironii sp. nov.

Bacterial mycetoma is a neglected disease mainly observed in tropical area countries and typically associated with rural conditions, making its presence in developed countries of temperate climate areas rare. However, we report the first case of an autochthonous mycetoma case in continental France that originated from a new Nocardia species. A Gram-positive filamentous bacterium (OFN 14.177T) was isolated from a pus sample from the mycetoma of a male French patient 92 years old suffering from chronic lymphocytic leukemia. The isolate was analyzed by a polyphasic taxonomic approach by coupling morphological, biochemical, physiological, and chemotaxonomic aspects to genomic and phylogenetic analyses. Multilocus sequence analysis (MLSA) using four housekeeping genes (16S rRNA gene, secA1, hsp65, and sod) combined with phylogenetic analysis revealed that the strain OFN 14.177T is phylogenetically closer not only to Nocardia altamirensis but also to all other species comprising the Nocardia brasiliensis clade (i.e., N. brasiliensis, N. altamirensis, N. vulneris, N. iowensis, and N. tenerifensis), some of which present cutaneous tropism. The G+C content of isolate OFN 14.177T was 68.2 mol%. DNA-DNA hybridization analyses demonstrated 38.25% relative reassociation with N. altamirensis. The strain OFN 14.177T is different from the closest species at genetic and phenotypical levels, and the data obtained indicate that it should be recognized as a new species, for which the name of Nocardia boironii sp. nov. is proposed. The type strain is OFN 14.177T (= EML 1451 = DSM 101696). IMPORTANCE Bacterial mycetoma is an endemic infection in areas with tropical and subtropical climates. Thus, its presence in temperate climate areas remains rare. We report here the first case of autochthonous actinomycetoma in continental France originating from a Nocardia species other than N. brasiliensis, namely, Nocardia boironii. Considering the history of the patient, the infection source of strain OFN 14.177T may be from frequent contact with the soil over many years because of his gardening activities. The discovery of a French autochthonous Nocardia species responsible for actinomycetoma reveals the importance of considering the possibility of having autochthonous infections of this type in nontropical countries, not only imported cases from tropical countries. However, further studies are needed to elucidate the real incidence of this new species.

Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments.

RATIONALE: Evidence links alterations in α5-containing nicotinic receptors (α5*-nAChRs) to nicotine addiction. Notably, the rs16969968 polymorphism in the α5 gene (α5SNP) increases the risk for heavy smoking and impairs nicotine-rewarding properties in mice. Additional work is needed to understand how native and polymorphic α5*-nAChRs contribute to processes associated with the risk for nicotine addiction. OBJECTIVES: We aimed at understanding the contribution of α5*-nAChRs to endophenotypes like increased responses to novelty and anxiety, known to promote vulnerability to addiction, and to the response of the dopamine and serotonin systems to nicotine. METHODS: Behavioural phenotypes were investigated in mice lacking the α5 gene (α5(-/-)). Nicotine injections were performed to test the consequences of nicotine exposure on the phenotypes identified. Dopamine and serotonin signalling were assessed using in vivo microdialysis and electrophysiology. We used lentiviral vectors to compare the consequences of re-expressing either the α5 wild-type allele or the α5SNP in specific brain areas of α5(-/-) mice. RESULTS: α5(-/-) mice did not exhibit high responses to novelty but showed decreased novelty-induced rearing behaviour together with high anxiety. Exposure to high doses of nicotine rescued these phenotypes. We identified altered spontaneous and nicotine-elicited serotonin and dopamine activity in α5(-/-) mice. Re-expression of α5 in the ventral tegmental area and hippocampus rescued rearing and anxiety levels in α5(-/-) mice, respectively. When expressing the α5SNP instead, this resulted in a knockout-like phenotype for both behaviours. CONCLUSIONS: We propose that altered α5*-nAChR cholinergic signalling contributes to emotional/behavioural impairments that may be alleviated by nicotine consumption.

Odorant Metabolism Analysis by an Automated Ex Vivo Headspace Gas-Chromatography Method.

In the olfactory epithelium (OE), odorant metabolizing enzymes have the dual function of volatile component detoxification and active clearance of odorants from the perireceptor environment to respectively maintain the integrity of the tissues and the sensitivity of the detection. Although emphasized by recent studies, this enzymatic mechanism is poorly documented in mammals. Thus, olfactory metabolism has been characterized mainly in vitro and for a limited number of odorants. The automated ex vivo headspace gas-chromatography method that was developed here was validated to account for odorant olfactory metabolism. This method easily permits the measurement of the fate of an odorant in the OE environment, taking into account the odorant gaseous state and the cellular structure of the tissue, under experimental conditions close to physiological conditions and with a high reproducibility. We confirmed here our previous results showing that a high olfactory metabolizing activity of the mammary pheromone may be necessary to maintain a high level of sensitivity toward this molecule, which is critical for newborn rabbit survival. More generally, the method that is presented here may permit the screening of odorants metabolism alone or in mixture or studying the impact of aging, pathology, polymorphism or inhibitors on odorant metabolism.

Role of ß4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. ß4-containing (ß4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of ß4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive ß4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 µg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that ß4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of ß4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of ß4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that ß4* nAChRs in the IPN have a role in maintaining nicotine IVSA.