The nasal tissues have the main consecutive roles of moistening and heating the air entering the respiratory tract and detecting odor via the activation of olfactory receptors in the neuro-olfactory ...epithelium. Initially, nasal toxicology was investigated to better assess the risk of nasal injuries caused by environmental toxicants or their active metabolites. Later, the characterization of the nasal toxicological barrier was a research concern for the purposes of intranasal drug delivery. Both fields allowed for an increase in our knowledge of the nasal xenobiotic-metabolizing enzymes and transporters that are highly expressed in this tissue. In addition to airborne toxicants or drugs, the main substrates for these proteins are natural volatiles known as odorants that emanate from our daily environment (food, perfume, plants, materials, congeners, etc.). Accordingly, another emerging field of interest has been developed that aims to understand the function of odorant-metabolizing enzymes (OMEs) in olfaction. Early in this field of research, OMEs were suspected to participate in the clearance of odorants from the receptor environment to avoid their saturation and thus maintain the sensitivity of neuronal detection. Other roles of OMEs that could significantly modulate olfaction were also considered, such as the involvement of odorant primary metabolites in the olfactory response. By combining enzymatic, physiological and sensory experimental approaches, recent advances have markedly improved our understanding of the contributions of OMEs to the olfactory process. This review combines recent data from the literature regarding nasal OME identification, localization, and activity and highlights the function of OMEs in olfaction.
Odorant metabolizing enzymes (OMEs) are expressed in the olfactory epithelium (OE) where they play a significant role in the peripheral olfactory process by catalyzing the fast biotransformation of ...odorants leading either to their elimination or to the synthesis of new odorant stimuli. The large family of OMEs gathers different classes which interact with a myriad of odorants alike and complementary to olfactory receptors. Thus, it is necessary to increase our knowledge on OMEs to better understand their function in the physiological process of olfaction. This study focused on a major olfactory UDP-glucuronosyltransferase (UGT): UGT2A1. Immunohistochemistry and immunogold electronic microscopy allowed to localize its expression in the apical part of the sustentacular cells and originally at the plasma membrane of the olfactory cilia of the olfactory sensory neurons, both locations in close vicinity with olfactory receptors. Moreover, using electroolfactogram, we showed that a treatment of the OE with beta-glucuronidase, an enzyme which counterbalance the UGTs activity, increased the response to eugenol which is a strong odorant UGT substrate. Altogether, the results supported the function of the olfactory UGTs in the vertebrate olfactory perireceptor process.
Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated ...instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.
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.
The long-term survival of knee arthrodesis using an arthrodesis nail for failed infected TKA is acceptable.
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.
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).
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.
IV; Retrospective cohort study.
Stressful life events are primary environmental factors that markedly contribute to depression by triggering brain cellular maladaptations. Dysregulation of ventral tegmental area (VTA) dopamine ...neurons has been causally linked to the appearance of social withdrawal and anhedonia, two classical manifestations of depression. However, the relevant inputs that shape these dopamine signals remain largely unknown. We demonstrate that chronic social defeat (CSD) stress, a preclinical paradigm of depression, causes marked hyperactivity of laterodorsal tegmentum (LDTg) excitatory neurons that project to the VTA. Selective chemogenetic-mediated inhibition of cholinergic LDTg neurons prevent CSD-induced VTA DA neurons dysregulation and depressive-like behaviors. Pro-depressant outcomes are replicated by pairing activation of LDTg cholinergic terminals in the VTA with a moderate stress. Prevention of CSD outcomes are recapitulated by blocking corticotropin-releasing factor receptor 1 within the LDTg. These data uncover a neuro-circuitry of depressive-like disorders and demonstrate that stress, via a neuroendocrine signal, profoundly dysregulates the LDTg.
Abstract
Sensory processing relies on fast detection of changes in environment, as well as integration of contextual cues over time. The mechanisms by which local circuits of the cerebral cortex ...simultaneously perform these opposite processes remain obscure. Thalamic “specific” nuclei relay sensory information, whereas “nonspecific” nuclei convey information on the environmental and behavioral contexts. We expressed channelrhodopsin in the ventrobasal specific (sensory) or the rhomboid nonspecific (contextual) thalamic nuclei. By selectively activating each thalamic pathway, we found that nonspecific inputs powerfully activate adapting (slow-responding) interneurons but weakly connect fast-spiking interneurons, whereas specific inputs exhibit opposite interneuron preference. Specific inputs thereby induce rapid feedforward inhibition that limits response duration, whereas, in the same cortical area, nonspecific inputs elicit delayed feedforward inhibition that enables lasting recurrent excitation. Using a mean field model, we confirm that cortical response dynamics depends on the type of interneuron targeted by thalamocortical inputs and show that efficient recruitment of adapting interneurons prolongs the cortical response and allows the summation of sensory and contextual inputs. Hence, target choice between slow- and fast-responding inhibitory neurons endows cortical networks with a simple computational solution to perform both sensory detection and integration.
Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. ...A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned placepreference protocol so as to mediate Pavlovian conditioning.
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.
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.
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.
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.
Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
PDF
