102 research outputs found
Nicotinic Acetylcholine Receptors in the Respiratory Tract
Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and nonneuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent
findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement
of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR
in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic
obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential
regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the
α3ÎČ4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and
the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases
with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the
inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment.
However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that
more detailed research into this topic and possible pharmaceutical applications could represent
a valuable tool to alleviate the symptoms of diverse airway diseases
Large-scale cross-sectional online survey on patient-neurologist communication, burden of disease assessment and disease monitoring in people with multiple sclerosis
Background
Management of multiple sclerosis (MS) requires a high level of communication between health care professionals (HCPs) and people with MS (pwMS) including profound investigation and discussion of symptoms to identify therapeutic needs. For treatment decisions, monitoring of disease activity is important, in this respect self-monitoring devices and apps, as well as magnetic resonance imaging are important tools.
Methods
MS Perspectives is a cross-sectional online survey conducted in Germany which was designed to collect data, among others, on the communication between pwMS and HCPs regarding treatment goals, symptom assessment, usage of devices and apps to self-monitor health functions, as well as to identify patients' attitude toward the role of magnetic resonance imaging (MRI). Between December 2021 and February 2022, 4,555 pwMS completed the survey.
Results
In total, 63.7% of participants reported that treatment goals have been discussed with their HCPs. Symptoms worsening in the past 12 months independent of relapses was more often reported by pwMS than inquired by HCPs, according to patients' report. Devices or apps for health monitoring were used by less than half of participants. Frequency of MRI controls was much lower in participants with longer compared to shorter disease duration (47.5 vs. 86.3%). The proportion of patients with annual or semiannual scans was highest among pwMS receiving infusion therapy (93.5%), followed by oral medication (82.5%) and injectables (73.4%), and lowest for pwMS without immunotherapy (58.2%).
Conclusion
MS Perspectives identified a rather low patient involvement regarding treatment goals and symptom assessment in clinical practice. Regarding this and our findings for health self-monitoring and MRI usage, strategies for improving patient-HCP communication and disease monitoring may be considered
Chemosensory cells in the respiratory tract as crucial regulators of innate immune responses
During recent years chemosensory cells in extraoral tissues have been established as mediators for the detection and regulation of innate immune processes in response to pathogens. Under physiological conditions, chemosensory cells are present throughout the respiratory epithelium of the upper and lower airways as well as in the main olfactory epithelium. Additionally, they emerge in the alveolar region of the lung upon viral infections. Chemosensory cells in the upper and the lower airways detect signalling molecules from gram-positive and gram-negative bacteria as well as aeroallergens and fungi. Upon stimulation they release multiple molecules, such as the transmitter acetylcholine, the cysteinyl leukotriene E4 and the cytokine interleukin-25, which act as autocrine and paracrine signals and thereby orchestrate the innate immune responses in the respiratory system. Activation of chemosensory cells stimulates various immune cells, e.g. type 2 innate lymphoid cells, modulates mucociliary clearance and induces a protective neurogenic inflammation. This review compiles and discusses recent findings regarding chemosensory cell function in the respiratory tract
Prolonged-release fampridine for the treatment of myoclonus after cervical myelitis: a case report
Prolonged-release fampridine (PR-FAM), a potassium channel blocker, is approved for improving walking ability in patients with multiple sclerosis (MS). Beyond this, positive effects on other MS symptoms like fatigue, cognition, and tremor have been described. To our knowledge, a positive effect of PR-FAM on spinal myoclonus has not been described so far. Here, we report a 32-year-old female with myoclonus after cervical myelitis affecting both hands which markedly improved after administration of PR-FAM. Treatments used before such as carbamazepine or levetiracetam had to be withdrawn because of intolerable side effects or lack of efficacy. The positive effect of PR-FAM could be confirmed by transient suspension. PR-FAM may be considered as a treatment option in refractory spinal myoclonus after myelitis in selected cases
Nicotine stimulates ion transport via metabotropic ÎČ4 subunit containing nicotinic ACh receptors
Background and Purpose
Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown.
Experimental Approach
Transepithelial short circuit currents (ISC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca2+]i were studied on freshly dissociated mouse tracheal epithelial cells.
Key Results
Apical application of the nAChR agonist nicotine transiently increased ISC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. αâBungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3ÎČ2, α4ÎČ2, α4ÎČ4 and α3ÎČ4) and Aâ85380 (α4ÎČ2 and α3ÎČ4) increased ISC. The antagonists dihydroâÎČâerythroidine (α4ÎČ2, α3ÎČ2, α4ÎČ4 and α3ÎČ4), αâconotoxin MII (α3ÎČ2) and αâconotoxin PnIA (α3ÎČ2) reduced the nicotine effect. Nicotineâ and epibatidineâinduced currents were unaltered in ÎČ2â/âmice, but in ÎČ4â/â mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca2+âATPase inhibitor) or the ryanodine receptor antagonists JTVâ519 and dantrolene there was a reduction in the nicotineâeffect, indicating involvement of Ca2+ release from intracellular stores. Additionally, the PKA inhibitor Hâ89 and the TMEM16A (Ca2+âactivated chloride channel) inhibitor T16AinhâA01 significantly reduced the nicotineâeffect.
Conclusion and Implications
α3ÎČ4 nAChRs are responsible for the nicotineâinduced current changes via Ca2+ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A
Correlation of room acoustic parameters and noise level in eating establishments
This article addresses the impact of the occupancy level, the average acoustic absorption and the so-called acoustic capacity of a space, which is proportional with the volume and inversely proportional with the reverberation time, on the behavior of talking people in an eating establishments. Four different settings were compared: two casual dining restaurants, a self-service student canteen and a small faculty club. The Lombard effect was observed in all cases. In a restaurant with an average amount of absorbing surface of 2.4Â m2 or more per person, the sound pressure level increased with more than 3Â dB per doubling of the number of people. Results for the student canteen show that people started to communicate less when the number of people present was so high that the absorbing surface dropped under 1.5Â m2/person (80 people). The level even stopped to increase with increasing occupancy from 150 people present and beyond, corresponding with 0.8Â m2 of absorbing surface per person. This is roughly consistent with an estimated value for the acoustic capacity of that space, which was 189 people (corresponding with a table occupancy of about 72%). In the latter circumstances, the background noise level, as expressed by LA,95 was as high as 69Â dB. Overcoming this level for oral communication would require a not sustainable vocal effort. In the tests performed in other restaurants, the observed occupancy was below 60%, which, thanks to the higher number of absorbing surfaces in those restaurants, was well below the acoustic capacity
Human airway tuft cells influence the mucociliary clearance through cholinergic signalling
Background Airway tuft cells, formerly called brush cells have long been described only morphologically in human
airways. More recent RNAseq studies described a chemosensory cell population, which includes tuft cells, by a distinct
gene transcription signature. Yet, until which level in the tracheobronchial tree in native human airway epithelium tuft
cells occur and if they function as regulators of innate immunity, e.g., by regulating mucociliary clearance, remained
largely elusive.
Methods We performed immunohistochemistry, RT-PCR and immunoblotting analyses for various tuft cell markers
to confirm the presence of this cell type in human tracheal samples. Immunohistochemistry was conducted to
study the distribution of tuft cells along the intrapulmonary airways in humans. We assessed the influence of bitter
substances and the taste transduction pathway on mucociliary clearance in mouse and human tracheal samples by
measuring particle transport speed.
Results Tuft cells identified by the expression of their well-established marker POU class 2 homeobox 3 (POU2F3)
were present from the trachea to the bronchioles. We identified choline acetyltransferase in POU2F3 expressing cells
as well as the transient receptor potential melastatin 5 (TRPM5) channel in a small population of tracheal epithelial
cells with morphological appearance of tuft cells. Application of bitter substances, such as denatonium, led to an
increase in mucociliary clearance in human tracheal preparations. This was dependent on activation of the TRPM5
channel and involved cholinergic and nitric oxide signalling, indicating a functional role for human tuft cells in the
regulation of mucociliary clearance. Conclusions We were able to detect tuft cells in the tracheobronchial tree down to the level of the bronchioles.
Moreover, taste transduction and cholinergic signalling occur in the same cells and regulate mucociliary clearance.
Thus, tuft cells are potentially involved in the regulation of innate immunity in human airways
Giant cell arteritis with vertebral artery involvementâbaseline characteristics and follow-up of a monocentric patient cohort
Vertebral artery (VA) involvement in giant cell arteritis (GCA) has rarely been reported. We aimed to evaluate the prevalence, patientsâ characteristics, and immunotherapies used in patients with GCA and VA involvement at diagnosis and 1 year follow-up, retrospectively including patients being diagnosed between January 2011 and March 2021 in our department. Clinical features, laboratory data, VA imaging, immunotherapy, and 1âyear follow-up data were analyzed. Baseline characteristics were compared to GCA patients without VA involvement. Among all 77 cases with GCA, 29 patients (37.7%) had VA involvement, as diagnosed by imaging and/or clinical signs and symptoms. Gender distribution and erythrocyte sedimentation rate (ESR) were significantly different in the groups with and without VA involvement, with more women being affected (38/48 patients, 79.2%) and a significantly higher median ESR in patients without VA involvement (62 vs. 46 mm/h; pâ=â0.012). MRI and/or CT showed vertebrobasilar stroke at GCA diagnosis in 11 cases. 67/77 patients (87.0%) received high-dose intravenous glucocorticosteroids (GCs) at diagnosis, followed by oral tapering. Six patients were treated with methotrexate (MTX), one with rituximab, and five with tocilizumab (TCZ). 2/5 TCZ patients achieved clinical remission after 1 year, vertebrobasilar stroke within the first year occurred in 2/5 patients. Diagnosis of VA involvement might be underrecognized in GCA patients. VA imaging should be performed in elderly patients with vertebrobasilar stroke presenting with GCA symptoms, not to miss GCA as the etiology of stroke. Efficacy of immunotherapies in GCA with VA affection and long-term outcomes need to be investigated further
Outcomes After decompressive surgery for severe cerebral venous sinus thrombosis associated or not associated with vaccine-induced immune thrombosis with thrombocytopenia: a multicenter cohort study
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