Mepolizumab in CRSwNP/ECRS and NP: the phase III randomised MERIT trial in Japan, China, and Russia.

BACKGROUND: This randomised, double-blind, placebo-controlled, parallel-group, 52-week Phase III study (MERIT; NCT04607005) assessed mepolizumab efficacy and safety in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS (ECRS) in Japan, Russia, and China, for which data are limited. METHODOLOGY: Eligible patients (enrolled at 60 centres) had blood eosinophil count >2%, endoscopic bilateral NP score ≥5, nasal obstruction visual analogue scale (VAS) score >5, ≥2 sinonasal symptoms, and either previous sinus surgery or systemic corticosteroid use/intolerance. Patients were randomised (1:1) to receive mepolizumab 100 mg subcutaneously or placebo every 4 weeks, plus standard of care. Co-primary endpoints: change from baseline in total endoscopic NP score (ENPS) (Week 52) and nasal obstruction VAS score (Weeks 49-52). Post hoc analyses conducted in a modified intent-to-treat (mITT) population excluded patients from two study sites, related to Good Clinical Practice violations by the Site Management Organisation overseeing these sites. These were considered the primary efficacy analyses. RESULTS: In the mITT population, mepolizumab (n=80) versus placebo (n=83) significantly improved nasal obstruction VAS score from baseline to Week 49-52 and was associated with a trend of total ENPS improvements at Week 52. Mepolizumab/placebo on-treatment adverse events (AEs) occurred in 68/84 and 65/85 patients in the safety population (treatment-related AEs: 2/84 and 5/85, respectively), and on-treatment serious AEs in 0/84 and 4/85 patients, respectively (no fatalities reported). CONCLUSIONS: Mepolizumab was effective and well-tolerated in patients with CRSwNP/ECRS from Japan, Russia, and China.

A systematic review of the effect of L-tryptophan supplementation on mood and emotional functioning.

L-tryptophan (TRP), one of the essential amino acids in humans, is a precursor of serotonin, and hence its intake is closely related to the suppression of depressed and anxious moods. We did a systematic review of RCTs to examine the effects of tryptophan intake on the mood of healthy adults by searching PubMed, the Cochrane Library, and Ichu-shi according to PRISMA guidelines. As a result, 11 RCTs met the criteria and were accepted. Four RCTs showed the effects of tryptophan intake on negative feelings and happy feelings in healthy individuals, with significant differences between the treatment and the control groups. This suggests that TRP intake may be an effective approach to decrease anxiety and increase positive mood in healthy individuals. On the other hand, the effectiveness of TRP for aggressive feelings was not recognized. Reviewing these 11 RCTs, we concluded that taking 0.14-3 g of TRP per day in addition to the usual meal can be expected to improve the mood of healthy individuals. In order to estimate the optimum amount of TRP intake more accurately, further studies need to be conducted with more appropriate settings of intake period, intake frequency, and intake method.

Assessment of the AAV-mediated expression of channelrhodopsin-2 and halorhodopsin in brainstem neurons mediating auditory signaling.

The physiology and circuitry associated with dorsal cochlear nucleus neurons (DCN) have been well described. The ability to remotely manipulate neuronal activity in these neurons would represent a step forward in the ability to understand the specific function of DCN neurons in hearing. Although, optogenetics has been used to study the function of pathways in other systems for several years, in the auditory system only neurons in the auditory cortex have been studied using this technique. Adeno-associated viral vectors with either channelrhodopsin-2 fused with GFP (ChR2-GFP) or halorhodopsin fused with mCherry (HaloR-mCherry), capable of expressing light sensitive cation channels or chloride pumps, respectively, were delivered into the dorsal cochlear nucleus (DCN). One to 18 months later, expression of ChR2 and HaloR was observed throughout the DCN. Rhodopsin distribution within the DCN was determined to be within several cell types identified based on morphology and location within the DCN. Expression of ChR2-GFP and HaloR-mCherry was found at both the injection site as well as in regions receiving projections from the site. Wavelength appropriate optical stimulation in vivo resulted in neuronal activity that was significantly increased over pre-stimulation levels with no return to baseline levels during the time of the light exposure. We also examined the effects of optically driven neuronal activity on subsequent tone driven responses in the DCN. In the DCN 75% of the 16 electrode sites showed decreased neuronal activity in response to a tone immediately following light stimulation while six percent were decreased following tone stimulation and 19% of the electrode sites showed no change. This is in contrast to tone driven neuronal activity prior to the light exposure in which the majority of electrode sites showed increased neuronal activity. Our results indicate that expression and activation of rhodopsin within neurons involved in auditory processing does not appear to have deleterious effects on hearing even 18 months following expression. In addition, virally targeted rhodopsins may be useful as tract tracers to delineate as well as modulate the activity of pathways and specific neurons. In the future rhodopsins can be targeted to specific subpopulations of auditory neurons. Ultimately, photostimulation may provide a physiologically relevant method for modulating the function of auditory neurons and affecting hearing outcomes. This article is part of a Special Issue entitled Optogenetics (7th BRES).

Multiple-site optical recording of mouse brainstem evoked by vestibulocochlear nerve stimulation.

We used optical imaging to investigate the mouse cochlear and vestibular nucleus in brainstem slices using a voltage-sensitive dye, RH 155. As a result, the spatiotemporal patterns of excitatory propagation were shown. These optical signals consisted of two components consisting of a spike-like fast signal and a long-lasting slow signal. All responses were abolished by tetrodotoxin. The slow signals were eliminated under a Ca(2+)-free solution. In addition, synaptic fatigue was also observed. The present study indicated the feasibility of optical recording for visually revealing the synaptic transmission in both the vestibular and cochlear nucleus.

Optical recording of membrane potential in dissociated mouse vestibular ganglion cells using a voltage-sensitive dye.

We investigated membrane electrophysiological features of dissociated vestibular ganglion neurons, using a voltage-sensitive dye and a multiple site optical imaging system. The neuronal nature of the cultured vestibular ganglion cells was confirmed by positive staining with the anti-neurofilament 200 kDa antibody, using immunocytochemical methods. Optical absorption of the dye which binds to the external surface of neuron membranes increased while the cells were depolarized during perfusion with 150 mM potassium solution. The relative ratio (deltaI/I) of optical absorption change was 0.23 +/- 0.08% (means +/- S.D., n = 16). These optical responses were wavelength dependent, therefore, the optical response apparently originated from the voltage-sensitive dye. Under our experimental conditions, photodynamic damage and pharmacological effects of the dye were either absent or insignificant. We therefore concluded that optical recording is a new, practical and non-invasive method to simultaneously monitor changes in membrane potential from cultured vestibular ganglion cells. Optical recording is expected to provide further insight into mechanisms of information processing by vestibular ganglion neurons.

[Clinical study of parotid tumors: a 20 year statistical analysis of 633 cases].

During the 20 years from 1977 to 1996, 633 cases underwent excisions of parotid tumors (539 benign and 94 malignant) in the department of Otolaryngology of Kansai Medical University. The incidence of Warthin's tumors in the years from (1987 to 1996) was higher than that in the years from 1977 to 1986. On the other hand, the incidence of mucoepidermoid carcinomas was less than in previous reports. Tumors accompanied with spontaneous pain or facial nerve palsy and with invasion to both lobes frequently indicated malignancy. Facial nerve palsy caused by either benign or malignant tumors before operation showed no improvement after surgery. The incidences of facial nerve palsy (1.0% in benign, and 18.3% in malignant) and Frey's syndrome (17.8% in benign, and 18.3% in malignant) after surgery were lower than those in other reports of both benign and malignant tumors. Five-year mortality was 76.1%. All deaths that occurred five years after operation involved highly grade malignant tumors.

Spatial and temporal patterns of evoked neural activity from auditory nuclei in chick brainstem detected by optical recording.

In order to detect the spatial patterning of the auditory projection of the embryonic chick brainstem, anatomical methods such as orthograde transport of horseradish peroxidase have been used. However, these methods do not provide the continuous information required about the absolute value and time-course of varying neural excitement. Furthermore, the use of conventional electrophysiological methods makes it difficult or impossible to detect the transmembrane voltage change because of the small size and fragility of the cells of the young chick brainstem. We thus believe that optical measurement of membrane potential might be beneficial in circumstances where electrodes are difficult to use for reasons of cell size, complexity, or membrane topology. In the present work, we therefore examined the feasibility of an optical method for delineating the synaptic transmission of afferent input in the auditory nuclei in the chick brainstem. We used embryonic chick brainstem slice preparations featuring an intact eighth nerve, and loaded depolarizing square current pulses from tungsten microelectrodes into the auditory nerve for stimulation of these preparations. In this approach, we used a multiple-site optical recording system comprising a 16 x 16-element photodiode array and a voltage sensitive dye (NK-2761). Neural excitation evoked by stimulation to the left auditory nerve was propagated to the dorsal side of the brainstem. This area in which the optical signal was detected is located on the auditory nuclei. Since the physiological spatial patterning of the auditory nerve projection could be roughly estimated by the optical technique, the technique is considered useful for examining the electrical activity generated from auditory nuclei in the brainstem. This is the first report of spatial patterning of auditory neurons in the embryonic chick brainstem generated through optical recording.

The presence of platelet-activating factor-acetylhydrolase in human middle ear effusions.

Factors related to inflammation, including platelet-activating factor (PAF), apparently have a role in chronic otitis media with effusion. PAF is metabolized to the biologically inactive lyso-PAF by the enzyme PAF-acetylhydrolase (PAF-AH). We have obtained evidence that PAF-AH activity is present in human middle ear effusions in patients with chronic otitis media with effusion. The present study revealed the enzyme in human middle ear effusions to be the plasma type PAF-AH. We suggest that PAF-AH may be involved in regulating inflammation in the middle ear by inactivating PAF, the potent proinflammatory autacoid.

Optical recording of membrane potential on isolated spiral ganglion cells of newborn mice using a voltage-sensitive dye.

Optical imaging methods make monitoring of the membrane potential feasible. With this technique, one can observe different optical signals depending on optical properties, in response to membrane potential, using voltage-sensitive dyes. We used the multiple-site optical imaging system to investigate membrane potentials of the isolated, cultured spiral ganglion cells (SCGs) from newborn mice. We used a voltage-sensitive absorption dye. With high potassium (150 mM K+) exposure, the absorbency of SGCs stained with voltage-sensitive dye increased temporarily under a 700-nm interference filter at approximately 0.3%. This detection of the depolarization of SGCs using an optical recording technique with a voltage-sensitive dye is important because it shows that the simultaneous measurement of activity in a variety of regions is possible, as is the exploring of the intercellular signalling pathway.

An increase in laryngeal aerosol deposition by ultrasonic nebulizer therapy with intermittent vocalization.

In acute or chronic laryngitis as well as pharyngitis, nebulization with steroid and antibiotics is considered to be a safe and effective treatment. However, the optimal dose, frequency, duration, and method of administration by ultrasonic nebulization is not known. To evaluate whether there is continual improvement using ultrasonic nebulizer therapy, the deposition rate of aerosol particles into the upper airway was studied. We analyzed the deposition rate in the upper airway by a counting system of radioactive isotope (99mTc-diethylene triaminepentaacetic acid; 99mTc DTPA). Volunteers in good health inhaled an aerosol containing 99mTc DTPA under various conditions of inhalation. Deep and slow inhalation at a respiratory rate of 12 breaths/minute resulted in a high deposition rate of 99mTc DTPA in the lung and a low deposition rate in the larynx. In contrast, faster inhalation at a respiratory rate of 36 breaths/minute resulted in an increase in the isotope deposition rate in the larynx. Furthermore, when the volunteers vocalized intermittently during the fast inhalation at a respiratory rate of 36 breaths/minute, the isotope deposition rate in the volunteer's larynx was higher than in all other inhalation conditions. These results suggest that fast inhalation with intermittent vocalization is one of the important inhalation methods used to improve the deposition rate of aerosol particles into the upper airway with an ultrasonic nebulizer.