These authors equally contributed to this work.Keywords: cystic fibrosis, CFTR, autophagy, cysteamine, epigallocatechin gallate, sweat chloride Abbreviations: BECN1/Beclin 1, autophagy-related; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; CSNK2, casein kinase 2; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL8, chemokine (C-X-C motif) ligand 8; EGCG, epigallocatechin gallate; FEV, forced expiratory volume; PM, plasma membrane; RPD, rectal potential difference; SQSTM1, sequestosome 1; TGM2, transglutaminase 2; TNF, tumor necrosis factor.Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr F508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/ TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

2b. Laryngoscope, 128:E339-E345, 2018.

No abstract

Dupilumab is a fully human monoclonal antibody targeting interleukin (IL) 4 and IL13 pathways. We performed a retrospective observational study to evaluate the efficacy of dupilumab for the treatment of adult patients referred to our department, from January 2019 to May 2021, with a diagnosis of moderate to severe atopic dermatitis (AD) and concomitant chronic rhinosinusitis with nasal polyps (CRSwNP), with a clinical indication for dupilumab treatment. Skin disease activity was assessed using EASI, Numerical Rating Scale (NRS) for pruritus (P-NRS) and sleep (S-NRS), and Dermatology Life Quality Index (DLQI). The CRSwNP activity was evaluated using 22-item Sino-Nasal Outcome Test (SNOT-22), endoscopic nasal polyp score (ENPS), nasal congestion or obstruction score (scale 0-3), loss-of-smell score (scale 0-3), and rhinosinusitis disease severity (visual analog scale 0-10 cm). A significant improvement of all the score values was recorded assessing patients at baseline, week (W)16, and W24. In particular, concerning the CRSwNP, a reduction of ENPS score (baseline:

The thrombin-gelatin matrix could represent a valuable tool when other haemostatic strategies are ineffective or suboptimal. It is safe and biocompatible when compared with haemostatic agents currently in use.

In deaf children, huge emphasis was given to language; however, emotional cues decoding and production appear of pivotal importance for communication capabilities. Concerning neurophysiological correlates of emotional processing, the gamma band activity appears a useful tool adopted for emotion classification and related to the conscious elaboration of emotions. Starting from these considerations, the following items have been investigated: (i) whether emotional auditory stimuli processing differs between normal-hearing (NH) children and children using a cochlear implant (CI), given the non-physiological development of the auditory system in the latter group; (ii) whether the age at CI surgery influences emotion recognition capabilities; and (iii) in light of the right hemisphere hypothesis for emotional processing, whether the CI side influences the processing of emotional cues in unilateral CI (UCI) children. To answer these matters, 9 UCI (9.47 ± 2.33 years old) and 10 NH (10.95 ± 2.11 years old) children were asked to recognize nonverbal vocalizations belonging to three emotional states: positive (achievement, amusement, contentment, relief), negative (anger, disgust, fear, sadness), and neutral (neutral, surprise). Results showed better performances in NH than UCI children in emotional states recognition. The UCI group showed increased gamma activity lateralization index (LI) (relative higher right hemisphere activity) in comparison to the NH group in response to emotional auditory cues. Moreover, LI gamma values were negatively correlated with the percentage of correct responses in emotion recognition. Such observations could be explained by a deficit in UCI children in engaging the left hemisphere for more demanding emotional task, or alternatively by a higher conscious elaboration in UCI than NH children. Additionally, for the UCI group, there was no difference between the CI side and the contralateral side in gamma activity, but a higher gamma activity in the right in comparison to the left hemisphere was found. Therefore, the CI side did not appear to influence the physiologic hemispheric lateralization of emotional processing. Finally, a negative correlation was shown between the age at the CI surgery and the percentage of correct responses in emotion recognition and then suggesting the occurrence of a sensitive period for CI surgery for best emotion recognition skills development.

Efficacy of the SPEAK and ACE coding strategies was compared with that of a new strategy, MP3000™, by 37 European implant centers including 221 subjects. The SPEAK and ACE strategies are based on selection of 8–10 spectral components with the highest levels, while MP3000 is based on the selection of only 4–6 components, with the highest levels relative to an estimate of the spread of masking. The pulse rate per component was fixed. No significant difference was found for the speech scores and for coding preference between the SPEAK/ACE and MP3000 strategies. Battery life was 24% longer for the MP3000 strategy. With MP3000 the best results were found for a selection of six components. In addition, the best results were found for a masking function with a low-frequency slope of 50 dB/Bark and a high-frequency slope of 37 dB/Bark (50/37) as compared to the other combinations examined of 40/30 and 20/15 dB/Bark. The best results found for the steepest slopes do not seem to agree with current estimates of the spread of masking in electrical stimulation. Future research might reveal if performance with respect to SPEAK/ACE can be enhanced by increasing the number of channels in MP3000 beyond 4–6 and it should shed more light on the optimum steepness of the slopes of the masking functions applied in MP3000.