Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses

Glutamate is the major excitatory neurotransmitter in the CNS binding to a variety of glutamate receptors. Metabotropic glutamate receptors (mGluR1 to mGluR8) can act excitatory or inhibitory, depending on associated signal cascades. Expression and localization of inhibitory acting mGluRs at inner hair cells (IHCs) in the cochlea are largely unknown. Here, we analyzed expression of mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, and mGluR8 and investigated their localization with respect to the presynaptic ribbon of IHC synapses. We detected transcripts for mGluR2, mGluR3, and mGluR4 as well as for mGluR7a, mGluR7b, mGluR8a, and mGluR8b splice variants. Using receptor-specific antibodies in cochlear wholemounts, we found expression of mGluR2, mGluR4, and mGluR8b close to presynaptic ribbons. Super resolution and confocal microscopy in combination with 3-dimensional reconstructions indicated a postsynaptic localization of mGluR2 that overlaps with postsynaptic density protein 95 on dendrites of afferent type I spiral ganglion neurons. In contrast, mGluR4 and mGluR8b were expressed at the presynapse close to IHC ribbons. In summary, we localized in detail 3 mGluR types at IHC ribbon synapses, providing a fundament for new therapeutical strategies that could protect the cochlea against noxious stimuli and excitotoxicity

Expression of Collagen Types I, II and III in Juvenile Angiofibromas

Extracellular matrix components have rarely been the focus of interest in juvenile angiofibroma (JA) studies. Although JAs are known to be collagen-rich tumours, single collagens have not been analysed so far. This investigation aimed to study the expression of the fibrillar collagen types I, II and III in JAs using quantitative RT-PCR (n = 15), Western blot analysis (n = 7) and immunohistochemical staining (n = 9). Nasal mucosa (NM) specimens were used as control tissues. ELISA investigation (n = 3) was performed to determine the concentration of C-terminal propeptide of type I collagen in blood serum before and after JA resection. Quantitative RTPCR found significantly elevated Col1A1 (p ! 0.001), Col1A2 (p ! 0.001) and Col3A1 (p ! 0.001) mRNA levels in JAs, compared with NM. Western blot analysis and immunhistochemical staining proved that there is a significant collagen type I and III protein expression in JAs. In none out of 3 patients, ELISA investigation found evidence for elevated concentrations of C-terminal propeptide of type I collagen before tumour resection, compared with postsurgical measurements. Results of the findings using quantitative RT-PCR, Western blot analysis and immunohistochemistry determined that type II collagen is practically absent in JAs. Based on these findings, type I and III collagen are confirmed as being major components of the extracellular matrix in JAs. However, our findings are not encouraging as regards the use of C-terminal Col I propeptid as a suitable serum tumour marker. Our findings confirming that collagen type II expression is practically absent in JAs refutes the theory that JAs originate in cartilage tissue

SOURCE 3: 1-year outcomes post-transcatheter aortic valve implantation using the latest generation of the balloon-expandable transcatheter heart valve

AIMS: Transcatheter aortic valve implantation (TAVI) has developed from a procedure for patients with aortic stenosis inoperable or high risk for surgery, into a treatment option even for intermediate risk elderly patients. This development has been facilitated by the clinical learning curve and constant improvements of transcatheter heart valves used. We present total 1-year results of SOURCE 3, the European post-approval multicentre registry of the latest generation balloon expandable SAPIEN 3TM (Edwards Lifesciences, Irvine, CA, USA). METHODS AND RESULTS: Participating centres have submitted their consecutive experience with the SAPIEN 3, dependent on patients consent. Data were prospectively collected and all end point-related outcomes adjudicated according to VARC-2 definitions by an independent committee. Between July 2014 and October 2015, in total 1946 patients (mean age 81.6\u2009\ub1\u20096.7\u2009years, 52% male) were enrolled in 80 centres from 10 European countries. At 1\u2009year, all-cause mortality was 12.6%, cardiovascular mortality 8.0%, stroke 3.1%, disabling stroke 1.4%, and rate of new pacemakers 13.2%. Causes of death were 62.0% cardiovascular and 38.0% non-cardiovascular, with heart failure (13.4%) and pulmonary complications (12.7%) being the main reasons for fatal outcomes. Multivariable analysis identified New York Heart Association Class IV and renal insufficiency as predictors of mortality, while higher BMI's improved survival. Severe (zero) and moderate paravalvular leakage (2.6%) was rare at 1\u2009year. CONCLUSION: In SOURCE 3, we observe a low complication rate and mortality at 1\u2009year. Given the low incidence of higher degree paravalvular leakages, this variable did no longer affect outcome. Clinicaltrial.gov number: NCT02698956

Factors associated with safe early discharge after transcatheter aortic valve implantation

  Background: As transcatheter aortic valve implantation (TAVI) becomes more straightforward, a larger proportion of patients will be well enough to be discharged early. This study sought to charac­terise the clinical features that allowed patients to be discharged early after TAVI and to evaluate the safety of an early discharge policy. Methods: All patients undergoing TAVI at the above cited center from August 2007 to March 2015 were included in this study. Baseline characteristics, in-hospital outcomes, re-admissions and mortality were compared. Results: Three hundred thirty-seven TAVIs were performed during the study period, and 18 died in-hospital (18/337, 5.3%). Of the remaining patients, 56 were discharged within 3 days of the index procedure (‘early discharge group’ 56/319, 17.5%). There was no difference between the early discharge and late discharge group in terms of Valve Academic Research Consortium-2 (VARC-2) criteria out­comes, all-cause re-admission rates and the need for permanent pacemaker implantation. Mortality at 1 year was better among the early discharge group (3.6% vs. 15.6%, p = 0.014); a reflection of baseline clinical differences. Conclusion: Early discharge of clinically selected TAVI patients is safe and appropriate. Lower logistic EuroSCORE, smaller delta creatinine and not developing any complications are factors associated with early discharge. (Cardiol J 2018; 25, 1: 14–23

Effect of Ligament Fibers on Dynamics of Synthetic, Self-Oscillating Vocal Folds in a Biomimetic Larynx Model

Synthetic silicone larynx models are essential for understanding the biomechanics of physiological and pathological vocal fold vibrations. The aim of this study is to investigate the effects of artificial ligament fibers on vocal fold vibrations in a synthetic larynx model, which is capable of replicating physiological laryngeal functions such as elongation, abduction, and adduction. A multi-layer silicone model with different mechanical properties for the musculus vocalis and the lamina propria consisting of ligament and mucosa was used. Ligament fibers of various diameters and break resistances were cast into the vocal folds and tested at different tension levels. An electromechanical setup was developed to mimic laryngeal physiology. The measurements included high-speed video recordings of vocal fold vibrations, subglottal pressure and acoustic. For the evaluation of the vibration characteristics, all measured values were evaluated and compared with parameters from ex and in vivo studies. The fundamental frequency of the synthetic larynx model was found to be approximately 200–520 Hz depending on integrated fiber types and tension levels. This range of the fundamental frequency corresponds to the reproduction of a female normal and singing voice range. The investigated voice parameters from vocal fold vibration, acoustics, and subglottal pressure were within normal value ranges from ex and in vivo studies. The integration of ligament fibers leads to an increase in the fundamental frequency with increasing airflow, while the tensioning of the ligament fibers remains constant. In addition, a tension increase in the fibers also generates a rise in the fundamental frequency delivering the physiological expectation of the dynamic behavior of vocal folds.</p

Nicotinic Acetylcholine Receptors in Head and Neck Cancer and Their Correlation to Tumor Site and Progression

Background: Nicotine contributes to tumorigenesis through stimulation of nicotinic acetylcholine receptors (nAChRs) in head and neck squamous cell carcinoma (SCC). Although many factors have been found to be involved in the pathogenesis of head and neck cancer, the effect of nAChRs is still unclear. The study provides information on different subtypes in SCC and normal mucosa (NM) and their clinicopathological correlation to tumor progression. Methods: SCC (n = 34) of oropharynx, hypopharynx, larynx and corresponding NM (n = 38) were analyzed by quantitative real-time polymerase chain reaction, immunoblotting and immunohistochemistry and correlated to tumor grading and Union for International Cancer Control (UICC) stage. Results: nAChR subtypes α1, α3, α5 and α7 were found in NM and SCC of the upper aerodigestive tract with high rates of α1 and α5 in SCC. An overexpression of α1 was found in laryngeal and hypopharyngeal SCC, while α3 and α7 subunits were downregulated. The expression of α1 and α5 subunits increased with tumor progression. Conclusion: The nAChR subunit pattern shows a difference between NM and SCC and changes in the process of tumor progression. Therefore, it is conceivable that it contributes to tumorigenesis. The findings provide a basis for further studies in prognostic assessment and identifying carcinogenic changes from NM to SCC

SOURCE 3 Registry Design and 30-Day Results of the European Postapproval Registry of the Latest Generation of the SAPIEN 3 Transcatheter Heart Valve

BACKGROUND: The SOURCE 3 Registry (SAPIEN Aortic Bioprosthesis European Outcome) is a European multicenter, observational registry of the latest generation of transcatheter heart valve, the SAPIEN 3 (Edwards Lifesciences, Irvine, CA). Its purpose is to document outcomes of clinical safety and performance after European approval was given. METHODS: Here, we present the 30-day outcome of the SOURCE 3 Registry. All data are self-reported, and all participating centers have committed to support their consecutive experience with the SAPIEN 3 transcatheter heart valve, dependent on patient consent, before the start of the study. Adverse events are defined with Valve Academic Research Consortium 2 criteria and adjudicated by an independent clinical events committee. RESULTS: A total of 1950 patients from 80 centers in 10 countries were enrolled between July 2014 and October 2015. Of those, 1947 patients underwent transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 (mean age, 81.6 +/- 6.6 years; 48.1% female). Main comorbidities included coronary artery disease (51.5%), renal insufficiency (27.4%), diabetes mellitus (29.5%), chronic obstructive pulmonary disease (16.0%), and a mean logistic EuroSCORE of 18.3 +/- 13.2. Transfemoral access was used in 87.1% (n=1695); nontransfemoral, in 252 patients. Conscious sedation was used in 59.9% of transfemoral procedures, and in 50% of patients, TAVI was performed without aortic balloon valvuloplasty. Implantation success (1 valve in the intended location) was 98.3%. Conversion to conventional surgery (0.6%) and use of cardiopulmonary bypass (0.7%) were rare. Adverse events were low, with site-reported 30-day all-cause mortality of 2.2%, cardiovascular mortality of 1.1%, stroke of 1.4%, major vascular complications of 4.1%, life-threatening bleeding of 5%, and post-TAVI pacemaker implantation of 12%. Moderate or greater paravalvular regurgitation was observed in 3.1% of reporting patients. CONCLUSIONS: Results from the SOURCE 3 Registry demonstrate contemporary European trends and good outcomes of TAVI in daily practice when this third-generation TAVI device is used.Peer reviewe