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Middle-ear adenoma is a rare benign endocrine tumor with slow progression, and can, in very rare cases, lead to recurrent peripheral facial palsy. A young man experienced three episodes of right peripheral facial palsy of incremental intensity, suggestive of barotrauma. CT and MRI found a tissue mass in the tympanic cavity, and biopsy diagnosed middle-ear adenoma. Electroneuromyography found 50% impairment of facial function. Closed right tympanoplasty with complete tumor resection enabled complete recovery of facial function within 1 month. Middle-ear adenoma is diagnosed on histology, as imaging on MRI can be non-specific, mimicking chronic otitis. Facial involvement is rare and is due to edematous compression of the vasa nervorum. Treatment is surgical, and follow-up should be prolonged. Palsy assessment on electroneuromyography indicates the urgency of treatment. [ABSTRACT FROM AUTHOR]

Abstract Targeted vasopeptide therapies have significantly advanced the management of pulmonary arterial hypertension (PAH). However, due to insufficient preclinical evidence regarding the involvement of the endothelin-1 (ET-1) pathway in chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology, the potential of ET-1 receptor antagonism in treating CTEPH remains uncertain. In this study, we investigated the role of the ET-1 pathway in CTEPH microvasculopathy using a multifaceted approach. Plasma ET-1 levels were measured in a cohort of 59 CTEPH patients and 41 healthy controls. Additionally, we evaluated the expression of key ET-1 pathway members in pulmonary explants from CTEPH, idiopathic PAH, and control patients. We used an in vitro system to test the hypothesis that the turbulent flow, observed near the vascular obstructions pathognomonic of CTEPH, enhances ET-1 expression. Our findings were further validated in vivo using a CTEPH piglet model that contains distinct regions representing pre- and post-thrombus lung territories. We found a twofold increase in circulating ET-1 levels in CTEPH patients compared to healthy subjects. Pulmonary explants from CTEPH patients exhibited pronounced overexpression of ET-1, endothelin receptor A (ETA), and phosphorylated myosin light chain (p-MLC) in muscularized pulmonary microvessels, suggesting heightened vascular contraction. In vitro experiments showed that turbulent flow facilitates ET-1 secretion compared to laminar flow regions. Additionally, in the CTEPH piglet model, elevated plasma ET-1 levels were observed compared to controls. Immunofluorescence and confocal microscopy analyses confirmed increased ETA and p-MLC in remodeled arteries from both pulmonary territories. However, ET-1 protein elevation was exclusively observed in the obstructed territory. These findings collectively indicate impaired vascular tone in microvessels of CTEPH patients and the CTEPH piglet model. Furthermore, our data implicates the ET-1 pathway in microvasculopathy, with turbulent flow playing a pathological role. These insights underscore the potential utility of ET-1 receptor antagonists as a promising therapeutic approach for CTEPH treatment.

Hypothermic perfusion is associated with a decrease of ischemia/reperfusion injuries in kidney and liver transplantation. Whether lung hypothermic perfusion could be suitable for lung preservation remains unknown. The aim of the study was to compare lung hypothermic perfusion to cold storage. Seven pairs of swine lungs were retrieved and have been preserved for 6 hours. One lung was randomly allocated for static cold storage (SCS) and the other one for continuous hypothermic perfusion (HP). HP lungs were perfused using cold preservation solution (Perfadex®) with controlled pulmonary pressure under 5mmHg and graft temperature of 10°C. Both lungs were maintained inflated. Physiologic parameters were monitored during the 6h perfusion. Graft temperature was assessed either by external thermometer (SCS group) or thermal camera (HP group). At the end of the procedure, graft edema was assessed by CTscan, wet/dry ratio and weight. Lung biopsy, bronchioalveolar lavage and transpulmonary flush samples were collected for HES staining and inflammatory cytokine level assessment. Functional assessment of pulmonary artery rings were performed as well. During 6h, pulmonary pressure remained stable at 5 mmHg and pulmonary flow was estimated between 100 and 150 mL/min. Preservation temperature was significantly lower in SCS group (Median 2.9°C vs. 10.7°C, p < 10−6). Lung graft weight increased by an average of 40.3% in HP group compared to 2% decrease in SCS group (p<0,0001). Median Weight to dry ratio was 6.1 in the HP group vs. 4.9 in the SCS group (p 0.09).At the end of the procedure, lactate level was higher (0.6 mmol/L vs 0.3 mmol/L, p 0.025), glucose concentration was lower (0.85 vs 0.76 g/L, p < 0.0001) and PCO2 was higher in the HP group (8.5 mmHg vs 7.7 mmHg, p 0.023) IL12 concentration in the perfusate was higher in HP group after 6 hours (mean HP 39,44 pg/L vs 22,76 pg/L, p adjusted 0,020). Pulmonary artery rings relaxation did not differ between groups. Histological analysis shown perilobular thickness with inflated lymphatics vessels in HP group only. Controlled-pressure hypothermic perfusion using Perfadex allowed controlled and stable preservation temperature. However, it did not prove better physiological results when compared to cold storage and ended with significant pulmonary edema after 6h of perfusion. [ABSTRACT FROM AUTHOR]

Background: Anti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aβ peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aβ immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies., Methods: To address these limitations, we have engineered SAR228810, a humanized monoclonal antibody (mAb) with limited Fc effector functions that binds specifically to soluble protofibrillar and fibrillar forms of Aβ peptide and we tested it together with its murine precursor SAR255952 in vitro and in vivo., Results: Unlike gantenerumab and BAN2401, SAR228810 and SAR255952 do not bind to Aβ monomers, low molecular weight Aβ oligomers or, in human brain sections, to Aβ diffuse deposits which are not specific of AD pathology. Both antibodies prevent Aβ42 oligomer neurotoxicity in primary neuronal cultures. In vivo, SAR255952, a mouse aglycosylated IgG1, dose-dependently prevented brain amyloid plaque formation and plaque-related inflammation with a minimal active dose of 3 mg/kg/week by the intraperitoneal route. No increase in plasma Aβ levels was observed with SAR255952 treatment, in line with its lack of affinity for monomeric Aβ. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. Brain penetration and decoration of cerebral amyloid plaques was documented in live animals and postmortem. SAR255952 (up to 50 mg/kg/week intravenously) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice while 3D6, the murine version of bapineuzumab, did. In immunotolerized mice, the clinical candidate SAR228810 demonstrated the same level of efficacy as the murine SAR255952., Conclusion: Based on the improved efficacy/safety profile in non-clinical models of SAR228810, a first-in-man single and multiple dose administration clinical study has been initiated in AD patients.

Heterologous expression and lesioning studies were conducted to identify possible subunit assembly partners in nicotinic acetylcholine receptors (nAChR) containing alpha6 subunits (alpha6(*) nAChR). SH-EP1 human epithelial cells were transfected with the requisite subunits to achieve stable expression of human alpha6beta2, alpha6beta4, alpha6beta2beta3, alpha6beta4beta3, or alpha6beta4beta3alpha5 nAChR. Cells expressing subunits needed to form alpha6beta4beta3alpha5 nAChR exhibited saturable [(3)H]epibatidine binding (K(d) = 95.9 +/- 8.3 pM and B(max) = 84.5 +/- 1.6 fmol/mg of protein). The rank order of binding competition potency (K(i)) for prototypical nicotinic compounds was alpha-conotoxin MII (6 nM) > nicotine (156 nM) approximately methyllycaconitine (200 nM) > alpha-bungarotoxin (>10 microM), similar to that for nAChR in dopamine neurons displaying a distinctive pharmacology. 6-Hydroxydopamine lesioning studies indicated that beta3 and alpha5 subunits are likely partners of the alpha6 subunits in nAChR expressed in dopaminergic cell bodies. Similar to findings in rodents, quantitative real-time reverse transcription-polymerase chain reactions of human brain indicated that alpha6 subunit mRNA expression was 13-fold higher in the substantia nigra than in the cortex or the rest of the brain. Thus, heterologous expression studies suggest that the human alpha5 subunit makes a critical contribution to alpha6beta4beta3alpha5 nAChR assembly into a ligand-binding form with native alpha6(*)-nAChR-like pharmacology and of potential physiological and pathophysiological relevance.

Electrophysiological and pharmacological studies have shown that peripheral-type benzodiazepine receptors modulate voltage-sensitive calcium channels in the heart. We have compared these binding sites with binding sites for [3H]dihydropyridines, which are believed to label such channels. Although no direct or allosteric interaction could be demonstrated between the two sites, their subcellular distribution--sarcolemma and ryanodine-sensitive sarcoplasmic reticulum--was parallel. Size determination of the two sites suggests that the receptors for these two classes of compounds are separate molecules packaged in the same membrane compartment.