Project description:Epibatidine is an alkaloid toxin that binds with high affinity to nicotinic and muscarinic acetylcholine receptors, and has been extensively used as a research tool. To examine binding interactions at the nicotinic receptor, it has been co-crystallised with the structural homologue acetylcholine binding protein (AChBP; PDB ID 2BYQ), and with an AChBP chimaera (3SQ6) that shares 64% sequence identity with the α7 nACh receptor. However, the binding orientations revealed by AChBP co-crystal structures may not precisely represent their receptor homologues and experimental evidence is needed to verify the ligand poses. Here we identify potential binding site interactions between epibatidine and AChBP residues, and substitute equivalent positions in the α7 nACh receptor. The effects of these are probed by [3H]epibatidine binding following the expression α7 nACh receptor cysteine mutants in HEK 293 cells. Of the sixteen mutants created, the affinity of epibatidine was unaffected by the substitutions Q55C, L106C, L116C, T146C, D160C and S162C, reduced by C186A and C187A, increased by Q114C and S144C, and abolished by W53C, Y91C, N104C, W145C, Y184C and Y191C. These results are consistent with the predicted orientations in AChBP and suggest that epibatidine is likely to occupy a similar location at α7 nACh receptors. We speculate that steric constraints placed upon the C-5 position of the pyridine ring in 3SQ6 may account for the relatively poor affinities of epibatidine derivatives that are substituted at this position.
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an uncommon autosomal dominant disorder that has been characterized by slow progression. Neuromuscular disease is one of several etiologies of pulmonary volume restriction from extrinsic or parenchymatous causes and can lead to pulmonary hypertension and right-sided heart failure, which is consistent with cor pulmonale. Here we describe a case of an OPMD patient with cor pulmonale that was reversed using mechanically-assisted ventilation. <Learning objective: Although respiratory muscle weakness is an uncommon cause of respiratory failure and a rare cause of cor pulmonale, the specific physical signs for it could evoke those serious respiratory and cardiac conditions as well as underlying neuromuscular disease. Abdominal paradox is the most characteristic physical sign of dysfunction of the diaphragm, the principal muscle of respiration. However, it is often not easy to notice the sign, especially in the patients with neuromuscular disease.>.
Project description:Coronavirus disease-19 (COVID-19)-related severe acute respiratory distress syndrome can lead to acute cor pulmonale. We report a case of acute cor pulmonale secondary to severe COVID-19 acute respiratory distress syndrome diagnosed with transesophageal echocardiography. Almitrine infusion allowed rapid enhancement of right ventricular function as well as improvement in oxygenation. (Level of Difficulty: Intermediate.).
Project description:Intravenous hyperosmotic NaCl infusion is an effective treatment for circulatory shock. However, a fast infusion rate (2 mL/kg at the rate of 1 mL/s) induces transient hypotension. This response has been reported to be due to decreased total peripheral resistance and/or decreased cardiac performance. Although the hypotension is transient and recovers within 2 min without detrimental consequences, it is important to understand the associated hemodynamics and mechanisms. We found that the hypotensive effect was larger with intravenous NaCl infusion than with intra-aortic infusion, indicating that change in cardiac performance played a more significant role than change in peripheral resistance. NaCl infusion induced an increase in pulmonary vascular resistance and central venous pressure and a decrease in right ventricular dP/dt max, suggesting acute cor pulmonale. Diastolic ventricular crosstalk-induced left ventricular failure was also observed. Hyperosmotic NaCl-induced hypotension was therefore mainly due to a combination of acute cor pulmonale and left ventricular failure.
Project description:BackgroundThe risk factors for mortality might differ between patients with acute exacerbation of chronic pulmonary heart disease in plains and plateaus, while there is a lack of evidence.MethodPatients diagnosed with cor pulmonale at Qinghai Provincial People's Hospital were retrospectively included between January 2012 and December 2021. The symptoms, physical and laboratory examination findings, and treatments were collected. Based on the survival within 50 days, we divided the patients into survival and death groups.ResultsAfter 1:10 matching according to gender, age, and altitude, 673 patients were included in the study, 69 of whom died. The multivariable Cox proportional hazards analysis showed that NYHA class IV (HR = 2.03, 95%CI: 1.21-3.40, P = 0.007), type II respiratory failure (HR = 3.57, 95%CI: 1.60-7.99, P = 0.002), acid-base imbalance (HR = 1.82, 95%CI: 1.06-3.14, P = 0.031), C-reactive protein (HR = 1.04, 95%CI: 1.01-1.08, P = 0.026), and D-dimer (HR = 1.07, 95%CI: 1.01-1.13, P = 0.014) were risk factors for death in patients with cor pulmonale at high altitude. Among patients living below 2500 m, cardiac injury was a risk factor for death (HR = 2.47, 95%CI: 1.28-4.77, P = 0.007), while no significant association was observed at ≥ 2500 m (P = 0.057). On the contrary, the increase of D-dimer was only a risk factor for the death of patients living 2500 m and above (HR = 1.23, 95% CI: 1.07-1.40, P = 0.003).ConclusionNYHA class IV, type II respiratory failure, acid-base imbalance, and C- reactive protein may increase the risk of death in patients with cor pulmonale. Altitude modified the association between cardiac injury, D-dimer, and death in patients with cor pulmonale.