A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.

Substrate mechanics unveil early structural and functional pathology in iPSC micro-tissue models of hypertrophic cardiomyopathy.

Hypertension is a major cause of morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM), suggesting a potential role for mechanics in HCM pathogenesis. Here, we developed an in vitro physiological model to investigate how mechanics acts together with HCM-linked myosin binding protein C (MYBPC3) mutations to trigger disease. Micro-heart muscles (µHM) were engineered from induced pluripotent stem cell (iPSC)-derived cardiomyocytes bearing MYBPC3+/- mutations and challenged to contract against substrates of different elasticity. µHMs that worked against substrates with stiffness at or exceeding the stiffness of healthy adult heart muscle exhibited several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in MYBPC3+/- µHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+ intake through membrane-embedded channels underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease with iPSC technology.

Giant Left Ventricular Aneurysm With Dynamic Right Ventricular Compression and Subsequent End-Stage Heart Failure.

We report a case of a patient with a missed anterior myocardial infarction and associated ischemic cardiomyopathy. The patient had a massive true left ventricular aneurysm causing dynamic right ventricular compression, with associated cardiogenic shock, for which a heart transplantation was ultimately performed.

The importance of professional responsibility and fetal viability in the management of abortion.

In June 2022, the Dobbs v. Jackson Women's Health Organization Supreme Court decision ended the constitutional right to the professional practice of abortion throughout the United States. The removal of the constitutional right to abortion has significantly altered the practice of obstetricians and gynecologists across the US. It potentially increases risks to pregnant patients, leads to profound changes in how physicians can provide care, especially in states with strict bans or gestational limits to abortion, and has introduced personal challenges, including moral distress and injury as well as legal risks for patients and clinicians alike. The professional responsibility model is based on the ethical concept of medicine as a profession and has been influential in shaping medical ethics in the field of obstetrics and gynecology. It provides the framework for the importance of ethical and professional conduct in obstetrics and gynecology. Viability marks a stage where the fetus is a patient with a claim to access to medical care. By allowing unrestricted abortions past this stage without adequate justifications, such as those concerning the life and health of the pregnant individual, or in instances of serious fetal anomalies, the states may not be upholding the equitable ethical consideration owed to the fetus as a patient. Using the professional responsibility model, we emphasize the need for nuanced, evidence-based policies that allow abortion management prior to viability without restrictions and allow abortion after viability to protect the pregnant patient's life and health, as well as permitting abortion for serious fetal anomalies.

A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.