Depolarization and Hyperexcitability of Cortical Motor Neurons after Spinal Cord Injury Associates with Reduced HCN Channel Activity.

A spinal cord injury (SCI) damages the axonal projections of neurons residing in the neocortex. This axotomy changes cortical excitability and results in dysfunctional activity and output of infragranular cortical layers. Thus, addressing cortical pathophysiology after SCI will be instrumental in promoting recovery. However, the cellular and molecular mechanisms of cortical dysfunction after SCI are poorly resolved. In this study, we determined that the principal neurons of the primary motor cortex layer V (M1LV), those suffering from axotomy upon SCI, become hyperexcitable following injury. Therefore, we questioned the role of hyperpolarization cyclic nucleotide gated channels (HCN channels) in this context. Patch clamp experiments on axotomized M1LV neurons and acute pharmacological manipulation of HCN channels allowed us to resolve a dysfunctional mechanism controlling intrinsic neuronal excitability one week after SCI. Some axotomized M1LV neurons became excessively depolarized. In those cells, the HCN channels were less active and less relevant to control neuronal excitability because the membrane potential exceeded the window of HCN channel activation. Care should be taken when manipulating HCN channels pharmacologically after SCI. Even though the dysfunction of HCN channels partakes in the pathophysiology of axotomized M1LV neurons, their dysfunctional contribution varies remarkably between neurons and combines with other pathophysiological mechanisms.

Spinal Cord Injury and Loss of Cortical Inhibition.

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI.

Emerging and Re-Emerging Pathogens in Valvular Infective Endocarditis: A Review.

Infective endocarditis (IE) is a microbial infection of the endocardial surface, most commonly affecting native and prosthetic valves of the heart. The epidemiology and etiology of the disease have evolved significantly over the last decades. With a growing elderly population, the incidence of degenerative valvopathies and the use of prosthetic heart valves have increased, becoming the most important predisposing risk factors. This change in the epidemiology has caused a shift in the underlying microbiology of the disease, with Staphylococci overtaking Streptococci as the main causative pathogens. Other rarer microbes, including Streptococcus agalactiae, Pseudomonas aeruginosa, Coxiella burnetti and Brucella, have also emerged or re-emerged. Valvular IE caused by these pathogens, especially Staphylococcus aureus, is often associated with a severe clinical course, leading to high rates of morbidity and mortality. Therefore, prompt diagnosis and management are crucial. Due to the high virulence of these pathogens and an increased incidence of antimicrobial resistances, surgical valve repair or replacement is often necessary. As the epidemiology and etiology of valvular IE continue to evolve, the diagnostic methods and therapies need to be progressively advanced to ensure satisfactory clinical outcomes.

Optimal antithrombotic strategy following valve-in-valve transcatheter aortic and mitral valve replacement.

The treatment of aortic and mitral valve disease requiring replacement has shifted to an increasing use of bioprosthetic heart valves. Due to their limited durability, there is a growing need for reintervention in the setting of failing bioprosthesis. Even though the gold standard for the treatment of failed bioprosthesis remains surgical repair or replacement, valve-in-valve (ViV) transcatheter aortic and mitral valve replacement have emerged as safe and effective alternatives for patients who are at high or prohibitive risk for surgery. Both procedures are associated with a substantial risk of postprocedural thromboembolic events and valvular thrombosis that is often higher than transcatheter replacement of native valves. With guidelines lacking specific protocols and a limited number of available studies, the optimal postprocedural antithrombotic therapy remains to be clarified. Multiple factors including valvular hemodynamics, the characteristics of the failing surgical valve, and the choice of the new transcatheter heart valve (THV) must be considered. Additionally, patients are often at an advanced age with multiple comorbidities and may require oral anticoagulation (OAC) due to other indications such as atrial fibrillation. Although the recommended antithrombotic strategy for native transcatheter aortic valve replacement (TAVR) is antiplatelet monotherapy with aspirin or a P2Y12 inhibitor in the absence of another anticoagulation indication, the use of oral anticoagulants including vitamin K antagonists (VKAs) and direct thrombin inhibitors has been shown to be effective in reducing valvular thrombosis and are commonly used after ViV procedures. Prospective studies investigating these results specifically for ViV transcatheter aortic and mitral valve replacement are needed to identify the optimal antithrombotic therapy.

The awakening of dormant neuronal precursors in the adult and aged brain.

Beyond the canonical neurogenic niches, there are dormant neuronal precursors in several regions of the adult mammalian brain. Dormant precursors maintain persisting post-mitotic immaturity from birth to adulthood, followed by staggered awakening, in a process that is still largely unresolved. Strikingly, due to the slow rate of awakening, some precursors remain immature until old age, which led us to question whether their awakening and maturation are affected by aging. To this end, we studied the maturation of dormant precursors in transgenic mice (DCX-CreERT2 /flox-EGFP) in which immature precursors were labelled permanently in vivo at different ages. We found that dormant precursors are capable of awakening at young age, becoming adult-matured neurons (AM), as well as of awakening at old age, becoming late AM. Thus, protracted immaturity does not prevent late awakening and maturation. However, late AM diverged morphologically and functionally from AM. Moreover, AM were functionally most similar to neonatal-matured neurons (NM). Conversely, late AM were endowed with high intrinsic excitability and high input resistance, and received a smaller amount of spontaneous synaptic input, implying their relative immaturity. Thus, late AM awakening still occurs at advanced age, but the maturation process is slow.