Spitoni, C. | bioRxiv Science

bioRxiv2026

The nanoscopic submyelin space mediates efficient K+ uptake and shapes nodal action potentials

Myelin membranes are tightly connected to the axon, forming an electrical route for rapid saltatory conduction of action potentials from node to node. Beneath the myelin, adjacent to the node, lie voltage-gated potassium (K+) channels, whose fundamental role in conduction remains poorly understood. Constrained by biological data, we developed a finite element model of a node of Ranvier encompassing an adaxonal membrane separating oligodendrocyte cytoplasm from the periaxonal space, and solved the full coupled set of physical equations governing electrodiffusion and voltage profiles at the nanoscale. Remarkably, we find that nodal action potentials invert at the inner adaxonal myelin membrane. The hyperpolarization-driven opening of myelinic Kir4.1 channels produces an instantaneous, powerful K+ prebuffering, clamping the periaxonal K+ concentration and enabling high-frequency action potential generation. Together, these findings indicate that the periaxon maintains an electrical feedback loop with the node, and suggest a key evolutionary advantage of juxtaparanodal K+ channel positioning.

neuroscience↗

bioRxiv2017

Cardiac events after macrolides or fluoroquinolones in patients hospitalized for community-acquired pneumonia: post-hoc analysis of a cluster-randomized trial

BackgroundGuidelines recommend macrolides and fluoroquinolones in patients hospitalized with community-acquired pneumonia (CAP), but their use has been associated with cardiac events.\n\nObjectiveTo quantify associations between macrolide and fluoroquinolone use and cardiac events in patients hospitalized with CAP in non-ICU wards.\n\nDesignPost-hoc analysis of a cluster-randomized trial\n\nSettingSix hospitals in the Netherlands\n\nPatientsCAP patients admitted to non-ICU wards and without a cardiac event on admission\n\nMeasurementsCause-specific hazard ratios (HRs) were calculated for effects of time-dependent macrolide and fluoroquinolone exposure on cardiac events, defined as occurrence of new or worsening heart failure, arrhythmia, or myocardial ischemia during hospitalization.\n\nResultsCardiac events occurred in 146 (6.9%) of 2,107 patients and included episodes of heart failure (n=101, 4.8%), arrhythmia (n=53, 2.5%), and myocardial ischemia (n=14, 0.7%). Cardiac events occurred in 11 of 207 (5.3%), 18 of 250 (7.2%), and 31 of 277 (11.2%) patients exposed to azithromycin, clarithromycin, and erythromycin for at least one day, respectively, and in 9 of 234 (3.8%), 5 of 194 (2.6%), and 23 of 566 (4.1%) patients exposed to ciprofloxacin, levofloxacin, and moxifloxacin, respectively. Hazard ratios for any cardiac event, adjusted for confounding, were 0.89 (95% confidence interval (CI) 0.48 to 1.67), 1.06 (95% CI 0.61 to 1.83) and 1.68 (95% CI 1.07 to 2.62) for azithromycin, clarithromycin, and erythromycin, respectively, and adjusted hazard ratios were 0.86 (95% CI 0.47 to 1.57), 0.42 (95% CI 0.18 to 0.96) and 0.62 (95% CI 0.39 to 0.99) for ciprofloxacin, levofloxacin, and moxifloxacin, respectively. Erythromycin was associated with an adjusted hazard ratio of 2.08 (95% CI 1.25 to 3.46) for heart failure.\n\nLimitationsPossibility of confounding by indication and observational bias\n\nConclusionsAmong patients with CAP hospitalized to non-ICU wards, erythromycin use was associated with a 68% increased risk of hospital-acquired cardiac events, mainly heart failure. Levofloxacin and moxifloxacin were associated with a lower risk of heart failure.\n\nRegistrationThe original trial was registered under ClinicalTrials.gov Identifier NCT01660204\n\nFunding SourceThe Netherlands Organization for Health Research and Development (ZONmw, Health care efficiency research, project id: 171202002).

epidemiology↗