Nest Carbon Dioxide Masks GABA-Dependent Seizure Susceptibility in the Naked Mole-Rat.

African naked mole-rats were likely the first mammals to evolve eusociality, and thus required adaptations to conserve energy and tolerate the low oxygen (O2) and high carbon dioxide (CO2) of a densely populated fossorial nest. As hypercapnia is known to suppress neuronal activity, we studied whether naked mole-rats might demonstrate energy savings in GABAergic inhibition. Using whole-colony behavioral monitoring of captive naked mole-rats, we found a durable nest, characterized by high CO2 levels, where all colony members spent the majority of their time. Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). A histidine missense substitution mutation at this locus in the human ortholog of KCC2, found previously in patients with febrile seizures and epilepsy, has been demonstrated to diminish neuronal Cl- extrusion capacity, and thus impairs GABAergic inhibition. Seizures were observed, without pharmacological intervention, in adult naked mole-rats exposed to a simulated hyperthermic surface environment, causing systemic hypocapnic alkalosis. Consistent with the diminished function of KCC2, adult naked mole-rats demonstrate a reduced efficacy of inhibition that manifests as triggering of seizures at room temperature by the GABAA receptor (GABAAR) positive allosteric modulator diazepam. These seizures are blocked in the presence of nest-like levels of CO2 and likely to be mediated through GABAAR activity, based on in vitro recordings. Thus, altered GABAergic inhibition adds to a growing list of adaptations in the naked mole-rat and provides a plausible proximate mechanism for nesting behavior, where a return to the colony nest restores GABA-mediated inhibition.

Effect of renal function loss on NT-proBNP level variations.

OBJECTIVE: NT-proBNP level is used for the detection of acute CHF and as a predictor of survival. However, a number of factors, including renal function, may affect the NT-proBNP levels. This study aims to provide a more precise way of interpreting NT-proBNP levels based on GFR, independent of age. METHODS: This study includes 247 pts in whom CHF and known confounders of elevated NT-proBNP were excluded, to show the relationship of GFR in association with age. The effect of eGFR on NT-proBNP level was adjusted by dividing 1000 x log(NT-proBNP) by eGFR then further adjusting for age in order to determine a normalized NT-proBNP value. RESULTS: The normalized NT-proBNP levels were affected by eGFR independent of the age of the patient. CONCLUSION: A normalizing function based on eGFR eliminates the need for an age-based reference ranges for NT-proBNP.