Temperature elevations can induce switches to homoclinic action potentials that alter neural encoding and synchronization

The article processing charge was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 491192747 and the Open Access Publication Fund of Humboldt-Universität zu Berlin.Almost seventy years after the discovery of the mechanisms of action potential generation, some aspects of their computational consequences are still not fully understood. Based on mathematical modeling, we here explore a type of action potential dynamics – arising from a saddle-node homoclinic orbit bifurcation - that so far has received little attention. We show that this type of dynamics is to be expected by specific changes in common physiological parameters, like an elevation of temperature. Moreover, we demonstrate that it favours synchronization patterns in networks – a feature that becomes particularly prominent when system parameters change such that homoclinic spiking is induced. Supported by in-vitro hallmarks for homoclinic spikes in the rodent brain, we hypothesize that the prevalence of homoclinic spikes in the brain may be underestimated and provide a missing link between the impact of biophysical parameters on abrupt transitions between asynchronous and synchronous states of electrical activity in the brain.Peer Reviewe

Treatment of chronic plantar fasciopathy with extracorporeal shock waves (review)

There is an increasing interest by doctors and patients in extracorporeal shock wave therapy (ESWT) for chronic plantar fasciopathy (PF), particularly in second generation radial extracorporeal shock wave therapy (RSWT). The present review aims at serving this interest by providing a comprehensive overview on physical and medical definitions of shock waves and a detailed assessment of the quality and significance of the randomized clinical trials published on ESWT and RSWT as it is used to treat chronic PF. Both ESWT and RSWT are safe, effective, and technically easy treatments for chronic PF. The main advantages of RSWT over ESWT are the lack of need for any anesthesia during the treatment and the demonstrated long-term treatment success (demonstrated at both 6 and 12 months after the first treatment using RSWT, compared to follow-up intervals of no more than 12 weeks after the first treatment using ESWT). In recent years, a greater understanding of the clinical outcomes in ESWT and RSWT for chronic PF has arisen in relationship not only in the design of studies, but also in procedure, energy level, and shock wave propagation. Either procedure should be considered for patients 18 years of age or older with chronic PF prior to surgical intervention

In Vitro Comparison of Novel Polyurethane Aortic Valves and Homografts After Seeding and Conditioning

The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds' inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement

Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin administration, but predicted by the interaction between childhood trauma and attachment insecurity

Individuals with borderline personality disorder (BPD) show self-regulatory deficits, associated with reduced heart-rate variability (HRV). However, results on reduced HRV in BPD remain heterogeneous, thus encouraging the search for developmental constructs explaining this heterogeneity. The present study first examined predictors of reduced resting-state HRV in BPD, namely the interaction between self-reported adult attachment insecurity and childhood trauma. Second, we investigated if alterations in resting-state HRV are modified by intranasal oxytocin administration, as oxytocin may enhance HRV and is implicated in the interaction between childhood trauma and disturbed attachment for the pathogenesis of BPD. In a randomized, placebo-controlled trial, 53 unmedicated women with BPD and 60 healthy controls (HC) self-administered either 24 I.U. of oxytocin or placebo and underwent a 4-min electrocardiogram. Our results replicate significantly reduced HRV in women with BPD, explained up to 16% by variations in childhood trauma and attachment insecurity. At high levels of acute attachment insecurity, higher levels of childhood trauma significantly predicted reduced HRV in BPD. However, our results do not support a significant effect of oxytocin on mean HRV, and no interaction effect emerged including childhood trauma and attachment insecurity. Our findings highlight a complex interaction between reduced vagal activity and developmental factors in BPD

Correction: A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations

Abstract Background The role of mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of SPINK1 mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore SPINK1 mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (CASR) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far. Methods We studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and SPINK1 (N34S) gene using melting curve analysis. Mutations within CASR gene were identified by DNA sequencing. Results A N34S SPINK1 mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the CASR gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein. Conclusion Mutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that SPINK1 mutations act as disease modifier and suggests an even more complex genetic model in SPINK1 related chronic pancreatitis.</p

The Crystal Structure of the Signal Recognition Particle in Complex with Its Receptor

Cotranslational targeting of membrane and secretory proteins is mediated by the universally conserved signal recognition particle (SRP). Together with its receptor (SR), SRP mediates the guanine triphosphate (GTP)–dependent delivery of translating ribosomes bearing signal sequences to translocons on the target membrane. Here, we present the crystal structure of the SRP:SR complex at 3.9 angstrom resolution and biochemical data revealing that the activated SRP:SR guanine triphosphatase (GTPase) complex binds the distal end of the SRP hairpin RNA where GTP hydrolysis is stimulated. Combined with previous findings, these results suggest that the SRP:SR GTPase complex initially assembles at the tetraloop end of the SRP RNA and then relocalizes to the opposite end of the RNA. This rearrangement provides a mechanism for coupling GTP hydrolysis to the handover of cargo to the translocon

Excitatory microcircuits within superficial layers of the medial entorhinal cortex

The distinctive firing pattern of grid cells in the medial entorhinal cortex (MEC) supports its role in the representation of space. It is widely believed that the hexagonal firing field of grid cells emerges from neural dynamics that depends on the local microcircuitry. However, local networks within the MEC are still not sufficiently characterized. Here, applying up to eight simultaneous whole-cell recordings in acute brain slices, we demonstrate the existence of unitary excitatory connections between principal neurons in the superficial layers of the MEC. In particular, we find prevalent feed-forward excitation from pyramidal neurons in layer III and layer II onto stellate cells in layer II, which might contribute to the generation or the inheritance of grid-cell patterns

In vitro and in vivo anti-epileptic efficacy of eslicarbazepine acetate in a mouse model of KCNQ2-related self-limited epilepsy

Background and purpose: The KCNQ2 gene encodes for the Kv 7.2 subunit of non-inactivating potassium channels. KCNQ2-related diseases range from autosomal dominant neonatal self-limited epilepsy, often caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S-Lic) in a mouse model of self-limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated. Experimental approach: Effects of S-Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2+/- ) and Kcnq2+/+ mice were investigated. ESL in vivo efficacy was investigated in the 6-Hz psychomotor seizure model in both Kcnq2+/- and Kcnq2+/+ mice. Key results: S-Lic increased the amplitude and decreased the incidence of physiological sharp wave-ripples in a concentration-dependent manner and slightly decreased gamma oscillations frequency. 4-Aminopyridine-evoked seizure-like events were blocked at high S-Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2+/+ and Kcnq2+/- mice, although the EC50 estimation implicated higher efficacy in Kcnq2+/- animals. In vivo, Kcnq2+/- mice had a lower seizure threshold than Kcnq2+/+ mice. In both genotypes, ESL dose-dependently displayed protection against seizures. Conclusions and implications: S-Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2+/- mice is effectively targeted by S-Lic high concentrations, presumably by blocking diverse sodium channel subtypes