[Regional comparison of specialized outpatient and (partial) inpatient pain medicine care in Germany].

Background And Objective: Chronic pain requires graduated and staged levels of care. The aim of this study is to provide a regional overview regarding the accessibility of specialized outpatient and (partial) inpatient pain medicine care from the patient's perspective in Germany.

Material And Methods: For 1000 model patients randomly generated from German postal code location combinations, the travelling time by car (individual transport, IT) and available public transport connections (PTC) to the nearest specialized outpatient and inpatient pain medicine clinics and units were assessed using a route planner.

Redistribution of ASIC1a channels triggered by IL-6: Potential role of ASIC1a in neuroinflammation.

Cytokines, particularly IL-6, play a crucial role in modulating immune responses in the central nervous system (CNS). Elevated IL-6 levels have been observed in neuroinflammatory conditions, as well as in the sera and brains of patients with neurodegenerative diseases such as Parkinson's, Huntington's, Multiple Sclerosis, and Alzheimer's. Additionally, alterations in regional brain pH have been noted in these conditions.

Segmental Upregulation of ASIC1 Channels in the Formalin Acute Pain Mouse Model.

Background: Hindpaw injection of formalin in rodents is used to assess acute persistent pain. The response to formalin is biphasic. The initial response (first minutes) is thought to be linked to inflammatory, peripheral mechanisms, while the latter (around 30 min after the injection), is linked to central mechanisms.

Dynamic Distribution of ASIC1a Channels and Other Proteins within Cells Detected through Fractionation.

Proteins in eukaryotic cells reside in different cell compartments. Many studies require the specific localization of proteins and the detection of any dynamic changes in intracellular protein distribution. There are several methods available for this purpose that rely on the fractionation of the different cell compartments.

Signaling Pathways in Proton and Non-proton ASIC1a Activation.

Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases as well as pain conditions. Classically, ASICs are described as transiently activated by a reduced pH, followed by desensitization; the activation allows sodium influx, and in the case of ASIC1a-composed channels, also calcium to some degree. Several factors are emerging and extensively analyzed as modulators, activating, inhibiting, and potentiating specific channel subunits.

Preliminary examination of early neuroconnectivity features in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MRI.

During the last decades, advances in the understanding of genetic, cellular, and microstructural alterations associated to Huntington's disease (HD) have improved the understanding of this progressive and fatal illness. However, events related to early neuropathological events, neuroinflammation, deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown. Ultra-high field diffusion MRI (UHFD-MRI) techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD.

Ion channels and pain in Fabry disease.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation.

Upregulation of ASIC1a channels in an in vitro model of Fabry disease.

Neuropathic pain is one of the key features of the classical phenotype of Fabry disease (FD). Acid sensing ion channels (ASICs) are H-gated cation channels, which belong to the epithelial sodium channel/DeGenerin superfamily, sensitive to the diuretic drug Amiloride. Molecular cloning has identified several distinct ASIC subunits.

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra-high field MRI and diffusion tensor metrics.

Objective: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.

Methods: Ultra-high field MRI and DTI data at 17.

Diffusion Tensor Imaging in Preclinical and Human Studies of Huntington's Disease: What Have we Learned so Far?

Background: Huntington's Disease is an irreversible neurodegenerative disease characterized by the progressive deterioration of specific brain nerve cells. The current evaluation of cellular and physiological events in patients with HD relies on the development of transgenic animal models. To explore such events in vivo, diffusion tensor imaging has been developed to examine the early macro and microstructural changes in brain tissue.

Synaptic signals mediated by protons and acid-sensing ion channels.

Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca currents through multivesicular release in ribbon-type synapses is a proven phenomenon.

Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS.

Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation.

Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis.

Conventional kinesin: Biochemical heterogeneity and functional implications in health and disease.

Intracellular trafficking events powered by microtubule-based molecular motors facilitate the targeted delivery of selected molecular components to specific neuronal subdomains. Within this context, we provide a brief review of mechanisms underlying the execution of axonal transport (AT) by conventional kinesin, the most abundant kinesin-related motor protein in the mature nervous system. We emphasize the biochemical heterogeneity of this multi-subunit motor protein, further discussing its significance in light of recent discoveries revealing its regulation by various protein kinases.

The power of methods.

Major advances in science are usually launched by new methods or techniques. Because this essay is not intended as a history of science, I shall not invoke the invention of the microscope or telescope as the gateways to inner and outer space, but will restrict myself to developments I have witnessed, or almost witnessed, during my scientific lifetime.

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents.

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells.

Acquisition of drug resistance and dependence by prions.

We have reported that properties of prion strains may change when propagated in different environments. For example, when swainsonine-sensitive 22L prions were propagated in PK1 cells in the presence of swainsonine, drug-resistant variants emerged. We proposed that prions constitute quasi- populations comprising a range of variants with different properties, from which the fittest are selected in a particular environment.

Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties.

The agents responsible for transmissible spongiform encephalopathies (TSEs), or prion diseases, contain as a major component PrP(Sc), an abnormal conformer of the host glycoprotein PrP(C). TSE agents are distinguished by differences in phenotypic properties in the host, which nevertheless can contain PrP(Sc) with the same amino-acid sequence. If PrP alone carries information defining strain properties, these must be encoded by post-translational events.

Acute effects of pregabalin on the function and cellular distribution of Ca(V)2.1 in HEK293t cells.

We established a cell model to study the acute effects of pregabalin (PGB), a drug widely used in epilepsy and neuropathic pain, on voltage gated Ca(V)2.1 (P/Q-type) calcium channels function and distribution at the membrane level. HEK293t cells were transfected with plasmids coding for all subunits of the Ca(V)2.

Propagation of RML prions in mice expressing PrP devoid of GPI anchor leads to formation of a novel, stable prion strain.

PrP(C), a host protein which in prion-infected animals is converted to PrP(Sc), is linked to the cell membrane by a GPI anchor. Mice expressing PrP(C) without GPI anchor (tgGPI⁻ mice), are susceptible to prion infection but accumulate anchorless PrP(Sc) extra-, rather than intracellularly. We investigated whether tgGPI⁻ mice could faithfully propagate prion strains despite the deviant structure and location of anchorless PrP(Sc).

The end of the road.

After some 60 years in research, a few months before my final retirement (there were a few temporary ones), the time has come to reminisce.

The extended cell panel assay characterizes the relationship of prion strains RML, 79A, and 139A and reveals conversion of 139A to 79A-like prions in cell culture.

Three commonly used isolates of murine prions, 79A, 139A, and RML, were derived from the so-called Chandler isolate, which was obtained by propagating prions from scrapie-infected goat brain in mice. RML is widely believed to be identical with 139A; however, using the extended cell panel assay (ECPA), we here show that 139A and RML isolates are distinct, while 79A and RML could not be distinguished. We undertook to clone 79A and 139A prions by endpoint dilution in murine neuroblastoma-derived PK1 cells.