Mechanisms of chronic pain

Chronic pain is classified as nociceptive or neuropathic, depending on whether the integrity of the somatosensory nervous system is compromised by the underlying disease. Nociceptive pain results from the activation of receptors (nociceptors) sensitive to noxious stimuli. Prolonged or intense exposure to these stimuli, for example, chemical mediators released during inflammation, enhances the responsiveness of nociceptive nerve fibers. This process, termed peripheral sensitization, involves a shift in the activation threshold of nociceptors and upregulation of voltage-gated sodium channels. Peripheral sensitization leads to increased action potential firing and transmitter release in the dorsal horn of the spinal cord, where somatosensory information is processed. Dorsal horn neurons react to the rising input with heightened excitability, a process termed central sensitization. Enhanced depolarization leads to the recruitment of N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA and neuropeptide receptor activation produces a sharp increase in intracellular calcium, triggering signaling pathways and gene expression changes that promote a long-term shift in the activity of nociceptive circuits. In some aspects, central sensitization even resembles long-term potentiation of excitatory transmission in the hippocampus. Central sensitization generates an exaggerated response to painful stimuli (hyperalgesia) and contributes to pain elicited by normally nonpainful stimuli (allodynia). Clinical findings suggest that pain hypersensitivity produces structural changes in the brain over time. These changes are, however, reversible upon pain relief. The pathophysiology of neuropathic pain is fundamentally different. Peripheral nerve lesion evokes stimulus-independent (ectopic) activity in nerve fibers. Innate immune cells react at the lesion site, in the dorsal root ganglion, where the cell bodies of peripheral somatosensory neurons reside, and in the dorsal horn of the spinal cord. Active microglia of the dorsal horn releases chemical mediators that modulate the activity of neurons in the vicinity. One of these mediators, brain-derived neurotrophic factor, reduces the inhibitory effect of γ-aminobutyric acid (GABA) and glycine. Disinhibition opens polysynaptic connections in the dorsal horn, further enhancing the abnormal input from the lesioned nerve. Similarly to nociceptive pain, central sensitization occurs. Worsened by a relative deficit in transmitter uptake, increased glutamatergic transmission causes excitotoxic cell death, reducing the number of inhibitory interneurons. Their loss and a shift in descending modulatory pathways from the brainstem produce a profound imbalance between inhibition and excitation. The complexity of chronic pain mechanisms poses a major therapeutic challenge. Without biomarkers, it will remain difficult to develop targeted strategies for chronic pain reduction or prevention in the individual patient. Disclosures: No conflict of interest

On the Interaction of Neomycin with the Slow Vacuolar Channel of Arabidopsis thaliana

This study investigates the interaction of the aminoglycoside antibiotic neomycin with the slow vacuolar (SV) channel in vacuoles from Arabidopsis thaliana mesophyll cells. Patch-clamp experiments in the excised patch configuration revealed a complex pattern of neomycin effects on the channel: applied at concentrations in the submicromolar to millimolar range neomycin (a) blocked macroscopic SV currents in a voltage- and concentration-dependent manner, (b) slowed down activation and deactivation kinetics of the channel, and most interestingly, (c) at concentrations above 10 μM, neomycin shifted the SV activation threshold towards negative membrane potentials, causing a two-phasic activation at high concentrations. Single channel experiments showed that neomycin causes these macroscopic effects by combining a decrease of the single channel conductance with a concomitant increase of the channel's open probability. Our results clearly demonstrate that the SV channel can be activated at physiologically relevant tonoplast potentials in the presence of an organic effector molecule. We therefore propose the existence of a cellular equivalent regulating the activity of the SV channel in vivo

Harmonization of growth hormone measurements with different immunoassays by data adjustment

Background: The aim of our study was to evaluate the between-assay variability of commercially available immunoassays for the measurement of human growth hormone (hGH). In addition, we asked whether the comparability of the diagnosis of childhood onset growth hormone deficiency could be improved by adjusting hGH results by statistical methods, such as linear regression, conversion factors, and quantile transformation. Methods: In archived sera from 312 children and adolescents (age: 17 days-17 years) hGH values between 0.01 and 16.5 ng/mL were determined by using the following immunoassays: AutoDELFIA (PerkinElmer), BC-IRMA (Beckman-Coulter), ELISA (Mediagnost), IMMULITE 2000 (Siemens), iSYS (IDS), Liaison (DiaSorin), UniCel DxI 800 Access (BeckmanCoulter) and "In house"-RIA (Tubingen). Results: The assays differed in median hGH concentrations by as much as 5.44 ng/mL (Immulite), and as little as 2.67 ng/mL (BC-IRMA). The mean difference between assays ranged from 0.35 to 2.71 ng/mL, whereas several samples displayed differences up to 11.4 ng/mL. The best correlation (r=0.992) was found between AutoDELFIA and Liasion, the lowest (r=0.864) was between an in-house RIA and iSYS. The between-assay CV (mean +/- SD) of values within the cut-off range was 24.3%+/- 7.4%, resulting in an assay-dependent diagnosis of growth hormone deficiency (GHD) in more than 27% of patients. Yet, adjustment of this data by linear regression or a conversion factor reduced the CV below 14%, and the ratio of assay-dependent diagnoses below 8%. Using quantile transformation, the CV and ratio were reduced to 11.4% and < 1%, respectively. Conclusions: hGH measurements using different assays vary significantly. Linear regression, conversion factors, or particularly quantile transformation are useful tools to improve comparability in the diagnostic procedure for the confirmation of GHD in childhood and adolescence

Trigeminal neuralgia: new classification and diagnostic grading for practice and research

Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic. Diagnostic certainty is graded possible when pain paroxysms occur in the distribution of the trigeminal nerve branches. Triggered paroxysms permit the designation of clinically established TN and probable neuropathic pain. Imaging and neurophysiologic tests that establish the etiology of classical or secondary TN determine definite neuropathic pain

The impact of the AO foundation on fracture care : an evaluation of 60 years AO foundation

Objectives Sixty years ago, the Association of Osteosynthesis (AO) was founded with the aim to improve fracture treatment and has since grown into one of the largest medical associations worldwide. Aim of this study was to evaluate AO's impact on science, education, patient care and the MedTech business. Design/methods Impact evaluations were conducted as appropriate for the individual domains: Impact on science was measured by analyzing citation frequencies of publications promoted by AO. Impact on education was evaluated by analyzing the evolution of number and location of AO courses. Impact on patient care was evaluated with a health economic model analyzing cost changes and years of life gained through the introduction of osteosynthesis in 17 high-income countries (HICs). Impact on MedTech business was evaluated by analyzing sales data of AO-associated products. Results Thirty-five AO papers and 2 major AO textbooks are cited at remarkable frequencies in high ranking journals with up to 2000 citations/year. The number of AO courses steadily increased with a total of 645'000 participants, 20‘000 teaching days and 2‘500 volunteer faculty members so far. The introduction of osteosynthesis saved at least 925 billion Swiss Francs [CHF] in the 17 HICs analyzed and had an impact on avoiding premature deaths comparable to the use of antihypertensive drugs. AO-associated products generated sales of 55 billion CHF. Conclusion AO's impact on science, education, patient care, and the MedTech business was significant because AO addressed hitherto unmet needs by combining activities that mutually enriched and reinforced each other

Towards Sustainable Innovation

With sustainability having gained a lot of momentum over the last years and companies implementing strategies to create corporate sustainability, there are lots of opportunities for innovation. Thus, the two concepts of sustainability and innovation should not be considered separately – they are closely interlinked with one another. The main goal of sustainable innovation is to develop new products and technologies that have a positive impact on the company’s triple-bottom-line. To meet this aim, they have to be ecologically and economically beneficial as well as socially balanced. In order to help companies to improve their sustainable innovation process practically, this book is structured into five possible phases of a sustainable innovation process: Awareness of a sustainability problem Identification & Definition of the problem Ideation & Evaluation of the solutions Testing & Enrichment of the solutions Implementation of the solutions & Green Marketin

9‐cis Retinoic acid and 1.25‐dihydroxyvitamin D 3 drive differentiation into IgA + secreting plasmablasts in human naïve B cells

Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27+ CD38+ plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-β promoter thus inducing TGF-β expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction