GABA increases electrical excitability in a subset of human unmyelinated peripheral axons

A proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to chemical mediators of inflammation as well as naturally occurring algogens, thermogens and pruritogens. The neurotransmitter GABA is interesting in this respect because in animal models of neuropathic pain GABA pre-synaptically regulates nociceptive input to the spinal cord. However, the effect of GABA on human peripheral unmyelinated axons has not been established

Searching for success: Development of a combined patient-reported-outcome (“PRO”) criterion for operationalizing success in multi-modal pain therapy

BACKGROUND: There is a need for a way to measure success in multi-modal pain therapy that researchers and clinicians can agree upon. According to developments in health services research, operationalizing success should take patient-reported outcomes into account. We will present a success criterion for pain therapy that combines different patient-reported variables and includes validity measures. The usable criterion should be part of a statistically significant and satisfactory model identifying predictors of successful pain therapy. METHODS: Routine data from 375 patients treated with multi-modal pain therapy from 2008 to 2013 were used. The change scores of five constructs were used for the combined success criterion: pain severity, disability due to pain, depressiveness, and physical- and mental-health-related quality of life. According to the literature, an improvement of at least ½ standard deviation was required on at least four of the five constructs to count as successful. A three-step analytical approach including multiple binary logistic regression analysis was chosen to identify the predictors of therapy success with the success criterion as the dependent variable. RESULTS: A total of 58.1 % of the patients were classified as successful. Convergent and predictive validity data show significant correlations between the criterion and established instruments, while discriminative validity could also be shown. A multiple binary logistic regression analysis confirmed the feasibility; a significant model (Chi(2) (8) = 52.585; p < .001) that explained 17.6 % of the variance identified the following predictors of therapy success: highest pain severity in the last 4 weeks, disability due to pain, and number of physician visits in the last 6 months. CONCLUSIONS: It is possible to develop a feasible success criterion that combines several variables and includes patient-reported outcomes (“PROs”) with routine data that can be used in a predictor analysis in multi-modal pain therapy. The criterion was based on basic constructs used in pain therapy and used widespread validated self-rating instruments. Thus, it should be easy to transfer this criterion to other institutions

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Na(v)1.6 in peripheral pain pathways

Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Na-v pathways. Using selective inhibitors and knockout animals, we found that Na(v)1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K+-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Na(v)1.6 blockers. Intraplantar injection of the Na(v)1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Na(v)1.6 in multiple peripheral pain pathways including cold allodynia. (c) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved

Competitive balance and assortative matching in the German Bundesliga

In this paper we consider trends in the distribution of player talent across association football clubs over time. Player talent is the most important prerequisite for team success in professional sports leagues and changes in players’ assortativeness in regard to the clubs they play for may arguably be an important factor for changes in competitive balance. We offer a new approach for measuring player talent and its distribution - the partial correlation of each player with the goal margin. We use this measure to analyze the degree of competitive balance over time. This approach enables us to examine how player mobility drives competitive balance over time. Empirical results are based on 19 seasons of the first two divisions of the German Bundesliga as well as domestic cup games. Our results show a decrease in competitive balance over time; better teams tend to attract increasingly better players. We show that this is driven by an increasingly unequal inter-divisional distribution of teams, coaches and players, as well as increasing assortativeness in the 1st Bundesliga. We further demonstrate that player transfers between Bundesliga teams results in assortative matching between players and teams. These domestic transfers do not, however, explain the reduction in competitive balance over time. Furthermore, we show that UEFA Champions League payments may have contributed to the reduction in competitive balance over the last two decades

Prevalence and determinants of painful and painless neuropathy in type 1 diabetes mellitus

Aims: To evaluate (1) the prevalence of diabetic distal symmetrical sensory-motor polyneuropathy (DSPN) and painful DSPN among patients with type 1 diabetes mellitus (DM1) aged over 18 years and (2) the determinant factors of neuropathy and pain in those patients. Materials and Methods: An epidemiological, cross-sectional, observational study was performed; 330,386 people were included, and a total of 444 people were diagnosed with DM1. After exclusion of possible confounders, 360 patients were assessed for painless and painful DSPNs using neurological examination and questionnaires for neuropathy and pain. Odds ratio (OR) and confidence intervals (95% CI) were estimated using multinomial logistic regression models. The analysis was based on a framework with four conceptual levels that consider feasible pathways between several risk factors: (1) socio-demographic factors and diabetes duration, (2) patient habits, (3) co-morbidities, and (4) metabolic factors and disease complications. Results: The prevalence of DSPN and painful DSPN were 42.8 and 18.9%, respectively. Diabetes duration was positively associated with painful (OR = 1.107, 95% CI: 1.107-1.139) and painless DSPN (OR = 1.069, 95% CI: 1.043-1.096). Education level was negatively associated with painful DSPN (OR = 0.889, 95% CI: 0.826-0.957). Sex (female) was positively associated only with painless DSPN (OR = 1.769, 95% CI: 1.007-3.107). Being a current or former smoker was positively associated only with painless DSPN (OR = 1.940, 95% CI: 1.069-3.518). Hypertension was positively associated with painful DSPN (OR = 2.474, 95% CI: 1.110-5.512) and painless DSPN (OR = 2.565, 95% CI: 1.252-5.256). Glycated hemoglobin (HbA1c) was positively associated only with painless DSPN (OR = 1.193, 95% CI: 1.018-1.399). Conclusions: Diabetes duration and hypertension have a direct impact on the development of painful and painless DSPN. However, female sex and HbA1c have a direct effect only on the development of painless DSPN, and education level has an indirect effect on the development of painful DSPN. Therefore, it can be concluded that different etiological factors have different contributions to the development of neuropathy and pain.The authors received study funding from the Associação dos Amigos do Serviço de Endocrinologia do Hospital de S. João

Impact of Enzymatic Degradation on the Material Properties of Poly(Ethylene Terephthalate)

With macroscopic litter and its degradation into secondary microplastic as a major source of environmental pollution, one key challenge is understanding the pathways from macro- to microplastic by abiotic and biotic environmental impact. So far, little is known about the impact of biota on material properties. This study focuses on recycled, bottle-grade poly(ethylene terephthalate) (r-PET) and the degrading enzyme PETase from Ideonella sakaiensis. Compact tension (CT) specimens were incubated in an enzymatic solution and thermally and mechanically characterized. A time-dependent study up to 96 h revealed the formation of steadily growing colloidal structures. After 96 h incubation, high amounts of BHET dimer were found in a near-surface layer, affecting crack propagation and leading to faster material failure. The results of this pilot study show that enzymatic activity accelerates embrittlement and favors fragmentation. We conclude that PET-degrading enzymes must be viewed as a potentially relevant acceleration factor in macroplastic degradation

Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial

Background: Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine’s clinical profile. Trial design: To investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT). Methods: Threshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm. Results: Flupirtine (3-30 μM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.). Conclusions: Clinical doses of flupirtine reduce the excitability of peripheral myelinated axons. Trial registration: ClinicalTrials registration is NCT01450865