Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naive animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems

Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder

Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes.A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology

Acceptability of app-based contact tracing for COVID-19: cross-country survey evidence

Background: The COVID-19 pandemic is the greatest public health crisis of the last 100 years. Countries have responded with various levels of lockdown to save lives and stop health systems from being overwhelmed. At the same time, lockdowns entail large socioeconomic costs. One exit strategy under consideration is a mobile phone app that traces the close contacts of those infected with COVID-19. Recent research has demonstrated the theoretical effectiveness of this solution in different disease settings. However, concerns have been raised about such apps because of the potential privacy implications. This could limit the acceptability of app-based contact tracing in the general population. As the effectiveness of this approach increases strongly with app uptake, it is crucial to understand public support for this intervention. Objective: The objective of this study is to investigate the user acceptability of a contact-tracing app in five countries hit by the pandemic. Methods: We conducted a largescale, multicountry study (N=5995) to measure public support for the digital contact tracing of COVID-19 infections. We ran anonymous online surveys in France, Germany, Italy, the United Kingdom, and the United States. We measured intentions to use a contact-tracing app across different installation regimes (voluntary installation vs automatic installation by mobile phone providers) and studied how these intentions vary across individuals and countries. Results: We found strong support for the app under both regimes, in all countries, across all subgroups of the population, and irrespective of regional-level COVID-19 mortality rates. We investigated the main factors that may hinder or facilitate uptake and found that concerns about cybersecurity and privacy, together with a lack of trust in the government, are the main barriers to adoption. Conclusions: Epidemiological evidence shows that app-based contact tracing can suppress the spread of COVID-19 if a high enough proportion of the population uses the app and that it can still reduce the number of infections if uptake is moderate. Our findings show that the willingness to install the app is very high. The available evidence suggests that app-based contact tracing may be a viable approach to control the diffusion of COVID-19.</p

Umwelterziehung in Schule und Erwachsenenbildung

Technische Informationsbibliothek Hannover: AC 5703. / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Heat shock protein 60 as a mediator of adipose tissue inflammation and insulin resistance

The stress protein heat shock protein 60 (Hsp60) induces secretion of proinflammatory mediators from murine adipocytes. This study aimed to study Hsp60 as a mediator of adipose tissue inflammation and skeletal muscle cell (SkMC) insulin sensitivity and to quantify plasma Hsp60 concentrations in lean and obese individuals. Regulation of Hsp60 release and Hsp60-induced cytokine secretion and signaling was measured in human adipocytes and SkMCs. Adipocytes exhibited higher Hsp60 release than preadipocytes and SkMCs, which was further stimulated by cytokines and Toll-like receptor (TLR)-4 activation. Hsp60 activated extracellular signal-related lcinase (ERK)-1/2, Jun NH2-terminal kinase (JNK), p38, nuclear factor (NF)-kappa B, and impaired insulin-stimulated Akt phosphorylation in adipocytes. Furthermore, Hsp60 stimulated adipocytes to secrete tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. In SkMCs, Hsp60 activated ERK1/2, JNK, and NF-kappa B and inhibits insulin signaling and insulin-stimulated glucose uptake. SkMCs released IL-6, IL-8, and monocyte chemoattractant protein-1 on Hsp60 stimulation. Plasma Hsp60 was higher in obese males than in lean males and correlated positively with BMI, blood pressure, leptin, and homeostasis model assessment-insulin resistance. In summary, Hsp60 is released by human adipocytes, increased in plasma of obese humans, and induces insulin resistance. This is accompanied by activation of proinflammatory signaling in human adipocytes and SkMCs. Thus, Hsp60 might be a factor underlying adipose tissue inflammation and obesity-associated metabolic disorders