Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction

Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair

Maximum skin hyperaemia induced by local heating: possible mechanisms

Background: Maximum skin hyperaemia (MH) induced by heating skin to 42°C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. Methods: MH was achieved by local heating of skin to 42-43°C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H1 receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). Results: MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. Conclusion: NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating

A Qualitative and Quantitative Proteomic Study of Human Microdialysate and the Cutaneous Response to Injury

The extracellular fluid space is the site of intercellular communication and represents an important source of mediators that can shed light on the parenchymal environment. Sampling of this compartment using continuous microdialysis allows assessment of the temporal changes in extracellular mediators involved in tissue homeostasis and disease processes. However, novel biomarker identification is limited by the current need to utilize specific, targeted molecular assays. The aim of our study was to explore the use of qualitative and quantitative proteomic approaches to define the protein content of dermal dialysate. Timed dermal dialysate samples were collected from healthy human volunteers for 5 h following probe insertion, using a 3,000-kDa MWCO membrane perfused at a rate of 3 μl/min. Dialysate proteins were identified using GeLC–MS/MS and iTRAQ approaches and functions assigned according to the Gene Ontology classification system. More than 80 proteins (size range 11–516 kDa) originating from both extracellular and intracellular fluid space were identified using the qualitative approach of GeLC–MS/MS. Quantitative iTRAQ data were obtained for 27 proteins with relative change ratios between consecutive timed samples showing changes of >1.5-fold. Interstitial proteins can be identified and measured using shotgun proteomic techniques and changes detected during the acute inflammatory response. Our findings provide a platform from which to explore novel protein biomarkers and their modulation in health and disease

Systemic ropivacaine diminishes pain sensitization processes: A randomized, double-blinded, placebo-controlled, crossover study in healthy volunteers

Introduction: Ropivacaine is a local anesthetic widely used for regional anesthesia. One of its advantages is low toxicity at plasma concentrations reached systemically during continuous peripheral or central nervous block. The objective of this study was to test the effect of systemic ropivacaine on pain, hyperalgesia, dynamic allodynia, and flare response. Methods: This randomized, double-blinded, placebo-controlled, crossover study was carried out in at the Clinical Trials Centre, University of Zurich, Switzerland. Twenty healthy male volunteers were included in the study. Exclusion criteria were contraindications or hypersensitivity to local anesthetics, vulnerable subjects (intellectually or mental impaired), drug, alcohol or nicotine abuse, known peripheral neuropathies, diabetes mellitus and/or congestive heart disease. Ropivacaine and saline were infused intravenously during a subcutaneous electrical stimulation. The stimulation software adjusted the stimulus strength according to the rating on a numeric rating scale (NRS; 0–10) maintaining a NRS of 5. Areas of punctate hyperalgesia, dynamic allodynia, and flare response were measured before and after the infusion. Results: The area of hyperalgesia increased significantly with saline (303 ± 380%, P < 0.05) and ropivacaine (186 ± 137%, P < 0.05). The area of allodynia (253 ± 299%, P < 0.05) and flare response (112 ± 24%, P < 0.05) increased only during the placebo infusion. Conclusion: The results of this study imply that systemic ropivacaine may diminish pain sensitization processes

The clinical role of NMDA receptor antagonists for the treatment of postoperative pain.

Recent advances in the understanding of postoperative pain have demonstrated its association with sensitization of the central nervous system (CNS) which clinically elicits pain hypersensitivity. N-methyl-D-aspartate (NMDA) receptors play a major role in synaptic plasticity and are specifically implicated in CNS facilitation of pain processing. Therefore, NMDA receptor antagonists, and specifically ketamine commonly used in clinical practice, have been implicated in perioperative pain management. At subanesthetic (i.e. low) doses, ketamine exerts a specific NMDA blockade and hence modulates central sensitization induced both by the incision and tissue damage and by perioperative analgesics such as opioids. However, the mechanisms underlying ketamine anti-hyperalgesic effect are not totally understood, and neither is the relationship between central sensitization and the risk of developing residual pain after surgery. This chapter examines the role of low doses of ketamine as an adjuvant drug in current perioperative pain management and questions the anti-hyperalgesic mechanisms involved