Nuovi trattamenti per il dolore infiammatorio e neuropatico

New treatments for neuropathic pain Stefano Cobianchi, Institute of Neuroscience, CNR, Rome (Italy). Experiment 1: Botulinum neurotoxins. Aim. Botulinum neurotoxins have been successfully used in clinical practice for the treatment of dystonias and a number of syndromes associated to hyperfunctioning of cholinergic terminals. Recent data support the use of Botulinum neurotoxins (BoNTs) as new therapeutic agents in pain relief. It has been demonstrated that the Botulinum neurotoxin serotype-A is able to induce analgesia in inflammatory pain conditions (1). In this study we investigated the effects of two different serotypes, A and B (BoNT/A and BoNT/B), in the development and recovering from neuropathic pain in mice subjected to the sciatic nerve ligation (Chronic Constriction Injury, Bennett and Xie model) (2, 3). Methods. Mice were subcutaneously injected into the plantar surface of both hindpaws either with BoNT/A (two doses: 7.5 or 15 pg/paw), BoNT/B (3.75 pg/paw) or saline, on different days before and after CCI. The temporal trend of neuropathy over a long time interval (80 days) was analyzed measuring the mechanical allodynic response to the Dynamic Aesthesiometer Test. Functional recovery of the injured paw was followed examining the mice walking pattern, measured by the Sciatic Static Index (SSI) (4), as well as by the weight bearing (Incapacitance test). Results. Remarkably, a single administration of BoNT/A, but not BoNT/B, was sufficient to induce antiallodynic effects starting from the day after the injection. The effect was dose-dependent and lasted for at least 3 weeks. The administration of BoNT/A before the CCI was ineffective. Furthermore, BoNT/A injection accelerated the functional recovery, enhancing the SSI scores and restoring the normal weight bearing. Conclusion. This result is particularly relevant since neuropathic pain is poorly treated by current drug therapies. The different modulatory action of the two botulinum serotypes is an important and useful result to take into account for both the study and the comprehension of the mechanisms involved in their action and for the use of the BoNTs in the clinical practice. Experiment 2: Treadmill locomotion. Aim. Treadmill locomotion is widely used for physical rehabilitative therapy. Although several studies demonstrate the positive effects of treadmill running on the functional recovery after a peripheral nerve injury (5, 6, 7), the effects on pain symptoms have not been investigated. In this study we analyzed which treadmill protocol could be effective both on functional recovery and on alleviation of neuropathic pain symptoms. Methods. The CCI model was used to induce neuropathy in mice. We measured the onset of mechanical allodynia in mice undergoing short- (1 week) or long-lasting (8 weeks) daily sessions of treadmill exercise. Functional recovery of the injured paw was examined by analyzing weight bearing of hind limb, walking track analysis and SSI. Behavioural data were correlated with data deriving from immunofluorescence staining for markers of cellular proliferation (Cdc2, GAP-43) in injured nerves and of activated glial cells (Cd11b, GFAP) in lumbar spinal cord. Results. An early mild and short-lasting treadmill exercise was effective in counteracting the development of mechanical allodynia induced by CCI and to speed up the functional recovery of injured paw, as demonstrated by the normalization of the weight bearing and of walking pattern of mice. On the contrary, long-lasting treadmill exercise did not show substantial beneficial effects compared to animals that were not subjected to treadmill. Behavioural data strongly correlated with nerve regeneration immunofluorescence markers. Only the short-lasting treadmill exercise was coupled, with an increased expression in injured sciatic nerves of Cdc2 and GAP-43. In the same mice, a reduced expression of Cd11b and GFAP-labeled glial cells was also observed in the lumbar spinal cord. Conclusion. Results show that only an immediate short-lasting exercise induces pain relief, stimulates nerve regeneration, and speeds up the complete functional recovery. When prolonged for more than a week, treadmill exercise can have deleterious effects after peripheral nerve injury. Supported by research grants FISR-CNR Neurobiotecnologia 2003 and FILAS Regione Lazio (Italy). References (1) Luvisetto S, Marinelli S, Lucchetti F, Marchi F, Cobianchi S, Rossetto O, Montecucco C, Pavone F, 2006. Botulinum neurotoxins and formalin-induced pain: central vs. peripheral effects in mice. Brain Res 1082:124. (2) Bennet GJ, Xie YK,1988. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107. (3) Luvisetto S, Marinelli S, Cobianchi S and Pavone F, 2007. Anti-allodynic efficacy of Botulinum neurotoxin A in a model of neuropathic pain. Neurosci 145:1-4. (4) Baptista AF, de Souza Gomes JR, Oliveira JT, Santos SMG, Vannier-Santos MA, Martinez AMB, 2007. A new approach to assess function after sciatic nerve lesion in the mouse – Adaptation of the sciatic static index. J Neurosci Meth 161:259-264. (5) Marqueste T, Alliez JR, Alluin O, Jammes Y, Decherchi P, 2004. Neuromuscular rehabilitation by treadmill running or electrical stimulation after peripheral nerve injury and repair. J Appl Physiol 96:1988-1995. (6) Sabatier MJ, Redmon N, Schwartz G, English AW, 2008. Treadmill training promotes axon regeneration in injured peripheral nerves. Exp Neurol 211:489-493. (7) Seo TB, Han IS, Yoon JH, Hong KE, Yoon SJ, Namgung U, 2006. Involvement of Cdc2 in axonal regeneration enhanced by exercise training in rats. Med Sci Sports Exerc 38:1267-1276

Editorial: New frontiers in pancreatic cancer care: Multidisciplinary approaches, the role of Pancreas Units, and their organizational impacts

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Tubulization with chitosan guides for the repair of long gap peripheral nerve injury in the rat

Biosynthetic guides can be an alternative to nerve grafts for reconstructing severely injured peripheral nerves. The aim of this study was to evaluate the regenerative capability of chitosan tubes to bridge critical nerve gaps (15 mm long) in the rat sciatic nerve compared with silicone (SIL) tubes and nerve autografts (AGs). A total of 28 Wistar Hannover rats were randomly distributed into four groups (n = 7 each), in which the nerve was repaired by SIL tube, chitosan guides of low (∼2%, DAI) and medium (∼5%, DAII) degree of acetylation, and AG. Electrophysiological and algesimetry tests were performed serially along 4 months follow-up, and histomorphometric analysis was performed at the end of the study. Both groups with chitosan tubes showed similar degree of functional recovery, and similar number of myelinated nerve fibers at mid tube after 4 months of implantation. The results with chitosan tubes were significantly better compared to SIL tubes (P < 0.01), but lower than with AG (P < 0.01). In contrast to AG, in which all the rats had effective regeneration and target reinnervation, chitosan tubes from DAI and DAII achieved 43 and 57% success, respectively, whereas regeneration failed in all the animals repaired with SIL tubes. This study suggests that chitosan guides are promising conduits to construct artificial nerve grafts

Cardiology in a Digital Age: Opportunities and Challenges for e-Health: A Literature Review

To date, mortality rates associated with heart diseases are dangerously increasing, making them the leading cause of death globally. From this point of view, digital technologies can provide health systems with the necessary support to increase prevention and monitoring, and improve care delivery. The present study proposes a review of the literature to understand the state of the art and the outcomes of international experiences. A reference framework is defined to develop reflections to optimize the use of resources and technologies, favoring the development of new organizational models and intervention strategies. Findings highlight the potential significance of e-health and telemedicine in supporting novel solutions and organizational models for cardiac illnesses as a response to the requirements and restrictions of patients and health systems. While privacy concerns and technology-acceptance-related issues arise, new avenues for research and clinical practice emerge, with the need to study ad hoc managerial models according to the type of patient and disease

Prophylactic mesh augmentation after laparotomy for elective and emergency surgery: meta-analysis

Background: Incisional hernia is a common short- and long-term complication of laparotomy and can lead to significant morbidity. The aim of this systematic review and meta-analysis is to provide an up-to-date overview of the laparotomy closure method in elective and emergency settings with the prophylactic mesh augmentation technique. Methods: The Scopus, PubMed, and Web of Science databases were screened without time restrictions up to 21 June 2022 using the keywords 'laparotomy closure', 'mesh', 'mesh positioning', and 'prophylactic mesh', and including medical subject headings terms. Only RCTs reporting the incidence of incisional hernia and other wound complications after elective or emergency midline laparotomy, where patients were treated with prophylactic mesh augmentation or without mesh positioning, were included. The primary endpoint was to explore the risk of incisional hernia at different follow-up time points. The secondary endpoint was the risk of wound complications. The risk of bias for individual studies was assessed according to the Revised Cochrane risk-of-bias tools for randomized trials. Results: Eighteen RCTs, including 2659 patients, were retrieved. A reduction in the risk of incisional hernia at every time point was highlighted in the prophylactic mesh augmentation group (1 year, risk ratio 0.31, P = 0.0011; 2 years, risk ratio 0.44, P &lt; 0.0001; 3 years, risk ratio 0.38, P = 0.0026; 4 years, risk ratio 0.38, P = 0.0257). An increased risk of wound complications was highlighted for patients undergoing mesh augmentation, although this was not significant. Conclusions: Midline laparotomy closure with prophylactic mesh augmentation can be considered safe and effective in reducing the incidence of incisional hernia. Further trials are needed to identify the ideal type of mesh and technique for mesh positioning, but surgeons should consider prophylactic mesh augmentation to decrease incisional hernia rate, especially in high-risk patients for fascial dehiscence and even in emergency settings

Correction: Surgeons’ perspectives on artificial intelligence to support clinical decision-making in trauma and emergency contexts: results from an international survey

Correction: Surgeons' perspectives on artificial intelligence to support clinical decision-making in trauma and emergency contexts: results from an international surve

Chronic electrical stimulation reduces hyperalgesia and associated spinal changes induced by peripheral nerve injury

Altres ajuts: This work was supported by Grant EPIONE (FP7-602547) from the European Commission (EC), and TERCEL and CIBERNED funds from the Instituto de Salud Carlos III of Spain, and FEDER fundsObjectives: We aimed to investigate if different protocols of electrical stimulation following nerve injury might improve neuropathic pain outcomes and modify associated plastic changes at the spinal cord level. Materials and Methods: Adult rats were subjected to sciatic nerve transection and repair, and distributed in four groups: untreated (SNTR, n = 12), repeated acute electrical stimulation (rAES, 50 Hz, one hour, n = 12), chronic electrical stimulation (CES, 50 Hz, one hour, n = 12), and increasing-frequency chronic electrical stimulation (iCES, one hour, n = 12) delivered during two weeks following the lesion. The threshold of nociceptive withdrawal to mechanical stimuli was evaluated by means of a Von Frey algesimeter during three weeks postlesion. Spinal cord samples were processed by immunohistochemistry for labeling glial cells, adrenergic receptors, K -Cl cotransporter 2 (KCC2) and GABA. Results: Acute electrical stimulation (50 Hz, one hour) delivered at 3, 7, and 14 days induced an immediate increase of mechanical pain threshold that disappeared after a few days. Chronic electrical stimulation given daily reduced mechanical hyperalgesia until the end of follow-up, being more sustained with the iCES than with constant 50 Hz stimulation (CES). Chronic stimulation protocols restored the expression of β2 adrenergic receptor and of KCC2 in the dorsal horn, which were significantly reduced by nerve injury. These treatments decreased also the activation of microglia and astrocytes in the dorsal horn. Conclusion: Daily electrical stimulation, especially if frequency-patterned, was effective in ameliorating hyperalgesia after nerve injury, and partially preventing the proinflammatory and hyperalgesic changes in the dorsal horn associated to neuropathic pain

Surgeons' perspectives on artificial intelligence to support clinical decision-making in trauma and emergency contexts: results from an international survey

Background Artificial intelligence (AI) is gaining traction in medicine and surgery. AI-based applications can offer tools to examine high-volume data to inform predictive analytics that supports complex decision-making processes. Time-sensitive trauma and emergency contexts are often challenging. The study aims to investigate trauma and emergency surgeons’ knowledge and perception of using AI-based tools in clinical decision-making processes. Methods An online survey grounded on literature regarding AI-enabled surgical decision-making aids was created by a multidisciplinary committee and endorsed by the World Society of Emergency Surgery (WSES). The survey was advertised to 917 WSES members through the society’s website and Twitter profile. Results 650 surgeons from 71 countries in five continents participated in the survey. Results depict the presence of technology enthusiasts and skeptics and surgeons' preference toward more classical decision-making aids like clinical guidelines, traditional training, and the support of their multidisciplinary colleagues. A lack of knowledge about several AI-related aspects emerges and is associated with mistrust. Discussion The trauma and emergency surgical community is divided into those who firmly believe in the potential of AI and those who do not understand or trust AI-enabled surgical decision-making aids. Academic societies and surgical training programs should promote a foundational, working knowledge of clinical AI