Browsing by Author "Campero, Mario"
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Item A search for activation of C-nociceptors by sympathetic fibers in complex regional pain syndrome(2010) Campero, Mario; Bostock, Hugh; Baumann, Thomas; Ochoa, JoséObjective—Although the term ‘reflex sympathetic dystrophy’ has been replaced by ‘complex regional pain syndrome’ (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain [“sympathetically maintained pain” (SMP)], even in the absence of detectable neuropathophysiology. Methods—We have used microneurography to evaluate possible electrophysiological interactions in 24 patients diagnosed with CRPS I (n=13), or CRPS II (n=11) by simultaneously recording from single identified sympathetic efferent fibers and C nociceptors, while provoking sympathetic neural discharges in cutaneous nerves. Results—We assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors, recorded in CRPS I (26 nociceptors) and CRPS II patients (28 nociceptors). No evidence of activation of nociceptors related to sympathetic discharge was found, although nociceptors in 6 CRPS II patients exhibited unrelated spontaneous pathological nerve impulse activity. Conclusion—We conclude that activation of nociceptors by sympathetic efferent discharges is not a cardinal pathogenic event in either CRPS I or CRPS II patients. Significance—This study shows that sympathetic-nociceptor interactions, if they exist in patients communicating chronic neuropathic pain, must be the exceptionItem Actividad espontánea de nociceptores cutáneos en pacientes con neuropatía de fibras delgadas(2012) Campero, Mario; Campero, SebastiánPainful polyneuropathy may result from selective impairment of small diameter nerve fibers, while tactile and motor functions are preserved. In these patients clinical and electrophysiological assessment is usually unrevealing. We report three patients with a pure painful polyneuropathy. One of them had neurogenic pruritus additionally. Quantitative sensory analysis disclosed a slight warm hypoesthesia (3/3) and paradoxical hot sensation (2/3) in the feet. Intraneural recordings from the peroneal nerve demonstrated abnormal spontaneous activity in 8 of 17 nociceptive afferents. One of them displayed double firing reflecting impulse multiplication. These results support the notion that patients with pain or pruritus with a distal distribution similar to a polyneuropathy, could have small diameter afferent fiber damage, despite normal function of large diameter fibers.Item Activity-dependent slowing properties of an unmyelinated low thresh old mechanoreceptor inhuman hairy skin(2011) Campero, Mario; Bostock, Hugh; Baumann, Thomas K.; Ochoa, Jose L.It has been previously shown that unmyelinated afferent fibres in human skin are differentiated not only by their receptor characteristics, but also by their profiles of activity-dependent slowing. One type of profile, described originally as 'type 3', is different from that of nociceptors (type 1), cold afferents (type 2) and sympathetic efferents (type 4), in that these fibres display a minimal activity-dependent slowing (similar to 1% at 2 Hz). However, their function remains to be determined. Here we describe one unit with a typical 'type 3' activity-dependent slowing profile recorded from an undamaged fascicle of the superficial peroneal nerve of a patient. Its conduction velocity was 1.8 ms(-1) and it slowed by 1.3% during the 2 Hz tetanus. This unit had a mechanical receptive field in the hairy skin and responded readily to weak mechanical stimuli, and not to cold. This suggests that the low threshold unmyelinated mechanoreceptors recently described in human hairy skin are probably endowed with a 'type 3' activity-dependent profile. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Item ALS-linked protein disulfide isomerase variants cause motor dysfunction(European Molecular Biology Organization by IRL Press, 2016) Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando; Andreu, Catherine; Torres, mauricio; Valenzuela, Vicente; Medinas, Danilo; Rozas, Pablo; Vidal, René; López-González, Rodrigo; Salameh, Johnny; Fernández-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisén, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; González-Pérez, Paloma; Campero, MarioDisturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.Item Caso clínico: Rabdomiolisis secundaria al consumo de cocaína(2018) Domínguez, J. I.; Campero, Mario; Reyes, M.; San Martín, M. F.Introducción: Las múltiples causas de Rabdomiolisis se pueden separar en 5 categorías según el mecanismo de daño del miocito: Hipóxicas, físicas, químicas, biológicas e idiopáticas. Como primera causa se describe el consumo de drogas ilícitas/alcohol, seguido por medicamentos, trauma, inmovilidad y ejercicio extenuante. Las causas químicas representan hasta el 80% de los casos de rabdomiolisis. En esta categoría se encuentran los medicamentos, alcohol y drogas donde destaca la cocaína. Se presenta el caso de un paciente masculino que cursa con insuficiencia renal aguda secundario a una rabdomiolisis por consumo de cocaína.Item Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus(2018) Gregorio, Cristian De; Contador, David; Campero, Mario; Ezquer, Marcelo; Ezquer, FernandoDiabetes mellitus (DM) is one of most common chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS diabetic (db/db) mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display progressive sensory loss and electrophysiological impairments in the early-to-mid phases of the disease. Furthermore, we detected an early decrease in intraepidermal nerve fiber (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN – like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve – were altered in mid-to-late phases of the disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied.Item Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice(2020) Gregorio, Cristian De; Contador, David; Díaz, Diego; Cárcamo, Constanza; Santapau, Daniela; Lobos-González, Lorena; Acosta, Cristian; Campero, Mario; Carpio, Daniel; Gabriele, Caterina; Gaspari, Marco; Aliaga-Tobar, Víctor; Maracaja-Coutinho, Vinicius; Ezquer, Marcelo; Ezquer, FernandoBackground: Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods: Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results: Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions: Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.Item Nerve excitability and structural changes in myelinated axons from diabetic mice(Georg Thieme Verlag KG, 2015) Campero, Mario; Ezquer, Marcelo; Ezquer, FernandoOBJECTIVE: The mechanisms associated with nerve dysfunction and axonal loss in diabetes has not been fully clarified. Excitability and pathological aspects in nerves from diabetic mice were studied in order to explore the pathophysiology of diabetic neuropathy. METHODS: Myelinated nerve fibres from the sciatic nerve of BKS.Cg-m (+/+) Lepr (db) /J mice were studied by registering the CMAP controlled by an automated threshold tracking method. The sciatic nerve was also studied pathologically. RESULTS: Diabetic mice displayed longer latencies, higher thresholds and lower amplitudes compared to controls and had a rightward shift in the stimulus response curves. Strength-duration time constant was lower in diabetic mice but not reaching statistical significance (p=0.09). Diabetics displayed an increase in accommodation, with a smaller change in excitability in threshold electrotonus. Refractoriness, mean superexcitability and late subexcitability were reduced in diabetic mice. Diabetic mice had a larger number of myelinated fibres compared to controls (p<0.05), but larger than 9 μm were virtually absent, accounting for near 7% in control animals. CONCLUSIONS: Db/db mice develop electrophysiological changes suggestive of membrane depolarization as the result of Na(+)/K(+) pump impairment. Loss of large myelinated fibres might also contribute to the nerve excitability profiles in this model.Publication Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group.(2022) Verdugo, Renato; Matamala, José; Inui, Koji; Kakigi, Ryusuke; Valls-Solé, Josep; Hansson, Per; Nilsen, Kristian Bernhard; Lombardi, Raffaella; Lauria, Giuseppe; Petropoulos, Ioannis N.; Malik, Rayaz A.; Treede, Rolf-Detlef; Baumgärtner, Ulf; Jara, Paula A.; Campero, MarioNerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.Item Unmyelinated afferents in human skin and their responsiveness to low temperature(2010) Campero, Mario; Bostock, HughIn humans, there are different types of cutaneous cold-sensitive afferents responsible for cold sensation and cold pain. Innocuous cold is primarily mediated by a population of slow A delta afferents, based on psychophysical and neurophysiological studies. Noxious cold (usually below 15 ◦C) is mediated, at least in part, by polymodal nociceptors. There is also a population of unmyelinated afferents responsive to innocuous low temperature, some of which also respond to heat, whose sensory function has not been completely defined. A paradoxical hot/burning evoked by cooling is unmasked by A-fibre block, and similar sensations are evoked by applying simultaneous cool and warm stimuli to adjacent skin areas. These unmyelinated fibres activated by innocuous cooling (and heating) may contribute to this hot/burning sensation, along with other thermoregulatory functions.