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Introduction Small fiber neuropathy usually presents with gradual and progressive chronic length-dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford-AstraZeneca ChAdOx1-S vaccination are described. Patients and Methods Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Results Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within two weeks of vaccination. On clinical examination there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra-epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Conclusions Three cases of definite acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination are described. At follow up, neuropathic pain was present in two of the patients.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic condition in which mutations in the type VII collagen gene ( COL7A1 ) lead to decreased expression of this anchoring protein of the skin, causing the loss of stability at the dermo-epidermal junction. Most patients with RDEB experience neuropathic pain and itch due to the development of a small fibre neuropathy, characterised by decreased intraepidermal innervation and thermal hypoaesthesia. To understand the physiopathology of this neuropathy, we used a mouse model of RDEB (Col7a1 flNeo/flNeo ) and performed a detailed characterisation of the somatosensory system. Col7a1 flNeo/flNeo mice showed a decrease in heat sensitivity, an increase in spontaneous scratching, and a significant decrease in intraepidermal nerve fibre density in the hindpaw; these changes were distal because there was no significant loss of unmyelinated or myelinated fibres in the nerve trunk. Of interest, we observed a decrease in axon diameter in both myelinated and unmyelinated fibres. This axonal damage was not associated with inflammation of the dorsal root ganglion or central projection targets at the time of assessment. These results suggest that in RDEB, there is a distal degeneration of axons produced by exclusive damage of small fibres in the epidermis, and in contrast with traumatic and acute neuropathies, it does not induce sustained neuroinflammation. Thus, this animal model emphasizes the importance of a healthy cutaneous environment for maintenance of epidermal innervation and faithfully replicates the pathology in humans, offering the opportunity to use this model in the development of treatments for pain for patients with RDEB.

Instituto de Salud Carlos III (ISCIII), European Regional Development Fund/European Social Fund "A way to make Europe"/" Investing in your future" [PI18/0004, PI20/0320, PT17/0015/0043]; ISCIII; MCIN; Pro-CNIC Foundation; Severo Ochoa Centers of Excellence program [CEX2020-001041-S]; ISCIII [CM20/00101], Frutos F. de, Ochoa JP, Navarro-Peñalver M, Baas A, Bjerre JV, Zorio E, Méndez I, Lorca R, Verdonschot JAJ, García-Granja PE, Bilinska Z, Fatkin D, Fuentes-Cañamero ME, García-Pinilla JM, García-Álvarez MI, Girolami F, Barriales-Villa R, Díez-López C, Lopes LR, Wahbi K, García-Álvarez A, Rodríguez-Sánchez I, Rekondo-Olaetxea J, Rodríguez-Palomares JF, Gallego-Delgado M, Meder B, Kubanek M, Hansen FG, Restrepo-Córdoba MA, Palomino-Doza J, Ruiz-Guerrero L, Sarquella-Brugada G, Perez-Perez AJ, Bermúdez-Jiménez FJ, Ripoll-Vera T, Rasmussen TB, Jansen M, Sabater-Molina M, Elliot PM, Garcia-Pavia P; European Genetic Cardiomyopathies Initiative Investigators

BACKGROUND Center-based cardiac rehabilitation programs (CRPs) reduce morbidity and mortality after an ischemic cardiac event; however, they are widely underused. Home-based CRP has emerged as an alternative to improve patient adherence; however, its safety and efficacy remain unclear, especially for older patients and female patients. OBJECTIVE This study aimed to develop a holistic home-based CRP for patients with ischemic heart disease and evaluate its safety and impact on functional capacity, adherence to a healthy lifestyle, and quality of life. METHODS The 8-week home-based CRP included patients of both sexes, with no age limit, who had overcome an acute myocardial infarction in the previous 3 months, had a left ventricular ejection fraction of ≥40%, and had access to a tablet or mobile device. The CRP was developed using a dedicated platform designed explicitly for this purpose and included 3 weekly exercise sessions combining tailored aerobic and strength training and 2 weekly educational session focused on lifestyle habits, therapeutic adherence, and patient empowerment. RESULTS We initially included 62 patients, of whom 1 was excluded for presenting with ventricular arrhythmias during the initial stress test, 5 were excluded because of incompatibility, and 6 dropped out because of a technological barrier. Ultimately, 50 patients completed the program: 85% (42/50) were male, with a mean age of 58.9 (SD 10.3) years, a mean left ventricular ejection fraction of 52.1% (SD 6.72%), and 25 (50%) New York Heart Association functional class I and 25 (50%) New York Heart Association II-III. The CRP significantly improved functional capacity (+1.6 metabolic equivalent tasks), muscle strength (arm curl test +15.5% and sit-to-stand test +19.7%), weekly training volume (+803 metabolic equivalent tasks), adherence to the Mediterranean diet, emotional state (anxiety), and quality of life. No major complications occurred, and adherence was excellent (>80%) in both the exercise and educational sessions. In the subgroup analysis, CRP showed equivalent beneficial effects irrespective of sex and age. In addition, patient preferences for CRP approaches were equally distributed, with one-third (14/50, 29%) of the patients preferring a face-to-face CRP, one-third (17/50, 34%) preferring a telematic CRP, and one-third (18/50, 37%) preferring a hybrid approach. Regarding CRP duration, 63% (31/50) of the patients considered it adequate, whereas the remaining 37% (19/50) preferred a longer program. CONCLUSIONS A holistic telematic CRP dedicated to patients after an ischemic cardiac event, irrespective of sex and age, is safe and, in our population, has achieved positive results in improving maximal aerobic capacity, weekly training volume, muscle strength, quality of life, compliance with diet, and anxiety symptoms. The preference for a center- or home-based CRP approach is diverse among the study population, emphasizing the need for a tailored CRP to improve adherence and completion rates.

Small fiber neuropathy usually presents with gradual and progressive chronic length-dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford-AstraZeneca ChAdOx1-S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra-epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination are described. At follow up, neuropathic pain was present in two of the patients.

COVID-19 has shown significant morbidity with the involvement of multiple systems, including the cardiovascular system. Cardiovascular manifestations in the acute phase can include myocardial injury itself, myocardial infarction, venous thromboembolic events, myocarditis, Takotsubo syndrome, and different arrhythmic events. Myocardial injury defined by the rise of cardiac biomarkers in blood has been found in multiple studies with a prevalence of about 20%. Its presence is related to worse clinical outcomes and in-hospital mortality. The mechanisms of myocardial injury have been the subject of intense research but still need to be clarified. The characterization of the cardiac affectation with echocardiography and cardiac magnetic resonance has found mixed results in different studies, with a striking incidence of imaging criteria for myocarditis. Regarding post-acute and chronic follow-up results, the persistence of symptoms and imaging changes in recovered COVID-19 patients has raised concerns about the duration and the possible significance of these findings. Even though the knowledge about this disease has increased incredibly in the last year, many aspects are still unclear and warrant further research.

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Background Youth experiencing homelessness are more likely than housed youth to experience premature death, suicide, drug overdose, pregnancy, substance use, and mental illness. Yet while youth experiencing homelessness are 6 to 12 times more likely to become infected with HIV than housed youth, with HIV prevalence as high as 16%, many do not access the prevention services they need. Despite adversities, youth experiencing homelessness are interested in health promotion programs, can be recruited and retained in interventions and research studies, and demonstrate improved outcomes when programs are tailored and relevant to them. Objective The study aims to compare the efficacy of a nurse case management HIV prevention and care intervention, titled Come As You Are, with that of usual care among youth experiencing homelessness aged 16 to 25 years. Methods The study is designed as a 2-armed randomized wait-list controlled trial. Participants (n=450) will be recruited and followed up for 9 months after the intervention for a total study period of 12 months. Come As You Are combines nurse case management with a smartphone-based daily ecological momentary assessment to develop participant-driven HIV prevention behavioral goals that can be monitored in real-time. Youth in the city of Houston, Texas will be recruited from drop-in centers, shelters, street outreach programs, youth-serving organizations, and clinics. Results Institutional review board approval (Committee for the Protection of Human Subjects, University of Texas Health Science Center at Houston) was obtained in November 2018. The first participant was enrolled in November 2019. Data collection is ongoing. To date, 123 participants have consented to participate in the study, 89 have been enrolled, and 15 have completed their final follow-up. Conclusions There is a paucity of HIV prevention research regarding youth experiencing homelessness. Novel and scalable interventions that address the full continuum of behavioral and biomedical HIV prevention are needed. This study will determine whether a personalized and mobile HIV prevention approach can reduce HIV risk among a hard-to-reach, transient population of youth at high risk. International Registered Report Identifier (IRRID) DERR1-10.2196/26716

The exact mechanisms leading to myocardial injury in the coronavirus disease 2019 (COVID-19) are still unknown. In this retrospective observational study, we include all consecutive COVID-19 patients admitted to our center. They were divided into two groups according to the presence of myocardial injury. Clinical variables, Charlson Comorbidity Index (CCI), C-reactive protein (CRP), CAC (COVID-19-associated coagulopathy), defined according to the ISTH score, treatment and in-hospital events were collected. Between March and April 2020, 331 COVID-19 patients were enrolled, 72 of them (21.8%) with myocardial injury. Patients with myocardial injury showed a higher CCI score (median (interquartile range), 5 (4–7) vs. 2 (1–4), p = 0.001), higher CRP values (18.3 (9.6–25.9) mg/dL vs. 12.0 (5.4–19.4) mg/dL, p ˂ 0.001) and CAC score (1 (0–2) vs. 0 (0–1), p = 0.001), and had lower use of any anticoagulant (57 patients (82.6%) vs. 229 patients (90.9%), p = 0.078), than those without. In the adjusted logistic regression, CRP, myocardial injury, CCI and CAC score were positive independent predictors of mortality, whereas anticoagulants resulted as a protective factor. Myocardial injury in COVID-19 patients is associated with inflammation and coagulopathy, resulting in a worse in-hospital prognosis. Treatment with anticoagulant agents may help to improve in-hospital outcomes.

The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes (JXP) of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study we compared two mouse models of constitutive Kv1.6 knock-out achieved by different methods: traditional gene trap via homologous recombination, and CRISPR-mediated excision. Both Kv1.6 knock-out mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of ‘meganeurites’ and impaired transmission to dorsal horn wide dynamic range (WDR) neurons. The anatomical defects were absent in CRISPR-mediated Kv1.6 knock-out mice (Kcna6 -/-) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathological defects in transgenic mice, which has confounding implications for the interpretation of gene knock-outs using lacZ. Nonetheless, in Kcna6 -/- mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.

BACKGROUND Youth experiencing homelessness are more likely than housed youth to experience premature death, suicide, drug overdose, pregnancy, substance use, and mental illness. Yet while youth experiencing homelessness are 6 to 12 times more likely to become infected with HIV than housed youth, with HIV prevalence as high as 16%, many do not access the prevention services they need. Despite adversities, youth experiencing homelessness are interested in health promotion programs, can be recruited and retained in interventions and research studies, and demonstrate improved outcomes when programs are tailored and relevant to them. OBJECTIVE The study aims to compare the efficacy of a nurse case management HIV prevention and care intervention, titled Come As You Are, with that of usual care among youth experiencing homelessness aged 16 to 25 years. METHODS The study is designed as a 2-armed randomized wait-list controlled trial. Participants (n=450) will be recruited and followed up for 9 months after the intervention for a total study period of 12 months. Come As You Are combines nurse case management with a smartphone-based daily ecological momentary assessment to develop participant-driven HIV prevention behavioral goals that can be monitored in real-time. Youth in the city of Houston, Texas will be recruited from drop-in centers, shelters, street outreach programs, youth-serving organizations, and clinics. RESULTS Institutional review board approval (Committee for the Protection of Human Subjects, University of Texas Health Science Center at Houston) was obtained in November 2018. The first participant was enrolled in November 2019. Data collection is ongoing. To date, 123 participants have consented to participate in the study, 89 have been enrolled, and 15 have completed their final follow-up. CONCLUSIONS There is a paucity of HIV prevention research regarding youth experiencing homelessness. Novel and scalable interventions that address the full continuum of behavioral and biomedical HIV prevention are needed. This study will determine whether a personalized and mobile HIV prevention approach can reduce HIV risk among a hard-to-reach, transient population of youth at high risk. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/26716

Highlights • After oxaliplatin treatment rats developed mechanical and cold hyperalgesia. • We observed intraepidermal nerve fiber degeneration, and mild spinal cord gliosis. • Co treatment with Metformin could prevent all these pathological outcomes. • This suggests metformin as a candidate drug to prevent oxaliplatin-induced neuropathy., Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic., Calvo et al. discuss how applying genetic techniques, from model organisms to human populations, can help us understand the pathophysiology of neuropathic pain. These strategies could soon reveal novel analgesic drug targets and aid both personalized risk prediction and treatment.

espanolEste trabajo plantea una propuesta de Entorno Personal de Aprendizaje Autonomo 2.0 (EPAA 2.0) que ayude a los estudiantes del Grado de Administracion y Direccion de Empresas en su proceso de aprendizaje. Para alacanzar el objetivo, se selecciona una muestra de 312 estudiantes matriculados en las asignaturas «Administracion de Empresas», «Sistema Fiscal. Imposicion Directa», «Sistemas de Informacion para la Direccion» e «Investigacion Comercial». Los datos se recogen mediante un cuestionario donde se presentan las aplicaciones de la Web 2.0 y se analizan aplicando el Modelo de Rasch. Los resultados muestran que el EPAA 2.0 se integra principalmente por aplicaciones que ayudan a organizar, crear y editar contenidos, acceder a la informacion y, compartir la informacion y los conocimientos. Ademas, senalar como hecho relevante las diferencias de genero a la hora de construir entornos de aprendizaje online. EnglishThis work proposes a proposal of Personal Autonomous Learning Environment 2.0 (PALE 2.0) that will help students Degree in Business Administration and Management in their learning process. To achieve the objective, a sample of 312 students enrolled in the subjects «Business Administration», «Fiscal System. Direct Taxation», «Information Systems Direction» and «Business Research». Data are collected through a questionnaire where Web 2.0 applications are presented and analyzed using the Rasch Model. The results show that APLE 2.0 is mainly integrated by applications that help to organize, create and edit content, access information and share information and knowledge. In addition, highlight gender differences when building online learning environments.

HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here, we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had (1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hind paw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.

Recessive dystrophic epidermolysis bullosa is a painful condition characterised by repeated blistering of the skin. Von Bischhoffshausen et al. report that in this condition, small sensory fibres in the skin are injured leading to neuropathic pain. These findings support the use of neuropathic pain treatment in recessive dystrophic epidermolysis bullosa., Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.

Summary Persistent pain is a sequela of several neurological conditions with a primary immune basis, such as Guillain-Barre syndrome and multiple sclerosis. Additionally, diverse forms of injury to the peripheral or the central nervous systems—whether traumatic, metabolic, or toxic—result in substantial recruitment and activation of immune cells. This response involves the innate immune system, but evidence also exists of T-lymphocyte recruitment, and in some patient cohorts antibodies to neuronal antigens have been reported. Mediators released by immune cells, such as cytokines, sensitise nociceptive signalling in the peripheral and central nervous systems. Preclinical data suggest an immune pathogenesis of neuropathic pain, but clinical evidence of a central role of the immune system is less clear. An important challenge for the future is to establish to what extent this immune response initiates or maintains neuropathic pain in patients and thus whether it is amenable to therapy.

This paper analyzes the factors technological context that uses Spanish hotels in the e-CRM systems. It is built on the model of Chang, Liao and Hsiao (2005). The data are collected from corporate web and analyzed using Rasch Model (1961). The results indicate that the technological context of e-CRM is based more on the analysis of customer information than in the integration of e-CRM technologies. Both factors are conditioned by the size of the hotel.

Neuropathic pain following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode) was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in rats and humans. Within the dorsal root (a site remote from injury) we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with α-DTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury. DOI: http://dx.doi.org/10.7554/eLife.12661.001, eLife digest Around 20% of the world’s population experiences long-lasting “chronic” pain, which often results in poor sleep, depression and anxiety. One of the most disabling forms of chronic pain is called neuropathic pain, which results from injuries to sensory nerves. Pain or discomfort is felt in response to touches that are not normally painful. Neuropathic pain is difficult to treat as we do not fully understand the molecular mechanisms that cause it. Stimulating a nerve causes it to produce action potentials. At a molecular level, these action potentials are generated by ions moving into and out of the neuron through proteins called ion channels. The movement of sodium ions into a neuron triggers an action potential, and the movement of potassium ions out of the neuron returns it to a resting state. After a sensory nerve is cut or otherwise damaged it becomes hyperactive and produces spontaneous electrical activity that the brain interprets as pain signals. However, it is not fully understood how cutting a nerve affects the ion channels in a way that generates this hyperactivity. Different types of ion channel are found in different regions of the nerve cell; for example, type 1 potassium channels are normally found in a region called the juxtaparanode at the axon of the neuron. Calvo et al. have now tracked what happens to type 1 potassium channels after nerve injury in rats. Soon after nerve damage occurred, nearly all of these ion channels disappeared from the juxtaparanode. At the same time, electrical activity in the cut nerve increased, and the recovering animals responded in ways that suggested they were hypersensitive to the nerve being touched. Three weeks after the injury, most rats lost their hypersensitivity and the electrical activity in the cut nerve returned to near-normal levels. Calvo et al. found that the recovering nerves contained new subtypes of type 1 potassium channels. These potassium channels did not just appear in the juxtaparanode: they also invaded the ‘fence’ region that normally separates potassium channels from sodium channels. The same was observed to happen in the nerves of patients that suffer from neuropathic pain due to a nerve injury. At this late time point after nerve injury, blocking the activity of potassium channels produced the same abnormal increase in the nerve’s electrical activity as seen immediately after the nerve had been cut. The rats’ hypersensitivity to touch also returned. This suggests that the appearance of the new potassium channel subtypes might be a protective mechanism that reduces the activity of a damaged nerve to decrease pain. These findings suggest new ways of treating neuropathic pain. Further studies are now needed to investigate whether drugs that can activate the new potassium channel subtypes could stop pain from an injured nerve becoming a long-term problem. DOI: http://dx.doi.org/10.7554/eLife.12661.002

Following peripheral nerve injury microglia accumulate within the spinal cord and adopt a proinflammatory phenotype a process which contributes to the development of neuropathic pain. We have recently shown that neuregulin-1, a growth factor released following nerve injury, activates erbB 2, 3, and 4 receptors on microglia and stimulates proliferation, survival and chemotaxis of these cells. Here we studied the intracellular signaling pathways downstream of neuregulin-1-erbB activation in microglial cells. We found that neuregulin-1 in vitro induced phosphorylation of ERK1/2 and Akt without activating p38MAPK. Using specific kinase inhibitors we found that the mitogenic effect of neuregulin-1 on microglia was dependant on MEK/ERK1/2 pathway, the chemotactic effect was dependant on PI3K/Akt signaling and survival was dependant on both pathways. Intrathecal treatment with neuregulin-1 was associated with microgliosis and development of mechanical and cold pain related hypersensitivity which was dependant on ERK1/2 phosphorylation in microglia. Spinal nerve ligation results in a robust microgliosis and sustained ERK1/2 phosphorylation within these cells. This pathway is downstream of neuregulin-1/erbB signaling since its blockade resulted in a significant reduction in microglial ERK1/2 phosphorylation. Inhibition of the MEK/ERK1/2 pathway resulted in decreased spinal microgliosis and in reduced mechanical and cold hypersensitivity after peripheral nerve damage. We conclude that neuregulin-1 released after nerve injury activates microglial erbB receptors which consequently stimulates the MEK/ERK1/2 pathway that drives microglial proliferation and contributes to the development of neuropathic pain. © 2011 Wiley-Liss, Inc.

En esta investigación, profundizo en el tema de la traducción especializada en una sociedad multicultural y “multilectal” como la de Estados Unidos, en la que la variedad de la lengua del receptor no está bien definida. Para ello, contrasto las traducciones de un corpus de 71 folletos médico-sanitarios divulgativos destinados al uso personal de los pacientes hispanohablantes. De estos textos, se extrajeron las variantes léxicas diferenciales y se recogieron en fichas terminológicas documentadas acompañadas de una propuesta de “traducción interlectal” para un hablante de español peninsular. Asimismo, se identificaron las características morfosintácticas y se estudiaron y clasificaron según el elemento de la oración afectado y el tipo de peculiaridad. Para comprobar la posible presencia de distintos geolectos en el país y esclarecer los motivos que llevan al traductor a decantarse por una u otra variedad del español al desempeñar su labor, seleccioné los folletos divulgativos procedentes de cuatro estados específicos: California y Texas, escogidos por la fuerte presencia de hispanohablantes en su territorio, y Maryland y Georgia, sede de tres organizaciones gubernamentales de reconocido prestigio responsables de un gran número de publicaciones distribuidas a nivel nacional. Tras la comparación de las características de los documentos estatales y nacionales, elaboré dos encuestas que fueron enviadas a traductores profesionales en el país para recoger sus impresiones de primera mano sobre las variedades del español y la forma de afrontar las diferencias lingüísticas en la traducción especializada. Los resultados obtenidos del estudio de los textos y las encuestas me permitieron redactar las conclusiones sobre las características del español y el trabajo de traducción en Estados Unidos., Departamento de Lengua Española

Background and aimsPain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of “negative” data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted.MethodsMembers of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting.ResultsMinimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed.ConclusionsMore systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics.ImplicationsWe are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Background The past decade has seen an abundance of transcriptional profiling studies of preclinical models of persistent pain, predominantly employing microarray technology. In this study we directly compare exon microarrays to RNA-seq and investigate the ability of both platforms to detect differentially expressed genes following nerve injury using the L5 spinal nerve transection model of neuropathic pain. We also investigate the effects of increasing RNA-seq sequencing depth. Finally we take advantage of the “agnostic” approach of RNA-seq to discover areas of expression outside of annotated exons that show marked changes in expression following nerve injury. Results RNA-seq and microarrays largely agree in terms of the genes called as differentially expressed. However, RNA-seq is able to interrogate a much larger proportion of the genome. It can also detect a greater number of differentially expressed genes than microarrays, across a wider range of fold changes and is able to assign a larger range of expression values to the genes it measures. The number of differentially expressed genes detected increases with sequencing depth. RNA-seq also allows the discovery of a number of genes displaying unusual and interesting patterns of non-exonic expression following nerve injury, an effect that cannot be detected using microarrays. Conclusion We recommend the use of RNA-seq for future high-throughput transcriptomic experiments in pain studies. RNA-seq allowed the identification of a larger number of putative candidate pain genes than microarrays and can also detect a wider range of expression values in a neuropathic pain model. In addition, RNA-seq can interrogate the whole genome regardless of prior annotations, being able to detect transcription from areas of the genome not currently annotated as exons. Some of these areas are differentially expressed following nerve injury, and may represent novel genes or isoforms. We also recommend the use of a high sequencing depth in order to detect differential expression for genes with low levels of expression.

HIV-associated sensory neuropathy is the most frequent manifestation of HIV disease, afflicting 40-50% of patients whose HIV disease is otherwise controlled by antiretroviral therapy. It often presents with significant neuropathic pain and is consistently associated with previous exposure to nucleoside reverse transcriptase inhibitors including stavudine (d4T), which is widely used in resource-limited settings. Here we investigated complex pain-related behaviours associated with d4T treatment using ethologically relevant thigmotaxis and burrowing behaviours in adult rats. Detailed neuropathological response was also examined using neurochemistry, electron microscopy, and proteomics. After 2 intravenous injections of d4T (50 mg/kg, 4 days apart), rats developed hind paw mechanical hypersensitivity, which plateaued at 21 days after initial d4T injection, a time that these animals also had significant changes in thigmotaxis and burrowing behaviours when compared to the controls; reductions in hind paw intraepidermal nerve fibre density and CGRP/IB4 immunoreactivity in L5 spinal dorsal horn, suggesting injury to both the peripheral and central terminals of L5 dorsal root ganglion neurons; and increases in myelinated and unmyelinated axon diameters in the sural nerve, suggesting axonal swelling. However, no significant glial and inflammatory cell response to d4T treatment was observed. Sural nerve proteomics at 7 days after initial d4T injection revealed down-regulated proteins associated with mitochondrial function, highlighting distal axons vulnerability to d4T neurotoxicity. In summary, we have reported complex behavioural changes and a distinctive neuropathology in a clinically relevant rat model of d4T-induced sensory neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.

Microglia are the resident macrophages in the central nervous system (CNS). Any insult to the CNS homeostasis will induce a rapid change in microglia morphology, gene expression profile and functional behaviour. These responses of microglia have been collectively known as 'microgliosis'. Interestingly, damage to the nervous system outside the CNS, such as axotomy of a peripheral nerve, can lead to microgliosis in the spinal cord. There is a variation in the degree of microgliosis depending on the model of nerve injury employed for instance this response is more marked following traumatic nerve injury than in models of chemotherapy induced neuropathy. Following peripheral nerve injury nociceptive inputs from sensory neurons appear to be critical in triggering the development of spinal microgliosis. A number of signalling pathways including growth factors such as Neuregulin-1, matrix metalloproteases such as MMP-9 and multiple chemokines enable direct communication between injured primary afferents and microglia. In addition, we describe a group of mediators which although not demonstrably shown to be released from neurons are known to modulate microglial phenotype. There is a great functional diversity of the microglial response to peripheral nerve injury which includes: Cellular migration, proliferation, cytokine release, phagocytosis, antigen presentation and recruitment of T cells. It should also be noted that in certain contexts microglia may have a role in the resolution of neuro-inflammation. Although there is still no direct evidence demonstrating that spinal microglia have a role in neuropathic pain in humans, these patients present a pro-inflammatory cytokine profile and it is a reasonable hypothesis that these cells may contribute to this inflammatory response. Modulating microglial functions offers a novel therapeutic opportunity following nerve injury which ideally would involve reducing the pro-inflammatory nature of these cells whilst retaining their potential beneficial functions.

Background: Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of longterm potentiation (LTP), a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCξ/PKMξ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results: Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ξ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs) following formalin administration. In addition, Complete Freund's Adjuvant (CFA)-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCξ/PKMξ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCξ/PKMξ in dorsal horn neurons, specifically PKMξ phosphorylation in formalin rats. Finally, inhibition of PKCξ/PKMξ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions: These results suggest that PKCξ, especially PKMξ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

Many persistent pain states (pain lasting for hours, days, or longer) are poorly treated because of the limitations of existing therapies. Analgesics such as nonsteroidal anti-inflammatory drugs and opioids often provide incomplete pain relief and prolonged use results in the development of severe side effects. Identification of the key mediators of various types of pain could improve such therapies. Here, we tested the hypothesis that hitherto unrecognized cytokines and chemokines might act as mediators in inflammatory pain. We used ultraviolet B (UVB) irradiation to induce persistent, abnormal sensitivity to pain in humans and rats. The expression of more than 90 different inflammatory mediators was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made polymerase chain reaction arrays. There was a significant positive correlation in the overall expression profiles between the two species. The expression of several genes [interleukin-1β (IL-1β), IL-6, and cyclooxygenase-2 (COX-2)], previously shown to contribute to pain hypersensitivity, was significantly increased after UVB exposure, and there was dysregulation of several chemokines (CCL2, CCL3, CCL4, CCL7, CCL11, CXCL1, CXCL2, CXCL4, CXCL7, and CXCL8). Among the genes measured, CXCL5 was induced to the greatest extent by UVB treatment in human skin; when injected into the skin of rats, CXCL5 recapitulated the mechanical hypersensitivity caused by UVB irradiation. This hypersensitivity was associated with the infiltration of neutrophils and macrophages into the dermis, and neutralizing the effects of CXCL5 attenuated the abnormal pain-like behavior. Our findings demonstrate that the chemokine CXCL5 is a peripheral mediator of UVB-induced inflammatory pain, likely in humans as well as rats.

A key component in the response of the nervous system to injury is the proliferation and switch to a “proinflammatory” phenotype by microglia (microgliosis). In situations where the blood–brain barrier is intact, microglial numbers increase via the proliferation and chemotaxis of resident microglia; however, there is limited knowledge regarding the factors mediating this response. After peripheral nerve injury, a dorsal horn microgliosis develops, which directly contributes to the development of neuropathic pain. Neuregulin-1 (NRG-1) is a growth and differentiation factor with a well characterized role in neural and cardiac development. Microglia express the NRG1 receptors erbB2, 3, and 4, and NRG1 signaling via the erbB2 receptor stimulated microglial proliferation, chemotaxis, and survival, as well as interleukin-1β releasein vitro. Intrathecal treatment with NRG1 resulted in microglial proliferation within the dorsal horn, and these cells developed an activated morphology. This microglial response was associated with the development of both mechanical and cold pain-related hypersensitivity. Primary afferents express NRG1, and after spinal nerve ligation (SNL) we observed both an increase in NRG1 within the dorsal horn as well as activation of erbB2 specifically within microglia. Blockade of the erbB2 receptor or sequestration of endogenous NRG after SNL reduced the proliferation, the number of microglia with an activated morphology, and the expression of phospho-P38 by microglia. Furthermore, consequent to such changes, the mechanical pain-related hypersensitivity and cold allodynia were reduced. NRG1-erbB signaling therefore represents a novel pathway regulating the injury response of microglia.

Patent ductus arteriosus (PDA) in the preterm neonate (PTN) with respiratory distress is frequent and there are controversies related to its medical and/or surgical treatment. The goal of the present study was to compare the outcome between the two groups of newborns with PDA, operated (group A) and not operated on (group B); and to determine the internal diameter (DI) in ductus arteriosus (DA) on outcome.The clinical records of PTN hospitalized from January 1999 to January 2002, discharged either by improvement or death, were retrolectively analyzed. Statistical analysis was carried out using the descriptive and inferential statistic. The statistical significance was considered at p0.05.The was significant difference in DI in DA in favor group A with p0.01; and DI of 2 mm or more showed significant difference too in favor of group A with a p=0.0006. The mortality was similar in the two groups.We concluded that in the PTN with significant PDA should intervene medical or surgically and without those data but with DI of 2 mm or more of DA, also.

In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis. © 2013 Gilthorpe JD et al.